Statin-induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: intermediacy of nitric oxide and antioxidant defence mechanisms.

PubMed

Kanugula, Anantha Koteswararao; Gollavilli, Paradesi Naidu; Vasamsetti, Sathish Babu; Karnewar, Santosh; Gopoju, Raja; Ummanni, Ramesh; Kotamraju, Srigiridhar

2014-08-01

Accumulating evidence from in vitro, in vivo, clinical and epidemiological studies shows promising results for the use of statins against many cancers including breast carcinoma. However, the molecular mechanisms responsible for the anti-proliferative and anti-invasive properties of statins still remain elusive. In this study, we investigated the involvement of nitric oxide, iron homeostasis and antioxidant defence mechanisms in mediating the anti-proliferative and anti-invasive properties of hydrophobic statins in MDA-MB-231, MDA-MB-453 and BT-549 metastatic triple negative breast cancer cells. Fluvastatin and simvastatin significantly increased cytotoxicity which was reversed with mevalonate. Interestingly, fluvastatin downregulated transferrin receptor (TfR1), with a concomitant depletion of intracellular iron levels in these cells. Statin-induced effects were mimicked by geranylgeranyl transferase inhibitor (GGTI-298) but not farnesyl transferase inhibitor (FTI-277). Further, it was observed that TfR1 downregulation is mediated by increased nitric oxide levels via inducible nitric oxide synthase (iNOS) expression. NOS inhibitors (asymmetric dimethylarginine and 1400W) counteracted and sepiapterin, a precursor of tetrahydrobiopterin, exacerbated statin-induced depletion of intracellular iron levels. Notably, fluvastatin increased manganese superoxide dismutase (by repressing the transcription factor DNA damage-binding protein 2), catalase and glutathione which, in turn, diminished H2 O2 levels. Fluvastatin-induced downregulation of TfR1, matrix metalloproteinase-2, -9 and inhibition of invasion were reversed in the presence of aminotriazole, a specific inhibitor of catalase. Finally, we conclude that fluvastatin, by altering iron homeostasis, nitric oxide generation and antioxidant defence mechanisms, induces triple negative breast cancer cell death. © 2014 FEBS.

Statin Exposure Is Associated with Decreased Asthma-related Emergency Department Visits and Oral Corticosteroid Use

PubMed Central

Li, Lingling; Butler, Melissa G.; Fung, Vicki; Kharbanda, Elyse O.; Larkin, Emma K.; Vollmer, William M.; Miroshnik, Irina; Rusinak, Donna; Weiss, Scott T.; Lieu, Tracy; Wu, Ann Chen

2013-01-01

Rationale: Statins, or HMG-CoA reductase inhibitors, may aid in the treatment of asthma through their pleiotropic antiinflammatory effects. Objectives: To examine the effect of statin therapy on asthma-related exacerbations using a large population-based cohort. Methods: Statin users aged 31 years or greater with asthma were identified from the Population-Based Effectiveness in Asthma and Lung population, which includes data from five health plans. Statin exposure and asthma exacerbations were assessed over a 24-month observation period. Statin users with a statin medication possession ratio greater than or equal to 80% were matched to non–statin users by age, baseline asthma therapy, site of enrollment, season at baseline, and propensity score, which was calculated based on patient demographics and Deyo-Charlson conditions. Asthma exacerbations were defined as two or more oral corticosteroid dispensings, asthma-related emergency department visits, or asthma-related hospitalizations. The association between statin exposure and each of the three outcome measures was assessed using conditional logistic regression. Measurements and Main Results: Of the 14,566 statin users, 8,349 statin users were matched to a nonuser. After adjusting for Deyo-Charlson conditions that remained unbalanced after matching, among statin users, statin exposure was associated with decreased odds of having asthma-related emergency department visits (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.53–0.77; P < 0.0001) and two or more oral corticosteroid dispensings (OR, 0.90; 95% CI, 0.81–0.99; P = 0.04). There were no differences in asthma-related hospitalizations (OR, 0.91; 95% CI, 0.66–1.24; P = 0.52). Conclusions: Among statin users with asthma, statin exposure was associated with decreased odds of asthma-related emergency department visits and oral corticosteroid dispensings. PMID:24093599

Do the frequencies of adverse events increase, decrease, or stay the same with long-term use of statins?

PubMed

Huddy, Karlyn; Dhesi, Pavittarpaul; Thompson, Paul D

2013-02-01

Statins are widely used for their cholesterol-lowering properties and proven reduction of cardiovascular disease risk. Many patients take statins as long-term treatment for a variety of conditions without a clear-cut understanding of how treatment duration affects the frequency of adverse effects. We aimed to evaluate whether the frequencies of documented adverse events increase, decrease, or remain unchanged with long-term statin use. We reviewed the established literature to define the currently known adverse effects of statin therapy, including myopathy, central nervous system effects, and the appearance of diabetes, and the frequency of these events with long-term medication use. The frequency of adverse effects associated with long-term statin therapy appears to be low. Many patients who develop side effects from statin therapy do so relatively soon after initiation of therapy, so the frequency of side effects from statin therapy when expressed as a percentage of current users decreases over time. Nevertheless, patients may develop side effects such as muscle pain and weakness years after starting statin therapy; however, the absolute number of patients affected by statin myopathy increases with treatment duration. Also, clinical trials of statin therapy rarely exceed 5 years, so it is impossible to determine with certainty the frequency of long-term side effects with these drugs.

Statins Are Associated With Reduced Mortality in Multiple Myeloma

PubMed Central

Keller, Jesse; Gage, Brian F.; Luo, Suhong; Wang, Tzu-Fei; Moskowitz, Gerald; Gumbel, Jason; Blue, Brandon; O’Brian, Katiuscia; Carson, Kenneth R.

2016-01-01

Purpose The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have activity in one of the pathways influenced by nitrogen-containing bisphosphonates, which are associated with improved survival in multiple myeloma (MM). To understand the benefit of statins in MM, we evaluated the association between statin use and mortality in a large cohort of patients with MM. Patients and Methods From the Veterans Administration Central Cancer Registry, we identified patients diagnosed with MM between 1999 and 2013. We defined statin use as the presence of any prescription for a statin within 3 months before or any time after MM diagnosis. Cox proportional hazards regression assessed the association of statin use with mortality, while controlling for known MM prognostic factors. Results We identified a cohort of 4,957 patients, of whom 2,294 received statin therapy. Statin use was associated with a 21% decrease in all-cause mortality (adjusted hazard ratio, 0.79; 95% CI, 0.73 to 0.86; P < .001) as well as a 24% decrease in MM-specific mortality (adjusted hazard ratio, 0.76; 95% CI, 0.67 to 0.86; P < .001). This association remained significant across all sensitivity analyses. In addition to reductions in mortality, statin use was associated with a 31% decreased risk of developing a skeletal-related event. Conclusion In this cohort study of US veterans with MM, statin therapy was associated with a reduced risk of both all-cause and MM-specific mortality. Our findings suggest a potential role for statin therapy in patients with MM. The putative benefit of statin therapy in MM should be corroborated in prospective studies. PMID:27646948

Exercise-induced myalgia may limit the cardiovascular benefits of statins.

PubMed

Opie, Lionel H

2013-12-01

The positive health benefits of statins extend beyond the cardiovascular and include increased flow mediated dilation, decreased atrial fibrillation, modest antihypertensive effects and reduced risks of malignancies. Prominent among the statin side-effects are myalgia and muscular weakness, which may be associated with a rise in circulating creatine kinase values. In increasing severity and decreasing incidence, the statin-induced muscle related conditions are myalgia, myopathy with elevated creatine kinase (CK) levels with or without symptoms, and rhabdomyolysis. Statin use may increase CK levels without decreasing average muscle strength or exercise performance. In one large study, only about 2 % had myalgia that could be attributed to statin use. A novel current hypothesis is that statins optimize cardiac mitochondrial function but impair the vulnerable skeletal muscle by inducing different levels of reactive oxygen species (ROS) in these two sites. In an important observational study, both statins and exercise reduced the adverse outcomes of cardiovascular disease, and the effects were additive. The major unresolved problem is that either can cause muscular symptoms with elevation of blood creatine kinase levels. There is, as yet, no clearly defined outcomes based policy to deal with such symptoms from use of either statins or exercise or both. A reasonable practical approach is to assess the creatine kinase levels, and if elevated to reduce the statin dose or the intensity of exercise.

The Association between Statin Use and the Diagnosis of Prostate Cancer in a Population-Based Cohort

PubMed Central

Breau, Rodney H.; Karnes, R. Jeffrey; Jacobson, Debra J.; McGree, Michaela E.; Jacobsen, Steven J.; Nehra, Ajay; Lieber, Michael M.; St. Sauver, Jennifer L.

2011-01-01

Purpose The effect of statin medication use on risk of prostate cancer is unknown. Materials and Methods We examined data from a longitudinal, population-based cohort of 2447 men between the ages of 40 and 79 that were followed from 1990 to 2007. Information on statin use was self-reported and obtained by biennial questionnaires. A randomly selected subset of men (634; 26%) completed biennial urologic examinations that included serum PSA measurements. Information on prostate biopsy and prostate cancer was obtained through review of community medical records. Results Of 634 statin users, 38 (6%) were diagnosed with prostate cancer compared to 186 (10%) of 1813 non-statin users. Statin use was associated with a decreased risk of receiving a prostate biopsy (HR: 0.31; 95% CI: 0.24, 0.40), prostate cancer diagnosis (HR: 0.36; 95% CI: 0.25, 0.53) and high-grade (Gleason ≥7) prostate cancer diagnosis (HR: 0.25; 95% CI: 0.11, 0.58). Statin use was also associated with a non-significant decreased risk of exceeding a PSA threshold of 4.0 ng/mL (HR: 0.63; 95% CI: 0.35, 1.13). In addition, longer duration of statin use was associated with lower risk of these outcomes (all tests for trend p<0.05). Conclusions Statin use is associated with a decreased risk of prostate cancer diagnosis. This association may be explained by decreased detection or cancer prevention. PMID:20620405

Virtual exploration of early stage atherosclerosis.

PubMed

Olivares, Andy L; González Ballester, Miguel A; Noailly, Jérôme

2016-12-15

Biological mechanisms contributing to atherogenesis are multiple and complex. The early stage of atherosclerosis (AS) is characterized by the accumulation of low-density lipoprotein (LDL) droplets, leading to the creation of foam cells (FC). To address the difficulty to explore the dynamics of interactions that controls this process, this study aimed to develop a model of agents and infer on the most influential cell- and molecule-related parameters. FC started to accumulate after six to eight months of simulated hypercholesterolemia. A sensitivity analysis revealed the strong influence of LDL oxidation rate on the risk of FC creation, which was exploited to model the antioxidant effect of statins. Combined with an empirical simulation of the drug ability to decrease the level of LDL, the virtual statins treatment led to reductions of oxidized LDL levels similar to reductions measured in vivo. An Open source software was used to develop the agent-based model of early AS. Two different concentrations of LDL agents were imposed in the intima layer to simulate healthy and hypercholesterolemia groups of 'virtual patients'. The interactions programmed between molecules and cells were based on experiments and models reported in the literature. A factorial sensitivity analysis explored the respective effects of the less documented model parameters as (i) agent migration speed, (ii) LDL oxidation rate and (iii) concentration of autoantibody agents. Finally, the response of the model to known perturbations was assessed by introducing statins agents, able to reduce the oxidation rate of LDL agents and the LDL boundary concentrations. jerome.noailly@upf.eduSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

CoQ10 and L-carnitine for statin myalgia?

PubMed

DiNicolantonio, James J

2012-10-01

Statins are a standard of care in many clinical settings such as acute myocardial infarction and for patients having or at risk of cardiovascular (CV) disease. This is based on a plethora of data showing reductions in CV events and mortality. The CV benefit of statins can be partly explained by their ability to inhibit of HMG-CoA reductase, which subsequently lowers cholesterol and decreases the formation of mevalonate. However, the inhibition of the mevalonate pathway decreases the formation of coenzyme Q10 (CoQ10) within the body. It has been a long-standing theory that statin-associated muscle pain (myalgia) is caused, or at least partly contributed by, a reduction in CoQ10 levels in muscle mitochondria. One of the main side effects of statins is myalgia, which causes the patient to either stop their statin or significantly reduce the dose of their statin. The question of whether CoQ10 can help treat statin myopathy is a common one encountered by clinicians in current day practice.

Atorvastatin and Simvastatin Promoted Mouse Lung Repair After Cigarette Smoke-Induced Emphysema.

PubMed

Pinho-Ribeiro, Vanessa; Melo, Adriana Correa; Kennedy-Feitosa, Emanuel; Graca-Reis, Adriane; Barroso, Marina Valente; Cattani-Cavalieri, Isabella; Carvalho, Giovanna Marcella Cavalcante; Zin, Walter Araújo; Porto, Luis Cristóvão; Gitirana, Lycia Brito; Lanzetti, Manuella; Valença, Samuel Santos

2017-06-01

Cigarette smoke (CS) induces pulmonary emphysema by inflammation, oxidative stress, and metalloproteinase (MMP) activation. Pharmacological research studies have not focused on tissue repair after the establishment of emphysema but have instead focused on inflammatory stimulation. The aim of our study was to analyze the effects of atorvastatin and simvastatin on mouse lung repair after emphysema caused by CS. Male mice (C57BL/6, n = 45) were divided into the following groups: control (sham-exposed), CSr (mice exposed to 12 cigarettes a day for 60 days and then treated for another 60 days with the vehicle), CSr+A (CSr mice treated with atorvastatin for 60 days), and CSr+S (CSr mice treated with simvastatin for 60 days). The treatment with atorvastatin and simvastatin was administered via inhalation (15 min with 1 mg/mL once a day). Mice were sacrificed 24 h after the completion of the 120-day experimental procedure. We performed biochemical, morphological, and physiological analyses. We observed decreased levels of leukocytes and cytokines in statin-treated mice, accompanied by a reduction in oxidative stress markers. We also observed a morphological improvement confirmed by a mean linear intercept counting in statin-treated mice. Finally, statins also ameliorated lung function. We conclude that inhaled atorvastatin and simvastatin improved lung repair after cigarette smoke-induced emphysema in mice.

How do we improve patient compliance and adherence to long-term statin therapy?

PubMed

Maningat, Patricia; Gordon, Bruce R; Breslow, Jan L

2013-01-01

Statins are highly effective drugs prescribed to millions of people to lower LDL-cholesterol and decrease cardiovascular risk. The benefits of statin therapy seen in randomized clinical trials will only be replicated in real-life if patients adhere to the prescribed treatment regimen. But, about half of patients discontinue statin therapy within the first year, and adherence decreases with time. Patient, physician and healthcare system-related factors play a role in this problem. Recent studies have focused more on the patients' perspectives on non-adherence. Adverse events are cited as the most common cause of statin discontinuation; thus, the healthcare provider must be willing to ally and dialogue with patients to address concerns and assess the risks and benefits of continued statin therapy.

Oxidative stress markers are associated to vascular recurrence in non-cardioembolic stroke patients non-treated with statins

PubMed Central

2012-01-01

Background Since atherogenesis is related to oxidative stress, our objective was to study the association of oxidative stress markers with the vascular recurrence in non-cardioembolic stroke. Methods Atherosclerotic and oxidative stress markers were evaluated on admission, in 477 patients suffering from a first non-cardioembolic stroke. Patients were followed at 6 and 12 months after inclusion, recording cardiovascular events. As markers of endothelial oxidative stress we used oxidized LDL, Cu/Zn superoxide dismutase and 8-OH deoxiguanosine. 136 patients were being treated with statins at the moment of serum samples acquisition. Results Patients who suffered vascular recurrence or vascular-origin death had higher levels of 8-OHDG (40.06±24.70vs33.11±15.18;p=0.003). We also found associations between vascular recurrence or vascular origin death and Cu/ZnSOD (OR,1.02; 95%CI,1.00-1.03;p=0.0001) and 8-OHDG (OR,1.12;95%CI,1.08-1.16;p<0.0001) in a subgroup of 333 patients that were not in treatment with statins on admission. We also found associations between 8-OHDG and intima media thickness (IMT) (OR,1.13;95%CI,1.09-1.16;p<0.0001), presence of ipsilatieral stenosis≥50% (OR,1.03;95%CI1.00-1.05;p=0.007) and other atherosclerotic plaque characteristics. Conclusions Specific oxidative stress markers were found to be markers of atherosclerosis plaque types and vascular recurrence in non-statins treated patients at admission. PMID:22862793

Effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors and antioxidant vitamins on free radical lipid oxidation in rat liver.

PubMed

Lankin, V Z; Ivanova, M V; Konovalova, G G; Tikhaze, A K; Kaminnyi, A I; Kukharchuk, V V

2007-04-01

We studied the effects of two inhibitors of beta-hydroxy-beta-methylglutaryl coenzyme A reductase, simvastatin and lovastatin, on the lag phase of ascorbate-dependent lipid oxidation in rat liver. Oxidizability of liver biological membranes significantly increased in intact animals and rats with induced hypercholesterolemia after peroral administration of these statins. The lag phase of ascorbate-dependent lipid oxidation in liver biomembranes decreased by 2.1 times in hypercholesterolemic rats. In animals of the lovastatin group this parameter decreased by 4.4 times compared to the control. In intact rats receiving simvastatin, the lag phase of oxidation in biomembranes from the liver decreased practically by 2 times. At the same time, in animals receiving simvastatin in combination with antioxidant vitamins (vitamins E and C, provitamin A) and selenium, the period of induction of oxidation increased by 3.3 times. Our results indicate that beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors produce a prooxidant effect on the liver, which can be prevented by administration of antioxidant agents.

Coenzyme Q10 Supplementation Decreases Statin-Related Mild-to-Moderate Muscle Symptoms: A Randomized Clinical Study

PubMed Central

Skarlovnik, Ajda; Janić, Miodrag; Lunder, Mojca; Turk, Martina; Šabovič, Mišo

2014-01-01

Background Statin use is frequently associated with muscle-related symptoms. Coenzyme Q10 supplementation has yielded conflicting results in decreasing statin myopathy. Herein, we tested whether coenzyme Q10 supplementation could decrease statin-associated muscular pain in a specific group of patients with mild-to-moderate muscle symptoms. Material/Methods Fifty patients treated with statins and reporting muscle pain were recruited. The Q10 group (n=25) received coenzyme Q10 supplementation over a period of 30 days (50 mg twice daily), and the control group (n=25) received placebo. The Brief Pain Inventory (BPI) questionnaire was used and blood testing was performed at inclusion in the study and after 30 days of supplementation. Results The intensity of muscle pain, measured as the Pain Severity Score (PSS), in the Q10 group was reduced from 3.9±0.4 to 2.9±0.4 (P<0.001). The Pain Interference Score (PIS) after Q10 supplementation was reduced from 4.0±0.4 to 2.6±0.4 (P<0.001). In the placebo group, PSS and PIS did not change. Coenzyme Q10 supplementation decreased statin-related muscle symptoms in 75% of patients. The relative values of PSS and PIS significantly decreased (−33.1% and −40.3%, respectively) in the Q10 group compared to placebo group (both P<0.05). From baseline, no differences in liver and muscle enzymes or cholesterol values were found. Conclusions The present results show that coenzyme Q10 supplementation (50 mg twice daily) effectively reduced statin-related mild-to-moderate muscular symptoms, causing lower interference of statin-related muscular symptoms with daily activities. PMID:25375075

Coenzyme Q10 supplementation decreases statin-related mild-to-moderate muscle symptoms: a randomized clinical study.

PubMed

Skarlovnik, Ajda; Janić, Miodrag; Lunder, Mojca; Turk, Martina; Šabovič, Mišo

2014-11-06

Statin use is frequently associated with muscle-related symptoms. Coenzyme Q10 supplementation has yielded conflicting results in decreasing statin myopathy. Herein, we tested whether coenzyme Q10 supplementation could decrease statin-associated muscular pain in a specific group of patients with mild-to-moderate muscle symptoms. Fifty patients treated with statins and reporting muscle pain were recruited. The Q10 group (n=25) received coenzyme Q10 supplementation over a period of 30 days (50 mg twice daily), and the control group (n=25) received placebo. The Brief Pain Inventory (BPI) questionnaire was used and blood testing was performed at inclusion in the study and after 30 days of supplementation. The intensity of muscle pain, measured as the Pain Severity Score (PSS), in the Q10 group was reduced from 3.9±0.4 to 2.9±0.4 (P<0.001). The Pain Interference Score (PIS) after Q10 supplementation was reduced from 4.0±0.4 to 2.6±0.4 (P<0.001). In the placebo group, PSS and PIS did not change. Coenzyme Q10 supplementation decreased statin-related muscle symptoms in 75% of patients. The relative values of PSS and PIS significantly decreased (-33.1% and -40.3%, respectively) in the Q10 group compared to placebo group (both P<0.05). From baseline, no differences in liver and muscle enzymes or cholesterol values were found. The present results show that coenzyme Q10 supplementation (50 mg twice daily) effectively reduced statin-related mild-to-moderate muscular symptoms, causing lower interference of statin-related muscular symptoms with daily activities.

Continuation of Statin Therapy and Vasopressor Use in Septic Shock.

PubMed

Zechmeister, Carrie; Hurren, Jeff; McNorton, Kelly

2015-07-01

Studies have evaluated the use of statins in sepsis; however, no human studies have explored their effect on vasopressor requirements in septic shock. The primary objective was to determine the effect of prehospital statin continuation on duration of vasopressor therapy in patients with septic shock. Secondary objectives included maximum and average vasopressor dose and in-hospital mortality. This was a retrospective, institutional board-approved, observational cohort study in a community teaching hospital; 119 adult intensive care unit (ICU) patients with an ICD-9 code for septic shock and prehospital statin therapy were evaluated. Multivariate analyses were performed to address confounders. Of the 1229 patients screened, 119 (10%) met inclusion criteria; 73 patients (61%) had a statin continued within 24 hours of ICU admission. Crude analysis demonstrated no difference in vasopressor duration in the statin versus no statin group (3.3 vs 4.8 days; P = 0.21). There was no difference in either maximum (17.9 ± 16.1 vs 23.8 ± 21.7 µg/min norepinephrine equivalents [NEQs]; P = 0.1) or average vasopressor dose (9.5 ± 8.4 vs 12.1 ± 11.5 µg/min NEQ; P = 0.17). There was a decrease in mortality in the statin patients (43% vs 67 %; P = 0.05). On adjustment for potential confounders, there was no difference in any outcome, with a persistent trend toward lower mortality in the statin group. Continuation of prehospital statin therapy decreased neither duration nor dose of vasopressors in patients with septic shock but yielded a trend toward decreased mortality. © The Author(s) 2015.

Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM{sub 10})

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyata, Ryohei; Hiraiwa, Kunihiko; Cheng, Jui Chih

Exposure to ambient air particulate matter (particles less than 10 μm or PM{sub 10}) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM{sub 10}. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM{sub 10}/saline exposure for 4 weeks ± lovastatin (5 mg/kg/day) treatment. PM{submore » 10} exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM{sub 10} impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM{sub 10} increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM{sub 10}. Taken together, statins protect against PM{sub 10}-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties. - Highlights: • Coarse particulate matter (PM{sub 10}) accelerated balloon injury-induced plaque formation. • Lovastatin decreased intimal macrophages, lipid accumulation, and intimal area. • Lovastatin promoted smooth muscle cell recruitment into plaques. • Lovastatin reduced the expression of vasoactive mediators (iNOS, COX-2, and ET-1). • Lovastatin did not reduce blood lipid levels in PM{sub 10}-exposed rabbits.« less

Statins Inhibit Monocyte Chemotactic Protein 1 Expression in Endometriosis

PubMed Central

Cakmak, Hakan; Basar, Murat; Seval-Celik, Yasemin; Osteen, Kevin G.; Duleba, Antoni J.; Taylor, Hugh S.; Lockwood, Charles J.; Arici, Aydin

2012-01-01

Statins are potent inhibitors of the endogenous mevalonate pathway. Besides inhibiting cholesterol biosynthesis, statins may also demonstrate anti-inflammatory properties. Inflammation is implicated in the attachment and invasion of endometrial cells to the peritoneal surface and growth of ectopic endometrium by inducing proliferation and angiogenesis. In this study, the effect of statins on monocyte chemotactic protein 1 (MCP-1) expression in endometriotic implants in nude mouse model and in cultured endometriotic cells was evaluated. In mouse model, simvastatin decreased MCP-1 expression in a dose-dependent manner in endometriotic implants (P < .05). Similarly, both simvastatin and mevastatin revealed a dose-dependent inhibition of MCP-1 production in cultured endometriotic cells (P < .01). This inhibitory effect of the statins on MCP-1 production was reversed by the downstream substrates of the mevalonate pathway. Moreover, statins decreased MCP-1 messenger RNA expression in cultured endometriotic cells (P < .05). In conclusion, statins exert anti-inflammatory effect in endometriotic cells and could provide a potential treatment of endometriosis in the future. PMID:22267540

Statin use and the risk of Clostridium difficile infection: a systematic review with meta-analysis.

PubMed

Tariq, Raseen; Mukhija, Dhruvika; Gupta, Arjun; Singh, Siddharth; Pardi, Darrell S; Khanna, Sahil

2018-01-01

Statins have pleiotropic effects beyond cholesterol lowering by immune modulation. The association of statins with primary Clostridium difficile infection (CDI) is unclear as studies have reported conflicting findings. We performed a systematic review and meta-analysis to evaluate the association between statin use and CDI. We searched MEDLINE, Embase, and Web of Science from January 1978 to December 2016 for studies assessing the association between statin use and CDI. The Newcastle-Ottawa Scale was used to assess the methodologic quality of included studies. Weighted summary estimates were calculated using generalized inverse variance with random-effects model. Eight studies (6 case-control and 2 cohort) were included in the meta-analysis, which comprised 156,722 patients exposed to statins and 356,185 controls, with 34,849 total cases of CDI available in 7 studies. The rate of CDI in patients with statin use was 4.3%, compared with 7.8% in patients without statin use. An overall meta-analysis of 8 studies using the random-effects model demonstrated that statins may be associated with a decreased risk of CDI (maximally adjusted odds ratio [OR], 0.80; 95% CI, 0.66-0.97; P =0.02). There was significant heterogeneity among the studies, with an I 2 of 79%. No publication bias was seen. Meta-analysis of studies that adjusted for confounders revealed no protective effect of statins (adjusted OR, 0.84; 95% CI, 0.70-1.01; P =0.06, I 2 =75%). However, a meta-analysis of only full-text studies using the random-effects model demonstrated a decreased risk of CDI with the use of statins (OR 0.77; 95% CI, 0.61-0.99; P =0.04, I 2 =85%). Meta-analyses of existing studies suggest that patients prescribed a statin may be at decreased risk for CDI. The results must be interpreted with caution given the significant heterogeneity and lack of benefit on analysis of studies that adjusted for confounders.

Statin Intake Is Associated With Decreased Insulin Sensitivity During Cardiac Surgery

PubMed Central

Sato, Hiroaki; Carvalho, George; Sato, Tamaki; Hatzakorzian, Roupen; Lattermann, Ralph; Codere-Maruyama, Takumi; Matsukawa, Takashi; Schricker, Thomas

2012-01-01

OBJECTIVE Surgical trauma impairs intraoperative insulin sensitivity and is associated with postoperative adverse events. Recently, preprocedural statin therapy is recommended for patients with coronary artery disease. However, statin therapy is reported to increase insulin resistance and the risk of new-onset diabetes. Thus, we investigated the association between preoperative statin therapy and intraoperative insulin sensitivity in nondiabetic, dyslipidemic patients undergoing coronary artery bypass grafting. RESEARCH DESIGN AND METHODS In this prospective, nonrandomized trial, patients taking lipophilic statins were assigned to the statin group and hypercholesterolemic patients not receiving any statins were allocated to the control group. Insulin sensitivity was assessed by the hyperinsulinemic-normoglycemic clamp technique during surgery. The mean, SD of blood glucose, and the coefficient of variation (CV) after surgery were calculated for each patient. The association between statin use and intraoperative insulin sensitivity was tested by multiple regression analysis. RESULTS We studied 120 patients. In both groups, insulin sensitivity gradually decreased during surgery with values being on average ∼20% lower in the statin than in the control group. In the statin group, the mean blood glucose in the intensive care unit was higher than in the control group (153 ± 20 vs. 140 ± 20 mg/dL; P < 0.001). The oscillation of blood glucose was larger in the statin group (SD, P < 0.001; CV, P = 0.001). Multiple regression analysis showed that statin use was independently associated with intraoperative insulin sensitivity (β = −0.16; P = 0.03). CONCLUSIONS Preoperative use of lipophilic statins is associated with increased insulin resistance during cardiac surgery in nondiabetic, dyslipidemic patients. PMID:22829524

Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing.

PubMed

Shrivastava-Ranjan, Punya; Flint, Mike; Bergeron, Éric; McElroy, Anita K; Chatterjee, Payel; Albariño, César G; Nichol, Stuart T; Spiropoulou, Christina F

2018-05-01

Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013-2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection in vitro Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD. IMPORTANCE Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.

Isoprostane 8-epi-PGF2alpha is frequently increased in patients with muscle pain and/or CK-elevation after HMG-Co-enzyme-A-reductase inhibitor therapy.

PubMed

Sinzinger, H; Lupattelli, G; Chehne, F; Oguogho, A; Furberg, C D

2001-08-01

Muscle pains with or without CK-elevation are among the most frequently observed side-effects in patients with hyperlipoproteinemia on various statins. The pathophysiological background, however, remains obscure. We examined isoprostane 8-epi-PGF2alpha, a marker of in-vivo oxidation injury, in plasma, serum and urine in these patients at baseline, when muscle problems manifested and different time intervals after withdrawing the respective statin. A healthy control group and a group of untreated patients with hyperlipoproteinemia were run as controls. The majority of patients with muscular side-effects show elevated 8-epi-PGF2alpha in plasma and urine, whereas serum values were elevated only to a lesser extent. Stopping statin therapy or successfully changing to another member of this family of compounds resulted in a normalization of the values in all patients. These findings indicate a significant involvement of oxidative injury in the muscular side-effects of statins in patients suffering from hyperlipoproteinemia.

Evaluation of skeletal muscle during calf exercise by 31-phosphorus magnetic resonance spectroscopy in patients on statin medications.

PubMed

Wu, Jim S; Buettner, Catherine; Smithline, Howard; Ngo, Long H; Greenman, Robert L

2011-01-01

Muscle pain is a common side effect of statin medications, but the cause is poorly understood. We characterized phosphocreatine (PCr) exercise recovery kinetics in 10 patients with hypercholesterolemia before and after a 4-week regimen of statin therapy using 31-phosphorus magnetic resonance spectroscopy ((31) P-MRS). (31) P spectra were obtained before, during, and after exercise on a calf flexion pedal ergometer. Creatine kinase (CK) serum levels were drawn before and after statin therapy. The mean metabolic recovery time constant in subjects increased from 28.1 s (SE = 6.5 s) to 55.4 s (SE = 7.4 s) after statin therapy. The unweighted mean of the pre/post-recovery time difference was -27.3 s (SE = 12.4 s; P = 0.02). Pre- and post-therapy CK levels were not significantly different (P = 0.50). Metabolic recovery time in the calf is prolonged in patients after statin use. This suggests that statins impair mitochondrial oxidative function, and (31) P MRS is a potential study model for statin-associated myopathy. Copyright © 2010 Wiley Periodicals, Inc.

Evaluation of skeletal muscle during calf exercise by 31P MR spectroscopy in patients on statin medications

PubMed Central

Buettner, Catherine; Smithline, Howard; Ngo, Long H; Greenman, Robert L.

2012-01-01

Introduction Muscle pain is a common side effect of statin medications, however, the cause is poorly understood. Methods We characterized phosphocreatine (PCr) exercise recovery kinetics in 10 patients with hypercholesterolemia before and after a 4 week regimen of statin therapy using 31P magnetic resonance spectroscopy (31P-MRS). 31P spectra were obtained before, during, and following exercise on a calf flexion pedal ergometer. Creatine kinase (CK) serum levels were drawn before and after statin therapy. Results The mean metabolic recovery time constant in subjects increased from 28.1s (SE=6.5s) to 55.4s (SE=7.4s) following statin therapy. The unweighted mean of the pre-post recovery time difference was -27.3s (SE=12.4s); (p-value = 0.02). Pre- and post-therapy CK levels were not significantly different (p-value = 0.50). Discussion Metabolic recovery time in the calf is prolonged in patients following statin use. This suggests that statins impair mitochondrial oxidative function, and 31P –MRS is a potential study model for statin-associated myopathy. PMID:21171098

Add-On Effect of Probucol in Atherosclerotic, Cholesterol-Fed Rabbits Treated with Atorvastatin

PubMed Central

Keyamura, Yuka; Nagano, Chifumi; Kohashi, Masayuki; Niimi, Manabu; Nozako, Masanori; Koyama, Takashi; Yasufuku, Reiko; Imaizumi, Ayako; Itabe, Hiroyuki; Yoshikawa, Tomohiro

2014-01-01

Objective Lowering the blood concentration of low-density lipoprotein (LDL) cholesterol is the primary strategy employed in treating atherosclerotic disorders; however, most commonly prescribed statins prevent cardiovascular events in just 30% to 40% of treated patients. Therefore, additional treatment is required for patients in whom statins have been ineffective. In this study of atherosclerosis in rabbits, we examined the effect of probucol, a lipid-lowering drug with potent antioxidative effects, added to treatment with atorvastatin. Methods and Results Atherosclerosis was induced by feeding rabbits chow containing 0.5% cholesterol for 8 weeks. Probucol 0.1%, atorvastatin 0.001%, and atorvastatin 0.003% were administered solely or in combination for 6 weeks, beginning 2 weeks after the start of atherosclerosis induction. Atorvastatin decreased the plasma concentration of non-high-density lipoprotein cholesterol (non-HDLC) dose-dependently; atorvastatin 0.003% decreased the plasma concentration of non-HDLC by 25% and the area of atherosclerotic lesions by 21%. Probucol decreased the plasma concentration of non-HDLC to the same extent as atorvastatin (i.e., by 22%) and the area of atherosclerotic lesions by 41%. Probucol with 0.003% atorvastatin decreased the plasma concentration of non-HDLC by 38% and the area of atherosclerotic lesions by 61%. Co-administration of probucol with atorvastatin did not affect the antioxidative effects of probucol, which were not evident on treatment with atorvastatin alone, such as prevention of in vitro LDL-oxidation, increase in paraoxonase-1 activity of HDL, and decreases in plasma and plaque levels of oxidized-LDL in vivo. Conclusions Probucol has significant add-on anti-atherosclerotic effects when combined with atorvastatin treatment; suggesting that this combination might be beneficial for treatment of atherosclerosis. PMID:24810608

Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion-exchange resins, omega-3 fatty acids: which drugs for which patients?

PubMed

Drexel, Heinz

2009-12-01

Classes of lipid lowering drugs differ strongly with respect to the types of lipids or lipoproteins they predominantly affect. Statins inhibit the de-novo synthesis of cholesterol. Consequently, the liver produces less VLDL, and the serum concentration primarily of LDL cholesterol (but, to a lesser extent, also of triglycerides) is lowered. Further, statins somewhat increase HDL cholesterol. There is abundant evidence that statins lower the rate of cardiovascular events. Cardiovascular risk reduction is the better, the lower the LDL cholesterol values achieved with statin therapy are. Some evidence is available that anion exchange resins which also decrease LDL cholesterol decrease vascular risk, too. This is not the case for the ezetimibe, which strongly lowers LDL cholesterol: its potential to decrease vascular risk remains to be proven. In contrast evidence for cardiovascular risk reduction through the mainly triglyceride lowering fibrates as well as for niacin is available. Niacin is the most potent HDL increasing drug currently available and besides increasing HDL cholesterol efficaciously lowers triglycerides and LDL cholesterol. Large ongoing trials address the decisive question whether treatment with fibrates and niacin provides additional cardiovascular risk reduction when given in addition to statin treatment.

Effect of early statin therapy after acute coronary syndromes: a concise review of the recent data.

PubMed

Bybee, Kevin A; Wright, R Scott; Kopecky, Stephen L

2002-01-01

HMG Co-A reductase inhibitors(statins) have been shown, in three large randomized trials, to decrease adverse cardiac events in patients with clinically evident coronary artery disease. All of these trials have excluded patients with an acute coronary syndrome within the three months prior to enrollment. Statin therapy is thought to stabilize coronary plaque and decrease the risk of plaque rupture. Statins have been shown to quickly reduce levels of LDL-C in addition to altering systemic inflammatory responses, improving endothelial function, and reducing platelet aggregation and activation. These mechanisms are potentially beneficial in the setting of acute coronary syndromes, a time of profound plaque instability. There is a growing body of evidence supporting the early initiation of statin therapy in the setting of acute coronary syndromes. This paper reviews the available data from randomized-controlled trials and observational studies evaluating the effect of early statin initiation during, or soon following, an acute coronary syndrome.

Comparison of different statin therapy to change low-density lipoprotein cholesterol and high-density lipoprotein cholesterol level in Korean patients with and without diabetes.

PubMed

Khang, Ah Reum; Song, Young Shin; Kim, Kyoung Min; Moon, Jae Hoon; Lim, Soo; Park, Kyong Soo; Jang, Hak Chul; Choi, Sung Hee

2016-01-01

It is difficult to apply the proper intensity of statin for new treatment guidelines in clinical settings because of few data about the statin efficacy in Asians. We conducted a retrospective, observational study to estimate the percentage changes in lipid parameters and glucose induced by different statins. We analyzed 3854 patients including those with nondiabetes and diabetes treated at the outpatient clinic between 2003 and 2013 who were statin-naïve and maintained fixed-dose of statin for at least 18 months. Moderate- and low-intensity statin therapy was effective in reducing low-density lipoprotein cholesterol (LDL-C) to <100 mg/dL (70.3%, 83.0%, and 87.2% of diabetic patients in the low-, moderate-, and high-intensity therapy groups, respectively). The rapid decrease of LDL-C was observed in the first 8 months, and LDL-C-lowering effect was maintained throughout the observation period in even the low-intensity statin group. The effects of statins in elevating high-density lipoprotein cholesterol were similar in each statin groups, except the ezetimibe-simvastatin group (4.5 ± 2.1%) and high-dose atorvastatin groups (9.7 ± 3.3% and 8.7 ± 2.4% for 40 mg and 80 mg of atorvastatin/day, respectively). High-density lipoprotein cholesterol increased less and LDL-C decreased more in diabetes than in nondiabetes. There were no significant changes of fasting glucose after statin use in nondiabetic patients. Moderate- or low-intensity statin was effective enough in reaching National Cholesterol Education Program Adult Treatment Panel III LDL-C target goals in Koreans. Low-intensity statin showed around 30% LDL-C reduction from the baseline level in Koreans, which is comparable to moderate-intensity statin in new guideline. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

The association of antidepressant and statin use with death and incident cardiovascular disease varies by depression severity.

PubMed

May, Heidi T; Bair, Tami L; Reiss-Brennan, Brenda; Knight, Stacey; Anderson, Jeffrey L; Horne, Benjamin D; Brunisholz, Kimberly D; Muhlestein, Joseph B

2017-09-01

Depression has been reported to be associated with a greater risk of death and cardiovascular disease (CVD); however, the impact of antidepressants (ADM) on CVD risk remains controversial. Statin use is known to decrease CVD risk. Whether the use of these medications together affects CVD risk has not been studied. Patients (N = 26,828) completing the patient health questionnaire (PHQ-9), ≥40 years of age, without prior CVD, and no prior ADM use were studied. Depressive severity was categorized as none-mild (PHQ-9 score ≤14, n = 21,517) and moderate-severe (PHQ-9 score ≥15, n = 5311). Cox hazard regression was used to evaluate the association of no ADM/no statin use (n = 23,104 [86.1%]), ADM/no statin use (n = 877 [3.3%]), no ADM/statin use (n = 2627 [9.8%]), and ADM/statin use (n = 220 [.8%]) with major adverse cardiovascular events (MACE: death, CAD, stroke). Patients averaged 56 ± 12 years; 61% female. There were 1182 (4.4%) 3 year MACE events. The association of ADM and statin use with MACE varied by depressive symptom severity, with statin therapy associated with a decreased risk in the none-mild group (HR = .78, p = .007) and ADM in the moderate-high group (HR = 0.58, p = 0.02). Concomitant use of ADMs and statins did not appear to provide additive benefit.

A Pilot Study: The Beneficial Effects of Combined Statin-exercise Therapy on Cognitive Function in Patients with Coronary Artery Disease and Mild Cognitive Decline.

PubMed

Toyama, Kensuke; Sugiyama, Seigo; Oka, Hideki; Hamada, Mari; Iwasaki, Yuri; Horio, Eiji; Rokutanda, Taku; Nakamura, Shinichi; Spin, Joshua M; Tsao, Philip S; Ogawa, Hisao

2017-01-01

Objective Hypercholesterolemia, a risk factor in cognitive impairment, can be treated with statins. However, cognitive decline associated with "statins" (HMG-CoA reductase inhibitors) is a clinical concern. This pilot study investigated the effects of combining statins and regular exercise on cognitive function in coronary artery disease (CAD) patients with prior mild cognitive decline. Methods We recruited 43 consecutive CAD patients with mild cognitive decline. These patients were treated with a statin and weekly in-hospital aerobic exercise for 5 months. We measured serum lipids, exercise capacity, and cognitive function using the mini mental state examination (MMSE). Results Low-density lipoprotein cholesterol levels were significantly decreased, and maximum exercise capacity (workload) was significantly increased in patients with CAD and mild cognitive decline after treatment compared with before. Combined statin-exercise therapy significantly increased the median (range) MMSE score from 24 (22-25) to 25 (23-27) across the cohort (p<0.01). Changes in body mass index (BMI) were significantly and negatively correlated with changes in the MMSE. After treatment, MMSE scores in the subgroup of patients that showed a decrease in BMI were significantly improved, but not in the BMI-increased subgroup. Furthermore, the patients already on a statin at the beginning of the trial displayed a more significant improvement in MMSE score than statin-naïve patients, implying that exercise might be the beneficial aspect of this intervention as regards cognition. In a multivariate logistic regression analysis adjusted for age >65 years, sex, and presence of diabetes mellitus, a decrease in BMI during statin-exercise therapy was significantly correlated with an increase in the MMSE score (odds ratio: 4.57, 95% confidence interval: 1.05-20.0; p<0.05). Conclusion Statin-exercise therapy may help improve cognitive dysfunction in patients with CAD and pre-existing mild cognitive decline.

Carotid atherosclerosis progression in familial hypercholesterolemia patients: a pooled analysis of the ASAP, ENHANCE, RADIANCE 1, and CAPTIVATE studies.

PubMed

Vergeer, Menno; Zhou, Rong; Bots, Michiel L; Duivenvoorden, Raphaël; Koglin, Joerg; Akdim, Fatima; Mitchel, Yale B; Huijgen, Roeland; Sapre, Aditi; de Groot, Eric; Sijbrands, Eric J G; Pasternak, Richard C; Gagné, Claude; Marais, A David; Ballantyne, Christie M; Isaacsohn, Jonathan L; Stalenhoef, Anton F; Kastelein, John J P

2010-07-01

Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression. We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies. In the 3 recent studies combined, mean cIMT increased at only 33%of the rate of the simvastatin-treated patients in the ASAP study (0.014 mm/2 years [95% confidence interval, -0.0003-0.028] versus 0.041 mm/2 years [95% confidence interval, 0.020-0.061]; P<0.05). Patients whose statin therapy could be intensified, as evidenced by an LDL-C decrease after the initiation of on-trial statin therapy, showed cIMT decrease in the first 6 to 12 months and a much lower cIMT increase measured over the full 2 years. In line with this, previously statin-naive HeFH patients showed a lower overall cIMT increase. Over the years, intensification of statin therapy in HeFH patients has resulted in an impressive decrease in carotid atherosclerosis progression. In studies that assess other antiatherosclerotic modalities, statin therapy may still induce rapid changes in cIMT. For future cIMT studies, our analyses suggest that patient populations other than intensively pretreated HeFH patients should be selected and that the statin regimen should not be changed on study initiation.

Single-dose rosuvastatin ameliorates lung ischemia-reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension.

PubMed

Matsuo, Satoshi; Saiki, Yuriko; Adachi, Osamu; Kawamoto, Shunsuke; Fukushige, Shinichi; Horii, Akira; Saiki, Yoshikatsu

2015-03-01

Lung ischemia-reperfusion (IR) injury during cardiopulmonary surgery is associated with postoperative morbidity and mortality, particularly in patients with pulmonary hypertension (PH). Using a rat model for monocrotaline-induced PH, we investigated the protective effect of rosuvastatin against IR injury in lungs affected by PH and attempted to elucidate its mechanism of action. Male Sprague-Dawley monocrotaline-treated rats were divided into 4 groups (n = 8-9): sham, control + IR, statin + IR, and statin + mevalonolactone + IR. Lung ischemia was induced by left pulmonary artery occlusion (1 hour), followed by reperfusion (4 hours). Rosuvastatin (2 mg/kg) was injected 18 hours before reperfusion and mevalonolactone (1 mg/kg) was injected immediately before reperfusion. The arterial oxygen tension/inspired oxygen fraction ratio was used as a measure of lung oxygenation. Left lung tissue was analyzed for the wet-to-dry lung weight ratio and protein expression of endothelial nitric oxide synthase (eNOS) and phospho-eNOS. Macrophage recruitment was assessed by CD68 immunostaining. Our results showed that rosuvastatin decreased IR lung injury (control + IR vs statin + IR) in terms of the arterial oxygen tension/inspired oxygen fraction ratio (272 ± 43 vs 442 ± 13), wet-to-dry ratio (5.7 ± 0.7 vs 4.8 ± 0.6), and macrophage infiltration (8.0 ± 0.6/field vs 4.0 ± 0.5/field) (P < .05 for all). eNOS and phospho-eNOS were downregulated by IR, which was blocked by rosuvastatin. Effects of rosuvastatin were blunted by mevalonolactone. Single-dose rosuvastatin decreased IR injury in lungs affected by PH via 2 anti-inflammatory mechanisms: preserving eNOS function and inhibiting macrophage infiltration. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Adding exercise training to rosuvastatin treatment: influence on serum lipids and biomarkers of muscle and liver damage.

PubMed

Coen, Paul M; Flynn, Michael G; Markofski, Melissa M; Pence, Brandt D; Hannemann, Robert E

2009-07-01

Statin treatment and exercise training can improve lipid profile when administered separately. The efficacy of exercise and statin treatment combined, and its impact on myalgia and serum creatine kinase (CK) have not been completely addressed. The purpose of this study was to determine the effect of statin treatment and the addition of exercise training on lipid profile, including oxidized low-density lipoprotein (oxLDL), and levels of CK and alanine transaminase. Thirty-one hypercholesterolemic and physically inactive subjects were randomly assigned to rosuvastatin (R) or rosuvastatin/exercise (RE) group. A third group of physically active hypercholesterolemic subjects served as an active control group (AC). The R and RE groups received rosuvastatin treatment (10 mg/d) for 20 weeks. From week 10 to week 20, the RE group also participated in a combined endurance and resistive exercise training program (3 d/wk). Lipid profile was determined for all subjects at week 0 (Pre), week 10 (Mid), and week 20 (Post). The CK and alanine transaminase levels were measured at the same time points in the RE and R groups and 48 hours after the first and fifth exercise bout in the RE group. Each RE subject was formally queried about muscle fatigue, soreness, and stiffness before each training session. Total, LDL, and oxLDL cholesterol was lower in the RE and R groups at Mid and Post time points when compared with Pre. Oxidized LDL was lower in the RE group compared with the R group at the Post time point. When treatment groups (R and RE) were combined, high-density lipoprotein levels were increased and triglycerides decreased across time. Creatine kinase increased in the RE group 48 hours after the first exercise bout, but returned to baseline levels 48 hours after the fifth exercise bout. Rosuvastatin treatment decreased total, LDL, and oxLDL cholesterol. The addition of an exercise training program resulted in a further decrease in oxLDL. There was no abnormal sustained increase in CK or reports of myalgia after the addition of exercise training to rosuvastatin treatment.

Encouraging generic use can yield significant savings.

PubMed

Zimmerman, Christina

2012-11-01

Key findings. (1) Zero copayment for generic drugs is the greatest influencer of generic statin utilization. (2) Both higher copayments for generic drugs and lower copayments for competing brands are associated with a decreased probability of using generic statins. (3) Prior authorization and step therapy requirements for brand-name statins are associated with an increased use of generic drugs. (4) Greater use of generic statins should reduce costs for patients, plans, and Medicare.

[Benefits and risks for primary prevention with statins in the elderly].

PubMed

Joseph, Jean-Philippe; Afonso, Mélanie; Berdaï, Driss; Salles, Nathalie; Bénard, Antoine; Gay, Bernard; Bonnet, Fabrice

2015-12-01

Statins in primary prevention before 75 years old reduce cardiovascular events from 20 to 30% and mortality from 10% with acceptable side effects. We investigated whether these results persisted for patients aged 75 and older taking statin. Methodic review of large randomized clinical trials and meta-analyzes that included patients 75 years and older treated with statins in primary prevention. Since the 1990s, a score of randomized controlled trials studying statins versus placebo in primary prevention were published and studied in meta-analyses. Exclusion criteria, including persons older than 70 years, are often restrictive. The impact on all-cause mortality in the four main studies and meta-analyses in over 75 years has not been demonstrated. On the other hand, a recent meta-analyses of observational studies including subjects between 70 and 89 years treated with statins found that low total cholesterol was associated with a moderate decrease in cardiovascular mortality, with no decrease in all-cause mortality. Moreover, in a common context of comorbidities in this age group, statins may be responsible for many adverse effects, drug interactions and impaired quality of life. Given the lack of formal evidence of effectiveness in terms of all-cause mortality and a high level of adverse effects, the benefit/risk of primary prevention with statins is not established in the elderly. The economic weight of statin prescriptions and their possible impact on quality of life justify an economic analysis of discontinuing statin therapy for people 75 years and older. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Statin use and peripheral sensory perception: a pilot study.

PubMed

West, Brenton; Williams, Cylie M; Jilbert, Elise; James, Alicia M; Haines, Terry P

2014-06-01

Peripheral sensory neuropathy is a neurological deficit resulting in decreased detection of sensation through the peripheral nervous system. Peripheral sensory neuropathy is commonly diagnosed with the use of a monofilament and either a tuning fork or neurothesiometer. Statins are a widely used medication and there has been some debate of association with their use and peripheral sensory neuropathy. This pilot study aimed to test the sensory perception of participants with long-term statin use and compare these results to their peers who were not taking statins. Thirty participants were recruited and equally divided into a statin and non-statin group. Healthy participants were screened by their medical and medication history, Australian Type 2 Diabetes Risk assessment, and random blood glucose level. An assessor who was blinded to the participant group conducted sensory assessments using a 10 g monofilament and neurothesiometer. There was no difference in monofilament testing results between the groups. The statin group was less sensate at the styloid process (p = 0.031) and medial malleolus (p = 0.003) than the control group. Results at the hallux were not statistically significant (p = 0.183). This result is suggestive of a potential association between long-term statin use and a decrease in peripheral sensory perception. This may be because of peripheral sensory neuropathy. Limitations such as consideration of participant height, participant numbers, and inability to analyze results against statin groups are reported. As statins are a life-saving medication, careful consideration should be applied to these results and further research be conducted to determine if these results are applicable to larger populations.

Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort.

PubMed

Cederberg, Henna; Stančáková, Alena; Yaluri, Nagendra; Modi, Shalem; Kuusisto, Johanna; Laakso, Markku

2015-05-01

The aim of this work was to investigate the mechanisms underlying the risk of type 2 diabetes associated with statin treatment in the population-based Metabolic Syndrome in Men (METSIM) cohort. A total of 8,749 non-diabetic participants, aged 45-73 years, were followed up for 5.9 years. New diabetes was diagnosed in 625 men by means of an OGTT, HbA1c ≥6.5% (48 mmol/mol) or glucose-lowering medication started during the follow-up. Insulin sensitivity and secretion were evaluated with OGTT-derived indices. Participants on statin treatment (N = 2,142) had a 46% increased risk of type 2 diabetes (adjusted HR 1.46 [95% CI 1.22, 1.74]). The risk was dose dependent for simvastatin and atorvastatin. Statin treatment significantly increased 2 h glucose (2hPG) and glucose AUC of an OGTT at follow-up, with a nominally significant increase in fasting plasma glucose (FPG). Insulin sensitivity was decreased by 24% and insulin secretion by 12% in individuals on statin treatment (at FPG and 2hPG <5.0 mmol/l) compared with individuals without statin treatment (p < 0.01). Decreases in insulin sensitivity and insulin secretion were dose dependent for simvastatin and atorvastatin. Statin treatment increased the risk of type 2 diabetes by 46%, attributable to decreases in insulin sensitivity and insulin secretion.

Statin and Atrial Fibrilation: When does it work?

PubMed

Fauchier, Laurent; Clementy, Nicolas; Pierre, Bertrand; Babuty, Dominique

2012-01-01

In the recent years, some clinical and experimental studies have suggested that the use of statins may protect against atrial fibrillation (AF). A relation between inflammation and the development of AF has been described, and the potent anti-inflammatory and antioxidant properties of statins may make them effective in preventing the development of AF. A global analysis of the literature suggests that the use of statins is associated with a decreased risk of incidence or recurrence of AF in some cases. However, this beneficial effect is not seen for all types of AF in all the patients. The use of statins seems associated 1) with a lack of benefit in primary prevention of AF, 2) with a significant but heterogeneous decreased risk of recurrence of AF in secondary prevention, and 3) with a very significant and homogeneous reduction for the risk of post operative AF. An intensive lipid lowering statin regimen does not provide greater protection against AF. Patients with coronary heart disease are curr ently treated with statins in most cases, and this may not have an impact on their treatment. In contrast, it remains to determine more accurately if statins may bring a significant benefit for some AF patients without any type of established atherosclerotic disease or with a low risk of atherogenesis. Since it remains uncertain whether the suppression of AF in these patients is beyond doubt beneficial, prescribing statins for this purpose alone should not be recommended at the present time.

Statin-related myotoxicity.

PubMed

Fernandes, Vera; Santos, Maria Joana; Pérez, Antonio

2016-05-01

Statin therapy has a very important role in decreasing cardiovascular risk, and treatment non-compliance may therefore be a concern in high cardiovascular risk patients. Myotoxicity is a frequent side effect of statin therapy and one of the main causes of statin discontinuation, which limits effective treatment of patients at risk of or with cardiovascular disease. Because of the high proportion of patients on statin treatment and the frequency of statin-related myotoxicity, this is a subject of concern in clinical practice. However, statin-related myotoxicity is probably underestimated because there is not a gold standard definition, and its diagnosis is challenging. Moreover, information about pathophysiology and optimal therapeutic options is scarce. Therefore, this paper reviews the knowledge about the definition, pathophysiology and predisposing conditions, diagnosis and management of statin-related myotoxicity, and provides a practical scheme for its management in clinical practice. Copyright © 2016 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

The effect of coenzyme Q10 in statin myopathy.

PubMed

Zlatohlavek, Lukas; Vrablik, Michal; Grauova, Barbora; Motykova, Eva; Ceska, Richard

2012-01-01

Statins significantly reduce CV morbidity and mortality. Unfortunately, one of the side effects of statins is myopathy, for which statins cannot be administered in sufficient doses or administered at all. The aim of this study was to demonstrate the effect of coenzyme Q10 in patients with statin myopathy. Twenty eight patients aged 60.6±10.7 years were monitored (18 women and 10 men) and treated with different types and doses of statin. Muscle weakness and pain was monitored using a scale of one to ten, on which patients expressed the degree of their inconvenience. Examination of muscle problems was performed prior to administration of CQ10 and after 3 and 6 months of dosing. Statistical analysis was performed using Friedman test, Annova and Students t-test. Pain decreased on average by 53.8% (p<0.0001), muscle weakness by 44.4% (p<0.0001). The CQ10 levels were increased by more than 194% (from 0,903 μg/ml to 2.66 μg/ml; p<0.0001). After a six-month administration of coenzyme Q10, muscle pain and sensitivity statistically significantly decreased.

Effect of statins on skeletal muscle function.

PubMed

Parker, Beth A; Capizzi, Jeffrey A; Grimaldi, Adam S; Clarkson, Priscilla M; Cole, Stephanie M; Keadle, Justin; Chipkin, Stuart; Pescatello, Linda S; Simpson, Kathleen; White, C Michael; Thompson, Paul D

2013-01-01

Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.

Possible modification of Alzheimer's disease by statins in midlife: interactions with genetic and non-genetic risk factors.

PubMed

Shinohara, Mitsuru; Sato, Naoyuki; Shimamura, Munehisa; Kurinami, Hitomi; Hamasaki, Toshimitsu; Chatterjee, Amarnath; Rakugi, Hiromi; Morishita, Ryuichi

2014-01-01

The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer's disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include β-amyloid (Aβ) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Aβ accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease.

A Peculiar Formula of Essential Amino Acids Prevents Rosuvastatin Myopathy in Mice

PubMed Central

D'Antona, Giuseppe; Tedesco, Laura; Ruocco, Chiara; Corsetti, Giovanni; Ragni, Maurizio; Fossati, Andrea; Saba, Elisa; Fenaroli, Francesca; Montinaro, Mery; Carruba, Michele O.; Valerio, Alessandra

2016-01-01

Abstract Aims: Myopathy, characterized by mitochondrial oxidative stress, occurs in ∼10% of statin-treated patients, and a major risk exists with potent statins such as rosuvastatin (Rvs). We sought to determine whether a peculiar branched-chain amino acid-enriched mixture (BCAAem), found to improve mitochondrial function and reduce oxidative stress in muscle of middle-aged mice, was able to prevent Rvs myopathy. Results: Dietary supplementation of BCAAem was able to prevent the structural and functional alterations of muscle induced by Rvs in young mice. Rvs-increased plasma 3-methylhistidine (a marker of muscular protein degradation) was prevented by BCAAem. This was obtained without changes of Rvs ability to reduce cholesterol and triglyceride levels in blood. Rather, BCAAem promotes de novo protein synthesis and reduces proteolysis in cultured myotubes. Morphological alterations of C2C12 cells induced by statin were counteracted by amino acids, as were the Rvs-increased atrogin-1 mRNA and protein levels. Moreover, BCAAem maintained mitochondrial mass and density and citrate synthase activity in skeletal muscle of Rvs-treated mice beside oxygen consumption and ATP levels in C2C12 cells exposed to statin. Notably, BCAAem assisted Rvs to reduce oxidative stress and to increase the anti-reactive oxygen species (ROS) defense system in skeletal muscle. Innovation and Conclusions: The complex interplay between proteostasis and antioxidant properties may underlie the mechanism by which a specific amino acid formula preserves mitochondrial efficiency and muscle health in Rvs-treated mice. Strategies aimed at promoting protein balance and controlling mitochondrial ROS level may be used as therapeutics for the treatment of muscular diseases involving mitochondrial dysfunction, such as statin myopathy. Antioxid. Redox Signal. 25, 595–608. PMID:27245589

Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women.

PubMed

Chan, K A; Andrade, S E; Boles, M; Buist, D S; Chase, G A; Donahue, J G; Goodman, M J; Gurwitz, J H; LaCroix, A Z; Platt, R

2000-06-24

Inhibitors of hydroxymethylglutaryl-coenzyme A reductase (statins) increase new bone formation in rodents and in human cells in vitro. Statin use is associated with increased bone mineral density of the femoral neck. We undertook a population-based case-control study at six health-maintenance organisations in the USA to investigate further the relation between statin use and fracture risk among older women. We investigated women aged 60 years or older. Exposure, outcome, and confounder information was obtained from automated claims and pharmacy data from October, 1994, to September, 1997. Cases had an incident diagnosis of non-pathological fracture of the hip, humerus, distal tibia, wrist, or vertebrae between October, 1996, and September, 1997. Controls had no fracture during this period. We excluded women with records of dispensing of drugs to treat osteoporosis. There were 928 cases and 2747 controls. Compared with women who had no record of statin dispensing during the previous 2 years, women with 13 or more statin dispensings during this period had a decreased risk of non-pathological fracture (odds ratio 0.48 [95% CI 0.27-0.83]) after adjustment for age, number of hospital admissions during the previous year, chronic disease score, and use of non-statin lipid-lowering drugs. No association was found between fracture risk and fewer than 13 dispensings of statins or between fracture risk and use of non-statin lipid-lowering drugs. Statins seem to be protective against non-pathological fracture among older women. These findings are compatible with the hypothesis that statins increase bone mineral density in human beings and thereby decrease the risk of osteoporotic fractures.

Therapeutic neovascularization by nanotechnology-mediated cell-selective delivery of pitavastatin into the vascular endothelium.

PubMed

Kubo, Mitsuki; Egashira, Kensuke; Inoue, Takahiro; Koga, Jun-ichiro; Oda, Shinichiro; Chen, Ling; Nakano, Kaku; Matoba, Tetsuya; Kawashima, Yoshiaki; Hara, Kaori; Tsujimoto, Hiroyuki; Sueishi, Katsuo; Tominaga, Ryuji; Sunagawa, Kenji

2009-06-01

Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization. In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice. NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.

Changes in muscle strength in patients with statin myalgia.

PubMed

Panza, Gregory A; Taylor, Beth A; Roman, William; Thompson, Paul D

2014-10-15

Statins can produce myalgia or muscle pain, which may affect medication adherence. We measured the effects of statins on muscle strength in patients with previous statin myalgia. Leg isokinetic extension average power at 60° per second (-8.8 ± 10.5N-M, p = 0.02) and average peak torque at 60° per second (-14.0 ± 19.7N-M, p = 0.04) decreased slightly with statin use, but 8 of 10 other variables for leg strength did not change (all p >0.13). Handgrip, muscle pain, respiratory exchange ratio, and daily activity also did not change (all p >0.09). In conclusion, statin myalgia is not associated with reduced muscle strength or muscle performance. Published by Elsevier Inc.

Effect of coenzyme q10 on myopathic symptoms in patients treated with statins.

PubMed

Caso, Giuseppe; Kelly, Patricia; McNurlan, Margaret A; Lawson, William E

2007-05-15

Treatment of hypercholesterolemia with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) is effective in the primary and secondary prevention of cardiovascular disease. However, statin use is often associated with a variety of muscle-related symptoms or myopathies. Myopathy may be related in part to statin inhibition of the endogenous synthesis of coenzyme Q10, an essential cofactor for mitochondrial energy production. The aim of this study is to determine whether coenzyme Q10 supplementation would reduce the degree of muscle pain associated with statin treatment. Patients with myopathic symptoms were randomly assigned in a double-blinded protocol to treatment with coenzyme Q10 (100 mg/day, n = 18) or vitamin E (400 IU/day, n = 14) for 30 days. Muscle pain and pain interference with daily activities were assessed before and after treatment. After a 30-day intervention, pain severity decreased by 40% (p <0.001) and pain interference with daily activities decreased by 38% (p <0.02) in the group treated with coenzyme Q10. In contrast, no changes in pain severity (+9%, p = NS) or pain interference with daily activities (-11%, p = NS) was observed in the group treated with vitamin E. In conclusion, results suggest that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs.

Statins, inflammation and deep vein thrombosis: a systematic review

PubMed Central

Rodriguez, April L.; Wojcik, Brandon M.; Wrobleski, Shirley K.; Myers, Daniel D.; Wakefield, Thomas W.

2012-01-01

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism. The 2009 JUPITER trial showed a significant decrease in DVT in non-hyperlipidemic patients, with elevated C-reactive protein (CRP) levels, treated with rosuvastatin. The effects of statins on thrombosis are unclear, prompting this literature review. A literature search was performed (1950 to February 2011) with MEDLINE, EMBASE, and PUBMED databases including the following keywords: “statins”, “hydroxymethylglutaryl-CoA reductase inhibitors”, “VTE”, “PE”, “DVT”, and either “anti-coagulation” or “inflammation”. Editorials, reviews, case reports, meta-analysis and duplicates were excluded. Inflammatory biomarkers of DVT, include interleukin (IL)-6, CRP, IL-8, and monocyte chemotactic protein 1 (MCP-1). Statin therapy reduces IL-6 expression of CRP and MCP-1, usually elevated in VTE. Reduction of IL-6 induced MCP-1 has been linked to vein wall fibrosis, promoting post thrombotic syndrome (PTS) and recurrent DVT in patients. Also, our review suggests that the anti-thrombotic effects are likely exhibited through the anti-inflammatory properties of statins. This work supports that statin therapy has the ability to decrease the incidence and recurrence of VTE and the potential to decrease PTS. This is mainly due to the anti-inflammatory effects of statins and may explain why normolipidemic patients, with elevated CRP, appear to have the greatest reduction in VTE. Given their low risk of bleeding, statins have the potential to serve as a safe adjunctive pharmacological therapy to current treatments in select patients with VTE, however further investigations into this concept are needed and essential. PMID:22278047

Protective effects of coenzyme q(10) on decreased oxidative stress resistance induced by simvastatin.

PubMed

Kettawan, Aikkarach; Takahashi, Takayuki; Kongkachuichai, Ratchanee; Charoenkiatkul, Somsri; Kishi, Takeo; Okamoto, Tadashi

2007-05-01

The effects of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), on oxidative stress resistance and the protective effects of coenzyme Q (CoQ) were investigated. When simvastatin was administered orally to mice, the levels of oxidized and reduced CoQ(9) and CoQ(10) in serum, liver, and heart, decreased significantly when compared to those of control. The levels of thiobarbituric acid reactive substances induced by Fe(2+)-ascorbate in liver and heart mitochondria also increased significantly with simvastatin. Furthermore, cultured cardiac myocytes treated with simvastatin exhibited less resistance to oxidative stress, decreased time to the cessation of spontaneous beating in response to H(2)O(2) addition, and decreased responsiveness to electrical field stimulation. These results suggested that oral administration of simvastatin suppresses the biosynthesis of CoQ, which shares the same biosynthesis pathway as cholesterol up to farnesyl pyrophosphate, thus compromising the physiological function of reduced CoQ, which possesses antioxidant activity. However, these undesirable effects induced by simvastatin were alleviated by coadministering CoQ(10) with simvastatin to mice. Simvastatin also reduced the activity of NADPH-CoQ reductase, a biological enzyme that converts oxidized CoQ to the corresponding reduced CoQ, while CoQ(10) administration improved it. These findings may also support the efficacy of coadministering CoQ(10) with statins.

The Effect of Statins on Skeletal Muscle Function

PubMed Central

Parker, Beth A.; Capizzi, Jeffrey A.; Grimaldi, Adam S.; Clarkson, Priscilla M.; Cole, Stephanie M.; Keadle, Justin; Chipkin, Stuart; Pescatello, Linda S.; Simpson, Kathleen; White, C. Michael; Thompson, Paul D.

2015-01-01

Background Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials and the effect of statins on muscle performance has not been carefully studied. Methods and Results The Effect of STatins On Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase (CK), exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo were administered for 6 months to 420 healthy, statin-naive subjects. No individual CK value exceeded 10 times normal, but average CK increased 20.8 ± 141.1 U/L (p<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 vs 10; p = 0.05). Myalgic subjects on atorvastatin or placebo decreased muscle strength in 5 of 14 and 4 of 14 variables respectively (p = 0.69). Conclusions These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average CK suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in CK should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. Clinical Trial Registration Information: www.clinicaltrials.gov; Identifier: NCT00609063. PMID:23183941

Efficacy and safety of statins and exercise combination therapy compared to statin monotherapy in patients with dyslipidaemia: A systematic review and meta-analysis.

PubMed

Gui, Ya-Jun; Liao, Cai-Xiu; Liu, Qiong; Guo, Yuan; Yang, Tao; Chen, Jing-Yuan; Wang, Ya-Ting; Hu, Jia-Hui; Xu, Dan-Yan

2017-06-01

Background Statin treatment in association with physical exercise can substantially reduce mortality in dyslipidaemic individuals. However, the available data to compare the efficacy and safety of statins and exercise combination therapy with statin monotherapy are limited. Design Systematic review and meta-analysis. Methods We systematically searched PubMed, Embase and the Cochrane Library from database inception until December 2016. We included randomised and non-randomised studies that compared the efficacy and safety of statins and exercise combination therapy with statin monotherapy in patients with dyslipidaemia. Standardised mean differences were calculated and pooled by means of fixed effects models. The risk of bias and heterogeneity among trials was also assessed. Seven articles were assessed in terms of the efficacy of therapy and 13 from the viewpoint of therapeutic safety. Results In terms of efficacy, statins and exercise combination decreased the incidence of diabetes mellitus, improved insulin sensitivity and inflammation, but caused no change in lipid profile compared to statins alone. In terms of safety, statins and exercise combination increased peak oxygen uptake (standardised mean difference 1.01, 95% confidence interval 0.46 to 1.57) compared to statins alone. In contrast to statin-induced myopathy, chronic exercise training prior to statin treatment could counteract statin-induced adverse effects in skeletal muscle. Conclusion Statins and exercise combination therapy is more effective than statin monotherapy in terms of insulin sensitivity, inflammation and exercise capacity. The small number of studies warrants the need for more randomised controlled trials evaluating the efficacy and safety of combination therapy.

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

NASA Astrophysics Data System (ADS)

Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S. G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

2014-01-01

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

Statin use and self-reported swimming performance in US masters swimmers.

PubMed

Terpak, Kyle; Guthrie, Sally; Erickson, Steven

2015-01-01

Exercise and treating hyperlipidaemia with statins are two integral components of the American Heart Association guidelines to reduce cardiovascular risk in adults. Since statins can cause myalgias and myopathies, they could affect the duration or intensity of an exercise regimen. To determine the impact of statin use in adult masters swimmers, a survey was distributed to examine the association between swimming performance and statin usage in adult swimmers (≥35 years). After excluding those with chronic diseases or taking drugs that reduce physical capacity, 749 swimmers (118 taking statins, 73 not taking statins to control elevated cholesterol and 558 controls) were included in a regression model to determine the factors significantly affecting the duration and intensity of swimming workouts. Age and gender were significantly (P ≤ 0.001) associated with the distance swam per 60 min. Younger, male swimmers completed more yards per 60-min workout. Use of statins was not significantly associated with yards swam per 60-min workout. Nor did statin usage affect the number of swim sessions per month or the length of swim session. Evidently, statins do not cause enough fatigue or pain in masters swimmers to require a decrease in the duration or intensity of workouts.

Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction.

PubMed

La Mura, Vincenzo; Pasarín, Marcos; Meireles, Cintia Z; Miquel, Rosa; Rodríguez-Vilarrupla, Aina; Hide, Diana; Gracia-Sancho, Jorge; García-Pagán, Juan Carlos; Bosch, Jaime; Abraldes, Juan G

2013-03-01

Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis. The present study explores liver vascular abnormalities and the effects of statins in a rat model of endotoxemia. For this purpose, lipopolysaccharide (LPS) or saline was given to: (1) rats treated with placebo; (2) rats treated with simvastatin (25 mg/kg, orally), given at 3 and 23 hours after LPS/saline challenge; (3) rats treated with simvastatin (25 mg/kg/24 h, orally) from 3 days before LPS/saline injection. Livers were isolated and perfused and sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine. The phosphorylated endothelial nitric oxide synthase (PeNOS)/endothelial nitric oxide synthase (eNOS) ratio was measured as a marker of eNOS activation. LPS administration induced an increase in baseline portal perfusion pressure and a decrease in vasodilation to acetylcholine (sinusoidal endothelial dysfunction). This was associated with reduced eNOS phosphorylation and liver inflammation. Simvastatin after LPS challenge did not prevent the increase in baseline portal perfusion pressure, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine and reduced liver inflammation. Both protocols of treatment restored a physiologic PeNOS/eNOS ratio. LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia. Copyright © 2012 American Association for the Study of Liver Diseases.

Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia

PubMed Central

Tan, Ricardo; Giral, Philippe; Robillard, Paul; Kontush, Anatol; Chapman, M. John

2016-01-01

Atherogenic mixed dyslipidemia associates with oxidative stress and defective HDL antioxidative function in metabolic syndrome (MetS). The impact of statin treatment on the capacity of HDL to inactivate LDL-derived, redox-active phospholipid hydroperoxides (PCOOHs) in MetS is indeterminate. Insulin-resistant, hypertriglyceridemic, hypertensive, obese males were treated with pitavastatin (4 mg/day) for 180 days, resulting in marked reduction in plasma TGs (−41%) and LDL-cholesterol (−38%), with minor effects on HDL-cholesterol and apoAI. Native plasma LDL (baseline vs. 180 days) was oxidized by aqueous free radicals under mild conditions in vitro either alone or in the presence of the corresponding pre- or poststatin HDL2 or HDL3 at authentic plasma mass ratios. Lipidomic analyses revealed that statin treatment i) reduced the content of oxidizable polyunsaturated phosphatidylcholine (PUPC) species containing DHA and linoleic acid in LDL; ii) preferentially increased the content of PUPC species containing arachidonic acid (AA) in small, dense HDL3; iii) induced significant elevation in the content of phosphatidylcholine and phosphatidylethanolamine (PE) plasmalogens containing AA and DHA in HDL3; and iv) induced formation of HDL3 particles with increased capacity to inactivate PCOOH with formation of redox-inactive phospholipid hydroxide. Statin action attenuated LDL oxidability Concomitantly, the capacity of HDL3 to inactivate redox-active PCOOH was enhanced relative to HDL2, consistent with preferential enrichment of PE plasmalogens and PUPC in HDL3. PMID:27581680

Long-term statin therapy could be efficacious in reducing the lipoprotein (a) levels in patients with coronary artery disease modified by some traditional risk factors.

PubMed

Xu, Ming-Xing; Liu, Chang; He, Yong-Ming; Yang, Xiang-Jun; Zhao, Xin

2017-05-01

Lipoprotein (a) [Lp (a)] is a well-established risk factor for coronary artery disease (CAD). However, up till now, treatment of patients with higher Lp (a) levels is challenging. This current study aimed to investigate the therapeutic effects of short-, medium and long-term statin use on the Lp (a) reduction and its modifying factors. The therapeutic duration was categorized into short-term (median, 39 days), medium term (median, 219 days) and long-term (median, 677 days). The lipid profiles before therapy served as baselines. Patients at short-, medium or long-term exactly matched with those at baseline. Every patient's lipid profiles during the follow-ups were compared to his own ones at baselines. The current study demonstrated that long-term statin therapy significantly decreased the Lp (a) levels in CAD patients while short-term or medium term statin therapy didn't. When grouped by statin use, only long-term simvastatin use significantly decreased the Lp (a) levels while long-term atorvastatin use insignificantly decreased the Lp (a) levels. Primary hypertension (PH), DM, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) could modify the therapeutic effects of statin use on the Lp (a) levels in CAD patients. The long-term statin therapy could be efficacious in reducing the Lp (a) levels in CAD patients, which has been modified by some traditional risk factors. In the era of commercial unavailability of more reliable Lp (a) lowering drugs, our findings will bolster confidence in fighting higher Lp (a) abnormalities both for patients and for doctors.

Statin use decreases coagulation in users of vitamin K antagonists.

PubMed

van Rein, Nienke; Biedermann, J S; Bonafacio, S M; Kruip, M J H A; van der Meer, F J M; Lijfering, W M

2016-12-01

The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test. Four hundred thirty-five phenprocoumon users (mean age 70 years, 60 % men) and 303 acenocoumarol users (mean age 69 years, 58 % men) were included. After start of statin use, the immediate phenprocoumon dosage was 0.02 mg/day (95 % CI, 0.00 to 0.03) lower. At 6 and 12 weeks, these phenprocoumon dosages were 0.03 (95 % CI, 0.01 to 0.05) and 0.07 mg/day (95 % CI, 0.04 to 0.09) lower as compared with the dosage before first statin use. In acenocoumarol users, VKA dosage was 0.04 mg/day (95%CI, 0.01 to 0.07) (immediate effect), 0.10 (95 % CI, 0.03 to 0.16) (at 6 weeks), and 0.11 mg/day (95 % CI, 0.04 to 0.18) (after 12 weeks) lower. Initiation of statin treatment was associated with an immediate and long-term minor although statistically significant decrease in VKA dosage in both phenprocoumon and acenocoumarol users, which suggests that statins may have anticoagulant properties.

Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells.

PubMed

Fujiwara, Daichiro; Tsubaki, Masanobu; Takeda, Tomoya; Tomonari, Yoshika; Koumoto, Yu-Ichi; Sakaguchi, Katsuhiko; Nishida, Shozo

2017-10-01

Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal-regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.

Statins: pros and cons.

PubMed

Pinal-Fernandez, Iago; Casal-Dominguez, Maria; Mammen, Andrew L

2018-05-23

Statins inhibit the critical step of cholesterol synthesis in which 3-hydroxy-3-methylglutaryl coenzyme A (HMGC) is transformed to mevalonate by the enzyme HMGC reductase. By doing so, they have a potent lipid-lowering effect that reduces cardiovascular risk and decreases mortality. Since the mevalonate pathway also influences endothelial function, the inflammatory response, and coagulation, the effects of statins reach well beyond their cholesterol lowering properties. As with all drugs, statins may have adverse effects; these include musculoskeletal symptoms, increased risk of diabetes, and higher rates of hemorrhagic stroke. However, the frequency of adverse effects is extremely low and, in selected patient populations, the benefits of statins considerably outweigh the potential risks. Published by Elsevier España, S.L.U.

Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

PubMed Central

Stroes, Erik S.; Thompson, Paul D.; Corsini, Alberto; Vladutiu, Georgirene D.; Raal, Frederick J.; Ray, Kausik K.; Roden, Michael; Stein, Evan; Tokgözoğlu, Lale; Nordestgaard, Børge G.; Bruckert, Eric; De Backer, Guy; Krauss, Ronald M.; Laufs, Ulrich; Santos, Raul D.; Hegele, Robert A.; Hovingh, G. Kees; Leiter, Lawrence A.; Mach, Francois; März, Winfried; Newman, Connie B.; Wiklund, Olov; Jacobson, Terry A.; Catapano, Alberico L.; Chapman, M. John; Ginsberg, Henry N.; Stroes, Erik; Thompson, Paul D.; Corsini, Alberto; Vladutiu, Georgirene D.; Raal, Frederick J.; Ray, Kausik K.; Roden, Michael; Stein, Evan; Tokgözoğlu, Lale; Nordestgaard, Børge G.; Bruckert, Eric; Krauss, Ronald M.; Laufs, Ulrich; Santos, Raul D.; März, Winfried; Newman, Connie B.; John Chapman, M.; Ginsberg, Henry N.; John Chapman, M.; Ginsberg, Henry N.; de Backer, Guy; Catapano, Alberico L.; Hegele, Robert A.; Kees Hovingh, G.; Jacobson, Terry A.; Leiter, Lawrence; Mach, Francois; Wiklund, Olov

2015-01-01

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential. PMID:25694464

Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.

PubMed

Stroes, Erik S; Thompson, Paul D; Corsini, Alberto; Vladutiu, Georgirene D; Raal, Frederick J; Ray, Kausik K; Roden, Michael; Stein, Evan; Tokgözoğlu, Lale; Nordestgaard, Børge G; Bruckert, Eric; De Backer, Guy; Krauss, Ronald M; Laufs, Ulrich; Santos, Raul D; Hegele, Robert A; Hovingh, G Kees; Leiter, Lawrence A; Mach, Francois; März, Winfried; Newman, Connie B; Wiklund, Olov; Jacobson, Terry A; Catapano, Alberico L; Chapman, M John; Ginsberg, Henry N

2015-05-01

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Pleiotropic Effects of Statins on the Cardiovascular System.

PubMed

Oesterle, Adam; Laufs, Ulrich; Liao, James K

2017-01-06

The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease. © 2017 American Heart Association, Inc.

Statin Use and Fatal Prostate Cancer: A Matched Case-Control Study

PubMed Central

Marcella, Stephen W.; David, Alice; Ohman-Strickland, Pamela A.; Carson, Jeffery; Rhoads, George G.

2015-01-01

Background Statins are one of the most commonly prescribed medications in medical practice and prostate cancer is the most common male malignancy. While there has been no consistent evidence that statins affect cancer incidence, including prostate cancer, several reports suggest they may decrease the rate of advanced prostate cancer. However, no study has examined statin use and prostate cancer mortality specifically. We report here a population-based case-control investigation that examines this association. Methods We conducted a matched case-control study. Cases were residents of New Jersey ages 55 – 79 who died from prostate cancer between 1997–2000. We individually matched population-based controls by five-year age-group and race. Medication data were obtained identically for cases and controls from blinded medical chart review. We used conditional logistic regression to adjust for confounders. Results We identified 718 cases and obtained cooperation from 77% of their spouses (N=553). After review of medical records, 387 were eligible and 380 were matched to a control. The unadjusted odds ratio was 0.49 (95% CI, 0.34–0.70) which decreased to 0.37 (p<0.0001) after adjustment for education, waist size, BMI, comorbidities, and anti-hypertensive medication. There was little difference between lipophilic and hydrophilic statins but more risk reduction was noted for hi-potency statins (73%, p<0.0001) as compared to low-potency statins (31%, p=0.32). Conclusion Statin use is associated with substantial protection against prostate cancer death, adding to the epidemiologic evidence for an inhibitory effect on prostate cancer. PMID:22180145

Statin Effects on Aggression: Results from the UCSD Statin Study, a Randomized Control Trial

PubMed Central

Golomb, Beatrice A.; Dimsdale, Joel E.; Koslik, Hayley J.; Evans, Marcella A.; Lu, Xun; Rossi, Steven; Mills, Paul J.; Criqui, Michael H.

2015-01-01

Background Low/ered cholesterol is linked to aggression in some study designs. Cases/series have reported reproducible aggression increases on statins, but statins also bear mechanisms that could reduce aggression. Usual statin effects on aggression have not been characterized. Methods 1016 adults (692 men, 324 postmenopausal women) underwent double-blind sex-stratified randomization to placebo, simvastatin 20mg, or pravastatin 40mg (6 months). The Overt-Aggression-Scale-Modified–Aggression-Subscale (OASMa) assessed behavioral aggression. A significant sex-statin interaction was deemed to dictate sex-stratified analysis. Exploratory analyses assessed the influence of baseline-aggression, testosterone-change (men), sleep and age. Results The sex-statin interaction was significant (P=0.008). In men, statins tended to decrease aggression, significantly so on pravastatin: difference=-1.0(SE=0.49)P=0.038. Three marked outliers (OASMa-change ≥40 points) offset otherwise strong significance-vs-placebo: statins:-1.3(SE=0.38)P=0.0007; simvastatin:-1.4(SE=0.43)P=0.0011; pravastatin:-1.2(SE=0.45)P=0.0083. Age≤40 predicted greater aggression-decline on statins: difference=-1.4(SE=0.64)P=0.026. Aggression-protection was emphasized in those with low baseline aggression: age<40-and-low-baseline-aggression (N=40) statin-difference-vs-placebo=-2.4(SE=0.71)P=0.0016. Statins (especially simvastatin) lowered testosterone, and increased sleep problems. Testosterone-drop on statins predicted aggression-decline: β=0.64(SE=0.30)P=0.034, particularly on simvastatin: β=1.29(SE=0.49)P=0.009. Sleep-worsening on statins significantly predicted aggression-increase: β=2.2(SE=0.55)P<0.001, particularly on simvastatin (potentially explaining two of the outliers): β=3.3(SE=0.83)P<0.001. Among (postmenopausal) women, a borderline aggression-increase on statins became significant with exclusion of one younger, surgically-menopausal woman (N=310) β=0.70(SE=0.34)P=0.039. The increase was significant, without exclusions, for women of more typical postmenopausal age (≥45): (N=304) β=0.68(SE=0.34)P=0.048 – retaining significance with modified age-cutoffs (≥50 or ≥55). Significance was observed separately for simvastatin. The aggression-increase in women on statins was stronger in those with low baseline aggression (N=175) β=0.84(SE=0.30)P=0.006. No statin effect on whole blood serotonin was observed; and serotonin-change did not predict aggression-change. Conclusion Statin effects on aggression differed by sex and age: Statins generally decreased aggression in men; and generally increased aggression in women. Both findings were selectively prominent in participants with low baseline aggression – bearing lower change-variance, rendering an effect more readily evident. Trial Registration Clinicaltrials.gov NCT00330980 PMID:26132393

Statin Use during Hospitalization and Short-Term Mortality in Acute Ischaemic Stroke with Chronic Kidney Disease.

PubMed

Zhang, Xinmiao; Jing, Jing; Zhao, Xingquan; Liu, Liping; Wang, Chunxue; Pan, Yuesong; Meng, Xia; Wang, Yilong; Wang, Yongjun

2018-05-31

Statin use during hospitalization improves prognosis in patients with ischaemic stroke. However, it remains uncertain whether acute ischaemic stroke patients with chronic kidney disease (CKD) benefit from statin therapy. We investigated the effect of statin use during hospitalization in reducing short-term mortality of patients with ischaemic stroke and CKD. Data of first-ever ischaemic stroke patients without a history of pre-stroke statin treatment was derived from the China National Stroke Registry. Patients were stratified according to estimated glomerular filtration rate (eGFR): normal renal function (eGFR ≥90 mL/min/1.73 m2), mild CKD (eGFR 60-90 mL/min/1.73 m2) and moderate CKD (eGFR < 60 mL/min/1.73 m2). Multivariate logistic regression analysis was used to evaluate the association between statin use during hospitalization and all-cause mortality with different renal functions at 3-month follow-up. Among 5,951 patients included, 2,595 (43.6%) patients were on statin use during hospitalization after stroke (45.7% in patients with normal renal function, 42.0% in patients with mild CKD, and 39.0% in patients with moderate CKD). Compared with the non-statin group, statin use during hospitalization was associated with decreased all-cause mortality in patients with normal renal function (OR 0.65, 95% CI 0.43-0.97, p = 0.04), mild CKD (OR 0.59, 95% CI 0.38-0.91, p = 0.02) and moderate CKD (OR 0.41, 95% CI 0.23-0.75, p = 0.004) at 3-month follow-up. Statin use during hospitalization was associated with decreased 3-month mortality of ischaemic stroke patients with mild and moderate CKD. However, the conclusion should be confirmed in further studies with larger population, especially with moderate CKD. © 2018 S. Karger AG, Basel.

Statin withdrawal: clinical implications and molecular mechanisms.

PubMed

Cubeddu, Luigi X; Seamon, Matthew J

2006-09-01

Retrospective analyses of data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), the National Registry of Myocardial Infarction 4, and the Global Registry of Acute Coronary Events (GRACE) trials revealed that the benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on acute coronary outcomes are rapidly lost and outcomes worsened if statins are discontinued during a patient's hospitalization for an acute coronary syndrome. Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-elevation myocardial infarction increased the hospital morbidity and mortality rate versus continued therapy (11.9% vs 5.7%, p<0.01). Data from the Treating New Targets (TNT) study, however, suggested that short-term discontinuation of statin therapy in patients with stable cardiac conditions may not substantially increase the risk of acute coronary syndromes. In patients with acute coronary syndromes who discontinue statins, the rapid increase in risk of an event may result not only from the lost benefits from the therapy, but also from rebound inhibition of vascular protective substances and activation of vascular deleterious substances. Statins inhibit cholesterol synthesis in vascular cells. By reducing levels of isoprenoid intermediates, statins increase the production of nitric oxide and downregulate angiotensin II AT(1) receptors, endothelin-1, vascular inflammatory adhesion molecules, and inflammatory cytokines. These benefits are rapidly lost and often transiently reversed when statins are acutely discontinued. Acute removal of pleiotropic effects and rebound vascular dysfunction may be more important in an acute coronary event, where inflammation promotes rupture of atherosclerotic plaques and inflammatory and prothrombosis markers are present in high concentration, than in stable chronic vascular disease. In the absence of data from randomized controlled trials, current information suggests that statin therapy should be continued, and possibly boosted, during hospitalization for an acute coronary syndrome. Because statins are discontinued during the early hospitalization of many patients, practitioners must ensure that statins are not omitted, unless contraindicated, from the treatment of patients with acute coronary syndromes.

Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education.

PubMed

Wei, Melissa Y; Ito, Matthew K; Cohen, Jerome D; Brinton, Eliot A; Jacobson, Terry A

2013-01-01

Although statins have been shown to reduce cardiovascular disease mortality, less than half of U.S. adults achieve their low-density lipoprotein cholesterol goal. In many patients initiated on a statin, adherence rates decrease over time. To characterize current and former statin users, identify reasons for the discontinuation or switching of statins, and identify factors associated with adherence. The USAGE survey is a cross-sectional, self-administered Internet-based survey of 10,138 U.S. adults fielded September to October 2011. The following statin users were identified and compared: adherent nonswitchers, adherent switchers, non-adherent switchers, and discontinuers. Univariate and multivariate models using a priori covariates for adherence and discontinuation were examined. Most participants were current statin users who adhered with their prescribed statin (82.5%, n = 8371). Former statin users or discontinuers (12%, n = 1220) cited muscle pain, a side effect, as the primary reason for discontinuation (60%), followed by cost (16%), and then perceived lack of efficacy (13%). Discontinuers were less satisfied with their physicians' explanation of cholesterol treatment, more likely to use the Internet to research statins, and less likely to undergo frequent cholesterol monitoring. Among adherent statin users, the primary reasons for switching were muscle side effects (33%) and cost (32%). Individuals at risk for non-adherence included those with low household income, those who experienced muscle pain as a side effect while on statin therapy, and those taking medication for cardiovascular disease. Statin-related muscle side effects are common and contribute significantly to rates of discontinuation, switching, and non-adherence. Improved physician patient communication about side effects and benefits of statins are necessary to improve both adherence and outcomes. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study.

PubMed

Haag, M D M; Hofman, A; Koudstaal, P J; Stricker, B H C; Breteler, M M B

2009-01-01

Cross-sectional reports suggest that statin users are less likely to have Alzheimer disease (AD). Prospective studies have provided inconsistent evidence. Moreover, it is unclear whether the association differs for lipophilic statins, those that could more easily pass the blood-brain barrier and hydrophilic statins. To prospectively evaluate whether use of statins is associated with the risk of AD, and to determine whether associations differ for lipophilic and hydrophilic statins. 6992 participants of the prospective, population-based Rotterdam Study were followed, from baseline (1990-1993) until January 2005 for incident AD. Data on all filled prescriptions came from pharmacy records. For each date on which each event occurred, cholesterol-lowering drug use for the person who experienced the event and all remaining persons in the cohort was categorised as "any" or "never" use. A distinction was made between statin, lipophilic and hydrophilic statins, and non-statin cholesterol-lowering drugs. Data were analysed with the Cox regression analysis, adjusting for sex, age and potential confounders. During follow-up (mean 9 years), 582 persons developed AD. Compared with never use of cholesterol-lowering drugs, statin use was associated with a decreased risk of AD (HR 0.57; 95% CI 0.37 to 0.90), but non-statin cholesterol-lowering drug use was not (HR 1.05; 95% CI 0.45 to 2.44). HRs were equal for lipophilic (HR 0.54; 95% CI 0.32 to 0.89) and hydrophilic statins (HR 0.54; 95% CI 0.26 to 1.11). In the general population, the use of statins, but not of non-statin cholesterol-lowering drugs, was associated with a lower risk of AD compared with never use of cholesterol-lowering drugs. The protective effect was independent of the lipophilicity of statins.

Adaptation to statins restricts human tumour growth in Nude mice

PubMed Central

2011-01-01

Background Statins have long been used as anti-hypercholesterolemia drugs, but numerous lines of evidence suggest that they may also bear anti-tumour potential. We have recently demonstrated that it was possible to isolate cancer cells adapted to growth in the continuous presence of lovastatin. These cells grew more slowly than the statin-sensitive cells of origin. In the present study, we compared the ability of both statin-sensitive and statin-resistant cells to give rise to tumours in Nude mice. Methods HGT-1 human gastric cancer cells and L50 statin-resistant derivatives were injected subcutaneously into Nude mice and tumour growth was recorded. At the end of the experiment, tumours were recovered and marker proteins were analyzed by western blotting, RT-PCR and immunohistochemistry. Results L50 tumours grew more slowly, showed a strong decrease in cyclin B1, over-expressed collagen IV, and had reduced laminin 332, VEGF and CD34 levels, which, collectively, may have restricted cell division, cell adhesion and neoangiogenesis. Conclusions Taken together, these results showed that statin-resistant cells developed into smaller tumours than statin-sensitive cells. This may be reflective of the cancer restricting activity of statins in humans, as suggested from several retrospective studies with subjects undergoing statin therapy for several years. PMID:22107808

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice.

PubMed

Schonewille, Marleen; de Boer, Jan Freark; Mele, Laura; Wolters, Henk; Bloks, Vincent W; Wolters, Justina C; Kuivenhoven, Jan A; Tietge, Uwe J F; Brufau, Gemma; Groen, Albert K

2016-08-01

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

PubMed Central

Schonewille, Marleen; Freark de Boer, Jan; Mele, Laura; Wolters, Henk; Bloks, Vincent W.; Wolters, Justina C.; Kuivenhoven, Jan A.; Tietge, Uwe J. F.; Brufau, Gemma; Groen, Albert K.

2016-01-01

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins. PMID:27313057

The effect of statins on influenza-like illness morbidity and mortality.

PubMed

Brassard, Paul; Wu, Jennifer W; Ernst, Pierre; Dell'Aniello, Sophie; Smiechowski, Brielan; Suissa, Samy

2017-01-01

The effect of statins on cytokine-mediated inflammatory responses may impact on the prognosis of influenza. We assessed whether statin use decreases the incidence of adverse influenza-related outcomes. Additionally, we used a new-user study design to minimize healthy user bias. We further examined the possibility of non-causal associations by using unrelated outcomes. We used the UK Clinical Practice Research Datalink to identify all patients aged 30 or older diagnosed with influenza-like illness during 1997-2010. Statin users were compared with propensity score-matched patients not receiving statins. The outcome was hospitalization for influenza or pneumonia or death in the 30 days following influenza diagnosis. Logistic regression estimated cumulative incidence ratios. The study cohort included 5181 statin users matched to 5181 non-users. The 30-day incidence of hospitalization or death was 3.5% in statin users and 5.2% in non-users, resulting in a 27% lower incidence with statin use (cumulative incidence ratio: 0.73, 95%CI: 0.59-0.89). New statin users were less protected against our composite outcome. The effect of statins was less pronounced among those with respiratory and cardiac disease. Statin use was shown to be associated with a non-statistically significant risk reduction of motor vehicle accident and burns. The attenuation of the effect of statins with the new-user design, supporting evidence from the assessment of effect modification, and additional sub-analyses evaluating the effect of statins on non-related outcomes suggest that the beneficial effect of statins on influenza-related adverse outcomes may be explained by a healthy user bias. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Statins improve the resolution of established murine venous thrombosis: reductions in thrombus burden and vein wall scarring.

PubMed

Kessinger, Chase W; Kim, Jin Won; Henke, Peter K; Thompson, Brian; McCarthy, Jason R; Hara, Tetsuya; Sillesen, Martin; Margey, Ronan J P; Libby, Peter; Weissleder, Ralph; Lin, Charles P; Jaffer, Farouc A

2015-01-01

Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins--lipid-lowering agents with anti-thrombotic and anti-inflammatory properties--in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy.

Statin use and fatal prostate cancer: a matched case-control study.

PubMed

Marcella, Stephen W; David, Alice; Ohman-Strickland, Pamela A; Carson, Jeffery; Rhoads, George G

2012-08-15

Statins are some of the most commonly prescribed medications in medical practice, and prostate cancer is the most common malignancy among men. Although there has been no consistent evidence that statins affect cancer incidence, including prostate cancer, several reports suggest they may decrease the rate of advanced prostate cancer. However, no study to date has specifically examined statin use and prostate cancer mortality. The authors conducted this population-based case-control investigation to examine this association. This was a matched case-control study. Cases were residents of New Jersey ages 55 to 79 years who died from prostate cancer between 1997 and 2000. The cases were matched individually to population-based controls by 5-year age group and race. Medication data were obtained identically for cases and controls from blinded medical chart review. Conditional logistic regression was used to adjust for confounders. In total, 718 cases were identified, and cooperation was obtained from 77% of their spouses (N = 553). After a review of medical records, 387 men were eligible, and 380 were matched to a control. The unadjusted odds ratio was 0.49 (95% confidence interval, 0.34-0.70) and decreased to 0.37 (P < .0001) after adjusting for education, waist size, body mass index, comorbidities, and antihypertensive medication. There was little difference between lipophilic and hydrophilic statins, but more risk reduction was noted for high-potency statins (73%; P < .0001) compared with low-potency statins (31%; P = .32). Statin use was associated with substantial protection against prostate cancer death, adding to the epidemiologic evidence for an inhibitory effect on prostate cancer. Copyright © 2011 American Cancer Society.

Simvastatin promotes NPC1-mediated free cholesterol efflux from lysosomes through CYP7A1/LXRα signalling pathway in oxLDL-loaded macrophages.

PubMed

Xu, Xiaoyang; Zhang, Aolin; Halquist, Matthew S; Yuan, Xinxu; Henderson, Scott C; Dewey, William L; Li, Pin-Lan; Li, Ningjun; Zhang, Fan

2017-02-01

Statins, 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors, are the first-line medications prescribed for the prevention and treatment of coronary artery diseases. The efficacy of statins has been attributed not only to their systemic cholesterol-lowering actions but also to their pleiotropic effects that are unrelated to cholesterol reduction. These pleiotropic effects have been increasingly recognized as essential in statins therapy. This study was designed to investigate the pleiotropic actions of simvastatin, one of the most commonly prescribed statins, on macrophage cholesterol homeostasis with a focus on lysosomal free cholesterol egression. With simultaneous nile red and filipin staining, analysis of confocal/multi-photon imaging demonstrated that simvastatin markedly attenuated unesterified (free) cholesterol buildup in macrophages loaded with oxidized low-density lipoprotein but had little effect in reducing the sizes of cholesteryl ester-containing lipid droplets; the reduction in free cholesterol was mainly attributed to decreases in lysosome-compartmentalized cholesterol. Functionally, the egression of free cholesterol from lysosomes attenuated pro-inflammatory cytokine secretion. It was determined that the reduction of lysosomal free cholesterol buildup by simvastatin was due to the up-regulation of Niemann-Pick C1 (NPC1), a lysosomal residing cholesterol transporter. Moreover, the enhanced enzymatic production of 7-hydroxycholesterol by cytochrome P450 7A1 and the subsequent activation of liver X receptor α underscored the up-regulation of NPC1. These findings reveal a novel pleiotropic effect of simvastatin in affecting lysosomal cholesterol efflux in macrophages and the associated significance in the treatment of atherosclerosis. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Blood Pressure and Metabolic Effects of Acetyl-l-Carnitine in Type 2 Diabetes: DIABASI Randomized Controlled Trial.

PubMed

Parvanova, Aneliya; Trillini, Matias; Podestà, Manuel A; Iliev, Ilian P; Aparicio, Carolina; Perna, Annalisa; Peraro, Francesco; Rubis, Nadia; Gaspari, Flavio; Cannata, Antonio; Ferrari, Silvia; Bossi, Antonio C; Trevisan, Roberto; Parameswaran, Sreejith; Chávez-Iñiguez, Jonathan S; Masnic, Fahrudin; Seck, Sidy Mohamed; Jiamjariyaporn, Teerayuth; Cortinovis, Monica; Perico, Luca; Sharma, Kanishka; Remuzzi, Giuseppe; Ruggenenti, Piero; Warnock, David G

2018-05-01

Acetyl-l-carnitine (ALC), a mitochondrial carrier involved in lipid oxidation and glucose metabolism, decreased systolic blood pressure (SBP), and ameliorated insulin sensitivity in hypertensive nondiabetic subjects at high cardiovascular risk. To assess the effects of ALC on SBP and glycemic and lipid control in patients with hypertension, type 2 diabetes mellitus (T2D), and dyslipidemia on background statin therapy. After 4-week run-in period and stratification according to previous statin therapy, patients were randomized to 6-month, double-blind treatment with ALC or placebo added-on simvastatin. Five diabetology units and one clinical research center in Italy. Two hundred twenty-nine patients with hypertension and dyslipidemic T2D >40 years with stable background antihypertensive, hypoglycemic, and statin therapy and serum creatinine <1.5 mg/dL. Oral ALC 1000 mg or placebo twice daily on top of stable simvastatin therapy. Primary outcome was SBP. Secondary outcomes included lipid and glycemic profiles. Total-body glucose disposal rate and glomerular filtration rate were measured in subgroups by hyperinsulinemic-euglycemic clamp and iohexol plasma clearance, respectively. SBP did not significantly change after 6-month treatment with ALC compared with placebo (-2.09 mm Hg vs -3.57 mm Hg, P = 0.9539). Serum cholesterol, triglycerides, and lipoprotein(a), as well as blood glucose, glycated hemoglobin, fasting insulin levels, homeostatic model assessment of insulin resistance index, glucose disposal rate, and glomerular filtration rate did not significantly differ between treatments. Adverse events were comparable between groups. Six-month oral ALC supplementation did not affect blood pressure, lipid and glycemic control, insulin sensitivity and kidney function in hypertensive normoalbuminuric and microalbuminuric T2D patients on background statin therapy.

Neuromuscular Effects of Rocuronium Bromide in Patients in Statin Therapy for at least Three Months.

PubMed

Ren, Hongwei; Lv, Huangwei

2016-12-01

Statins cause skeletal muscle myopathy. However, the neuromuscular effects of non-depolarizing neuromuscular-blocking agent in patients in long-term statin therapy remain unclear. Hence, we investigated the neuromuscular effects of rocuronium and muscle injury in patients in long-term statin therapy. Eighteen statin users using statins for at least 3 months were included in the statin group and 18 non-statin users were included in the non-statin group. General anaesthesia was induced with intravenous midazolam, etomidate, sufentanil and rocuronium 0.9 mg/kg (3ED 95 ) for intubation. Anaesthesia was maintained with 1% propofol and remifentanil. The onset time and duration 10% T 1 and 25% T 1 of rocuronium were recorded. Blood samples were obtained before induction and 5 min., 1 hr, 2 hr, 4 hr, 12 hr and 24 hr after rocuronium administration to measure creatine kinase (CK), myoglobin and potassium. Myalgia was determined at 2 and 24 hr after surgery. There were no significant differences in the basic clinical characteristics between the two groups. The onset time of the statin group was significantly shorter than that of the non-statin group (p = 0.02), while the duration 10% T 1 and duration 25% T 1 of the statin group were significantly longer than those of the non-statin group (p = 0.006; p = 0.045). The myoglobin and CK concentrations increased after rocuronium administration as compared to baseline in both groups. CK concentration in the statin group was significantly higher than in the non-statin group just at 24 hr (p = 0.000003). However, myoglobin showed no significant difference between the two groups. The onset time of rocuronium decreases and its duration time increases in patients in long-term statin therapy. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukuda, Kazuki; Matsumura, Takeshi, E-mail: takeshim@gpo.kumamoto-u.ac.jp; Senokuchi, Takafumi

Highlights: • Statins induce PPARγ activation in vascular smooth muscle cells. • Statin-induced PPARγ activation is mediated by COX-2 expression. • Statins suppress cell migration and proliferation in vascular smooth muscle cells. • Statins inhibit LPS-induced inflammatory responses by PPARγ activation. • Fluvastatin suppress the progression of atherosclerosis and induces PPARγ activation in the aorta of apoE-deficient mice. - Abstract: The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However,more » it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe{sup −/−} mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe{sup −/−} mice. In conclusion, statins mediate anti-atherogenic effects through PPARγ activation in SMCs. These effects of statins on SMCs may be beneficial for the prevention of atherosclerosis.« less

Pleiotropic Effects of Statins on the Cardiovascular System

PubMed Central

Oesterle, Adam; Laufs, Ulrich; Liao, James K

2017-01-01

The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins), have been used for thirty years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol (LDL-C). Statins may exert cardiovascular protective effects that are independent of LDL-C lowering called “pleiotropic” effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small guanosine triphosphate binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of pro-inflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify since the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-C reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease. PMID:28057795

The importance of age and statin therapy in the interpretation of Lp-PLA(2) in ACS patients, and relation to CRP.

PubMed

Franeková, J; Kettner, J; Kubíček, Z; Jabor, A

2015-01-01

C-reactive protein (CRP) is a marker of arterial inflammation while lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is related to plaque instability. The aim of this study was to evaluate the correlation between the risk of unstable plaque presenting as acute coronary syndrome (ACS) and Lp-PLA(2), and to assess the influence of statins on interpretation of Lp-PLA(2). A total of 362 consecutive patients presenting to the emergency department (ED) with acute chest pain suggestive of ACS were evaluated by cardiologists as STEMI, NSTEMI, or unstable angina, and non-ACS. Serum biomarkers measured on admission: troponin I, C-reactive protein (Abbott), and Lp-PLA(2) (DiaDexus). Four groups were defined according to the final diagnosis and history of statin medication: ACS/statin-; ACS/statin+; non-ACS/statin-; non-ACS/statin+. Lp-PLA(2) was highest in ACS/statin- group; statins decreased Lp-PLA(2) both in ACS and non-ACS of about 20 %. Lp-PLA(2) was higher in ACS patients in comparison with non-ACS patients group without respect to statin therapy (p<0.001). Lp-PLA(2) predicted worse outcome (in terms of acute coronary syndrome) effectively in patients up to 62 years; limited prediction was found in older patients. C-reactive protein (CRP) failed to discriminate four groups of patients. Statin therapy and age should be taken into consideration while interpreting Lp-PLA(2) concentrations and lower cut-off values should be used for statin-treated persons.

The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy

PubMed Central

Chung, Hae R.; Vakil, Mayand; Munroe, Michael; Parikh, Alay; Meador, Benjamin M.; Wu, Pei T.; Jeong, Jin H.; Woods, Jeffrey A.; Wilund, Kenneth R.; Boppart, Marni D.

2016-01-01

HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training. PMID:27936249

Update on the clinical utility of fenofibrate in mixed dyslipidemias: mechanisms of action and rational prescribing

PubMed Central

Farnier, Michel

2008-01-01

Mixed dyslipidemia is a common lipid disorder characterized by the presence of an atherogenic lipoprotein phenotype due to abnormalities in various atherogenic and anti-atherogenic lipoproteins. Despite the link between the decrease of LDL-cholesterol by statin treatment and the prevention of cardiovascular disease, a high residual risk is observed in statin trials. This residual risk is partly explained by lipoprotein abnormalities other than LDL. Fenofibrate exerts a favorable effect on the atherogenic lipid profile of mixed dyslipidemia and can effectively reduce cardiovascular disease in patients with mixed dyslipidemia. Fenofibrate may offer important treatment alternatives as a second-line therapy in several circumstances: in combination with a statin for patients with mixed dyslipidemias not at goals on statin mono-therapy; in monotherapy for patients intolerant or with contraindication to statin therapy; and in combination with other drugs (ezetimibe, colesevelam) for patients with mixed dyslipidemias, known intolerance, or contraindication to statin and not at goals on fenofibrate monotherapy. However, the role of fenofibrate-statin therapy and of other therapies involving fenofibrate in cardiovascular risk reduction strategies remains to be established. PMID:19183747

Efficacy of Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers in Coronary Artery Disease without Heart Failure in the Modern Statin Era: a Meta-Analysis of Randomized-Controlled Trials.

PubMed

Hoang, Vu; Alam, Mahboob; Addison, Daniel; Macedo, Francisco; Virani, Salim; Birnbaum, Yochai

2016-04-01

Current practice guidelines support the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) in patients with coronary artery disease (CAD) without heart failure (HF). However, a number of cited trials were performed prior to the era of prevalent statin use. Our objective was to evaluate the effectiveness of ACEi and ARBs in reducing cardiovascular events as well as the impact of statin therapy. We searched the MEDLINE and EMBASE databases for randomized-controlled trials (1/1/1980 - 8/31/2015) with ACEi or ARBs as the single intervention for patients with CAD without HF. We assessed the outcomes of non-fatal myocardial infarction (MI), stroke, cardiovascular mortality and all-cause mortality. The relationship between these outcomes and the percentages of patients on statin therapy was evaluated using meta-regression analysis. A total of ten ACEi trials and five ARB trials were included for analysis, with 78,761 patients followed for a mean of 36 months. Treatment with ACEi was associated with decreased non-fatal MI (RR 0.83; 95 % CI 0.75-0.91), stroke (RR 0.76; 95 % CI 0.68-0.86), cardiovascular mortality (RR 0.83; 95 % CI 0.72-0.95), and all-cause mortality (RR 0.86; 95 % CI 0.80-0.93). Treatment with ARBs was associated only with a decreased incidence of stroke (RR 0.92; 95 % CI 0.87-0.98). When adjusted for statin use, there was a trend towards an attenuated effect of ACEi in reducing cardiovascular mortality with increased use of statins (p-value = 0.063). In CAD patients without HF, ACEi, but not ARBs decreases the risk of non-fatal MI, cardiovascular mortality and all-cause mortality, while both ACEi and ARBs decrease the risk of stroke.

Statins and Hip Fracture Prevention – A Population Based Cohort Study in Women

PubMed Central

Helin-Salmivaara, Arja; Korhonen, Maarit J.; Lehenkari, Petri; Junnila, Seppo Y. T.; Neuvonen, Pertti J.; Ruokoniemi, Päivi; Huupponen, Risto

2012-01-01

Objective To study the association of long-term statin use and the risk of low-energy hip fractures in middle-aged and elderly women. Design A register-based cohort study. Setting Finland. Participants Women aged 45–75 years initiating statin therapy between 1996 and 2001 with adherence to statins ≥80% during the subsequent five years (n = 40 254), a respective cohort initiating hypertension drugs (n = 41 610), and women randomly selected from the population (n = 62 585). Main Outcome Measures Incidence rate of and hazard ratio (HR) for low-energy hip fracture during the follow-up extending up to 7 years after the 5-year exposure period. Results Altogether 199 low-energy hip fractures occurred during the 135 330 person-years (py) of follow-up in the statin cohort, giving an incidence rate of 1.5 hip fractures per 1000 py. In the hypertension and the population cohorts, the rates were 2.0 per 1000 py (312 fractures per 157 090 py) and 1.0 per 1000 py (212 fractures per 216 329 py), respectively. Adjusting for a propensity score and individual variables strongly predicting the outcome, good adherence to statins for five years was associated with a 29% decreased risk (HR 0.71; 95% CI 0.58–0.86) of a low-energy hip fracture in comparison with adherent use of hypertension drugs. The association was of the same magnitude when comparing the statin users with the population cohort, the HR being 0.69 (0.55–0.87). When women with poor (<40%), moderate (40 to 80%), and good adherence (≥80%) to statins were compared to those with good adherence to hypertension drugs (≥80%) or to the population cohort, the protective effect associated with statin use attenuated with the decreasing level of adherence. Conclusions 5-year exposure to statins is associated with a reduced risk of low-energy hip fracture in women aged 50–80 years without prior hospitalizations for fractures. PMID:23144731

Long-term effect of statins on the risk of new-onset osteoporosis: A nationwide population-based cohort study.

PubMed

Lin, Tsung-Kun; Chou, Pesus; Lin, Ching-Heng; Hung, Yi-Jen; Jong, Gwo-Ping

2018-01-01

Several observational cohort and meta-analytical studies in humans have shown that statin users have a lower risk of fractures or greater bone mineral densities (BMD) than nonusers. However, some studies including randomized clinical trials have the opposite results, particularly in Asian populations. This study investigates the impacts of statins on new-onset osteoporosis in Taiwan. In a nationwide retrospective population-based cohort study, 45,342 subjects aged between 50-90 years having received statin therapy (statin-users) since January 1 2001, and observed through December 31 2013 were selected from the National Health Insurance Research Database of Taiwan. Likewise, 115,594 patients had no statin therapy (statin-non-users) were included as controls in this study. Multivariable Cox proportional hazards analysis for drug exposures was employed to evaluate the association between statin treatment and new-onset of osteoporosis risk. We also used the long-rank test to evaluate the difference of probability of osteoporosis-free survival. During the 13-year follow-up period, 16,146 of all enrolled subjects (10.03%) developed osteoporosis, including 3097 statin-users (6.83%) and 13,049 statin-non-users (11.29%). Overall, statin therapy reduced the risk of new-onset osteoporosis by 48% (adjusted hazard ratio [HR] 0.52; 95% CI 0.50 to 0.54). A dose-response relationship between statin treatment and the risk of new-onset osteoporosis was observed. The adjusted hazard ratios for new-onset osteoporosis were 0.84 (95% CI, 0.78 to 0.90), 0.56 (95% CI, 0.52 to 0.60) and 0.23 (95% CI, 0.21 to 0.25) when cumulative defined daily doses (cDDDs) ranged from 28 to 90, 91 to 365, and more than 365, respectively, relative to nonusers. Otherwise, high-potency statins (rosuvastatin and atorvastatin) and moderate-potency statin (simvastatin) seemed to have a potential protective effect for osteoporosis. In this population-based cohort study, we found that statin use is associated with a decreased risk of osteoporosis in both genders. The osteoprotective effect of statins seemed to be more prominent with a dependency on the cumulative dosage and statin intensity.

Synergistic effect of atorvastatin and Cyanidin-3-glucoside on angiotensin II-induced inflammation in vascular smooth muscle cells.

PubMed

Pantan, Rungusa; Tocharus, Jiraporn; Suksamrarn, Apichart; Tocharus, Chainarong

2016-03-15

Statins have often been used in atherosclerosis treatment because of its pleiotropic effects on inflammation. However, some adverse effects of high doses of statin show reverse effects after withdrawal. Cyanidin-3-glucoside (C3G) is a powerful anti-inflammation and antioxidant that has been of interest for use in combination with low doses of statin, which may be alternative treatment for atherosclerosis. The objective is to investigate the synergistic effect of atorvastatin and C3G in angiotensin II (Ang II)-induced inflammation in vascular smooth muscle cells. Human aortic smooth muscle cells (HASMCs) were exposed to Ang II with or without atorvastatin and C3G alone, or in combination. The results revealed that the combination of atorvastatin and C3G produces synergism against inflammation and oxidative stress. The mechanism of the combination of atorvastatin and C3G suppressed the translocation of the p65 subunit of NF-κB from cytosol to nucleus, and attenuated the expression of proteins including inducible nitric oxide synthase, intracellular adhesion molecule 1(ICAM-1), and vascular cell adhesion molecule 1(VCAM-1), in addition to nitric oxide (NO) production. Moreover, C3G exerts the antioxidative properties of atorvastatin through down-regulating NOX1 and promoting the activity of the Nrf2(-)ARE signaling pathway and downstream proteins including heme oxygenase (HO-1), NAD(P)H:quinoneoxidoreductase 1 (NQO-1), and glutamate-cysteine ligase catalytic subunit (γ-GCLC), besides increasing the activity of superoxide dismutase (SOD) enzymes. Taken together, these results suggest that a combination of low dose statins and C3G might serve as a potential regulator of the atherosclerosis process which is mediated by attenuating oxidative stress, thereby inhibiting NF-κB and activating Nrf2 signaling pathways induced by Ang II. Copyright © 2016 Elsevier Inc. All rights reserved.

Mechanisms and assessment of statin-related muscular adverse effects

PubMed Central

Moßhammer, Dirk; Schaeffeler, Elke; Schwab, Matthias; Mörike, Klaus

2014-01-01

Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers. PMID:25069381

Randomized clinical trials and recent patterns in the use of statins.

PubMed

Wang, T J; Stafford, R S; Ausiello, J C; Chaisson, C E

2001-06-01

Three landmark trials involving 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) were published between 1994 and 1996 (the Scandinavian Simvastatin Survival Study [4S], the West of Scotland Coronary Prevention Study, and the Cholesterol and Recurrent Events trial). These trials provided evidence that lipid-lowering therapy decreases cardiovascular events, including mortality. Whether these recent data caused a shift toward statin use has not been evaluated. Data from the National Ambulatory Medical Care Survey in 1980, 1981, 1985, and 1989 through 1998 were used. We analyzed 5053 visits by patients taking lipid-lowering medications to office-based physicians selected by stratified random sampling. The main outcome measure was use of specific lipid-lowering medications, including statins. In 1980 resins and niacin were the most commonly used lipid-lowering medications. By 1985 rising use of fibrates caused reductions in niacin use and resin use. By 1989 statins replaced fibrates as the most heavily used medications. Statin use climbed continuously thereafter, accounting for 90% of visits by patients treated for hypercholesterolemia in 1998. In time series analyses, increases in overall statin use were temporally unrelated to the publication of clinical trials, although the 4S trial may have contributed to a shift from older statins to simvastatin. For patients receiving lipid-lowering therapy in 1993 to 1998, statin use was significantly more likely for female patients, white patients, and patients visiting cardiologists. Although the market for lipid-lowering medications is dominated by statins, the rise in statins predated the recent clinical trials supporting their use.

Pattern of risks of rheumatoid arthritis among patients using statins: A cohort study with the clinical practice research datalink.

PubMed

de Jong, Hilda J I; Cohen Tervaert, Jan Willem; Lalmohamed, Arief; de Vries, Frank; Vandebriel, Rob J; van Loveren, Henk; Klungel, Olaf H; van Staa, Tjeerd P

2018-01-01

We examined the association between statin use and the risk of rheumatoid arthritis (RA), with special focus on describing the patterns of risks of RA during statin exposure in a large population-based cohort in the United Kingdom. In the Clinical Practice Research Datalink, patients aged ≥40 years with at least one prescription of statins (1995-2009) were selected, and matched by age (+/-5 years), sex, practice and date of first prescription of statins to non-users. The follow-up period of statin use was divided into periods of current, recent and past exposure, with patients moving between these three exposure categories over time. Time-dependent Cox models were used to derive hazard ratios (HRs) of RA, adjusted for disease history and previous drug use. The study population included 1,023,240 patients, of whom 511,620 were statin users. No associations were found between RA and current (HRadj,1.06;99%CI:0.88-1.27) or past statin users (HRadj,1.18;99%CI:0.88-1.57). However, in patients who currently used statins, hazard rates were increased shortly after the first prescription of statins and then gradually decreased to baseline level. The risk of developing RA was increased in recent statin users, as compared to non-users (HRadj,1.39;99%CI:1.01-1.90). The risk of RA is substantially increased in the first year after the start of statins and then diminishes to baseline level. These findings may suggest that statins might accelerate disease onset in patients susceptible to develop RA, but in other patients, statins are probably safe and well tolerated, even after prolonged use. Alternatively, we cannot rule out that confounding by cardiovascular risk factors and ascertainment bias may have influenced the findings.

Pattern of risks of rheumatoid arthritis among patients using statins: A cohort study with the clinical practice research datalink

PubMed Central

de Jong, Hilda J. I.; Cohen Tervaert, Jan Willem; Lalmohamed, Arief; de Vries, Frank; Vandebriel, Rob J.; van Loveren, Henk; van Staa, Tjeerd P.

2018-01-01

We examined the association between statin use and the risk of rheumatoid arthritis (RA), with special focus on describing the patterns of risks of RA during statin exposure in a large population-based cohort in the United Kingdom. In the Clinical Practice Research Datalink, patients aged ≥40 years with at least one prescription of statins (1995–2009) were selected, and matched by age (+/-5 years), sex, practice and date of first prescription of statins to non-users. The follow-up period of statin use was divided into periods of current, recent and past exposure, with patients moving between these three exposure categories over time. Time-dependent Cox models were used to derive hazard ratios (HRs) of RA, adjusted for disease history and previous drug use. The study population included 1,023,240 patients, of whom 511,620 were statin users. No associations were found between RA and current (HRadj,1.06;99%CI:0.88–1.27) or past statin users (HRadj,1.18;99%CI:0.88–1.57). However, in patients who currently used statins, hazard rates were increased shortly after the first prescription of statins and then gradually decreased to baseline level. The risk of developing RA was increased in recent statin users, as compared to non-users (HRadj,1.39;99%CI:1.01–1.90). The risk of RA is substantially increased in the first year after the start of statins and then diminishes to baseline level. These findings may suggest that statins might accelerate disease onset in patients susceptible to develop RA, but in other patients, statins are probably safe and well tolerated, even after prolonged use. Alternatively, we cannot rule out that confounding by cardiovascular risk factors and ascertainment bias may have influenced the findings. PMID:29474418

Protective effects of l-carnitine and piracetam against mitochondrial permeability transition and PC3 cell necrosis induced by simvastatin.

PubMed

Costa, Rute A P; Fernandes, Mariana P; de Souza-Pinto, Nadja C; Vercesi, Aníbal E

2013-02-15

Mitochondrial oxidative stress followed by membrane permeability transition (MPT) has been considered as a possible mechanism for statins cytotoxicity. Statins use has been associated with reduced risk of cancer incidence, especially prostate cancer. Here we investigated the pathways leading to simvastatin-induced prostate cancer cell death as well as the mechanisms of cell death protection by l-carnitine or piracetam. These compounds are known to prevent and/or protect against cell death mediated by oxidative mitochondrial damage induced by a variety of conditions, either in vivo or in vitro. The results provide evidence that simvastatin induced MPT and cell necrosis were sensitive to either l-carnitine or piracetam in a dose-dependent fashion and mediated by additive mechanisms. When combined, l-carnitine and piracetam acted at concentrations significantly lower than they act individually. These results shed new light into both the cytotoxic mechanisms of statins and the mechanisms underlying the protection against MPT and cell death by the compounds l-carnitine and piracetam. Copyright © 2013 Elsevier B.V. All rights reserved.

Prevention of coronary atherosclerosis by the use of combination therapy with antioxidant coenzyme Q10 and statins.

PubMed

Chapidze, G; Kapanadze, S; Dolidze, N; Bachutashvili, Z; Latsabidze, N

2005-01-01

The goal of the present research was to assess the efficacy of combination treatment with antioxidant coenzyme Q10 and simvastatin as well as coenzyme Q10 without statin therapy in order to prevent coronary atherosclerosis. 42 outpatients were divided into 2 groups: receiving coenzyme Q10 (Hasco-Lek, Poland) 60mg daily and its combination with simvastatin (zocor, vasilip) 10mg daily for an 8-week period. The treatment with coenzyme Q10 demonstrated its potential independent role in positive modification of oxidative stress, antiatherogenic fraction of lipid profile, atherogenic ratio, platelet aggregability. Taking into consideration the obtained results the study supports the use of coenzyme Q10 in combination with statins. Suggested attractive approach may result in complete correction of dislipidemia, reverse of endothelial dysfunction, reduce degree of oxidative stress and platelet aggregability. Consequently such a combination may be beneficial in preventing of further development of atherosclerosis in native coronary arteries as well as in bypass grafts in all coronary heart disease patients with or without myocardial revascularization.

Statins: novel additions to the dermatologic arsenal?

PubMed

Namazi, M R

2004-06-01

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin and simvastatin, reduce atherogenesis and cardiovascular morbidity. Besides, there is growing evidence that statins have immunomodulatory activities. Statins downregulate the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1), on leucocytes and endothelial cells and, through binding to LFA-1, interfere with ICAM-1-LFA-1 interaction, which is crucial for activation of lymphocytes by antigen-presenting cells, ingress of leucocytes into the inflammation sites and immunologic cytotoxicity. Statins inhibit the inducible expression of major histocompatibility complex class II in several cell types including macrophages and downregulate the expression of T-helper-1 (Th1) chemokine receptors on T cells, leading further to inhibition of activation of lymphocytes and their infiltration into the inflammation sites. Statins block the induction of inducible nitric oxide synthase and the expression of several proinflammatory cytokines such as tumour necrosis factor-alpha and interferon-gamma in macrophages and possess antioxidant effects. These agents inhibit the proliferation of immunocytes and the activation of natural killer cells. Regarding the above facts and in view of their safety and inexpensiveness, statins may prove invaluable in the treatment of a multiplicity of dermatologic disorders, especially those characterized by ingress of activated leucocytes into the skin, such as alopecia areata, vitiligo, lichen planus, subacute cutaneous lupus erythematosus, erythema multiforme, psoriasis, bullous pemphigoid, systemic sclerosis, mycosis fungoides, toxic epidermal necrolysis and Behcet's disease.

Effect on Fasting Serum Glucose Levels of Adding Ezetimibe to Statins in Patients With Nondiabetic Hypercholesterolemia.

PubMed

Toth, Peter P; Catapano, Alberico L; Farnier, Michel; Foody, Joanne; Tomassini, Joanne E; Jensen, Erin; Polis, Adam B; Hanson, Mary E; Musliner, Thomas A; Tershakovec, Andrew M

2016-12-15

Statin therapy is associated with a slightly increased risk of developing diabetes mellitus and insulin resistance in patients without diabetes. Ezetimibe combined with statins may be considered for high-risk patients who do not achieve optimal low-density lipoprotein cholesterol lowering on statin monotherapy or who are statin intolerant. Changes in fasting serum glucose (FSG) levels during ezetimibe, ezetimibe/statin, and statin treatments were assessed using data pooled from clinical trials in hypercholesterolemic and heterozygous familial hypercholesterolemic patients, who were or were not receiving statin therapy. Study types included first-line trials in statin-naive/wash-out patients and second-line add-on and uptitration studies in patients on stable statin therapy. Similar analyses of FSG changes were performed separately for each study type in patients who were nondiabetic at baseline. Across all study types and treatments, mean FSG increases from baseline were small (0.5 to 3.7 mg/dl with ezetimibe/statin; 0.2 to 4.6 mg/dl with statins) and decreased over time; between-treatment differences (0.3 to 1.4 mg/dl) were nonsignificant for all comparisons. Proportions of patients with elevated FSG ≥126 mg/dl during therapy were low and similar for all treatments in the overall cohort (1.2% to 4.3%). Elevations were highest (3.3% to 25.7%) among patients with baseline factors characteristic of metabolic syndrome and prediabetes, including higher FSG, body mass index, and triglyceride levels, and numerically lower baseline high-density lipoprotein cholesterol; however, these factors were not related to FSG increases. Changes in low-density lipoprotein cholesterol, body mass index, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were not significantly correlated with FSG increases. In conclusion, statin therapy was associated with small FSG increases, and the addition of ezetimibe did not further increase FSG levels beyond those of statins when given to patients who are statin naive or those on statin therapy. Copyright © 2016 The Authors and Merck Sharp & Dohme Corp. Published by Elsevier Inc. All rights reserved.

Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies.

PubMed

Fong, Clifford W

2014-10-06

The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. Solvation free energies in water, n-octanol and n-octane have been determined using the SMD solvent model. The percentage hydrophilicity and hydrophobicity (or lipophilicity) of the statins in solution have been determined using (a) the differences in solvation free energies between n-octanol and n-octane as a measure of hydrophilicity, and the solvation energy in octane as a measure of hydrophobicity (b) the sum of the atomic electrostatic charges on the hydrogen bonding and polar bonding nuclei of the common pharmacophore combined with a solvent measure of hydrophobicity, and (c) using the buried surface areas after statin binding to HMGCR to calculate the hydrophobicity of the bound statins. The data suggests that clinical definitions of statins as either "hydrophilic" or "lipophilic" based on experimental partition coefficients are misleading. An estimate of the binding energy between rosuvastatin and HMGCR has been made using: (a) a coulombic electrostatic interaction model, (b) the calculated desolvation and resolvation of the statin in water, and (c) the first shell transfer solvation energy as a proxy for the restructuring of the water molecules immediately adjacent to the active binding site of HMGCR prior to binding. Desolvation and resolvation of the statins before and after binding to HMGCR are major determinants of the energetics of the binding process. An analysis of the amphiphilic nature of lovastatin anion, acid and lactone and fluvastatin anion and their abilities to cross the blood brain barrier has indicated that this process may be dominated by desolvation and resolvation effects, rather than the statin molecular size or statin-lipid interactions within the bilayer. The ionization energy and electron affinity of the statins are sensitive physical indicators of the ease that the various statins can undergo endogenous oxidative metabolism. The absolute chemical hardness is also an indicator of the stability of the statins, and may be a useful indicator for drug design. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

SIMVASTATIN RESTORES ISCHEMIC PRECONDITIONING IN THE PRESENCE OF HYPERGLYCEMIA THROUGH A NITRIC OXIDE-MEDIATED MECHANISM

PubMed Central

Gu, Weidong; Kehl, Franz; Krolikowski, John G.; Pagel, Paul S.; Warltier, David C.; Kersten, Judy R.

2015-01-01

Background A growing body of evidence indicates that statins decrease perioperative cardiovascular risk and that these drugs may be particularly efficacious in diabetes. Diabetes or hyperglycemia abolish the cardioprotective effects of ischemic preconditioning (IPC). We tested the hypothesis that simvastatin restores the beneficial effects of IPC during hyperglycemia through a nitric oxide (NO)-mediated mechanism. Methods Myocardial infarct size was measured in dogs (n=76) subjected to coronary artery occlusion and reperfusion in the presence or absence of hyperglycemia (300 mg/dl) with or without IPC in separate groups. Additional dogs received simvastatin (20 mg orally daily for 3 days) in the presence or absence of IPC and hyperglycemia. Other dogs were pretreated with N-nitro-L-arginine methyl ester (L-NAME; 30 mg intracoronary) with or without IPC, hyperglycemia and simvastatin. Results IPC significantly (P<0.05) reduced infarct size (n=7, 7±2%) as compared to control (n=7, 29±3%). Hyperglycemia (n=7), simvastatin (n=7) and L-NAME alone (n=7), and simvastatin with hyperglycemia (n=6) did not alter infarct size. Hyperglycemia (n=7, 24±2%), but not L-NAME (n=5, 10±1%), blocked the protective effects of IPC. Simvastatin restored the protective effects of IPC in the presence of hyperglycemia (n=7, 14±1%), and this beneficial action was blocked by L-NAME (n=7, 29±4%). Conclusions The results indicate that simvastatin restored the cardioprotective effects of IPC during hyperglycemia by NO-mediated signaling. The results also suggest that enhanced cardioprotective signaling could be a mechanism for statin-induced decreases in perioperative cardiovascular risk. PMID:18362595

The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis.

PubMed

Liu, Binliang; Yi, Zongbi; Guan, Xiuwen; Zeng, Yi-Xin; Ma, Fei

2017-07-01

Breast cancer is the most common cancer in females and the leading cause of death worldwide. The effects of statins on breast cancer prognosis have long been controversial; thus, it is important to investigate the relationship between statin type, exposure time, and breast cancer prognosis. This study sought to explore the effect of statins, as well as the different effects of statin solubility and variable follow-up times, on breast cancer prognosis. We searched the MEDLINE (via PubMed), EMBASE (via OvidSP), Cochrane Library, and ISI Web of Knowledge databases using combinations of the terms "breast neoplasms[MeSH]," "statins" or "lipid-lowering drug," "prognosis" or "survival," or "mortality" or "outcome" with no limit on the publication date. We searched the databases between inception and October 15, 2016. Reference lists of the included studies and relevant reviews were also manually screened. The initial search identified 71 publications, and 7 of these studies, which included a total of 197,048 women, met the selection criteria. Two authors independently screened each study for inclusion and extracted the data. The data were analyzed using Stata/SE 11.0. Overall statin use was associated with lower cancer-specific mortality and all-cause mortality, although the benefit appeared to be constrained by statin type and follow-up time. Lipophilic statins were associated with decreased breast cancer-specific and all-cause mortality; however, hydrophilic statins were weakly protective against only all-cause mortality and not breast cancer-specific mortality. Of note, one group with more than 4 years of follow-up did not show a significant correlation between statin use and cancer-specific mortality or all-cause mortality, whereas groups with less than 4 years of follow-up still showed the protective effect of statins against cancer-specific mortality and all-cause mortality. Although statins can reduce breast cancer patient mortality, the benefit appears to be constrained by statin type and follow-up time. Lipophilic statins showed a strong protective function in breast cancer patients, whereas hydrophilic statins only slightly improved all-cause mortality. Finally, the protective effect of statins could only be observed in groups with less than 4 years of follow-up. These findings are meaningful in clinical practice, although some conclusions contradict conventional wisdom and will thus require further exploration.

Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring

PubMed Central

Kessinger, Chase W.; Kim, Jin Won; Henke, Peter K.; Thompson, Brian; McCarthy, Jason R.; Hara, Tetsuya; Sillesen, Martin; Margey, Ronan J. P.; Libby, Peter; Weissleder, Ralph; Lin, Charles P.; Jaffer, Farouc A.

2015-01-01

Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins—lipid-lowering agents with anti-thrombotic and anti-inflammatory properties—in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy. PMID:25680183

Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia.

PubMed

Arai, Hidenori; Yamashita, Shizuya; Yokote, Koutaro; Araki, Eiichi; Suganami, Hideki; Ishibashi, Shun

2017-06-01

Substantial residual cardiovascular risks remain despite intensive statin treatment. Residual risks with high triglyceride and low high-density lipoprotein cholesterol are not the primary targets of statins. K-877 (pemafibrate) demonstrated robust efficacy on triglycerides and high-density lipoprotein cholesterol and a good safety profile as a monotherapy. The aim of these studies was to evaluate the efficacy and safety of K-877 add-on therapy to treat residual hypertriglyceridaemia during statin treatment. The objectives were investigated in two, multicentre, randomised, double-blind, placebo-controlled, parallel group comparison clinical trials: (A) K-877 0.1, 0.2, and 0.4 mg/day in combination with pitavastatin for 12 weeks in 188 patients, (B) K-877 0.2 (fixed dose) and 0.2 (0.4) (conditional up-titration) mg/day in combination with any statin for 24 weeks in 423 patients. In both studies, we found a robust reduction in fasting triglyceride levels by approximately 50% in all combination therapy groups, which was significant compared to the statin-monotherapy (placebo) groups (p < 0.001). High-performance liquid chromatography analysis for lipoprotein subfractions revealed that atherogenic lipoprotein profiles were ameliorated by K-877 add-on therapy, i.e. small low-density lipoproteins decreased whereas larger ones increased, and larger high-density lipoproteins decreased whereas smaller ones increased. The incidence rates of adverse events and adverse drug reactions in K-877 combination therapy groups were comparable to those in statin-monotherapy groups without any noteworthy event in both studies. These results strongly support the favourable benefit-to-risk ratio of K-877 add-on therapy in combination with statin treatment. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Trends in Statin Use in Seniors 1999 to 2013: Time Series Analysis.

PubMed

Minard, Laura V; Corkum, Amber; Sketris, Ingrid; Fisher, Judith; Zhang, Ying; Saleh, Ahmed

2016-01-01

To examine HMG-CoA reductase inhibitor (statin) drug dispensing patterns to Nova Scotia Seniors' Pharmacare program (NSSPP) beneficiaries over a 14-year period in response to: 1) rosuvastatin market entry in 2003, 2) JUPITER trial publication in 2008, and 3) generic atorvastatin availability in 2010. All NSSPP beneficiaries who redeemed at least one prescription for a statin from April 1, 1999 to March 31, 2013 were included. Aggregated, anonymous monthly prescription counts were extracted by the Nova Scotia Department of Health and Wellness (Nova Scotia, Canada) and changes in dispensing patterns of statins were measured. Data were analyzed using descriptive analyses and interrupted time series methods. The percentage of NSSPP beneficiaries dispensed any statin increased from 5.3% in April 1999 to 20.7% in March 2013. In 1999, most NSSPP beneficiaries were dispensed either simvastatin (29.5%) or atorvastatin (28.7%). When rosuvastatin was added to the NSSPP Formulary in August 2003, prescriptions dispensed for simvastatin, lovastatin, pravastatin, and fluvastatin declined significantly (slope change, -0.0027; 95% confidence interval (CI), (-0.0046, -0.0009)). This significant decline continued following the publication of JUPITER (level change, -0.1974; 95% CI, (-0.2991, -0.0957)) and the availability of generic atorvastatin (level change, -0.2436; 95% CI, (-0.3314, -0.1558)). Atorvastatin was not significantly affected by any of the three interventions, although it maintained an overall decreasing trend. Only upon the availability of generic atorvastatin did the upward trend in rosuvastatin use decrease significantly (slope change, -0.0010, 95% CI, (-0.0015, -0.0005)). The type and rate of statins dispensed to NSSPP beneficiaries changed from 1999 to 2013 in response to the availability of new agents and publication of the JUPITER trial. The overall proportion of NSSPP beneficiaries dispensed a statin increased approximately 4-fold during the study period. In 2013, rosuvastatin was the most commonly dispensed statin (44.1%) followed by atorvastatin (39.1%).

Statins as antiarrhythmics: a systematic review part I: effects on risk of atrial fibrillation.

PubMed

Abuissa, Hussam; O'Keefe, James H; Bybee, Kevin A

2009-10-01

Recent studies have demonstrated that statins may possess antiarrhythmic properties in addition to their lipid-lowering effects. Studies which reported the association of statins with the incidence of atrial arrhythmias were identified through a systematic review of published literature. One randomized, placebo-controlled trial of 200 patients undergoing cardiac surgery showed that atorvastatin decreased the incidence of postoperative atrial fibrillation by 61%. Observational studies in patients with stable coronary disease, left ventricular dysfunction, or those undergoing cardiac or noncardiac surgery show that statin therapy is associated with an approximately 50% lower rate of atrial fibrillation. Two small randomized trials reported conflicting results: one showing that atorvastatin reduced the recurrence of AF after electrical cardioversion and the other finding that pravastatin did not. Published data suggests that statins may possess antiarrhythmic properties that reduce the propensity for atrial fibrillation. Most of this data is observational; more randomized, placebo-controlled trials are needed.

The impact of generic reference pricing interventions in the statin market.

PubMed

Puig-Junoy, Jaume

2007-11-01

The objective of this study was to evaluate the intended and unintended impact on pharmaceutical use and sales of three public reimbursement reforms applied to the prescription of statins: a Spanish generic reference pricing system, and two competing policies introduced by the Andalusian Public Health Service. This study is designed as an interrupted time series analysis with comparison series of 46 monthly drug use and sales figures from January 2001 to October 2004 for each active ingredient. The mean monthly saving for the year after the introduction of reference pricing was 16.7% of total lovastatin sales, representing only 1.1% of total statins sales. Mean monthly savings for the 10 months after reference pricing being applied to simvastatin were 51.8% of simvastatin sales, and 13.9% of statin sales. Over the 46 months of the study, all analysed public interventions resulted in a 2.2% average monthly decrease in statin sales in the rest of Spain and savings non-significantly different from zero in Andalusia. RP has been effective at reducing the volume of sales growth of the off-patent statins, yet its overall impact on sales of all statins has been relatively modest.

Statins for stroke prevention: disappointment and hope.

PubMed

Amarenco, Pierre; Tonkin, Andrew M

2004-06-15

The occurrence of stroke increases with age, particularly affecting the older elderly, a population also at higher risk for coronary heart disease (CHD). Epidemiological and observational studies have not shown a clear association between cholesterol levels and all causes of stroke. Nonetheless, large, long-term statin trials in patients with established CHD or at high risk for CHD have shown that statins decrease stroke incidence in these populations. Combined data from 9 trials including 70,070 patients indicated relative and absolute risk reductions for stroke of 21% and 0.9%, respectively, with statins. The number of strokes prevented per 1000 patients treated for 5 years in patients with CHD is 9 for statins, compared with 17.3 for antiplatelet agents. Statins have not yet been shown to reduce stroke risk in the typical general population without known CHD, nor have they been shown to prevent recurrent stroke in patients with prior stroke. Potential reasons for the effects of statins on stroke and the non-cholesterol-lowering mechanisms that may be involved are discussed. Treatment strategies based on global cardiovascular risk may be most effective. Additional studies in patients representative of the typical stroke population are needed.

Influence of the use of statin on the stability of erythrocyte membranes in multiple sclerosis.

PubMed

de Freitas, Mariana Vaini; de Oliveira, Marcela Ramos; dos Santos, Diogo Fernandes; de Cássia Mascarenhas Netto, Rita; Fenelon, Sheila Bernardino; Penha-Silva, Nilson

2010-02-01

Multiple sclerosis (MS) probably occurs by oxidative, inflammatory and autoimmune mechanisms. This study investigated the influence of statin on the stability of erythrocyte membranes in MS patients. The population was composed of one group with simvastatin therapy (20 mg/day), another group without statin therapy and a healthy control group. The stability of erythrocytes was evaluated by the half-transition points, H(50) and D(50), obtained from the curves of hemolysis induced by hypotonic shock and ethanol action, respectively. Erythrocytes of MS patients were less stable against lysis by both chaotropes. This behavior may be merely a consequence of the lifestyle of MS patients or it may be intrinsically associated with the conjunct of factors responsible for the development of the disease. The use of statin by MS patients was associated with lower levels of LDL and total cholesterol, as expected, and with higher stability of erythrocytes against ethanol compared to the values of untreated MS patients.

Nonlinear Pricing in Drug Benefits and Medication Use: The Case of Statin Compliance in Medicare Part D

PubMed Central

Jung, Kyoungrae; Feldman, Roger; McBean, A Marshall

2014-01-01

Objective To examine how enrollees' statin compliance responds to expected prices in Medicare Part D, which features a nonlinear price schedule due to a coverage gap. Data Sources/Study Setting Prescription Drug Event data for a 5 percent random sample of Medicare Advantage Prescription Drug Plan enrollees in 2008 who did not receive a low-income subsidy. Study Design We analyze statin compliance prior to the coverage gap, where the “effective price” is higher than the actual copayment for drugs because consumers anticipate that more spending will make them more likely to reach the gap. We construct each enrollee's effective price as her expected price at the end of the year, which is the weighted average between pre-gap and in-gap copayments with the weight being the predicted probability of hitting the gap. Compliance is defined as at least 80 percent of days covered. Principal Findings Part D enrollees' pre-gap statin compliance decreases by 3.7–4.7 percentage points for a $10 increase in the effective price. Conclusion The presence of a coverage gap decreases statin compliance prior to the gap, suggesting that incorporating expected future prices is important to assess the full impact of cost sharing on drug compliance under nonlinear price schedules. PMID:24354765

Rosuvastatin safety: An experimental study of myotoxic effects and mitochondrial alterations in rats.

PubMed

El-Ganainy, Samar O; El-Mallah, Ahmed; Abdallah, Dina; Khattab, Mahmoud M; Mohy El-Din, Mahmoud M; El-Khatib, Aiman S

2017-01-04

Myopathy is the most commonly reported adverse effect of statins. All statins are associated with myopathy, though with different rates. Rosuvastatin is a potent statin reported to induce myopathy comparable to earlier statins. However, in clinical practice most patients could tolerate rosuvastatin over other statins. This study aimed to evaluate the myopathic pattern of rosuvastatin in rats using biochemical, functional and histopathological examinations. The possible deleterious effects of rosuvastatin on muscle mitochondria were also examined. The obtained results were compared to myopathy induced by atorvastatin in equimolar dose. Results showed that rosuvastatin induced a rise in CK, a slight increase in myoglobin level together with mild muscle necrosis. Motor activity, assessed by rotarod, showed that rosuvastatin decreased rats' performance. All these manifestations were obviously mild compared to the prominent effects of atorvastatin. Parallel results were obtained in mitochondrial dysfunction parameters. Rosuvastatin only induced a slight increase in LDH and a minor decrease in ATP (∼14%) and pAkt (∼12%). On the other hand, atorvastatin induced an increase in LDH, lactate/pyruvate ratio and a pronounced decline in ATP (∼80%) and pAkt (∼65%). These findings showed that rosuvastatin was associated with mild myotoxic effects in rats, especially when compared to atorvastatin. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Potential benefits of eicosapentaenoic acid on atherosclerotic plaques.

PubMed

Nelson, J R; Wani, O; May, H T; Budoff, M

2017-04-01

Residual cardiovascular (CV) risk remains in some patients despite optimized statin therapy and may necessitate add-on therapy to reduce this risk. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, lowers plasma triglyceride levels without raising low-density lipoprotein cholesterol levels and has potential beneficial effects on atherosclerotic plaques. Animal studies have shown that EPA reduces levels of pro-inflammatory cytokines and chemokines. In clinical trials utilizing a wide spectrum of plaque imaging modalities, EPA has shown beneficial effects on plaque characteristics. Studies of patients with coronary artery disease receiving statin therapy suggest that EPA may decrease plaque vulnerability and prevent plaque progression. EPA also decreased pentraxin-3 and macrophage accumulation. A large, randomized, Japanese study reported that EPA plus a statin resulted in a 19% relative reduction in major coronary events at 5years versus a statin alone in patients with hypercholesterolemia (P=0.011). Icosapent ethyl, a high-purity prescription form of EPA ethyl ester, has been shown to reduce triglyceride levels and markers of atherosclerotic inflammation. Results of an ongoing CV outcomes study will further define the potential clinical benefits of icosapent ethyl in reducing CV risk in high-risk patients receiving statin therapy. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of Statins on Renal Outcome in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis

PubMed Central

Sanguankeo, Anawin; Upala, Sikarin; Cheungpasitporn, Wisit; Ungprasert, Patompong; Knight, Eric L.

2015-01-01

Background HMG CoA reductase inhibitors (statins) are known to prevent cardiovascular disease and improve lipid profiles. However, the effects of statins on renal outcomes, including decline in estimated glomerular filtration rate (eGFR) and proteinuria in patients with chronic kidney disease (CKD), are controversial. This meta-analysis evaluated the impact of statins on renal outcomes in patients with CKD. Materials and Methods We comprehensively searched the databases of MEDLINE, EMBASE, and Cochrane Databases. The inclusion criteria were published RCT and cohort studies comparing statin therapy to placebo or active controls in patients with CKD (eGFR <60 ml/min/1.73 m2) not requiring dialysis. The primary outcome was the differences in the change of eGFR. We also examined change of protein concentration in urine as a secondary outcome. A meta-analysis comparing statin and its control groups and a subgroup analysis examining intensity of statin were performed. Results From 142 full-text articles, 10 studies were included in the meta-analysis. Overall, there was a significant difference in rate of eGFR change per year favoring statin group (mean difference (MD) = 0.10 ml/min/1.73 m2, 95% CI: 0.09 to 0.12). In our subgroup analysis, those who received high-intensity statins had a significant difference in eGFR with a MD of 3.35 (95% CI: 0.91 to 5.79) ml/min/1.73 m2 compared to control. No significant change in eGFR was found with moderate- and low-intensity statin therapy. Compared with the control group, the statin group did not have a difference in reduction of proteinuria with MD in change of proteinuria of 0.19 gm/day (95% CI: -0.02 to 0.40). Conclusion Overall, there was a difference in change of eGFR between the statin and control group. High-intensity statins were found to improve a decline in eGFR in population with CKD not requiring dialysis compared with control, but moderate- and low-intensity statins were not. Statins were not found to decrease proteinuria in patients with CKD. PMID:26151753

Statins - a role in breast cancer therapy?

PubMed

Borgquist, Signe; Bjarnadottir, Olöf; Kimbung, Siker; Ahern, Thomas P

2018-06-20

Statin drugs have been used for more than two decades to treat hypercholesterolemia and as cardio-preventive drugs, resulting in a marked decrease in cardiovascular morbidity and mortality worldwide. Statins halt hepatic cholesterol biosynthesis by inhibiting the rate-limiting enzyme in the mevalonate pathway, hydroxymethylglutaryl-coenzyme A reductase (HMGCR). The mevalonate pathway regulates a host of biochemical processes in addition to cholesterol production. Attenuation of these pathways is likely responsible for the myriad benefits of statin therapy beyond cholesterol reduction-the so-called pleiotropic effects of statins. Chief among these purported effects is anti-cancer activity. A considerable body of preclinical, epidemiologic, and clinical evidence shows that statins impair proliferation of breast cancer cells and reduce the risk of breast cancer recurrence. Potential mechanisms for this effect have been explored in laboratory models, but remain poorly understood and require further investigation. The number of clinical trials assessing the putative clinical benefit of statins in breast cancer is increasing. Currently, a total of 30 breast cancer/statin trials are listed at the global trial identifier website clinicaltrials. gov.Given the compelling evidence from performed trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant breast cancer setting. It would be imperative for such a trial to incorporate tumor biomarkers predictive of statin response in its design and analysis plan. Ongoing translational clinical trials aimed at biomarker discovery will help identify, which breast cancer patients are most likely to benefit from adjuvant statin therapy, and will add valuable clinical knowledge to the field. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Coenzyme Q10 and statins: biochemical and clinical implications.

PubMed

Littarru, Gian Paolo; Langsjoen, Peter

2007-06-01

Statins are drugs of known and undisputed efficacy in the treatment of hypercholesterolemia, usually well tolerated by most patients. In some cases treatment with statins produces skeletal muscle complaints, and/or mild serum CK elevation; the incidence of rhabdomyolysis is very low. As a result of the common biosynthetic pathway Coenzyme Q (ubiquinone) and dolichol levels are also affected, to a certain degree, by the treatment with these HMG-CoA reductase inhibitors. Plasma levels of CoQ10 are lowered in the course of statin treatment. This could be related to the fact that statins lower plasma LDL levels, and CoQ10 is mainly transported by LDL, but a decrease is also found in platelets and in lymphocytes of statin treated patients, therefore it could truly depend on inhibition of CoQ10 synthesis. There are also some indications that statin treatment affects muscle ubiquinone levels, although it is not yet clear to which extent this depends on some effect on mitochondrial biogenesis. Some papers indicate that CoQ10 depletion during statin therapy might be associated with subclinical cardiomyopathy and this situation is reversed upon CoQ10 treatment. We can reasonably hypothesize that in some conditions where other CoQ10 depleting situations exist treatment with statins may seriously impair plasma and possible tissue levels of coenzyme Q10. While waiting for a large scale clinical trial where patients treated with statins are also monitored for their CoQ10 status, with a group also being given CoQ10, physicians should be aware of this drug-nutrient interaction and be vigilant to the possibility that statin drugs may, in some cases, impair skeletal muscle and myocardial bioenergetics.

Statin and Its Association With Delirium in the Medical ICU.

PubMed

Mather, Jeffrey F; Corradi, John P; Waszynski, Christine; Noyes, Adam; Duan, Yinghui; Grady, James; Dicks, Robert

2017-09-01

To examine the association between statin use and the risk of delirium in hospitalized patients with an admission to the medical ICU. Retrospective propensity-matched cohort analysis with accrual from September 1, 2012, to September 30, 2015. Hartford Hospital, Hartford, CT. An initial population of patients with an admission to a medical ICU totaling 10,216 visits were screened for delirium by means of the Confusion Assessment Method. After exclusions, a population of 6,664 was used to match statin users and nonstatin users. The propensity-matched cohort resulted in a sample of 1,475 patients receiving statin matched 1:1 with control patients not using statin. None. Delirium defined as a positive Confusion Assessment Method assessment was the primary end point. The prevalence of delirium was 22.3% in the unmatched cohort and 22.8% in the propensity-matched cohort. Statin use was associated with a significant decrease in the risk of delirium (odds ratio, 0.47; 95% CI, 0.38-0.56). Considering the type of statin used, atorvastatin (0.51; 0.41-0.64), pravastatin (0.40; 0.28-0.58), and simvastatin (0.33; 0.21-0.52) were all significantly associated with a reduced frequency of delirium. The use of statins was independently associated with a reduction in the risk of delirium in hospitalized patients. When considering types of statins used, this reduction was significant in patients using atorvastatin, pravastatin, and simvastatin. Randomized trials of various statin types in hospitalized patients prone to delirium should validate their use in protection from delirium.

The additive effects of atorvastatin and insulin on renal function and renal organic anion transporter 3 function in diabetic rats.

PubMed

Thongnak, Laongdao; Pongchaidecha, Anchalee; Jaikumkao, Krit; Chatsudthipong, Varanuj; Chattipakorn, Nipon; Lungkaphin, Anusorn

2017-10-19

Hyperglycemia-induced oxidative stress is usually found in diabetic condition. 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, statins, are widely used as cholesterol-lowering medication with several "pleiotropic" effects in diabetic patients. This study aims to evaluate whether the protective effects of atorvastatin and insulin on renal function and renal organic anion transporter 3 (Oat3) function involve the modulation of oxidative stress and pancreatic function in type 1 diabetic rats. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin (50 mg/kg BW). Atorvastatin and insulin as single or combined treatment were given for 4 weeks after diabetic condition had been confirmed. Diabetic rats demonstrated renal function and renal Oat3 function impairment with an increased MDA level and decreased SOD protein expression concomitant with stimulation of renal Nrf2 and HO-1 protein expression. Insulin plus atorvastatin (combined) treatment effectively restored renal function as well as renal Oat3 function which correlated with the decrease in hyperglycemia and oxidative stress. Moreover, pancreatic inflammation and apoptosis in diabetic rats were ameliorated by the combined drugs treatment. Therefore, atorvastatin plus insulin seems to exert the additive effect in improving renal functionby alleviating hyperglycemiaand the modulation of oxidative stress, inflammation and apoptosis.

Statin prescribing for people with severe mental illnesses: a staggered cohort study of 'real-world' impacts.

PubMed

Blackburn, R; Osborn, D; Walters, K; Falcaro, M; Nazareth, I; Petersen, I

2017-03-07

To estimate the 'real-world effectiveness of statins for primary prevention of cardiovascular disease (CVD) and for lipid modification in people with severe mental illnesses (SMI), including schizophrenia and bipolar disorder. Series of staggered cohorts. We estimated the effect of statin prescribing on CVD outcomes using a multivariable Poisson regression model or linear regression for cholesterol outcomes. 587 general practice (GP) surgeries across the UK reporting data to The Health Improvement Network. All permanently registered GP patients aged 40-84 years between 2002 and 2012 who had a diagnosis of SMI. Exclusion criteria were pre-existing CVD, statin-contraindicating conditions or a statin prescription within the 24 months prior to the study start. One or more statin prescriptions during a 24-month 'baseline' period (vs no statin prescription during the same period). The primary outcome was combined first myocardial infarction and stroke. All-cause mortality and total cholesterol concentration were secondary outcomes. We identified 2944 statin users and 42 886 statin non-users across the staggered cohorts. Statin prescribing was not associated with significant reduction in CVD events (incident rate ratio 0.89; 95% CI 0.68 to 1.15) or all-cause mortality (0.89; 95% CI 0.78 to 1.02). Statin prescribing was, however, associated with statistically significant reductions in total cholesterol of 1.2 mmol/L (95% CI 1.1 to 1.3) for up to 2 years after adjusting for differences in baseline characteristics. On average, total cholesterol decreased from 6.3 to 4.6 in statin users and 5.4 to 5.3 mmol/L in non-users. We found that statin prescribing to people with SMI in UK primary care was effective for lipid modification but not CVD events. The latter finding may reflect insufficient power to detect a smaller effect size than that observed in randomised controlled trials of statins in people without SMI. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Statin therapy in lower limb peripheral arterial disease: Systematic review and meta-analysis.

PubMed

Antoniou, George A; Fisher, Robert K; Georgiadis, George S; Antoniou, Stavros A; Torella, Francesco

2014-11-01

To investigate and analyse the existing evidence supporting statin therapy in patients with lower limb atherosclerotic arterial disease. A systematic search of electronic information sources was undertaken to identify studies comparing cardiovascular outcomes in patients with lower limb peripheral arterial disease treated with a statin and those not receiving a statin. Estimates were combined applying fixed- or random-effects models. Twelve observational cohort studies and two randomised trials reporting 19,368 patients were selected. Statin therapy was associated with reduced all-cause mortality (odds ratio 0.60, 95% confidence interval 0.46-0.78) and incidence of stroke (odds ratio 0.77, 95% confidence interval 0.67-0.89). A trend towards improved cardiovascular mortality (odds ratio 0.62, 95% confidence interval 0.35-1.11), myocardial infarction (odds ratio 0.62, 95% confidence interval 0.38-1.01), and the composite of death/myocardial infarction/stroke (odds ratio 0.91, 95% confidence interval 0.81-1.03), was identified. Meta-analyses of studies performing adjustments showed decreased all-cause mortality in statin users (hazard ratio 0.77, 95% confidence interval 0.68-0.86). Evidence supporting statins' protective role in patients with lower limb peripheral arterial disease is insufficient. Statin therapy seems to be effective in reducing all-cause mortality and the incidence cerebrovascular events in patients diagnosed with peripheral arterial disease. Copyright © 2014 Elsevier Inc. All rights reserved.

High-Dose Statin Pretreatment Decreases Periprocedural Myocardial Infarction and Cardiovascular Events in Patients Undergoing Elective Percutaneous Coronary Intervention: A Meta-Analysis of Twenty-Four Randomized Controlled Trials

PubMed Central

Wang, Le; Peng, Pingan; Zhang, Ou; Xu, Xiaohan; Yang, Shiwei; Zhao, Yingxin; Zhou, Yujie

2014-01-01

Background Evidence suggests that high-dose statin pretreatment may reduce the risk of periprocedural myocardial infarction (PMI) and major adverse cardiac events (MACE) for certain patients; however, previous analyses have not considered patients with a history of statin maintenance treatment. In this meta-analysis of randomized controlled trials (RCTs), we reevaluated the efficacy of short-term high-dose statin pretreatment to prevent PMI and MACE in an expanded set of patients undergoing elective percutaneous coronary intervention. Methods We searched the PubMed/Medline database for RCTs that compared high-dose statin pretreatment with no statin or low-dose statin pretreatment as a prevention of PMI and MACE. We evaluated the incidence of PMI and MACE, including death, spontaneous myocardial infarction, and target vessel revascularization at the longest follow-up for each study for subgroups stratified by disease classification and prior low-dose statin treatment. Results Twenty-four RCTs with a total of 5,526 patients were identified. High-dose statin pretreatment was associated with 59% relative reduction in PMI (odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.34–0.49; P<0.00001) and 39% relative reduction in MACE (OR: 0.61; 95% CI: 0.45–0.83; P = 0.002). The benefit of high-dose statin pretreatment on MACE was significant for statin-naive patients (OR: 0.69; 95% CI: 0.50–0.95; P = 0.02) and prior low dose statin-treated patients (OR: 0.28; 95% CI: 0.12–0.65; P = 0.003); and for patients with acute coronary syndrome (OR: 0.52; 95% CI: 0.34–0.79; P = 0.003), but not for patients with stable angina (OR: 0.71; 95% CI 0.45–1.10; P = 0.12). Long-term effects on survival were less obvious. Conclusions High-dose statin pretreatment can result in a significant reduction in PMI and MACE for patients undergoing elective PCI. The positive effect of high-dose statin pretreatment on PMI and MACE is significant for statin-naïve patients and patients with prior treatment. The positive effect of high-dose statin pretreatment on MACE is significant for patients with acute coronary syndrome. PMID:25473831

Long-Term Outcomes of Short-Term Statin Use in Healthy Adults: A Retrospective Cohort Study.

PubMed

Mansi, Ishak A; English, Jenny; Zhang, Song; Mortensen, Eric M; Halm, Ethan A

2016-06-01

Data suggest that the beneficial cardiovascular effects of statins are maximized after the first year of statin use; yet, the timeline of statin-associated adverse events is not well delineated. To examine the associations of short-term statin use (≤1 year) with short- and long-term adverse events and beneficial cardiovascular outcomes in a 'healthy' cohort. A cohort study of a healthy Tricare population (fiscal year [FY] 2002 through FY 2011) who have no cardiovascular disease, major comorbidities requiring medications, or functional limitations. Statin users used statins for 90-365 days during FY 2005 as their only prescription medication. Nonusers had medical encounters but did not receive prescription medications during FY 2005, and did not receive any statins throughout the study period from FY 2002 to FY 2011. Outcomes were the occurrence of major acute cardiovascular events, diabetes mellitus and its complications, kidney diseases, musculoskeletal diseases, obesity, cataracts, malignancy, and death. We matched 1525 statin users to 1525 nonusers. During the follow-up period (FY 2006 to FY 2011), statin users had significantly higher odds of developing diabetes and diabetic complications that persisted throughout follow-up (odds ratio [OR] 1.93, 95 % confidence interval [CI] 1.55-2.41 and OR 2.15, 95 % CI 1.20-3.86, respectively). Short-term statin use was not associated with decreased odds of major acute cardiovascular events (OR 1.17, 95 % CI 0.72-1.92). There were no differences in risks of kidney diseases, musculoskeletal diseases, or malignancy. Short-term statin use for primary prevention in this healthy cohort was associated with an increased risk of long-term diabetes and diabetic complications without cardiovascular benefits. Further study using pragmatic studies and prospective observational studies appropriately equipped to eliminate unidentified confounders are urgently needed.

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy.

PubMed

Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L; Adams, Marvin E; Froehner, Stanley C

2015-10-13

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

PubMed Central

Whitehead, Nicholas P.; Kim, Min Jeong; Bible, Kenneth L.; Adams, Marvin E.; Froehner, Stanley C.

2015-01-01

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases. PMID:26417069

Vulnerabilities to Health Disparities and Statin Use in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study.

PubMed

Schroff, Praful; Gamboa, Christopher M; Durant, Raegan W; Oikeh, Asikhame; Richman, Joshua S; Safford, Monika M

2017-08-28

Statins may be underutilized in certain vulnerable populations, but the effect of cumulative vulnerabilities within 1 individual is not well described. We sought to determine the likelihood of receiving statins with an increasing number of vulnerabilities in an individual, after controlling for factors known to influence health services utilization. We identified 18 216 participants from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study who had a statin indication or who were taking statins, as verified by pill bottle review. Statin use was assessed with respect to 5 major vulnerability domains alone and in combination: older age, black race, female sex, high area-level poverty, and lack of health insurance. The study included 5286 white men, 4180 black men, 2791 white women, and 4194 black women; 5.6% of the sample had no vulnerabilities, 20.6% had 1 vulnerability, 29.2% had 2 vulnerabilities, 27.3% had 3 vulnerabilities, and 17.3% had 4 or 5 vulnerabilities. All race-sex groups were less likely than white men to use statins; prevalence of use was 0.80 in black women with reference to white men ( P <0.0001). In both unadjusted and adjusted models, as the number of vulnerabilities increased, statin use steadily decreased. After adjusting for factors that influence health services utilization, compared with those without any vulnerabilities, statin use prevalence was 0.91, 0.83, 0.74 and 0.68 ( P <0.0001) in those with 1, 2, 3, and 4 or 5 vulnerabilities, respectively. Participants with more simultaneously occurring vulnerabilities experienced the greatest disparities in statin use. Black women and those without health insurance were at particularly high risk of underutilization. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Statin use and breast cancer survival and risk: a systematic review and meta-analysis.

PubMed

Wu, Qi-Jun; Tu, Chao; Li, Yuan-Yuan; Zhu, Jingjing; Qian, Ke-Qing; Li, Wen-Jing; Wu, Lang

2015-12-15

The purpose of this study is to determine the associations between statin use and breast cancer survival and risk by performing a systematic review and meta-analysis. We searched PubMed, Embase and Web of Science up to August 2015 for identifying relevant prospective or case-control studies, or randomized clinical trials. Five prospective studies involving 60,911 patients reported the association between statin use and breast cancer mortality. Eleven prospective studies, 12 case-control studies and 9 randomized clinical trials involving 83,919 patients reported the association between statin use and breast cancer risk. After pooling estimates from all available studies, there was a significantly negative association between pre-diagnosis statin use and breast cancer mortality (for overall survival (OS): hazard ratio (HR) = 0.68, 95% confidence interval (CI) 0.54-0.84; for disease specific survival (DSS): HR = 0.72, 95% CI 0.53-0.99). There was also a significant inverse association between post-diagnosis statin use and breast cancer DSS (HR = 0.65, 95% CI 0.43-0.98), although the association with breast cancer OS did not reach statistical significance (HR = 0.71, 95% CI 0.48-1.07). Additionally, there was a non-linear relationship for the duration of post-diagnosis statin use with breast cancer specific mortality. On the other hand, with regards to the relationship between statin use and breast cancer risk, no significant association was detected. Our analyses suggest that although statin use may not influence breast cancer risk, the use of statin may be associated with decrease mortality of breast cancer patients. Further large-scale studies are warranted to validate our findings.

Achievement of cholesterol targets and prescribing of higher-cost statins: a cross-sectional study in general practice.

PubMed

Fleetcroft, Robert; Schofield, Peter; Duerden, Martin; Ashworth, Mark

2012-12-01

There is conflicting evidence as to whether achievement of cholesterol targets at the population level is dependent on the choice and cost of statin. To investigate the practice-level relationship between cholesterol quality indicators in patients with heart disease, stroke, and diabetes and prescribing of low-cost statins. Correlations and linear regression modelling of retrospective cross-sectional practice-level data with potential explanatory variables in 7909 (96.4%) general practices in England in 2008-2009. Quality indicator data were obtained from the Information Centre and prescribing data from the NHS Business Authority. A 'cholesterol quality indicator' score was constructed by dividing the numbers of patients achieving the target for cholesterol control of ≤5 mmol/l in stroke, diabetes, and heart disease by the numbers on each register. A 'low-cost statin' ratio score was constructed by dividing the numbers of defined daily doses of simvastatin and pravastatin by the total numbers of defined daily doses of statins. Simvastatin accounted for 83.3% (standard deviation [SD] = 15.7%) of low-cost statins prescribed and atorvastatin accounted for 85.7% (SD = 14.8%) of high-cost statins prescribed. The mean cholesterol score was 73.7% (SD = 6.0%). Practices using a higher proportion of the low-cost statins were less successful in achieving cholesterol targets. An increase of 10% in the prescribing of low-cost statins was associated with a decrease of 0.46% in the cholesterol quality indicator score (95% confidence interval = -0.54% to -0.38%, P<0.001). Greater use of low-cost statins was associated with a small reduction in cholesterol control.

Early statin use is an independent predictor of long-term graft survival.

PubMed

Moreso, Francesc; Calvo, Natividad; Pascual, Julio; Anaya, Fernando; Jiménez, Carlos; Del Castillo, Domingo; Sánchez-Plumed, Jaime; Serón, Daniel

2010-06-01

Background. Statin use in renal transplantation has been associated with a lower risk of patient death but not with an improvement of graft functional survival. The aim of this study is to evaluate the effect of statin use in graft survival, death-censored graft survival and patient survival using the data recorded on the Spanish Late Allograft Dysfunction Study Group.Patients and methods. Patients receiving a renal allograft in Spain in 1990, 1994, 1998 and 2002 were considered. Since the mean follow-up in the 2002 cohort was 3 years, statin use was analysed considering its introduction during the first year or during the initial 2 years after transplantation. Univariate and multivariate Cox regression analyses with a propensity score for statin use were employed to analyse graft survival, death-censored graft survival and patient survival.Results. In the 4682 evaluated patients, the early statin use after transplantation significantly increased from 1990 to 2002 (12.7%, 27.9%, 47.7% and 53.0%, P < 0.001). Statin use during the first year was not associated with graft or patient survival. Statin use during the initial 2 years was associated with a lower risk of graft failure (relative risk [RR] = 0.741 and 95% confidence interval [CI] = 0.635-0.866, P < 0.001) and patient death (RR = 0.806 and 95% CI = 0.656-0.989, P = 0.039). Death-censored graft survival was not associated with statin use during the initial 2 years.Conclusion. The early introduction of statin treatment after transplantation is associated with a significant decrease in late graft failure due to a risk reduction in patient death.

Early statin use is an independent predictor of long-term graft survival

PubMed Central

Moreso, Francesc; Calvo, Natividad; Pascual, Julio; Anaya, Fernando; Jiménez, Carlos; del Castillo, Domingo; Sánchez-Plumed, Jaime; Serón, Daniel

2010-01-01

Background. Statin use in renal transplantation has been associated with a lower risk of patient death but not with an improvement of graft functional survival. The aim of this study is to evaluate the effect of statin use in graft survival, death-censored graft survival and patient survival using the data recorded on the Spanish Late Allograft Dysfunction Study Group. Patients and methods. Patients receiving a renal allograft in Spain in 1990, 1994, 1998 and 2002 were considered. Since the mean follow-up in the 2002 cohort was 3 years, statin use was analysed considering its introduction during the first year or during the initial 2 years after transplantation. Univariate and multivariate Cox regression analyses with a propensity score for statin use were employed to analyse graft survival, death-censored graft survival and patient survival. Results. In the 4682 evaluated patients, the early statin use after transplantation significantly increased from 1990 to 2002 (12.7%, 27.9%, 47.7% and 53.0%, P < 0.001). Statin use during the first year was not associated with graft or patient survival. Statin use during the initial 2 years was associated with a lower risk of graft failure (relative risk [RR] = 0.741 and 95% confidence interval [CI] = 0.635–0.866, P < 0.001) and patient death (RR = 0.806 and 95% CI = 0.656–0.989, P = 0.039). Death-censored graft survival was not associated with statin use during the initial 2 years. Conclusion. The early introduction of statin treatment after transplantation is associated with a significant decrease in late graft failure due to a risk reduction in patient death. PMID:20508861

The Impact of CDH13 Polymorphism and Statin Administration on TG/HDL Ratio in Cardiovascular Patients

PubMed Central

Choi, Jung Ran; Kim Yoon, Sungjoo; Park, Jong Keun; Sorn, Sungbin Richard; Park, Mi-Young

2015-01-01

Purpose Adiponectin is expressed in adipose tissue, and is affected by smoking, obesity, and genetic factors, such as CDH13 polymorphism, contributing to the development of coronary vascular diseases (CVDs). Materials and Methods We investigated the effect of genetic variations of CDH13 (rs3865188) on blood chemistry and adiponectin levels in 345 CVD patients undergoing statin-free or statin treatment. Results Genetic variation in CDH13 was significantly correlated with several clinical factors, including adiponectin, diastolic blood pressure, triglyceride (TG), and insulin levels. Subjects with the T allele (mutant form) had significantly lower adiponectin levels than those with the A allele. Total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), TG/high-density lipoprotein cholesterol (HDLc) ratio, and HDL3b subtype were markedly decreased in statin treated subjects regardless of having the A or T allele. TG and TG/HDL in the statin-free group with TT genotype of the rs3865188 was higher than in the others but they were not different in the statin-treated subjects. We observed a significant difference in adiponectin levels between patients with the A and T alleles in the statin-free group; meanwhile, no difference in adiponectin levels was noted in the statin group. Plasma levels of other cytokines, leptin, visfatin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were not different among the CDH13 genotypes according to statin administration. Body mass index (BMI), TG, insulin, HDL3b, and TG/HDL ratio showed negative correlations with adiponectin levels. Conclusion Plasma adiponectin levels and TG/HDL ratio were significantly different according to variants of CDH13 and statin administration in Korean patients with CVD. PMID:26446643

The Impact of CDH13 Polymorphism and Statin Administration on TG/HDL Ratio in Cardiovascular Patients.

PubMed

Choi, Jung Ran; Jang, Yangsoo; Kim Yoon, Sungjoo; Park, Jong Keun; Sorn, Sungbin Richard; Park, Mi-Young; Lee, Myoungsook

2015-11-01

Adiponectin is expressed in adipose tissue, and is affected by smoking, obesity, and genetic factors, such as CDH13 polymorphism, contributing to the development of coronary vascular diseases (CVDs). We investigated the effect of genetic variations of CDH13 (rs3865188) on blood chemistry and adiponectin levels in 345 CVD patients undergoing statin-free or statin treatment. Genetic variation in CDH13 was significantly correlated with several clinical factors, including adiponectin, diastolic blood pressure, triglyceride (TG), and insulin levels. Subjects with the T allele (mutant form) had significantly lower adiponectin levels than those with the A allele. Total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), TG/high-density lipoprotein cholesterol (HDLc) ratio, and HDL3b subtype were markedly decreased in statin treated subjects regardless of having the A or T allele. TG and TG/HDL in the statin-free group with TT genotype of the rs3865188 was higher than in the others but they were not different in the statin-treated subjects. We observed a significant difference in adiponectin levels between patients with the A and T alleles in the statin-free group; meanwhile, no difference in adiponectin levels was noted in the statin group. Plasma levels of other cytokines, leptin, visfatin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were not different among the CDH13 genotypes according to statin administration. Body mass index (BMI), TG, insulin, HDL3b, and TG/HDL ratio showed negative correlations with adiponectin levels. Plasma adiponectin levels and TG/HDL ratio were significantly different according to variants of CDH13 and statin administration in Korean patients with CVD.

Comparison of the effects of high-dose atorvastatin and high-dose rosuvastatin on oxidative stress in patients with acute myocardial infarction: A pilot study.

PubMed

Kilit, Celal; Koçak, Fatma Emel; Paşalı Kilit, Türkan

2017-04-01

Oxidative stress is increased in patients with acute myocardial infarction (AMI). Statins reduce oxidative stress independent of their effect in reducing low-density lipoprotein cholesterol (LDL-C). The aim of the present study was to compare the effects of atorvastatin and rosuvastatin on oxidative status by investigating serum paraoxonase, serum arylesterase, total oxidant status, total antioxidant status (TAS) and oxidative stress index (OSI) in patients with AMI. Seventy patients with AMI were randomized into 2 groups; total of 55 patients (19 females, 36 males) aged 32 to 86 years completed the study and were included in the analysis. Patients were treated with 80 mg atorvastatin or 40 mg rosuvastatin for 4 weeks. Lipid parameters and parameters of oxidative status were measured at admission and after 4-week statin treatment. After 4-week treatment, atorvastatin and rosuvastatin were associated with significant reduction in TAS, OSI, total cholesterol, and LDL-C levels. Serum paraoxonase level was significantly increased in both groups, while high-density lipoprotein cholesterol (HDL-C) level was significantly reduced in atorvastatin group. No statistically significant differences were found between atorvastatin and rosuvastatin in terms of actual difference in oxidative stress parameters. Atorvastatin and rosuvastatin have similar effects on oxidative status in patients with AMI. Rosuvastatin affected HDL-C level more favorably than atorvastatin.

Comparative effectiveness of lipid-lowering treatments to reduce cardiovascular disease.

PubMed

Suh, Dong-Churl; Griggs, Scott K; Henderson, Emmett R; Lee, Seung-Mi; Park, Taehwan

2018-02-01

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is a new treatment option for patients with hypercholesterolemia. The objective of this study was to systematically review the cost-effectiveness of lipid-lowering agents. Areas covered: Based on Pubmed, Embase, and Cochrane Database of Systematic Reviews, we identified 29 relevant articles. Studies found statins were cost-effective compared with placebo or no treatment in general. Atorvastatin was reported to be cost-effective against simvastatin. In most cases, rosuvastatin was more cost-effective than atorvastatin or simvastatin. Additionally, ezetimibe was considered to be cost-effective compared with no treatment for statin intolerant patients. For patients not meeting treatment goals with their statins, switching to ezetimibe plus simvastatin was consistently reported cost-effective. The cost-effectiveness of ezetimibe plus a hybrid of a statin varied by the source of clinical data and cost of ezetimibe. Finally, the cost-effectiveness of PCSK9 inhibitor plus a statin against statin monotherapy was uncertain. The PCSK9 inhibitor plus a stain was cost-ineffective compared with ezetimibe plus a statin. Expert commentary: Drug costs and treatment efficacy were the key drivers of the cost-effectiveness results in prior analyses. Future evaluations are warranted to reflect the decreasing drug prices and the long-term treatment effects of PCSK9 inhibitors.

Steroids and statins: an old and a new anti-inflammatory strategy compared.

PubMed

Vukovic, Petar M; Maravic-Stojkovic, Vera R; Peric, Miodrag S; Jovic, Miomir Dj; Cirkovic, Milan V; Gradinac, Sinisa Dj; Djukanovic, Bosko P; Milojevic, Predrag S

2011-01-01

This study compared the anti-inflammatory effects of methylprednisolone (MP) and atorvastatin and analysed their influences on clinical variables in patients undergoing coronary revascularization. Ninety patients with compromised left ventricular ejection fraction (≤30%) undergoing elective coronary surgery were equally randomized to one of three groups: statin group, treatment with atorvastatin (20 mg/day) 3 weeks before surgery; methylprednisolone group, a single shot of methylpredniosolone (10mg/kg); and control group. Postoperative IL-6 was higher in the control group when compared to the methylprednisolone and statin groups (p<0.01). IL-6 was higher in the statin-treated patients (p<0.05 versus methylprednisolone). Administration of methylprednisolone as well as statin treatment increased postoperative cardiac index, left ventricular stroke work index, decreased postoperative atrial fibrilation rate and reduced ICU stay (p<0.05 versus control). The number of patients requiring inotropic support was lower in the methylprednisolone group when compared with the other two groups (p<0.01). Tracheal intubation time was reduced in patients who received methylprednisolone (p<0.01 versus control). Preoperative administration of either methylprednisolone or atorvastatin reduced pro-inflammatory cytokine release, improved haemodynamics, decreased postoperative atrial fibrilation rate and reduced ICU stay in patients with significantly impaired cardiac function undergoing coronary revascularization. Treatment with methylprednisolone was associated with less inotropic support requirements and reduced mechanical ventilation time.

Lipid abnormalities in women: data for risk, data for management.

PubMed

Wenger, Nanette K

2006-01-01

In multiple randomized, controlled clinical trials, statin treatment of elevated low-density lipoprotein cholesterol in women at increased risk of or with coronary heart disease decreased the risk of coronary events: coronary death, nonfatal myocardial infarction, and myocardial revascularization procedures. Total mortality was unchanged, potentially reflecting the underrepresentation of women in these trials and consequent small number of fatal events. Statin therapy provided comparable benefit for women and men with acute coronary syndromes. Application of lipid-lowering therapy with statin drugs is currently underutilized in women, and represents an opportunity to improve clinical cardiovascular outcomes for women.

Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka

Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30more » days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased both oxidative and nitrosative stress in thoracic aorta. • Atorvastatin regularized blood pressure, improved lipid profile and restored redox homeostasis.« less

Cardiorespiratory Fitness and Incidence of Type 2 Diabetes in United States Veterans on Statin Therapy.

PubMed

Kokkinos, Peter; Faselis, Charles; Narayan, Puneet; Myers, Jonathan; Nylen, Eric; Sui, Xuemei; Zhang, Jiajia; Lavie, Carl J

2017-10-01

Impact of cardiorespiratory fitness on statin-related incidence of type 2 diabetes has not been assessed. We assessed the cardiorespiratory fitness and diabetes incidence association in dyslipidemic patients on statins. We identified dyslipidemic patients with a normal exercise test performed during 1986 and 2014 at the Veterans Affairs Medical Centers in Washington, DC or Palo Alto, Calif. The statin-treated patients (n = 4092; age = 58.8 ± 10.9 years) consisted of 2701 Blacks and 1391 Whites. None had evidence of type 2 diabetes prior to statin therapy. We formed 4 fitness categories based on age and peak metabolic equivalents achieved: Least-fit (n = 954), Low-fit (n = 1201), Moderate-fit (n = 1242), and High-fit (n = 695). The non-statin-treated cohort (n = 3001; age = 57.2 ± 11.2 years) with no evidence of type 2 diabetes prior to the exercise test served as controls. Diabetes incidence was 24% higher in statin-treated compared with non-statin-treated patients (P <.001). In the statin-treated cohort, 1075 (26.3%) developed diabetes (average annual incidence rate of 30.6 events/1000 person-years). Compared with the Least-fit, adjusted risk decreased progressively with increasing fitness and was 34% lower for High-fit patients (hazard ratio [HR] 0.66; 95% confidence interval [CI], 0.53-0.82; P <.001). Compared with the nonstatin cohort, elevated risk was evident only in the Least-fit (HR 1.50; 95% CI, 1.30-1.73; P <.001) and Low-fit patients (HR 1.22; 95% CI, 1.06-1.41; P = .006). Risk of diabetes in statin-treated dyslipidemic patients was inversely and independently associated with cardiorespiratory fitness. The increased risk was evident only in relatively low-fitness patients. Improving fitness may modulate the potential diabetogenic effects of statins. Published by Elsevier Inc.

Evaluation of protein C and protein S levels in patients with diabetes mellitus receiving therapy with statins and ACE inhibitors or angiotensin II receptor blockers.

PubMed

Aktaş, Şerife; Uçak, Sema; Kurt, Fatma; Taşdemir, Mehmet; Kutlu, Orkide; Eker, Pınar

2018-01-01

To evaluate protein C, protein S level in patients with diabetes mellitus receiving statin and ACE inhibitor/ARB therapy. 95 patients were included in the study and divided into four groups depending on the use of statin and ACE inhibitor/ARB therapy. Group 1 comprised of patients receiving statin therapy (n = 15), Group 2 comprised of patients receiving ACE inhibitor/ARB therapy (n = 31), Group 3 comprised of patients receiving statin and ACE inhibitor/ARB therapy (n = 23), and Group 4 comprised of patients who did not receive either statin or ACE inhibitor/ARB therapy (n = 26). These four groups were compared with respect to protein C, protein S, fibrinogen, D-dimer, INR, and aPTT levels. There were statistically significant differences with respect to protein C levels. Group 1 and group 2 had higher protein C levels compared with group 4. (p < .01). Similarly, Group 3 had higher protein C levels compared with group 4. (p < .01). There was no significant difference between the groups with respect to protein S, INR, aPTT, and D-dimer levels. Diabetic patients receiving statin or ACE inhibitor/ARB therapy had higher protein C levels. Use of statin and ACE inhibitor/ARB therapy in diabetic patients decrease hypercoagulability and therefore could reduce the occurrence of cardiovascular events. Copyright © 2017 Elsevier B.V. All rights reserved.

Utilization Patterns of Lipid-lowering Therapies in Patients With Atherosclerotic Cardiovascular Disease or Diabetes: A Population-based Study in South Korea.

PubMed

Kim, Siin; Kim, Hyungtae; Kim, Eunju; Han, Sola; Rane, Pratik P; Fox, Kathleen M; Zhao, Zhongyun; Qian, Yi; Suh, Hae Sun

2018-06-01

We aimed to study the utilization patterns of lipid-lowering treatment (LLT), including treatment modification, adherence, and possible statin intolerance, in patients with atherosclerotic cardiovascular disease (ASCVD) or diabetes using national claims data in South Korea. A retrospective cohort study was conducted using data from the Korean Health Insurance Review & Assessment Service claims database. Patients aged ≥18 years with >1 outpatient pharmacy claim for a statin and/or ezetimibe dated January 1, 2012, to December 31, 2014, were identified and categorized into the following cohorts: patients with ASCVD, and patients with diabetes mellitus without ASCVD. LLT modification, adherence to index LLT, and possible statin intolerance were explored during the 12 months after the date of first prescription for a statin and/or ezetimibe. Among 1,399,872 patients who met the eligibility criteria, 807,547 (57.7%) were patients with ASCVD and 592,325 (42.3%) were patients with diabetes without ASCVD. About half of the patients had no modification in their index treatment (46.2% in the ASCVD cohort and 48.9% in the diabetes cohort), and the most common modification was permanent discontinuation (19.6% in the ASCVD cohort and 21.4% in the diabetes cohort). The mean medication possession ratios were 0.77 in the ASCVD cohort and 0.73 in the diabetes cohort and showed a decreasing trend during the 12-month follow-up period. Among patients who initiated a statin and/or ezetimibe, possible statin intolerance was observed in 53,921 patients (6.7%) in the ASCVD cohort and 42,172 patients (7.1%) in the diabetes cohort. In South Korea, a high rate of permanent discontinuation of statin therapy in patients with ASCVD or diabetes places these patients at high risk for cardiovascular events in the future. A decreasing trend of adherence to LLT implies that more intensive education and management are required to improve therapeutic effect and reduce the risk for ASCVD. The high rate of possible statin intolerance highlights an unmet need in the prevention and management of ASCVD in South Korea. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle.

PubMed

Simakova, Maria N; Bisen, Shivantika; Dopico, Alex M; Bukiya, Anna N

2017-12-01

Statins constitute the most commonly prescribed drugs to decrease cholesterol (CLR). CLR is an important modulator of alcohol-induced cerebral artery constriction (AICAC). Using rats on a high CLR diet (2% CLR) we set to determine whether atorvastatin administration (10mg/kg daily for 18-23weeks) modified AICAC. Middle cerebral arteries were pressurized in vitro at 60mmHg and AICAC was evoked by 50mM ethanol, that is within the range of blood alcohol detected in humans following moderate-to-heavy drinking. AICAC was evident in high CLR+atorvastatin group but not in high CLR diet+placebo. Statin exacerbation of AICAC persisted in de-endothelialized arteries, and was blunted by CLR enrichment in vitro. Fluorescence imaging of filipin-stained arteries showed that atorvastatin decreased vascular smooth muscle (VSM) CLR when compared to placebo, this difference being reduced by CLR enrichment in vitro. Voltage- and calcium-gated potassium channels of large conductance (BK) are known VSM targets of ethanol, with their beta1 subunit being necessary for ethanol-induced channel inhibition and resulting AICAC. Ethanol-induced BK inhibition in excised membrane patches from freshly isolated myocytes was exacerbated in the high CLR diet+atorvastatin group when compared to high CLR diet+placebo. Unexpectedly, atorvastatin decreased the amount and function of BK beta1 subunit as documented by immunofluorescence imaging and functional patch-clamp studies. Atorvastatin exacerbation of ethanol-induced BK inhibition disappeared upon artery CLR enrichment in vitro. Our study demonstrates for the first time statin's ability to exacerbate the vascular effect of a widely consumed drug of abuse, this exacerbation being driven by statin modulation of ethanol-induced BK channel inhibition in the VSM via CLR-mediated mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study.

PubMed

Puurunen, Johanna; Piltonen, Terhi; Puukka, Katri; Ruokonen, Aimo; Savolainen, Markku J; Bloigu, Risto; Morin-Papunen, Laure; Tapanainen, Juha S

2013-12-01

Statins have been shown to improve hyperandrogenism in women with polycystic ovary syndrome (PCOS). However, their use has also been associated with impairment of glucose metabolism and an increased risk of type 2 diabetes mellitus. Because women with PCOS are prone to disturbances in glucose metabolism, statin therapy could also have negative effects. Our objective was to explore the effects of atorvastatin therapy on hormonal and metabolic parameters in women with PCOS. We conducted a randomized, double-blind, placebo-controlled 6-month follow-up study conducted at Oulu University Hospital, Finland. Women with PCOS (Rotterdam criteria) were treated with atorvastatin (20 mg/d, n = 15) or placebo (n = 13) for 6 months. Fasting serum samples were collected at baseline and at 3 and 6 months. Oral and iv glucose tolerance tests were performed at 0 and 6 months. Androgen secretion and glucose metabolism were measured. Fasting levels and area under the curve of insulin increased significantly and insulin sensitivity (insulinogenic and Matsuda indexes) decreased during 6 months of atorvastatin therapy. Serum levels of dehydroepiandrosterone sulfate decreased in the atorvastatin group, whereas no change was observed in serum testosterone levels. Levels of C-reactive protein, total and low-density lipoprotein-cholesterol, and triglycerides decreased significantly during statin therapy. Atorvastatin therapy improves chronic inflammation and lipid profile, but it impairs insulin sensitivity in women with PCOS. Because women with PCOS have an increased risk of developing type 2 diabetes mellitus, the results suggest that statin therapy should be initiated on the basis of generally accepted criteria and individual risk assessment of cardiovascular disease, and not only because of PCOS.

Can pleiotropic effects of eicosapentaenoic acid (EPA) impact residual cardiovascular risk?

PubMed

Nelson, John R; True, Wayne S; Le, Viet; Mason, R Preston

2017-11-01

Residual cardiovascular (CV) risk persists even in statin-treated patients with optimized low-density lipoprotein cholesterol (LDL-C) levels. Other pathways beyond cholesterol contribute to CV risk and the key to reducing residual risk may be addressing non-cholesterol risk factors through pleiotropic mechanisms. The purpose of this review is to examine the literature relating to the potential role of the omega-3 fatty acid eicosapentaenoic acid (EPA) in reducing residual CV risk. The literature shows that EPA can robustly lower plasma triglyceride (TG) levels without raising LDL-C levels and documents EPA to have a broad range of beneficial effects on the atherosclerotic pathway, including those on lipids, lipoproteins, inflammation, oxidation, phospholipid membranes, and the atherosclerotic plaque itself. Clinical imaging studies have consistently demonstrated that EPA decreases plaque vulnerability and prevents plaque progression. The evidence therefore points to a potential role for EPA to reduce residual CV risk. A large randomized study of statin-treated Japanese patients demonstrated that EPA ethyl ester reduced major coronary events by 19% (P = 0.011). However, while there has been significant benefit demonstrated in this and another Japanese CV outcomes study, the question as to whether EPA can play a role in reducing residual CV risk remains to be addressed in broader populations. The large, global, ongoing, randomized, placebo-controlled REDUCE-IT study of high-risk statin-treated patients with persistent hypertriglyceridemia is currently underway to investigate the potential of icosapent ethyl (high-purity prescription EPA ethyl ester) as an add-on therapy to reduce residual CV risk.

Effective policy initiatives to constrain lipid-lowering drug expenditure growth in South Korea.

PubMed

Bae, Green; Park, Chanmi; Lee, Hyejin; Han, Euna; Kim, Dong-Sook; Jang, Sunmee

2014-03-03

The rapid growth of prescription drug expenditures is a major problem in South Korea. Accordingly, the South Korean government introduced a positive listing system in 2006. They also adopted various price reduction policies. Nevertheless, the total expenditure for lipid-lowering drugs have steadily increased throughout South Korea. The present study explores the factors that have influenced the increased expenditures of lipid-lowering drugs with a particular focus on the effects of statins in this process. This paper investigates the National Health Insurance claims data for prescribed lipid-lowering drugs collected between January 1, 2005 and December 31, 2009. We specifically focused on statins and assessed the yearly variation of statin expenditure by calculating the increased rate of paired pharmaceutical expenditures over a 2 year period. Our study classified statins into three categories: new entrants, core medicines and exiting medicines. For core medicines, we further examined influencing factors such as price, amount of drugs consumed by volume, and prescription changes (substitutes for other drug). Statin expenditure showed an average annual increase of 25.7% between 2005 and 2009. Among the different statins, the expenditure of atorvastatin showed a 36.6% annual increase rate, which was the most dramatic among all statins. Also we divided expenditure for core medicines by the price factor, volume factor, and prescription change. The result showed that annual weighted average prices of individual drug decreased each year, which clearly showed that price influenced statin expenditure in a negative direction. The use of generic drugs containing the same active ingredient as name-brand drugs increased and negatively affected statin expenditure (Generic Mix effect). However, the use of relatively expensive ingredients within statin increase, Ingredient Mix effect contributed to increased statin expenditure (Ingredient Mix effect). In particular, the volume effect was found to be critical for increasing statin expenditure as the amount of statin consumed increased steadily throughout the study period. The recent rapid increase in statin expenditure can largely be attributed to an increase in consumption volume. In order to check drug expenditures effectively in our current situation, in which chronic diseases remain steadily on the rise, it is necessary to not only have supply-side initiatives such as price reduction, but also demand-side initiatives that could control drug consumption volume, for example: educational programs for rational prescription, generic drug promotional policies, and policies providing prescription targets.

Atherosclerosis, cholesterol, nutrition, and statins – a critical review

PubMed Central

Gebbers, Jan-Olaf

2007-01-01

Atherosclerosis, which causes approximately half of all deaths of adults over age 60 in industrialized nations, is a pandemic among inappropriately nourished and/or physically hypoactive children, adolescents, and adults world wide. Although nowadays statins are widely prescribed to middle age and elderly adults with high blood lipid levels as pharmacological prevention for the late complications of atherosclerosis, from a critical point of view statins seem not to solve the problem, especially when compared with certain natural ingredients of our nutrition like micronutrients as alternative strategy. Statin ingestion is associated with lowering of serum cholesterol and low-density lipoprotein concentrations; some prospective studies have shown statistical associations with subsequent modest reduction of mortality from cardiovascular disease. However, specific biochemical pathways and pharmacological roles of statins in prevention of atherosclerosis, if any, are unknown. Moreover, there have been no systematic cost-benefit analyses of life-style prophylaxis versus statin prophylaxis versus combined life-style plus statin prophylaxis versus neither life-style nor statin prophylaxis for clinically significant complications of cardiovascular diseases in the elderly. Further, in the trials of effectiveness statins were not compared with management of nutrition, which is the most appropriate alternative intervention. Such studies seem to be important, as the ever increasing world population, especially in developing countries, now demand expensive statins, which may be unaffordable for mitigating the pandemic. Studies of this kind are necessary to identify more precisely those patients for whom cardiovascular benefits will outweigh the risks and costs of the statin treatment in comparison with nutritional interventions. Against the background of the current pathogenetic concept of atherogenesis some of its possible risk factors, particularly the roles of cholesterol and homocysteine, and the effects of statins versus nutritional (micronutrients) interventions in prevention and treatment of the disease are discussed. The prevailing opinion that serum cholesterol as a mediator of the disease is increased by eating saturated fats and decreased by eating polyunsaturated fats is being challenged. Evidently, the beneficial effects of statins in atherosclerosis are not mainly due to its cholesterol lowering effect, rather than to its “pleiotropic effects”. Other pathogenetic factors in atherosclerosis are involved, like inflammatory and immunologic processes, that can be modulated by statins as well as by other drugs or by the Mediterranean-style nutrition and by micronutrients (folate, B-vitamins). PMID:19675712

Effect of vildagliptin and pravastatin combination on cholesterol efflux in adipocytes.

PubMed

Mostafa, Ahmed M; Hamdy, Nadia M; Abdel-Rahman, Sherif Z; El-Mesallamy, Hala O

2016-07-01

Many reports suggested that some statins are almost ineffective in reducing triglycerides or enhancing HDL-C plasma levels, although statin treatment was still efficacious in reducing LDL-C. In diabetic dyslipidemic patients, it may therefore be necessary to use a combination therapy with other drugs to achieve either LDL-C- and triglyceride-lowering or HDL-C-enhancing goals. Such ineffectiveness of statins can be attributed to their effect on the liver X receptor (LXR) which regulates the expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. A decrease in the expression of these transporters eventually leads to decreased cholesterol efflux from peripheral tissues leading to low levels of HDL-C. Although manipulating the LXR pathway may complement the effects of statins, LXR synthetic ligands as T091317 have shown significant hypertriglyceridemic action which limits their use. We recently found that the antidiabetic drug vildagliptin stimulates LXR expression leading to increased ABCB1/ABCG1 expression which improves cholesterol efflux from adipocytes. Therefore, a combination of vildagliptin and statin may provide a solution without the hypertriglyceridemic action observed with LXR agonist. We hypothesize that a combination of vildagliptin and pravastatin will improve cholesterol efflux in adipocytes. Statin-treated 3T3-L1 adipocytes were treated with vildagliptin, and the expression of LXR-ABCA1/ABCG1 cascade and the cholesterol efflux were then determined. Our data indicate that a combination of vildagliptin and pravastatin significantly induces the expression of LXR-ABCA1/ABCG1 cascade and improves cholesterol efflux (P > 0.05) in adipocytes. Our data may explain, at least in part, the improvement in HDL-C levels observed in patients receiving both medications. © 2016 IUBMB Life, 68(7):535-543, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

Effects of Simvastatin on Cholesterol Metabolism and Alzheimer Disease Biomarkers

PubMed Central

Serrano-Pozo, Alberto; Vega, Gloria L.; Lütjohann, Dieter; Locascio, Joseph J.; Tennis, Marsha K.; Deng, Amy; Atri, Alireza; Hyman, Bradley T.; Irizarry, Michael C.; Growdon, John H.

2013-01-01

Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-β (Aβ) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of Aβ and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment. PMID:20473136

Statin Use, Incident Dementia and Alzheimer Disease in Elderly African Americans.

PubMed

Hendrie, Hugh C; Hake, Ann; Lane, Kathleen; Purnell, Christianna; Unverzagt, Frederick; Smith-Gamble, Valerie; Murrell, Jill; Ogunniyi, Adesola; Baiyewu, Olusegun; Callahan, Chris; Saykin, Andrew; Taylor, Stanley; Hall, Kathleen; Gao, Su

2015-08-07

To investigate the association between statin use, incident dementia, and Alzheimer disease (AD) in a prospective elderly African American cohort. Two stage design with a screening interview followed by a comprehensive in-home assessment conducted over an eight-year period. Diagnoses of incident AD and dementia were made by consensus. Statin use was collected at each evaluation. Measurements of low-density lipoprotein cholesterol (LDL), C-reactive protein (CRP) and APOE genotype were obtained from baseline blood samples. Logistic regression models were used to test the association of statin use on incident dementia and AD and its possible association with lipid and CRP levels. Indianapolis, Indiana. From an original cohort of 2629 participants, a subsample of 974 African Americans aged >70 years with normal cognition, at least one follow up evaluation, complete statin information, and biomarker availability were included. Incident dementia and incident AD. After controlling for age at diagnosis, sex, education level, presence of the APOE ε4 allele and history of stroke for the incident dementia model, baseline use of statins was associated with a significantly decreased risk of incident dementia (OR=.44, P=.029) and incident AD (OR=.40, P=.029). The significant effect of statin use on reduced AD risk and trend for dementia risk was found only for those participants who reported consistent use over the observational period (incident AD: P=.034; incident dementia: P=.061). Additional models found no significant interaction between baseline statin use, baseline LDL, or CRP level and incident dementia/AD. Consistent use of statin medications during eight years of follow-up resulted in significantly reduced risk for incident AD and a trend toward reduced risk for incident dementia.

Patients with Acute Coronary Syndrome are at High Risk Prior to the Event and Lipid Management is Underachieved Pre- and Post- Hospitalization.

PubMed

Vlachopoulos, C; Andrikopoulos, G; Terentes-Printzios, D; Tzeis, S; Iliodromitis, E K; Richter, D; Mantas, I; Kartalis, A; Vasilikos, V; Stakos, D; Patsilinakos, S; Lampropoulos, S; Symeonidis, D; Kyrpizidis, C; Marinakis, N; Nikas, N; Lekakis, J; Tousoulis, D; Vardas, P

2018-01-01

Current European Guidelines suggest the use of cardiovascular risk categories and also recommend using high-intensity statins for patients with acute coronary syndromes (ACS). We examined the risk of ACS patients prior to the event, as well as the overall use and intensity of statins. We enrolled 687 ACS patients (mean age 63 years, 78% males). Low-density lipoprotein cholesterol (LDL-C) levels upon admission were used to assess attainment of LDL-C targets. Patients were categorized as very high, high, moderate and low risk based on their prior to admission cardiovascular (CV) risk. We examined statin use and dosage intensity among patients discharged from the hospital. Patients were followed for a median period of 189 days. The majority of the patients (n=371, 54%) were at very high CV risk prior to admission, while 101 patients were at high risk (15%), 147 (21%) moderate risk and 68 (10%) low risk. Interestingly, LDL-C target attainment decreased as the risk increased (p<0.001). The majority (96%) of patients received statins at discharge; however, most of them (60.4%) received low/moderate intensity statins and just 35.9% received the suggested by the Guidelines high-intensity dose of statins. At follow-up, the rate of patients at high-intensity dose of statins remained similar (34.8%); 6% received no statins at all at follow-up. According to our study, the majority of ACS patients are already at high risk prior to their admission. Further, LDL-C targets are underachieved prior to the event and high-intensity statins are underutilized in ACS patients at, and post-discharge. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Statins reduce appropriate implantable cardioverter-defibrillator shocks in ischemic cardiomyopathy with no benefit in nonischemic cardiomyopathy.

PubMed

Contractor, Tahmeed; Beri, Abhimanyu; Gardiner, Joseph; Ardhanari, Sivakumar; Thakur, Ranjan

2012-11-01

Statins have been hypothesized to decrease ventricular arrhythmias through a direct antiarrhythmic effect. Clinical studies have demonstrated a clear reduction only in populations with underlying ischemic heart disease. This study was designed to compare the effect of statins on appropriate shocks between ischemic and nonischemic cardiomyopathy. Patients with an ejection fraction 35% or less who received an implantable cardioverter-defibrillator and had follow-up for at least 1 month were included. The ischemic and nonischemic groups were divided into statin treatment and control subgroups and the occurrence of appropriate shocks was compared. The frequency of shocks was analyzed using negative binomial models to account for overdispersion of the "count" data (number of appropriate shocks) and an adjusted intensity rate ratio was calculated for statin use. A total of 676 patients were included, of which statins were used by 65% (329 of 506) of the ischemic and 42% (72 of 170) of the nonischemic groups. Occurrence of appropriate shocks was significantly reduced with statins in ischemic (13.4% vs 20.9%; relative risk 0.64, P = 0.028), but not in the patients with nonischemic cardiomyopathy. Similarly, although use of statins lowered the intensity rate of appropriate shocks in ischemic patients (intensity rate ratio, 0.23; 95% confidence interval, 0.12-0.47), no such benefit was noted in the nonischemic group (intensity rate ratio, 1.27; 95% confidence interval, 0.37-4.40). In conclusion, statins reduced the occurrence and frequency of appropriate shocks for ventricular arrhythmias in ischemic but not in nonischemic cardiomyopathy. Larger, randomized controlled trials are needed to confirm these findings.

Statins in primary biliary cirrhosis: are they safe?

PubMed

Abu Rajab, Murad; Kaplan, Marshall M

2010-07-01

Although cholesterol levels are elevated in patients with primary biliary cirrhosis (PBC), most PBC patients are not at increased risk of dying from atherosclerotic heart disease. There is, however, a subgroup, approximately 10%, who have additional disorders of lipid metabolism. They might benefit from a cholesterol-lowering agent. However, there is concern about using statins in patients with pre-existing liver disease. We therefore reviewed our experience with statins in a large cohort of PBC patients who were seen at Tufts Medical Center during the past decade. From January 1, 1996, until June 30, 2006, 603 patients with PBC were seen by one of us (M.M.K.). Fifty-eight were on statins and five were on ezetimibe. The mean duration of usage was 41 months (range 3-125 months). Alanine aminotransferase (ALT) levels were measured at 3-month intervals. Statins were well tolerated. No patient complained of muscle pain or weakness. There was no increase in ALT levels. ALT levels were slightly elevated at the time that statins were begun (41.7 +/- 25.1 U/l), and were normal at the last time these patients were seen (39.0 +/- 21.0 U/l) (P

Impact of Ezetimibe Alone or in Addition to a Statin on Plasma PCSK9 Concentrations in Patients with Type 2 Diabetes and Hypercholesterolemia: A Pilot Study.

PubMed

Miyoshi, Toru; Nakamura, Keigo; Doi, Masayuki; Ito, Hiroshi

2015-06-01

The increase in proprotein convertase subtilisin/kexin type 9 (PCSK9) leads to low-density lipoprotein (LDL) receptor degradation. Statins significantly reduce LDL-cholesterol levels, but upregulate PCSK9. This study evaluated the effect of ezetimibe monotherapy or ezetimibe in combination with a statin on serum levels of PCSK9 in patients with type 2 diabetes and hypercholesterolemia. Ezetimibe treatment was given to ten patients with diabetes without statin therapy and ten patients with statin therapy. Plasma levels of PCSK9 were examined at baseline and 24 weeks after treatment. At baseline, PCSK9 concentrations in patients with statin therapy were significantly higher than those in patients without statin use and in control subjects [median (25th-75th percentile) 411 (272-467) and 382 (356-453) ng/mL, respectively, p < 0.01]. After ezetimibe treatment for 24 weeks, LDL-cholesterol, triglyceride and remnant-like lipoprotein cholesterol were significantly decreased in both groups. However, PCSK9 concentration did not change compared with baseline measurements in both groups. The percentage change in LDL-cholesterol after ezetimibe therapy for 24 weeks was not correlated with the percentage change in PCSK9 concentration. Ezetimibe may reduce LDL-cholesterol levels without affecting PCSK9 in patients with type 2 diabetes and hypercholesterolemia.

Matrix Conditions and KLF2-Dependent Induction of Heme Oxygenase-1 Modulate Inhibition of HCV Replication by Fluvastatin

PubMed Central

Singethan, Katrin; Sirma, Hüseyin; Keller, Amelie Dorothea; Rosal, Sergio René Perez; Schrader, Jörg; Loscher, Christine; Volz, Tassilo; Bartenschlager, Ralf; Lohmann, Volker; Protzer, Ulrike; Dandri, Maura; Lohse, Ansgar W.; Tiegs, Gisa; Sass, Gabriele

2014-01-01

Background & Aims HMG-CoA-reductase-inhibitors (statins) have been shown to interfere with HCV replication in vitro. We investigated the mechanism, requirements and contribution of heme oxygenase-1(HO-1)-induction by statins to interference with HCV replication. Methods HO-1-induction by fluva-, simva-, rosuva-, atorva- or pravastatin was correlated to HCV replication, using non-infectious replicon systems as well as the infectious cell culture system. The mechanism of HO-1-induction by statins as well as its relevance for interference with HCV replication was investigated using transient or permanent knockdown cell lines. Polyacrylamide(PAA) gels of different density degrees or the Rho-kinase-inhibitor Hydroxyfasudil were used in order to mimic matrix conditions corresponding to normal versus fibrotic liver tissue. Results All statins used, except pravastatin, decreased HCV replication and induced HO-1 expression, as well as interferon response in vitro. HO-1-induction was mediated by reduction of Bach1 expression and induction of the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) cofactor Krueppel-like factor 2 (KLF2). Knockdown of KLF2 or HO-1 abrogated effects of statins on HCV replication. HO-1-induction and anti-viral effects of statins were more pronounced under cell culture conditions mimicking advanced stages of liver disease. Conclusions Statin-mediated effects on HCV replication seem to require HO-1-induction, which is more pronounced in a microenvironment resembling fibrotic liver tissue. This implicates that certain statins might be especially useful to support HCV therapy of patients at advanced stages of liver disease. PMID:24801208

Changes in muscle strength in individuals with statin-induced myopathy: A summary of 3 investigations.

PubMed

Panza, Gregory A; Taylor, Beth A; Dada, Marcin R; Thompson, Paul D

2015-01-01

There are inconsistent findings regarding muscular weakness in individuals with statin-induced myalgia. We used rigorous muscle testing to compare findings from 3 investigations in 3 different study populations to determine if statin myalgia is associated with measurable weakness. In all 3 studies, we measured maximal isometric handgrip strength, resting respiratory exchange ratio (RER), and knee extensor isometric and isokinetic force. In 2 of the 3 studies, elbow flexor isometric and isokinetic force and knee endurance fatigue index were also assessed. Knee extensor and elbow flexor measurements were obtained using an isokinetic dynamometer. Resting RER was measured using a metabolic breath-by-breath collection method. Measurement outcomes were compared on vs off drug. In study 1, 18 participants fit the criteria for statin myalgia. Participants taking atorvastatin 80 mg daily had significantly lower muscle strength in 5 (P < .05) of 14 measured variables. Participants on placebo (N = 10) with myalgia had significantly lower muscle strength in 4 (P < .05) of 14 measured variables. In study 2, 18 participants tested positive for statin-induced myalgia when receiving simvastatin 20 mg daily and displayed no significant muscle strength changes (all P > .05). In study 3, 11 patients with statin-induced myalgia completed the study and had a significant decrease in 2 (P < .05) of 10 leg muscle strength variables. In all 3 studies, no significant changes were shown for handgrip strength or RER (all P > .05). Our results indicate that after a short-term treatment with statin therapy, a rigorous muscle strength protocol does not show decrements of muscle strength in subjects with statin myalgia. Short-term treatment with statin therapy is not common in clinical practice. Thus, future studies should examine the effects of prolonged statin therapy on muscle strength. Published by Elsevier Inc.

Evaluation of the impact of statin therapy on the obesity paradox in patients with acute myocardial infarction: A propensity score matching analysis from the Korea Acute Myocardial Infarction Registry.

PubMed

Won, Ki-Bum; Hur, Seung-Ho; Nam, Chang-Wook; Ann, Soe Hee; Park, Gyung-Min; Lee, Sang-Gon; Kim, Hyo-Eun; Cho, Yun-Kyeong; Yoon, Hyuck-Jun; Park, Hyoung-Seob; Kim, Hyungseop; Han, Seongwook; Jeong, Myung-Ho; Ahn, Young-Keun; Rha, Seung-Woon; Kim, Chong-Jin; Cho, Myeong-Chan; Kim, Hyo-Soo; Chae, Shung-Chull; Kim, Kee-Sik; Kim, Young-Jo; Kim, Kwon-Bae; Barter, Philip

2017-09-01

The phenomenon of obesity paradox after acute myocardial infarction (AMI) has been reported under strong recommendation of statin therapy. However, the impact of statin therapy on this paradox has not been investigated. This study investigated the impact of statin therapy on 1-year mortality according to obesity after AMI. A total of 2745 AMI patients were included from the Korea Acute Myocardial Infarction Registry after 1:4 propensity score matching analysis (n = 549 for nonstatin group and n = 2196 for statin group). Primary and secondary outcomes were all-cause and cardiac death, respectively. During 1-year follow-up, the incidence of all-cause (8.4% vs 3.7%) and cardiac (6.2% vs 2.3%) death was higher in nonstatin group than in statin (P < .001, respectively). In nonstatin group, the incidence of all-cause (7.2% vs 9.0%) and cardiac (5.5% vs 6.5%) death did not differ significantly between obese and nonobese patients. However, in statin group, obese patients had lower 1-year rate of all-cause (1.7% vs 4.8%) and cardiac (1.2% vs 2.9%) death (P < .05, respectively), and lower cumulative rates by Kaplan-Meier analysis of all-cause and cardiac death compared with nonobese patients (log-rank P < .05, respectively). The overall risk of all-cause death was significantly lower in obese than in nonobese patients only in statin group (hazard ratio: 0.35; P = .001). After adjusting for confounding factors, obesity was independently associated with decreased risk of all-cause death in statin group. In conclusion, the greater benefit of statin therapy for survival in obese patients is further confirmation of the obesity paradox after AMI.

Effects of High Intensity Statin Therapy in the Treatment of Diabetic Dyslipidemia in Patients with Coronary Artery Disease.

PubMed

Vavlukis, Marija; Kedev, Sasko

2018-01-01

Diabetic dyslipidemia has specifics that differ from dyslipidemia in patients without diabetes, which contributes to accelerated atherosclerosis equally as dysglycemia. The aim of this study was to deduce the interdependence of diabetic dyslipidemia and cardiovascular diseases (CVD), therapeutic strategies and the risk of diabetes development with statin therapy. We conducted a literature review of English articles through PubMed, PubMed Central and Cochrane, on the role of diabetic dyslipidemia in atherosclerosis, the antilipemic treatment with statins, and the role of statin therapy in newly developed diabetes, by using key words: atherosclerosis, diabetes mellitus, diabetic dyslipidemia, CVD, statins, nicotinic acid, fibrates, PCSK9 inhibitors. hyperglycemia and dyslipidemia cannot be treated separately in patients with diabetes. It seems that dyslipidemia plays one of the key roles in the development of atherosclerosis. High levels of TG, decreased levels of HDL-C and increased levels of small dense LDL- C particles in the systemic circulation are the most specific attributes of diabetic dyslipidemia, all of which originate from an inflated flux of free fatty acids occurring due to the preceding resistance to insulin, and exacerbated by elevated levels of inflammatory adipokines. Statins are a fundamental treatment for diabetic dyslipidemia, both for dyslipidemia and for CVD prevention. The use of statin treatment with high intensity is endorsed for all diabetes-and-CVD patients, while a moderate - intensity treatment can be applied to patients with diabetes, having additional risk factors for CVD. Statins alone are thought to possess a small, although of statistical significance, risk of incident diabetes, outweighed by their benefits. As important as hyperglycemia and glycoregulation are in CVD development in patients with diabetes, diabetic dyslipidemia plays an even more important role. Statins remain the cornerstone of antilipemic treatment in diabetic dyslipidemia, and their protective effects in CVD progression overcome the risk of statin- associated incident diabetes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

High-Intensity Statin Therapy Is Associated With Improved Survival in Patients With Peripheral Artery Disease.

PubMed

Foley, T Raymond; Singh, Gagan D; Kokkinidis, Damianos G; Choy, Ho-Hin K; Pham, Thai; Amsterdam, Ezra A; Rutledge, John C; Waldo, Stephen W; Armstrong, Ehrin J; Laird, John R

2017-07-15

The relative benefit of higher statin dosing in patients with peripheral artery disease has not been reported previously. We compared the effectiveness of low- or moderate-intensity (LMI) versus high-intensity (HI) statin dose on clinical outcomes in patients with peripheral artery disease. We reviewed patients with symptomatic peripheral artery disease who underwent peripheral angiography and/or endovascular intervention from 2006 to 2013 who were not taking other lipid-lowering medications. HI statin use was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg. Baseline demographics, procedural data, and outcomes were retrospectively analyzed. Among 909 patients, 629 (69%) were prescribed statins, and 124 (13.6%) were treated with HI statin therapy. Mean low-density lipoprotein level was similar in patients on LMI versus HI (80±30 versus 87±44 mg/dL, P =0.14). Demographics including age (68±12 versus 67±10 years, P =0.25), smoking history (76% versus 80%, P =0.42), diabetes mellitus (54% versus 48%, P =0.17), and hypertension (88% versus 89%, P =0.78) were similar between groups (LMI versus HI). There was a higher prevalence of coronary artery disease (56% versus 75%, P =0.0001) among patients on HI statin (versus LMI). After propensity weighting, HI statin therapy was associated with improved survival (hazard ratio for mortality: 0.52; 95% confidence interval, 0.33-0.81; P =0.004) and decreased major adverse cardiovascular events (hazard ratio: 0.58; 95% confidence interval 0.37-0.92, P =0.02). In patients with peripheral artery disease who were referred for peripheral angiography or endovascular intervention, HI statin therapy was associated with improved survival and fewer major adverse cardiovascular events compared with LMI statin therapy. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

The Biochemical Basis of Hydroxymethylglutaryl-CoA Reductase Inhibitors as Neuroprotective Agents in Aneurysmal Subarachnoid Hemorrhage

PubMed Central

Wong, George Kwok Chu; Poon, Wai Sang

2010-01-01

Aneurysmal subarachnoid hemorrhage (SAH) has the highest morbidity and mortality rates of all types of stroke. Many aneurysmal SAH patients continue to suffer from significant neurological morbidity and mortality directly related to delayed cerebral ischemia. Pilot clinical studies of the use of Hydroxymethylglutaryl-CoA Reductase Inhibitors (statins) in aneurysmal SAH patients have reported a reduction in delayed cerebral ischemia and better clinical outcomes. We review the biochemical effects of statins on endothelium vascular function, glutamate-mediated neurotoxicity, inflammatory changes, and oxidative injuries, with reference to their possible neuroprotective effects in aneurysmal SAH.

Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death.

PubMed

Sierra, Saleta; Ramos, Maria C; Molina, Pilar; Esteo, Cynthia; Vázquez, Jose Antonio; Burgos, Javier S

2011-01-01

There is growing evidence to support the hypothesis that statins may act as neuroprotectants in several neuropathological conditions, including Alzheimer's disease. The mechanisms for neuroprotection are only partially understood, however, and pleiotropic phenomena could be involved. We have made a comparative study of 9 statins (lovastatin, mevastatin, pravastatin, simvastatin, cerivastatin, atorvastatin, fluvastatin, pitavastatin, and rosuvastatin), analyzing several parameters that could be related to neuroprotection, such as chemical structure, lipophilicity, potential blood-brain-barrier penetration (BBB), 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibition, cholesterol modulation in neurons, glia, and human hepatocyte cell lines, and protection against neurodegeneration caused by tau hyperphosphorylation induced by okadaic acid. Our results indicate that monacolin J derivatives (natural and semi-synthetic statins) are the best candidates for the prevention of neurodegenerative conditions due to their higher potential BBB penetration capacity, cholesterol lowering effect on neurons with a satisfactory safety profile, and in vitro protection against cell death caused by okadaic acid in culture. Among the nine statins studied, simvastatin presented the best characteristics for preventing neurodegenerative conditions.

No significant detectable anti-infection effects of aspirin and statins in chronic obstructive pulmonary disease.

PubMed

Yayan, Josef

2015-01-01

Past studies have shown that aspirin and statins decrease the rate and severity of exacerbation, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). Although these studies are relatively new, there is evidence that new therapeutic strategies could prevent exacerbation of COPD. This article examines retrospectively the possibility of using aspirin and statins to prevent exacerbation and infection in patients with COPD. All patients with COPD were identified from hospital charts in the Department of Internal Medicine, Saarland University Medical Center, Germany, between 2004 and 2014. The study examined 514 medical reports and secured a study population of 300 with COPD. The mean age was 69 ± 10 years (206 men, 68.7%, 95% CI, 63.4-73.9; 94 women, 31.3%, 95% CI, 26.1-36.6). The study results did not show a causal relationship between aspirin and statins and prevention of exacerbation and infection in patients with COPD. In contrast, in this study, the exacerbation and infection rates increased under medication with aspirin and statins (p = 0.008).

Treatment Strategy for Dyslipidemia in Cardiovascular Disease Prevention: Focus on Old and New Drugs

PubMed Central

Zodda, Donatella; Giammona, Rosario; Schifilliti, Silvia

2018-01-01

Prevention and treatment of dyslipidemia should be considered as an integral part of individual cardiovascular prevention interventions, which should be addressed primarily to those at higher risk who benefit most. To date, statins remain the first-choice therapy, as they have been shown to reduce the risk of major vascular events by lowering low-density lipoprotein cholesterol (LDL-C). However, due to adherence to statin therapy or statin resistance, many patients do not reach LDL-C target levels. Ezetimibe, fibrates, and nicotinic acid represent the second-choice drugs to be used in combination with statins if lipid targets cannot be reached. In addition, anti-PCSK9 drugs (evolocumab and alirocumab) provide an effective solution for patients with familial hypercholesterolemia (FH) and statin intolerance at very high cardiovascular risk. Recently, studies demonstrated the effects of two novel lipid-lowering agents (lomitapide and mipomersen) for the management of homozygous FH by decreasing LDL-C values and reducing cardiovascular events. However, the costs for these new therapies made the cost–effectiveness debate more complicated. PMID:29361723

Lovastatin

MedlinePlus

... is also used to decrease the amount of cholesterol (a fat-like substance) and other fatty substances ... statins). It works by slowing the production of cholesterol in the body to decrease the amount of ...

Effective policy initiatives to constrain lipid-lowering drug expenditure growth in South Korea

PubMed Central

2014-01-01

Background The rapid growth of prescription drug expenditures is a major problem in South Korea. Accordingly, the South Korean government introduced a positive listing system in 2006. They also adopted various price reduction policies. Nevertheless, the total expenditure for lipid-lowering drugs have steadily increased throughout South Korea. The present study explores the factors that have influenced the increased expenditures of lipid-lowering drugs with a particular focus on the effects of statins in this process. Methods This paper investigates the National Health Insurance claims data for prescribed lipid-lowering drugs collected between January 1, 2005 and December 31, 2009. We specifically focused on statins and assessed the yearly variation of statin expenditure by calculating the increased rate of paired pharmaceutical expenditures over a 2 year period. Our study classified statins into three categories: new entrants, core medicines and exiting medicines. For core medicines, we further examined influencing factors such as price, amount of drugs consumed by volume, and prescription changes (substitutes for other drug). Results Statin expenditure showed an average annual increase of 25.7% between 2005 and 2009. Among the different statins, the expenditure of atorvastatin showed a 36.6% annual increase rate, which was the most dramatic among all statins. Also we divided expenditure for core medicines by the price factor, volume factor, and prescription change. The result showed that annual weighted average prices of individual drug decreased each year, which clearly showed that price influenced statin expenditure in a negative direction. The use of generic drugs containing the same active ingredient as name-brand drugs increased and negatively affected statin expenditure (Generic Mix effect). However, the use of relatively expensive ingredients within statin increase, Ingredient Mix effect contributed to increased statin expenditure (Ingredient Mix effect). In particular, the volume effect was found to be critical for increasing statin expenditure as the amount of statin consumed increased steadily throughout the study period. Conclusions The recent rapid increase in statin expenditure can largely be attributed to an increase in consumption volume. In order to check drug expenditures effectively in our current situation, in which chronic diseases remain steadily on the rise, it is necessary to not only have supply-side initiatives such as price reduction, but also demand-side initiatives that could control drug consumption volume, for example: educational programs for rational prescription, generic drug promotional policies, and policies providing prescription targets. PMID:24589172

Effects of pitavastatin add-on therapy on chronic kidney disease with albuminuria and dyslipidemia.

PubMed

Ohsawa, Masato; Tamura, Kouichi; Wakui, Hiromichi; Kanaoka, Tomohiko; Azushima, Kengo; Uneda, Kazushi; Haku, Sona; Kobayashi, Ryu; Ohki, Kohji; Haruhara, Kotaro; Kinguchi, Sho; Toya, Yoshiyuki; Umemura, Satoshi

2015-12-09

In non-dialysis chronic kidney disease (CKD) patients with dyslipidemia, statin therapy is recommended to prevent cardiovascular complications. Dyslipidemia has been also shown to be an independent risk factor for the progression of CKD. However, it is still unclear whether statin therapy exerts an inhibitory effect on renal deterioration in CKD patients with dyslipidemia. The purpose of the present study was to examine possible therapeutic effects of statin add-on therapy on renal function as well as parameters of lipid and glucose metabolism, arterial stiffness and oxidative stress, in comparison to diet therapy, in CKD patients with dyslipidemia. This study was a randomized, open-label, and parallel-group trial consisted of a 12-months treatment period in non-dialysis CKD patients with alubuminuria and dyslipidemia. Twenty eight patients were randomly assigned either to receive diet counseling alone (diet therapy group) or diet counseling plus pitavastatin (diet-plus-statin therapy group), to achieve the LDL-cholesterol (LDL-C) target of <100 mg/dl. The statin treatment by pitavastatin was well tolerated in all of the patients without any significant adverse events and the average dose of pitavastatin was 1.0 ± 0.0 mg daily after treatment. After the 12-months treatment period, LDL-C was significantly lower in the diet-plus-statin therapy group compared with the diet therapy group (diet vs diet-plus-statin: LDL-C, 126 ± 5 vs 83 ± 4 mg/dL, P < 0.001). On the other hand, the diet-plus-statin therapy did not significantly reduce albuminuria or delay the decline in eGFR compared with the diet therapy, and there was no relationship between the change in LDL-C and the change in eGFR or albuminuria. However, diet therapy as well as diet-plus-statin therapy exerted similar lowering effects on the pentosidine levels (diet therapy group, baseline vs 12 months: 40 ± 4 vs 24 ± 3 ng/mL, P = 0.001; diet-plus-statin therapy, 46 ± 7 vs 34 ± 6 ng/mL, P = 0.008). Furthermore, the results of multivariate regression analysis indicated that the change in pentosidine was a significant contributor to the change in eGFR (β = -0.536, P = 0.011). Although statin add-on therapy did not show additive renal protective effects, the diet therapy as well as the diet-plus-statin therapy could contribute to the reduction in plasma pentosidine in CKD patients with albuminuria and dyslipidemia.

Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).

PubMed

Ballantyne, Christie M; Bays, Harold E; Kastelein, John J; Stein, Evan; Isaacsohn, Jonathan L; Braeckman, Rene A; Soni, Paresh N

2012-10-01

AMR101 is an ω-3 fatty acid agent containing ≥96% pure icosapent-ethyl, the ethyl ester of eicosapentaenoic acid. The efficacy and safety of AMR101 were evaluated in this phase 3, multicenter, placebo-controlled, randomized, double-blinded, 12-week clinical trial (ANCHOR) in high-risk statin-treated patients with residually high triglyceride (TG) levels (≥200 and <500 mg/dl) despite low-density lipoprotein (LDL) cholesterol control (≥40 and <100 mg/dl). Patients (n = 702) on a stable diet were randomized to AMR101 4 or 2 g/day or placebo. The primary end point was median percent change in TG levels from baseline versus placebo at 12 weeks. AMR101 4 and 2 g/day significantly decreased TG levels by 21.5% (p <0.0001) and 10.1% (p = 0.0005), respectively, and non-high-density lipoprotein (non-HDL) cholesterol by 13.6% (p <0.0001) and 5.5% (p = 0.0054), respectively. AMR101 4 g/day produced greater TG and non-HDL cholesterol decreases in patients with higher-efficacy statin regimens and greater TG decreases in patients with higher baseline TG levels. AMR101 4 g/day decreased LDL cholesterol by 6.2% (p = 0.0067) and decreased apolipoprotein B (9.3%), total cholesterol (12.0%), very-low-density lipoprotein cholesterol (24.4%), lipoprotein-associated phospholipase A(2) (19.0%), and high-sensitivity C-reactive protein (22.0%) versus placebo (p <0.001 for all comparisons). AMR101 was generally well tolerated, with safety profiles similar to placebo. In conclusion, AMR101 4 g/day significantly decreased median placebo-adjusted TG, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, lipoprotein-associated phospholipase A(2), and high-sensitivity C-reactive protein in statin-treated patients with residual TG elevations. Copyright © 2012 Elsevier Inc. All rights reserved.

Statins and protein prenylation in cancer cell biology and therapy.

PubMed

Garcia-Ruiz, Carmen; Morales, Albert; Fernandez-Checa, Jose C

2012-05-01

The use of statins has scaled up to become one of the most prescribed medicines in the world and have been very useful in the manegement of cardiovascular diseases and related mortality. The disclosure of their chemical structure similar to that of hydroxy methyl glutaryl-CoA (HMG-CoA) revealed their ability to compete with and inhibit the rate-limiting enzyme HMG-CoA reductase that catalyzes the synthesis of mevalonate, which then serves as the precursor for isoprenoids and cholesterol in the mevalonate pathway. While most of the effects of statins are associated with the lowering of cellular cholesterol levels, it is clear that they also blunt the non-sterol branch of the mevalonate pathway, decreasing formation of isoprenoids and altering protein-prenylation, a critical event in the posttranslational modulation of proteins involved in the regulation of cell cycle progression, proliferation and signaling pathways. Randomized controlled trials for the prevention of cardiovascular diseases indicated that statins elicited provocative and unexpected benefits for reducing a number of different types of cancers, including colorectal carcinoma, melanoma, prostate and hepatocellular carcinoma, although in other cancer types the preclinical expectations of statins were dissapointing. In this review, we will describe the evidence and mechanisms underlying the potential beneficial use of statins and the role of protein prenylation in cancer prevention. Of relevance, the combination of statins with other anti cancer drugs may be a significant asset in malignancies resistant to current therapy.

Statin Medications and the Risk of Gynecomastia.

PubMed

Skeldon, Sean C; Carleton, Bruce; Brophy, James; Sodhi, Mohit; Etminan, Mahyar

2018-06-19

Case reports have suggested an increased risk of gynecomastia with HMG-CoA reductase inhibitors (i.e. statins). A recent meta-analysis also found that statins decrease circulating testosterone levels in men. We investigated whether statin use was associated with an increased risk of gynecomastia. Case control study. A cohort of patients from a random sample of 9,053,240 US subjects from the PharMetrics Plus ™ health claims database from 2006 to 2016 was created. New cases of gynecomastia requiring at least two ICD-9 codes were identified from the cohort and matched to 10 controls by follow-up time and age using density-based sampling. Rate ratios (RRs) for past users of statins were computed using conditional logistic regression adjusting for alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, obesity, hypogonadism, hyperprolactinemia and use of spironolactone, ketoconazole, H 2 receptor antagonists (H 2 blockers), risperidone, testosterone and androgen deprivation therapy. Our cohort included 6,147 cases of gynecomastia and 61,470 corresponding matched controls. The adjusted RR for current, recent and past statin use with respect to gynecomastia was 1.19 (1.04-1.36), 1.38 (1.15-1.65) and 1.20 (1.03-1.40) respectively. Statin use is associated with an increased risk of developing gynecomastia. Clinicians should be cognizant of this effect and educate patients accordingly. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Statins: Do they have potential in the treatment of polycystic ovary syndrome?

PubMed Central

Kodaman, Pinar H.; Duleba, Antoni J.

2010-01-01

Many women of reproductive age are affected by polycystic ovary syndrome (PCOS), a heterogeneous endocrinopathy characterized by androgen excess, chronic oligo-anovulation and/or polycystic ovarian morphology. In addition, PCOS is often associated with insulin resistance, systemic inflammation and oxidative stress which, on one hand, lead to endothelial dysfunction and dyslipidemia with subsequent cardiovascular sequelae and, on the other hand, to hyperplasia of the ovarian theca compartment with resultant hyperandrogenism and anovulation. While traditionally statins have been used to treat dyslipidemia by blocking HMG-CoA reductase, the rate limiting step in cholesterol biosynthesis; in fact, they possess pleiotropic actions, resulting in antioxidant, anti-inflammatory and anti-proliferative effects. Statins offer a novel therapeutic approach to PCOS in that they address the dyslipidemia associated with the syndrome, as well as hyperandrogenism/hyperandrogenemia. These actions may be due to an inhibition of the effects of systemic inflammation and insulin resistance/hyperinsulinemia. Evidence to date, both in vitro and in vivo, suggests that statins have potential in the treatment of PCOS; however, further clinical trials are needed before they can be considered a standard of care in the medical management of this common endocrinopathy. PMID:18181091

Reduced incidence of new-onset diabetes mellitus after renal transplantation with 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins).

PubMed

Prasad, G V Ramesh; Kim, S Joseph; Huang, Michael; Nash, Michelle M; Zaltzman, Jeffrey S; Fenton, Stanley S A; Cattran, Daniel C; Cole, Edward H; Cardella, Carl J

2004-11-01

Statins have anti-inflammatory effects, modify endothelial function and improve peripheral insulin resistance. We hypothesized that statins influence the development of new-onset diabetes mellitus in renal transplant recipients. The records of all previously non-diabetic adults who received an allograft in Toronto between January 1, 1999 and December 31, 2001 were reviewed with follow-up through December 31, 2002. All patients receiving cyclosporine or tacrolimus, mycophenolate mofetil and prednisone were included. New-onset diabetes was diagnosed by the Canadian Diabetic Association criteria: fasting plasma glucose > or =7.0 mmol/L or 2-h postprandial glucose > or =11.1 mmol/L on more than two occasions. Statin use prior to diabetes development was recorded along with other variables. Cox proportional hazards models analyzing statin use as a time-dependent covariate were performed. Three hundred fourteen recipients met study criteria, of whom 129 received statins. New-onset diabetes incidence was 16% (n = 49). Statins (p = 0.0004, HR 0.238[0.109-0.524]) and ACE inhibitors/ARB (p = 0.01, HR 0.309[0.127-0.750]) were associated with decreased risk. Prednisone dose (p = 0.0001, HR 1.007[1.003-1.010] per 1 mg/d at 3 months), weight at transplant (p = 0.02, HR 1.022[1.003-1.042] per 1 kg), black ethnicity (p = 0.02, HR 1.230[1.023-1.480]) and age > or =45 years (p = 0.01, HR 2.226[1.162-4.261]) were associated with increased diabetes. Statin use is associated with reduced new-onset diabetes development after renal transplantation.

The gene-treatment interaction of paraoxonase-1 gene polymorphism and statin therapy on insulin secretion in Japanese patients with type 2 diabetes: Fukuoka diabetes registry.

PubMed

Sumi, Akiko; Nakamura, Udai; Iwase, Masanori; Fujii, Hiroki; Ohkuma, Toshiaki; Ide, Hitoshi; Jodai-Kitamura, Tamaki; Komorita, Yuji; Yoshinari, Masahito; Hirakawa, Yoichiro; Hirano, Atsushi; Kubo, Michiaki; Kitazono, Takanari

2017-12-12

Although statins deteriorate glucose metabolism, their glucose-lowering effects have emerged in some situations. Here, we assessed whether these effects are a consequence of statins' interaction with paraoxonase (PON)1 enzyme polymorphism. Adult Japanese type 2 diabetes patients (n = 3798) were enrolled in a cross-sectional study. We used Q192R polymorphism of the PON1 gene as a representative single-nucleotide polymorphism and focused on the effects of the wild-type Q allele, in an additive manner. For patients with and without statin therapy, the associations of this allele with fasting plasma glucose (FPG), HbA 1c , C-peptide, HOMA2-%β, and HOMA2-IR were investigated separately using a linear regression model, and were compared between groups by testing interactions. Sensitivity analyses were performed using propensity score to further control the imbalance of characteristics between groups. Among patients with statin therapy, there were linear associations of the number of Q alleles with decreased FPG and HbA 1c , and with increased serum C peptide and HOMA2-%β (all P < 0.01 for trends), while such associations were not observed among those without statin therapy. These differences were statistically significant only for serum C peptide and HOMA2-%β (P < 0.01 for interactions). These associations remained significant after multiple explanatory variable adjustment. Sensitivity analyses using propensity score showed broad consistency of these associations. Patients with the Q allele of the PON1 Q192R polymorphism who were treated with statins exhibited improvement in glucose metabolism, especially in insulin secretion, suggesting the importance of genotyping PON1 Q192R to identify those who could benefit from statin therapy.

Activation of hepatic Nogo-B receptor expression—A new anti-liver steatosis mechanism of statins

PubMed Central

Zhang, Wenwen; Yang, Xiaoxiao; Chen, Yuanli; Hu, Wenquan; Liu, Lipei; Zhang, Xiaomeng; Liu, Mengyang; Sun, Lei; Liu, Ying; Yu, Miao; Li, Xiaoju; Li, Luyuan; Zhu, Yan; Miao, Qing Robert; Han, Jihong; Duan, Yajun

2017-01-01

Deficiency of hepatic Nogo-B receptor (NgBR) expression activates liver X receptor α (LXRα) in an adenosine monophosphate-activated protein kinase α (AMPKα)-dependent manner, thereby inducing severe hepatic lipid accumulation and hypertriglyceridemia. Statins have been demonstrated non-cholesterol lowering effects including anti-nonalcoholic fatty liver disease (NAFLD). Herein, we investigated if the anti-NAFLD function of statins depends on activation of NgBR expression. In vivo, atorvastatin protected apoE deficient or NgBR floxed, but not hepatic NgBR deficient mice, against Western diet (WD)-increased triglyceride levels in liver and serum. In vitro, statins reduced lipid accumulation in nonsilencing small hairpin RNA-transfected (shNSi), but not in NgBR small hairpin RNA-transfected (shNgBRi) HepG2 cells. Inhibition of cellular lipid accumulation by atorvastatin is related to activation of AMPKα, and inactivation of LXRα and lipogenic genes. Statin also inhibited expression of oxysterol producing enzymes. Associated with changes of hepatic lipid levels by WD or atorvastatin, NgBR expression was inversely regulated. At cellular levels, statins increased NgBR mRNA and protein expression, and NgBR protein stability. In contrast to reduced cellular cholesterol levels by statin or β-cyclodextrin, increased cellular cholesterol levels decreased NgBR expression suggesting cholesterol or its synthesis intermediates inhibit NgBR expression. Indeed, mevalonate, geranylgeraniol or geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or farnesol, blocked atorvastatin-induced NgBR expression. Furthermore, we determined that induction of hepatic NgBR expression by atorvastatin mainly depended on inactivation of extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase B (Akt). Taken together, our study demonstrates that statins inhibit NAFLD mainly through activation of NgBR expression. PMID:29217477

Impact of high-dose atorvastatin therapy and clinical risk factors on incident aortic valve stenosis in patients with cardiovascular disease (from TNT, IDEAL, and SPARCL).

PubMed

Arsenault, Benoit J; Boekholdt, S Matthijs; Mora, Samia; DeMicco, David A; Bao, Weihang; Tardif, Jean-Claude; Amarenco, Pierre; Pedersen, Terje; Barter, Philip; Waters, David D

2014-04-15

Clinical trials have not provided evidence for a role of statin therapy in reducing aortic valve stenosis (AVS) severity in patients with documented AVS. However, whether statin therapy could prevent the onset of AVS is unknown. Our objectives were (1) to compare the incidence rates of AVS among patients treated with high-dose versus usual-dose statin or placebo and (2) to identify clinical risk factors associated with the development of AVS. We conducted post hoc analyses in 23,508 participants from 3 large-scale multicenter atorvastatin randomized blinded clinical trials: Treating to New Targets, the Incremental Decrease in End Points Through Aggressive Lipid Lowering, and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels. The main outcome measure was the incidence of clinical AVS over a median follow-up of 4.9 years (82 cases). Among patients who developed AVS, 39 (47.6%) were treated with atorvastatin 80 mg and 43 (52.4%) were treated with lower dose statin (atorvastatin 10 mg in Treating to New Targets, simvastatin 20 to 40 mg in Incremental Decrease in End Points Through Aggressive Lipid Lowering, or placebo in Stroke Prevention by Aggressive Reduction in Cholesterol Levels; hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.59 to 1.41, p=0.67). In multivariate analyses forcing treatment, sex, and race into the model, factors that were significantly associated with AVS included age (HR 2.17, 95% CI 1.61 to 2.93, p<0.0001 per 1-SD increment), diabetes (HR 1.67, 95% CI 1.00 to 2.80, p=0.05), vitamin K antagonist use (HR 3.25, 95% CI 2.06 to 5.16, p<0.0001), and previous statin use (HR 2.65, 95% CI 1.54 to 4.60, p=0.0008). In conclusion, random allocation to high-dose versus usual-dose statin therapy or placebo did not impact the incidence of AVS among patients without known AVS. Age, diabetes, vitamin K antagonists, and previous statin use were significant predictors of incident AVS in these high-risk patients. Copyright © 2014 Elsevier Inc. All rights reserved.

PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia

PubMed Central

Santos, Raul D.

2016-01-01

Abstract Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid‐modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low‐density lipoprotein cholesterol, as well as reductions in non‐high‐density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long‐term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid‐modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia. PMID:27195910

Ezetimibe Attenuates Atherosclerosis Associated with Lipid Reduction and Inflammation Inhibition.

PubMed

Tie, Chunmiao; Gao, Kanglu; Zhang, Na; Zhang, Songzhao; Shen, Jiali; Xie, Xiaojie; Wang, Jian-An

2015-01-01

Ezetimibe, as a cholesterol absorption inhibitor, has been shown protecting against atherosclerosis when combined with statin. However, side by side comparison has not been made to evaluate the beneficial effects of ezetimibe alone versus statin. Herein, the study aimed to test whether ezetimibe alone would exhibit similar effects as statin and the combination therapy would be necessary in a moderate lesion size. ApoE-/- male mice that were fed a saturated-fat supplemented diet were randomly assigned to different therapeutic regimens: vehicle, ezetimibe alone (10 mg/kg/day), atorvastatin (20 mg/kg/day) or combination of ezetimibe and atorvastatin through the drinking water. On 28 days, mice were sacrificed and aorta and sera were collected to analyze the atherosclerotic lesion and blood lipid and cholesterol levels. As a result, ezetimibe alone exerted similar protective effects on atherosclerotic lesion sizes as atorvastatin, which was mediated by lowering serum cholesterol concentrations, inhibiting macrophage accumulation in the lesions and reducing circulatory inflammatory cytokines, such as monocyte chemoattractant protein (MCP-1) and tumor necrosis factor (TNF-α). In contrast to ezetimibe administration, atorvastatin alone attenuated atherosclerotic lesion which is dependent on its anti-inflammation effects. There were no significance differences in lesion areas and serum concentrations of cholesterol, oxidized LDL and inflammatory cytokines between combination therapy and monotherapy (either ezetimibe or atorvastatin). There were significant correlations between the lesion areas and serum concentrations of cholesterol, MCP-1 and TNF-α, respectively. However, there were no significant correlations between the lesion areas and serum concentrations of TGF-β1 and oxLDL. Ezetimibe alone played the same protection against a moderate atherosclerotic lesion as atorvastatin, which was associated with lowering serum cholesterol, decreasing circulating inflammatory cytokines, and inhibiting macrophage accumulation in the lesions.

Ezetimibe Attenuates Atherosclerosis Associated with Lipid Reduction and Inflammation Inhibition

PubMed Central

Tie, Chunmiao; Gao, Kanglu; Zhang, Na; Zhang, Songzhao; Shen, Jiali; Xie, Xiaojie; Wang, Jian-an

2015-01-01

Background Ezetimibe, as a cholesterol absorption inhibitor, has been shown protecting against atherosclerosis when combined with statin. However, side by side comparison has not been made to evaluate the beneficial effects of ezetimibe alone versus statin. Herein, the study aimed to test whether ezetimibe alone would exhibit similar effects as statin and the combination therapy would be necessary in a moderate lesion size. Methods and Results ApoE-/- male mice that were fed a saturated-fat supplemented diet were randomly assigned to different therapeutic regimens: vehicle, ezetimibe alone (10 mg/kg/day), atorvastatin (20 mg/kg/day) or combination of ezetimibe and atorvastatin through the drinking water. On 28 days, mice were sacrificed and aorta and sera were collected to analyze the atherosclerotic lesion and blood lipid and cholesterol levels. As a result, ezetimibe alone exerted similar protective effects on atherosclerotic lesion sizes as atorvastatin, which was mediated by lowering serum cholesterol concentrations, inhibiting macrophage accumulation in the lesions and reducing circulatory inflammatory cytokines, such as monocyte chemoattractant protein (MCP-1) and tumor necrosis factor (TNF-α). In contrast to ezetimibe administration, atorvastatin alone attenuated atherosclerotic lesion which is dependent on its anti-inflammation effects. There were no significance differences in lesion areas and serum concentrations of cholesterol, oxidized LDL and inflammatory cytokines between combination therapy and monotherapy (either ezetimibe or atorvastatin). There were significant correlations between the lesion areas and serum concentrations of cholesterol, MCP-1 and TNF-α, respectively. However, there were no significant correlations between the lesion areas and serum concentrations of TGF-β1 and oxLDL. Conclusions Ezetimibe alone played the same protection against a moderate atherosclerotic lesion as atorvastatin, which was associated with lowering serum cholesterol, decreasing circulating inflammatory cytokines, and inhibiting macrophage accumulation in the lesions. PMID:26555472

Comparative effects of cholesteryl ester transfer protein inhibition, statin or ezetimibe on lipid factors: The ACCENTUATE trial.

PubMed

Nicholls, Stephen J; Ray, Kausik K; Ballantyne, Christie M; Beacham, Lauren A; Miller, Debra L; Ruotolo, Giacomo; Nissen, Steven E; Riesmeyer, Jeffrey S

2017-06-01

The optimal approaches to management of patients treated with moderate statin doses on lipid parameters are unknown. The ACCENTUATE study aimed to compare the effects of adding the cholesteryl ester transfer protein inhibitor (CETP) evacetrapib, ezetimibe or increasing statin dose in atorvastatin-treated high-vascular risk patients on lipid parameters. 366 patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg plus placebo, daily for 90 days at 64 centers in the United States. Lipid parameters, safety and tolerability were measured. Addition of evacetrapib significantly reduced LDL-C (-33%) compared with ezetimibe (-27%, p=0.045), increasing statin dose (-6%) and statin alone (0%, p<0.001). Evacetrapib also decreased apoB by 23% compared to 19% with ezetimibe (p=0.06) and 7% with increased statin dose (p<0.001), and reduced Lp(a) by 29% (p<0.001 vs. other groups). Evacetrapib increased HDL-C (+125%), apoA-I (+46%), apoC-III (+50%) and apoE (+28%) (p<0.001 vs. other groups). Non-ABCA1-mediated efflux increased by 53% (p<0.001 vs. other groups) with evacetrapib. ABCA1-mediated efflux also increased by 13% with evacetrapib (p<0.001 vs. ezetimibe, p=0.002 vs. increasing statin dose, and p=0.004 vs. statin alone). Addition of evacetrapib to atorvastatin produced an increase in hsCRP compared with ezetimibe (p=0.02). While evacetrapib improved traditional atherogenic and putative protective lipid measures compared with ezetimibe and increasing statin dose in patients with ASCVD and/or diabetes, it also adversely affected novel atherogenic risk factors. These findings may contribute to the lack of clinical benefit observed in the ACCELERATE trial. Copyright © 2017 Elsevier B.V. All rights reserved.

Rosiglitazone increases LDL particle size and buoyancy and decreases C-reactive protein in patients with type 2 diabetes on statin therapy.

PubMed

Yu, Dahong; Murdoch, Susan J; Parikh, Shamik J; Marcovina, Santica M; Cobitz, Alexander; Chen, Hongzi; Brunzell, John D

2006-12-01

A substantial number of individuals with type 2 diabetes mellitus (T2DM) demonstrate a predominance of small dense low-density lipoprotein (sdLDL), which is associated with an increased risk of cardiovascular disease (CVD). In some cases, sdLDL persists after treatment with a statin to reduce levels of LDL. The effect of the addition of a thiazolidinedione, rosiglitazone (RSG) (4 mg/day or 8 mg/day) to statin therapy on LDL phenotype and C reactive protein (CRP) levels was investigated in a 12- week, placebo-controlled study of 72 T2DM patients who were well controlled and on a statin, but who had persistently predominant sdLDL. Addition of RSG 8 mg to statin therapy significantly increased LDL buoyancy (relative flotation +0.014, p = 0.003) and LDL particle size (+4.2A, p = 0.001) from baseline and relative to the change with placebo (+0.014 and +3.8A; p = 0.03 and p = 0.04, respectively), and was associated with a non-significant decrease in sdLDL. RSG 8 mg moderately, but significantly, increased total cholesterol (by 12.2%, p = 0.004), LDL-cholesterol (11.2%, p = 0.02) and intermediate-density lipoprotein (IDL)-cholesterol from baseline but did not increase total or LDL apolipoprotein B. RSG 4 mg and 8 mg significantly reduced CRP compared with placebo (-44.9% and -48.0%; p = 0.008 and p = 0.004, respectively), and significantly reduced insulin resistance and fasting plasma glucose from baseline. Addition of RSG to statin therapy may further reduce cardiovascular risk by improving the LDL phenotype, as well as reducing insulin resistance and CRP levels. However, the increase in IDL may be proatherogenic and must be considered when assessing the benefits of rosiglitazone.

PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future.

PubMed

Shimada, Yuichi J; Cannon, Christopher P

2015-09-21

Reduction in low-density lipoprotein cholesterol (LDL-C), mainly with statins, has decreased the risk of cardiovascular events over the last few decades. However, there are several patient populations that warrant further decrease in LDL-C by additional cholesterol-lowering therapy other than statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of drugs that have been shown to further decrease LDL-C by 50-70% when administered as a monotherapy or on a background therapy with statins. Proprotein convertase subtilisin/kexin type 9 inhibitors are also an excellent example of drug development in which discovery of gene mutations and its clinical effects have rapidly progressed into successful preclinical and clinical studies with multiple Phases 1-3 clinical trials completed or ongoing to date. This review summarizes the rapid evolution of the drug from genetic discovery to identification of targets for the drugs, to animal and human testing, and to large clinical outcomes trials, followed by discussion on foreseeable challenges of PCSK9 inhibitors. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Statins Increase Plasminogen Activator Inhibitor Type 1 Gene Transcription through a Pregnane X Receptor Regulated Element

PubMed Central

Stanley, Frederick M.; Linder, Kathryn M.; Cardozo, Timothy J.

2015-01-01

Plasminogen activator inhibitor type 1 (PAI-1) is a multifunctional protein that has important roles in inflammation and wound healing. Its aberrant regulation may contribute to many disease processes such as heart disease. The PAI-1 promoter is responsive to multiple inputs including cytokines, growth factors, steroids and oxidative stress. The statin drugs, atorvastatin, mevastatin and rosuvastatin, increased basal and stimulated expression of the PAI-1 promoter 3-fold. A statin-responsive, nuclear hormone response element was previously identified in the PAI-1 promoter, but it was incompletely characterized. We characterized this direct repeat (DR) of AGGTCA with a 3-nucleotide spacer at -269/-255 using deletion and directed mutagenesis. Deletion or mutation of this element increased basal transcription from the promoter suggesting that it repressed PAI-1 transcription in the unliganded state. The half-site spacing and the ligand specificity suggested that this might be a pregnane X receptor (PXR) responsive element. Computational molecular docking showed that atorvastatin, mevastatin and rosuvastatin were structurally compatible with the PXR ligand-binding pocket in its agonist conformation. Experiments with Gal4 DNA binding domain fusion proteins showed that Gal4-PXR was activated by statins while other DR + 3 binding nuclear receptor fusions were not. Overexpression of PXR further enhanced PAI-1 transcription in response to statins. Finally, ChIP experiments using Halo-tagged PXR and RXR demonstrated that both components of the PXR-RXR heterodimer bound to this region of the PAI-1 promoter. PMID:26379245

Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.

PubMed

Borow, Kenneth M; Nelson, John R; Mason, R Preston

2015-09-01

Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through rupture. Specific salutary actions have been reported relating to endothelial function, oxidative stress, foam cell formation, inflammation, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture. EPA also improves atherogenic dyslipidemia characterized by reduction of triglycerides without raising low-density lipoprotein cholesterol. Other beneficial effects of EPA include vasodilation, resulting in blood pressure reductions, as well as improved membrane fluidity. EPA's effects are at least additive to those of statins when given as adjunctive therapy. In this review, we present data supporting the biologic plausibility of EPA as an anti-atherosclerotic agent with potential clinical benefit for prevention of CV events, as well as its cellular effects and molecular mechanisms of action. REDUCE-IT is an ongoing, randomized, controlled study evaluating whether the high-purity ethyl ester of EPA (icosapent ethyl) at 4 g/day combined with statin therapy is superior to statin therapy alone for reducing CV events in high-risk patients with mixed dyslipidemia. The results from this study are expected to clarify the role of EPA as adjunctive therapy to a statin for reduction of residual CV risk. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The effect of statins on erectile dysfunction: a meta-analysis of randomized trials.

PubMed

Kostis, John B; Dobrzynski, Jeanne M

2014-07-01

Erectile dysfunction (ED) is common in older men, especially those with comorbidities such as diabetes and atherosclerotic disease, conditions where statins are frequently prescribed. To examine the effect of statin therapy on ED using the five-item version of the International Inventory of Erectile Function (IIEF). We performed a random-effects meta-analysis of studies identified by a systematic search of MEDLINE, Web of Knowledge, the Cochrane Database, and ClinicalTrials.gov. Examination of the 186 retrieved citations resulted in the selection of 11 randomized trials for inclusion in the meta-analysis. Change in the IIEF score. IIEF increased by 3.4 points (95% CI 1.7-5.0, P = 0.0001) with statins compared to control. This effect remained statistically significant after multiple sensitivity analyses, including analysis for publication bias, a cumulative meta-analysis, and 11 repeated analyses with each study omitted sequentially. The increase in IIEF with statins was approximately one-third to one-half of that previously reported with phosphodiesterase-5 inhibitors and larger than the effect of lifestyle modification. Metaregression showed an increase in benefit with decreasing lipophilicity. The average age of participants and the degree of LDL cholesterol lowering did not alter the effect on IIEF. Statins cause a clinically relevant improvement of erectile function as measured by the five-item version of the IIEF. © 2014 International Society for Sexual Medicine.

Downregulation of monocytic differentiation via modulation of CD147 by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

PubMed

Sasidhar, Manda V; Chevooru, Sai Krishnaveni; Eickelberg, Oliver; Hartung, Hans-Peter; Neuhaus, Oliver

2017-01-01

CD147 is an activation induced glycoprotein that promotes the secretion and activation of matrix metalloproteinases (MMPs) and is upregulated during the differentiation of macrophages. Interestingly, some of the molecular functions of CD147 rely on its glycosylation status: the highly glycosylated forms of CD147 induce MMPs whereas the lowly glycosylated forms inhibit MMP activation. Statins are hydroxy-methylglutaryl coenzyme A reductase inhibitors that block the synthesis of mevalonate, thereby inhibiting all mevalonate-dependent pathways, including isoprenylation, N-glycosylation and cholesterol synthesis. In this study, we investigated the role of statins in the inhibition of macrophage differentiation and the associated process of MMP secretion through modulation of CD147. We observed that differentiation of the human monocytic cell line THP-1 to a macrophage phenotype led to upregulation of CD147 and CD14 and that this effect was inhibited by statins. At the molecular level, statins altered CD147 expression, structure and function by inhibiting isoprenylation and N-glycosylation. In addition, statins induced a shift of CD147 from its highly glycosylated form to its lowly glycosylated form. This shift in N-glycosylation status was accompanied by a decrease in the production and functional activity of MMP-2 and MMP-9. In conclusion, these findings describe a novel molecular mechanism of immune regulation by statins, making them interesting candidates for autoimmune disease therapy.

Impact of statin related media coverage on use of statins: interrupted time series analysis with UK primary care data.

PubMed

Matthews, Anthony; Herrett, Emily; Gasparrini, Antonio; Van Staa, Tjeerd; Goldacre, Ben; Smeeth, Liam; Bhaskaran, Krishnan

2016-06-28

 To quantify how a period of intense media coverage of controversy over the risk:benefit balance of statins affected their use.  Interrupted time series analysis of prospectively collected electronic data from primary care.  Clinical Practice Research Datalink (CPRD) in the United Kingdom.  Patients newly eligible for or currently taking statins for primary and secondary cardiovascular disease prevention in each month in January 2011-March 2015.  Adjusted odds ratios for starting/stopping taking statins after the media coverage (October 2013-March 2014).  There was no evidence that the period of high media coverage was associated with changes in statin initiation among patients with a high recorded risk score for cardiovascular disease (primary prevention) or a recent cardiovascular event (secondary prevention) (odds ratio 0.99 (95% confidence interval 0.87 to 1.13; P=0.92) and 1.04 (0.92 to 1.18; P=0.54), respectively), though there was a decrease in the overall proportion of patients with a recorded risk score. Patients already taking statins were more likely to stop taking them for both primary and secondary prevention after the high media coverage period (1.11 (1.05 to 1.18; P<0.001) and 1.12 (1.04 to 1.21; P=0.003), respectively). Stratified analyses showed that older patients and those with a longer continuous prescription were more likely to stop taking statins after the media coverage. In post hoc analyses, the increased rates of cessation were no longer observed after six months.  A period of intense public discussion over the risks:benefit balance of statins, covered widely in the media, was followed by a transient rise in the proportion of people who stopped taking statins. This research highlights the potential for widely covered health stories in the lay media to impact on healthcare related behaviour. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Automated outreach to increase primary adherence to cholesterol-lowering medications.

PubMed

Derose, Stephen F; Green, Kelley; Marrett, Elizabeth; Tunceli, Kaan; Cheetham, T Craig; Chiu, Vicki Y; Harrison, Teresa N; Reynolds, Kristi; Vansomphone, Southida S; Scott, Ronald D

2013-01-14

Primary nonadherence occurs when new prescriptions are not dispensed. Little is known about how to reduce primary nonadherence. We performed a randomized controlled trial to evaluate an automated system to decrease primary nonadherence to statins for lowering cholesterol. Adult members of Kaiser Permanente Southern California with no history of statin use within the past year who did not fill a statin prescription after 1 to 2 weeks were passively enrolled. The intervention group received automated telephone calls followed 1 week later by letters for continued nonadherence; the control group received no outreach. The primary outcome was a statin dispensed up to 2 weeks after delivery of the letter. Secondary outcomes included refills at intervals up to 1 year. Intervention effectiveness was determined by intent-to-treat analysis and Fisher exact test. Subgroups were examined using logistic regression. There were 2606 participants in the intervention group and 2610 in the control group. Statins were dispensed to 42.3% of intervention participants and 26.0% of control participants (absolute difference, 16.3%; P < .001). The relative risk for the intervention vs control group was 1.63 (95% CI, 1.50-1.76). Intervention effectiveness varied slightly by age (P = .045) but was effective across all age strata. Differences in the frequency of statin dispensations persisted up to 1 year (P < .001). The intervention was effective in reducing primary nonadherence to statin medications. Because of low marginal costs for outreach, this strategy appears feasible for reducing primary nonadherence. This approach may generalize well to other medications and chronic conditions.

Statins and Risk of Lower Limb Revision Surgery: The Influence of Differences in Study Design Using Electronic Health Records From the United Kingdom and Denmark

PubMed Central

Lalmohamed, Arief; van Staa, Tjeerd P.; Vestergaard, Peter; Leufkens, Hubertus G. M.; de Boer, Anthonius; Emans, Pieter; Cooper, Cyrus; de Vries, Frank

2016-01-01

Abstract Previous observational studies on statins have shown variable results based on the methodology used. Our objective was to study the association between statins and orthopedic implant failure and to explore the influence of methodological differences in study design. Our study base consisted of patients with a primary total joint replacement in Denmark and the United Kingdom (n = 189,286; 1987–2012). We used 4 study designs: 1) case-control (each patient with revision surgery matched to 4 controls), 2) time-dependent cohort (postoperative statin use as a time-varying exposure variable), 3) immortal time cohort (misclassifying the time postoperatively before statin use), and 4) time-exclusion cohort (excluding the time postoperatively before statin use). Cox proportional hazards models and logistic regression were used to estimate incidence rate ratios. In the time-dependent cohort design, statin use was associated with a decreased risk of revision surgery (adjusted incidence rate ratio (IRR) = 0.90, 95% confidence interval (CI): 0.85, 0.96), which was similar to our case-control results (IRR = 0.87, 95% CI: 0.81, 0.93). In contrast, both time-fixed cohort designs yielded substantially lower risk estimates (IRR = 0.36 (95% CI: 0.34, 0.38) and IRR = 0.65 (95% CI: 0.63, 0.68), respectively). We discourage the use of time-fixed cohort studies, which may falsely suggest protective effects. The simple choice of how to classify exposure can substantially change results from biologically plausible to implausible. PMID:27317693

Statins for acute coronary syndrome.

PubMed

Vale, Noah; Nordmann, Alain J; Schwartz, Gregory G; de Lemos, James; Colivicchi, Furio; den Hartog, Frank; Ostadal, Petr; Macin, Stella M; Liem, Anho H; Mills, Edward; Bhatnagar, Neera; Bucher, Heiner C; Briel, Matthias

2011-06-15

The early period following the onset of acute coronary syndromes (ACS) represents a critical stage of coronary heart disease with a high risk for recurrent events and deaths. The short-term effects of early treatment with statins in patients suffering from ACS on patient-relevant outcomes are unclear. To assess the benefits and harms of early administered statins in patients with ACS from randomized controlled trials (RCTs). We searched CENTRAL, MEDLINE, EMBASE, and CINAHL (to 1 February 2010). No language restrictions were applied. We supplemented the search by contacting experts in the field, by reviewing reference lists of reviews and editorials on the topic, and by searching trial registries. RCTs comparing statins with placebo or usual care, initiation of statin therapy within 14 days following the onset of ACS, and follow-up of at least 30 days reporting at least one clinical outcome. Two authors independently assessed study quality and extracted data. We pooled treatment effects and calculated risk ratios (RRs) for all outcomes in the treatment and control groups using a random effects model. Eighteen studies (14,303 patients) compared early statin treatment versus placebo or usual care in patients with ACS. Compared to placebo or usual care, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction (MI), and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) and four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month and at four months, although there were favorable trends related to statin use for each of these endpoints. The incidence of episodes of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels > 10 times the upper limit of normal) in statin treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg. Based on available evidence, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS.

[Combination treatment with coenzyme Q10 and simvastatin in patients with coronary atherosclerosis].

PubMed

Chapidze G E; Kapanadze, S D; Dolidze, N K; Latsabidze, N E; Bakhutashvili, Z V

2006-01-01

In order to assess efficacy of one of natural antioxidants--coenzyme Q10 (90 mg daily) and its combination with simvastatin (10 mg daily) 44 outpatients with coronary atherosclerosis were examined. Twenty four patients had undergone coronary artery bypass surgery, 12--coronary angioplasty and in 8 coronary heart disease was confirmed by angiography. Duration of treatment was 12 weeks. Positive effects of coenzyme Q10 was particularly expressed in relation to antiatherogenic fraction of cholesterol which increased by 23%. Index of atherogenicity decreased by 27%. At the background of coenzyme Q10 treatment 30% reduction in plasma lipoperoxide levels occurred demonstrating potentially independent role of coenzyme Q10 in positive modification of oxidative stress. Coenzyme Q10 revealed antiaggregatory ability. It was not related to the improvement of endothelial function. Normalization of plasma nitric oxide concentrations was achieved only with combination of coenzyme Q10 and simvastatin. This fact may be explained by positive action of statins on endothelial function.

Identification of Patients with Statin Intolerance in a Managed Care Plan: A Comparison of 2 Claims-Based Algorithms.

PubMed

Bellows, Brandon K; Sainski-Nguyen, Amy M; Olsen, Cody J; Boklage, Susan H; Charland, Scott; Mitchell, Matthew P; Brixner, Diana I

2017-09-01

While statins are safe and efficacious, some patients may experience statin intolerance or treatment-limiting adverse events. Identifying patients with statin intolerance may allow optimal management of cardiovascular event risk through other strategies. Recently, an administrative claims data (ACD) algorithm was developed to identify patients with statin intolerance and validated against electronic medical records. However, how this algorithm compared with perceptions of statin intolerance by integrated delivery networks remains largely unknown. To determine the concurrent validity of an algorithm developed by a regional integrated delivery network multidisciplinary panel (MP) and a published ACD algorithm in identifying patients with statin intolerance. The MP consisted of 3 physicians and 2 pharmacists with expertise in cardiology, internal medicine, and formulary management. The MP algorithm used pharmacy and medical claims to identify patients with statin intolerance, classifying them as having statin intolerance if they met any of the following criteria: (a) medical claim for rhabdomyolysis, (b) medical claim for muscle weakness, (c) an outpatient medical claim for creatinine kinase assay, (d) fills for ≥ 2 different statins excluding dose increases, (e) decrease in statin dose, or (f) discontinuation of a statin with a subsequent fill for a nonstatin lipid-lowering therapy. The validated ACD algorithm identified statin intolerance as absolute intolerance with rhabdomyolysis; absolute intolerance without rhabdomyolysis (i.e., other adverse events); or as dose titration intolerance. Adult patients (aged ≥ 18 years) from the integrated delivery network with at least 1 prescription fill for a statin between January 1, 2011, and December 31, 2012 (first fill defined the index date) were identified. Patients with ≥ 1 year pre- and ≥ 2 years post-index continuous enrollment and no statin prescription fills in the pre-index period were included. The MP and ACD algorithms were applied to the population, and concordance was examined using individual (i.e., sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) and overall performance measures (i.e., accuracy, Cohen's kappa coefficient, balanced accuracy, F-1 score, and phi coefficient). After applying the inclusion criteria, 7,490 patients were evaluated for statin intolerance. The mean (SD) age of the population was 51.1 (8.5) years, and 55.7% were male. The MP and ACD algorithms classified 11.3% and 5.4% of patients as having statin intolerance, respectively. The concordance of the MP algorithm was mixed, with negative classification of statin intolerance measures having high concordance (specificity 0.91, NPV 0.97) and positive classification of statin intolerance measures having poor concordance (sensitivity 0.45, PPV 0.21). Overall performance measures showed mixed agreement between the algorithms. Both algorithms used a mix of pharmacy and medical claims and may be useful for organizations interested in identifying patients with statin intolerance. By identifying patients with statin intolerance, organizations may consider a variety of options, including using nonstatin lipid-lowering therapies, to manage cardiovascular event risk in these patients. This study was funded by Regeneron Pharmaceuticals and Sanofi US. Boklage is employed by, and owns stock in, Regeneron, and Charland is employed by Sanofi. Bellows has received fees from Avenir for advisory board membership and grants from Myriad Genetics, Biogen, Janssen, and National Institutes of Health. Brixner reports advisory board and consultancy fees and grants from Sanofi. Mitchell reports consultancy fees from Sanofi. Study concept and design were contributed by Bellows, Boklage, Charland, and Brixner. Bellows, Sainski-Nguyen, and Olsen took the lead in data collection, along with Mitchell. Data interpretation was performed by Mitchell, along with the other authors. The manuscript was written by Bellows, Sainski-Nguyen, and Olsen and revised by all the authors.

PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia.

PubMed

Ito, Matthew K; Santos, Raul D

2017-01-01

Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid-modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low-density lipoprotein cholesterol, as well as reductions in non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long-term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid-modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia. © 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

A low-dose atorvastatin and losartan combination directly improves aortic ring relaxation and diminishes ischaemic-reperfusion injury in isolated rat hearts

PubMed Central

Lunder, Mojca; Janić, Miodrag; Žiberna, Lovro; Drevenšek, Gorazd; Šabovič, Mišo

2012-01-01

Summary Background The cardiovascular pleiotropic effects of statins and angiotensin receptor blockers (ARBs) could be of interest for innovative preventive approaches. We aimed to investigate whether low-dose atorvastatin and losartan, separately not possessing protective cardiovascular pleiotropic effects, express them when combined. Material/Methods Forty-five adult male Wistar rats were anaesthetized and their thoracic aortas and hearts were isolated. Relaxation of aortic rings, coronary flow rate and the extent of myocardial ischaemic-reperfusion injury were measured. Different concentrations (0.01, 0.1, 1.0 μM) of atorvastatin and losartan added to a perfusion medium were first tested. The separate drugs, which were ineffective, were then combined at the same concentrations and the concentration was tested in the same model. Results Low concentrations of atorvastatin or losartan (0.1 and 1 μM, respectively) produced no effects in isolated aorta. However, surprisingly, when these drug concentrations were combined, a significantly improved endothelium-dependent relaxation of the thoracic aorta was observed. Similarly, when combining individually ineffective concentrations of atorvastatin or losartan (0.01 and 0.1 μM, respectively), significantly increased coronary flow and a decreased extent of myocardial injury were observed. By using a nitric oxide-synthase inhibitor, we demonstrated that the vasodilatory effects obtained were nitric oxide-dependent. The degree of effectiveness by the combination was comparable to that obtained by 10-fold (atorvastatin) or 100-fold (losartan) higher concentrations of the separate drugs. Conclusions Our results revealed that remarkable additive/synergistic effects exist between low-doses of a statin (atorvastatin) and an ARB (losartan), resulting in important cardiovascular protection. This new concept could be valuable in cardiovascular prevention. PMID:22936187

Effects of atorvastatin and T-786C polymorphism of eNOS gene on plasma metabolic lipid parameters.

PubMed

Zago, Vanessa Helena de Souza; Santos, José Eduardo Tanus dos; Danelon, Mirian Regina Gardin; Silva, Roger Marcelo Mesquita da; Panzoldo, Natália Baratella; Parra, Eliane Soler; Alexandre, Fernanda; Virgínio, Vítor Wilson de Moura; Quintão, Eder Carlos Rocha; Faria, Eliana Cotta de

2013-01-01

Endothelial nitric oxide synthase (eNOS) activity may be modulated by high-density lipoprotein cholesterol (HDL-C), statins or polymorphisms, such as the T-786C of eNOS. This study aimed at evaluating if the T-786C polymorphism is associated with changes of atorvastatin effects on the lipid profile, on the concentrations of metabolites of nitric oxide (NO) and of high sensitivity C-reactive protein (hsCRP). Thirty male volunteers, asymptomatic, aged between 18 and 56 years were genotyped and classified according to absence (TT, n = 15) or presence (CC, n = 15) of the polymorphism. They were randomly selected for the use of placebo or atorvastatin (10 mg/day/14 days). After each treatment lipids, lipoproteins, HDL2 and HDL3 composition, cholesteryl ester transfer protein (CETP) activity, metabolites of NO and hsCRP were evaluated. The comparisons between genotypes after placebo showed an increase in CETP activity in a polymorphism-dependent way (TT, 12±7; CC, 22±12; p < 0.05). The interaction analyses between treatments indicated that atorvastatin has an effect on cholesterol, LDL, nitrite and lipid-protein ratios (HDL2 and HDL3) (p < 0.001) in both genotypes. Interestingly, we observed genotype/drug interactions on CETP (p < 0.07) and lipoprotein (a) (Lp(a)) (p < 0.056), leading to a borderline decrease in CETP, but with no effect on Lp(a). HsCRP showed no alteration. These results suggest that statin treatment may be relevant for primary prevention of atherosclerosis in patients with the T-786C polymorphism of eNOS, considering the effects on lipid metabolism.

Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study.

PubMed

Musset, Lucile; Allenbach, Yves; Benveniste, Olivier; Boyer, Olivier; Bossuyt, Xavier; Bentow, Chelsea; Phillips, Joe; Mammen, Andrew; Van Damme, Philip; Westhovens, René; Ghirardello, Anna; Doria, Andrea; Choi, May Y; Fritzler, Marvin J; Schmeling, Heinrike; Muro, Yoshinao; García-De La Torre, Ignacio; Ortiz-Villalvazo, Miguel A; Bizzaro, Nicola; Infantino, Maria; Imbastaro, Tiziana; Peng, Qinglin; Wang, Guochun; Vencovský, Jiří; Klein, Martin; Krystufkova, Olga; Franceschini, Franco; Fredi, Micaela; Hue, Sophie; Belmondo, Thibaut; Danko, Katalin; Mahler, Michael

2016-10-01

In an effort to find naturally occurring substances that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experienced muscle pain and weakness during treatment. In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients that develop an immune-mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria. Copyright © 2016. Published by Elsevier B.V.

Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimoto, Tomoyuki; Ishikawa, Eiichiro; Anayama, Hisashi

2007-08-15

High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485,more » and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy.« less

The effect of statins on performance in the Morris water maze in guinea pig.

PubMed

Maggo, Simran; Clark, David; Ashton, John C

2012-01-15

Statins play a crucial role in reducing the risk of death from cardiovascular disease in millions of people worldwide. Recently, pharmacovigilance data has suggested that statin drugs may have rare but significant adverse psychiatric effects, such as amnesia, anxiety and even aggression. In order to investigate the effects of statins on cognitive function in an animal model, we studied the effect of 6 weeks of daily administration of oral simvastatin (1 mg/kg) or atorvastatin (0.5mg/kg) in guinea pig on performance in the Morris water maze (MWM). Animals were also re-tested in the MWM, 2 weeks after drug cessation, to test for any changes in performance as a result of drug de-challenge. Guinea pigs treated with either statin showed a significant (P<0.001) decrease in total cholesterol and low density lipoprotein-cholesterol (LDL-C), which remained partially reduced after the 2 week drug washout period. Guinea pigs receiving either statin did not show any difference in latency to reach the platform, nor any difference in total distance travelled during testing. Also, analysis of probe trials revealed no significant differences between drug and vehicle groups. However, both groups spent a significantly (P<0.01) greater proportion of time in the outer zone of the maze (indication of increased anxiety) and showed an increase in swimming speed (P<0.05) compared with the vehicle group. Differences between groups for swimming speed, and time spent in the outer zone, were not retained in the drug de-challenge phase. Our results show that low dose treatment with statins can induce mild but significant anxiety in guinea pigs. Copyright © 2011 Elsevier B.V. All rights reserved.

Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs.

PubMed

Nishimoto, Tomoyuki; Ishikawa, Eiichiro; Anayama, Hisashi; Hamajyo, Hitomi; Nagai, Hirofumi; Hirakata, Masao; Tozawa, Ryuichi

2007-08-15

High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy.

Effects of Different Types of Statins on Lipid Profile: A Perspective on Asians.

PubMed

Meor Anuar Shuhaili, Meor Fairuz Rizal; Samsudin, Intan Nureslyna; Stanslas, Johnson; Hasan, Shariful; Thambiah, Subashini C

2017-04-01

The present review aimed at reviewing the effects of different statins on lipid profile, particularly in Asians. PubMed searches were conducted using the keywords 'statin, effect, and lipid profile' from database inception through March 2016. In this review, 718 articles were retrieved from the primary search. After reviewing the titles, abstracts, and full texts, we found that 59 studies met our inclusion criteria. These also included subsequent reference searches of retrieved articles. CURVES study compared the effect on lipid profile between atorvastatin and other statins. This study demonstrated that low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG) were reduced more with atorvastatin compared to simvastatin, pravastatin, lovastatin, and fluvastatin. However, simvastatin provided a greater elevation of high-density lipoprotein cholesterol (HDL-C) compared to atorvastatin. The STELLAR trial was based on dose-to-dose comparisons between atorvastatin and rosuvastatin efficacy in reducing LDL-C. Te present study also revealed that as the doses of rosuvastatin, simvastatin, and pravastatin increased, HDL-C also increased, with rosuvastatin having the greatest effect. However, HDL-C levels decreased as the dose of atorvastatin increased. The DISCOVERY study involving the Asian population revealed that the percentage of patients achieving the European goals for LDL-C and TC at 12 weeks was higher in rosuvastatin group compared to atorvastatin group. The effects of statins on lipid profile are dose dependent. Most studies showed that rosuvastatin has the best effect on lipid profile. Prescribing lower doses of statins in Asians seems necessary.

Optical Isomers of Atorvastatin, Rosuvastatin and Fluvastatin Enantiospecifically Activate Pregnane X Receptor PXR and Induce CYP2A6, CYP2B6 and CYP3A4 in Human Hepatocytes

PubMed Central

Korhonova, Martina; Doricakova, Aneta; Dvorak, Zdenek

2015-01-01

Atorvastatin, fluvastatin and rosuvastatin are drugs used for treatment of hypercholesterolemia. They cause numerous drug-drug interactions by inhibiting and inducing drug-metabolizing cytochromes P450. These three statins exist in four optical forms, but they are currently used as enantiopure drugs, i.e., only one single enantiomer. There are numerous evidences that efficacy, adverse effects and toxicity of drugs may be enantiospecific. Therefore, we investigated the effects of optical isomers of atorvastatin, fluvastatin and rosuvastatin on the expression of drug-metabolizing P450s in primary human hepatocytes, using western blots and RT-PCR for measurement of proteins and mRNAs, respectively. The activity of P450 transcriptional regulators, including pregnane X receptor (PXR), aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR), was assessed by gene reporter assays and EMSA. Transcriptional activity of AhR was not influenced by any statin tested. Basal transcriptional activity of GR was not affected by tested statins, but dexamethasone-inducible activity of GR was dose-dependently and enantioselectively inhibited by fluvastatin. Basal and ligand-inducible transcriptional activity of PXR was dose-dependently influenced by all tested statins, and the potency and efficacy between individual optical isomers varied depending on statin and optical isomer. The expression of CYP1A1 and CYP1A2 in human hepatocytes was not influenced by tested statins. All statins induced CYP2A6, CYP2B6 and CYP3A4, and the effects on CYP2C9 were rather modulatory. The effects varied between statins and enantiomers and induction potency decreased in order: atorvastatin (RR>RS = SR>SS) > fluvastatin (SR>RS = SS>RR) >> rosuvastatin (only RS active). The data presented here might be of toxicological and clinical importance. PMID:26366873

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase.

PubMed

Würtz, Peter; Wang, Qin; Soininen, Pasi; Kangas, Antti J; Fatemifar, Ghazaleh; Tynkkynen, Tuulia; Tiainen, Mika; Perola, Markus; Tillin, Therese; Hughes, Alun D; Mäntyselkä, Pekka; Kähönen, Mika; Lehtimäki, Terho; Sattar, Naveed; Hingorani, Aroon D; Casas, Juan-Pablo; Salomaa, Veikko; Kivimäki, Mika; Järvelin, Marjo-Riitta; Davey Smith, George; Vanhala, Mauno; Lawlor, Debbie A; Raitakari, Olli T; Chaturvedi, Nish; Kettunen, Johannes; Ala-Korpela, Mika

2016-03-15

Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R(2) = 0.94, slope 1.00 ± 0.03). Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Statins for cardiovascular prevention according to different strategies: a cost analysis.

PubMed

Ito, Marcia K; Nanchen, David; Rodondi, Nicolas; Paccaud, Fred; Waeber, Gérard; Vollenweider, Peter; Marques-Vidal, Pedro

2011-01-01

Several studies have shown that treatment with HMG-CoA reductase inhibitors (statins) can reduce coronary heart disease (CHD) rates. However, the cost effectiveness of statin treatment in the primary prevention of CHD has not been fully established. To estimate the costs of CHD prevention using statins in Switzerland according to different guidelines, over a 10-year period. The overall 10-year costs, costs of one CHD death averted, and of 1 year without CHD were computed for the European Society of Cardiology (ESC), the International Atherosclerosis Society (IAS), and the US Adult Treatment Panel III (ATP-III) guidelines. Sensitivity analysis was performed by varying number of CHD events prevented and costs of treatment. Using an inflation rate of medical costs of 3%, a single yearly consultation, a single total cholesterol measurement per year, and a generic statin, the overall 10-year costs of the ESC, IAS, and ATP-III strategies were 2.2, 3.4, and 4.1 billion Swiss francs (SwF [SwF1 = $US0.97]). In this scenario, the average cost for 1 year of life gained was SwF352, SwF421, and SwF485 thousand, respectively, and it was always higher in women than in men. In men, the average cost for 1 year of life without CHD was SwF30.7, SwF42.5, and SwF51.9 thousand for the ESC, IAS, and ATP-III strategies, respectively, and decreased with age. Statin drug costs represented between 45% and 68% of the overall preventive cost. Changing the cost of statins, inflation rates, or number of fatal and non-fatal cases of CHD averted showed ESC guidelines to be the most cost effective. The cost of CHD prevention using statins depends on the guidelines used. The ESC guidelines appear to yield the lowest costs per year of life gained free of CHD.

The effect of testosterone on cardiometabolic risk factors in atorvastatin-treated men with late-onset hypogonadism.

PubMed

Krysiak, Robert; Gilowski, Wojciech; Okopień, Bogusław

2016-02-01

By reducing LDL cholesterol levels, statins may decrease androgen production. This study was aimed at investigating whether testosterone treatment has an impact on cardiometabolic risk factors in statin-treated men with late-onset hypogonadism (LOH). The study included 31 men with LOH who had been treated for at least 6 months with atorvastatin (20-40mg daily). On the basis of patient preference, atorvastatin-treated patients were divided into two matched groups of patients: receiving intramuscular testosterone enanthate (100mg weekly, n=16) and not treated with this hormone (n=15). Plasma lipids, glucose homeostasis markers, as well as plasma levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, and fibrinogen were assessed before and after 4 months of therapy. Compared with the control age-, weight, and lipid-matched statin-naïve subjects with LOH (n=12), atorvastatin-treated patients were characterized by decreased levels of testosterone, hsCRP, and homocysteine. In patients not receiving testosterone therapy, plasma lipids, glucose homeostasis markers, as well as plasma levels of the investigated risk factors remained at the similar levels throughout the whole period of atorvastatin treatment. In atorvastatin-naïve patients, testosterone increased its plasma levels and decreased HDL cholesterol. Apart from an increase in testosterone levels, if administered to atorvastatin-treated subjects with LOH, testosterone reduced plasma levels of LDL cholesterol, uric acid, hsCRP, homocysteine, and fibrinogen, as well as improved insulin sensitivity. Our study may suggest the clinical benefits associated with combination therapy with a statin and testosterone in elderly men with LOH. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Clinical implications of the IMPROVE-IT trial in the light of current and future lipid-lowering treatment options.

PubMed

Serban, Maria-Corina; Banach, Maciej; Mikhailidis, Dimitri P

2016-01-01

A residual risk of morbidity and mortality from cardiovascular (CV) disease remains despite statin therapy. This situation has generated an interest in finding novel approaches of combining statins with other lipid-lowering agents, or finding new lipid and non-lipid targets, such as triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, cholesterol ester transfer protein (CETP), lipoprotein (a), fibrinogen or C-reactive protein. The recent results from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated an incremental clinical benefit when ezetimibe, a non-statin agent, was added to simvastatin therapy. The results from IMPROVE-IT revalidated the concept that low-density lipoprotein cholesterol (LDL-C) levels are a clinically relevant treatment goal. This trial also suggested that further decrease of LDL-C levels (53 vs. 70 mg/dl; 1.4 vs. 1.8 mmol/l) was more beneficial in lowering CV events. This "even lower is even better" evidence for LDL-C levels may influence future guidelines and the use of new drugs. Furthermore, these findings make ezetimibe a more realistic option to treat patients with statin intolerance or those who cannot achieve LDL-C targets with statin monotherapy.

Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms.

PubMed

Carson, Ross A; Rudine, Anthony C; Tally, Serena J; Franks, Alexis L; Frahm, Krystle A; Waldman, Jacob K; Silswal, Neerupma; Burale, Suban; Phan, James V; Chandran, Uma R; Monaghan, A Paula; DeFranco, Donald B

2018-01-01

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs). To understand how statins could impact the developing brain, we studied effects of pravastatin and simvastatin on primary embryonic NSPC survival, proliferation, global transcription, and cell fate in vitro. We found that statins dose dependently decrease NSPC expansion by promoting cell death and autophagy of NSPCs progressing through the G1 phase of the cell cycle. Genome-wide transcriptome analysis demonstrates an increase in expression of CBP genes following pravastatin treatment, through activation of the SREBP2 transcription factor. Co-treatment with farnesyl pyrophosphate (FPP), a CBP metabolite downstream of HMG-CoA reductase, reduces SREBP2 activation and pravastatin-induced PARP cleavage. Finally, pravastatin and simvastatin differentially alter NSPC cell fate and mRNA expression during differentiation, through a non-CBP dependent pathway.

Efficacy and safety of a combination of red yeast rice and olive extract in hypercholesterolemic patients with and without statin-associated myalgia.

PubMed

Tshongo Muhindo, Christian; Ahn, Sylvie A; Rousseau, Michel F; Dierckxsens, Yvan; Hermans, Michel P

2017-12-01

Cholesfytol ® , a lipid-lowering dietary supplement with antioxidant and anti-atherosclerotic properties, combines red yeast rice (RYR) and olive extract (5mg hydroxytyrosol equivalent) and represents an alternative for patients who do not wish or are unable to use chemical statins, including individuals with previous statin-associated muscle symptoms (SAMS). A 2-months observational non-randomized study was performed to evaluate the efficacy, tolerance and safety of Cholesfytol ® (1 tablet/day) in 642 hypercholesterolemic patients (mean age: 59 yrs; total cholesterol (TC) ≥200; LDL-C ≥140mg/dl). Patients were followed by 126 GPs, and included irrespective of SAMS history and/or diabetes. None of the patients were taking statins or other lipid-modifying therapy at inclusion. At baseline, 26% had fasting glucose >100 ≤125mg/dL, and 5% >125mg/dL; 32% (n=194) had a SAMS history; and 21% had atherogenic dyslipidemia (AD). In the entire cohort, pre-treatment TC; non-HDL-C; LDL-C; and TG were 259; 200; 168; 158mg/dL, respectively, and decreased significantly on treatment (-17.5% (TC) and -23.3% (LDL-C)). Fasting glucose and HbA 1c decreased between visits. The reduction in lipids was greater in patients with higher values at baseline. For comparable pre-treatment values, patients with SAMS history had reductions in TC, LDL-C, non-HDL-C, and apoB 100 slightly less than patients without myalgia. AD patients had greater on-treatment decrease in TG. Overall, 13 patients reported minor side-effects, and 4 patients reporting myalgia had antecedent SAMS. In conclusion, a substantial decrease in LDL-C was obtained with a combination of RYR and olive extract in high-risk hypercholesterolemic patients, without inducing new-onset SAMS. Copyright © 2017 Elsevier Ltd. All rights reserved.

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional pro of CD4+T-lymphocytes in acute coronary syndromes

PubMed Central

Campioni, Mara; Flego, Davide; Angelini, Giulia; Pedicino, Daniela; Giglio, Ada Francesca; Trotta, Francesco; Giubilato, Simona; Pazzano, Vincenzo; Lucci, Claudia; Iaconelli, Antonio; Ruggio, Aureliano; Biasucci, Luigi Marzio

2017-01-01

Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms. Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 g/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-?-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P < 0.001). Atorvastatin increased the expression of 2 genes and decreased the expression of 12 genes (in particular, EGR1, FOS,CCR2 and toll like receptor-4; >3-fold changes). The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03). Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes. PMID:28407684

QRS/T-wave and calcium alternans in a type I diabetic mouse model for spontaneous postmyocardial infarction ventricular tachycardia: A mechanism for the antiarrhythmic effect of statins.

PubMed

Jin, Hongwei; Welzig, Charles M; Aronovitz, Mark; Noubary, Farzad; Blanton, Robert; Wang, Bo; Rajab, Mohammad; Albano, Alfred; Link, Mark S; Noujaim, Sami F; Park, Ho-Jin; Galper, Jonas B

2017-09-01

The incidence of sudden arrhythmic death is markedly increased in diabetics. The purpose of this study was to develop a mouse model for postmyocardial infarction (post-MI) ventricular tachycardia (VT) in the diabetic heart and determine the mechanism of an antiarrhythmic effect of statins. ECG transmitters were implanted in wild-type (WT), placebo, and pravastatin-treated type I diabetic Akita mice. MIs were induced by coronary ligation, and Ca 2+ transients were studied by optical mapping, and Ca 2+ transients and sparks in left ventricular myocytes (VM) by the Ionoptix system and confocal microscopy. Burst pacing of Akita mouse hearts resulted in rate-related QRS/T-wave alternans, which was attenuated in pravastatin-treated mice. Post-MI Akita mice developed QRS/T-wave alternans and VT at 2820 ± 879 beats per mouse, which decreased to 343 ± 115 in pravastatin-treated mice (n = 13, P <.05). Optical mapping demonstrated pacing-induced VT originating in the peri-infarction zone and Ca 2+ alternans, both attenuated in hearts of statin-treated mice. Akita VM displayed Ca 2+ alternans, and triggered activity as well as increased Ca 2+ transient decay time (Tau), Ca 2+ sparks, and cytosolic Ca 2+ and decreased SR Ca 2+ stores all of which were in part reversed in cells from statin treated mice. Homogenates of Akita ventricles demonstrated decreased SERCA2a/PLB ratio and increased ratio of protein phosphatase (PP-1) to the PP-1 inhibitor PPI-1 which were reversed in homogenates of pravastatin-treated Akita mice. Pravastatin decreased the incidence of post-MI VT and Ca 2+ alternans in Akita mouse hearts in part by revering abnormalities of Ca 2+ handling via the PP-1/PPI-1 pathway. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Bergamot polyphenolic fraction enhances rosuvastatin-induced effect on LDL-cholesterol, LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia.

PubMed

Gliozzi, Micaela; Walker, Ross; Muscoli, Saverio; Vitale, Cristiana; Gratteri, Santo; Carresi, Cristina; Musolino, Vincenzo; Russo, Vanessa; Janda, Elzbieta; Ragusa, Salvatore; Aloe, Antonio; Palma, Ernesto; Muscoli, Carolina; Romeo, Franco; Mollace, Vincenzo

2013-12-10

Statins are the most commonly prescribed drugs to reduce cardiometabolic risk. Besides the well-known efficacy of such compounds in both preventing and treating cardiometabolic disorders, some patients experience statin-induced side effects. We hypothesize that the use of natural bergamot-derived polyphenols may allow patients undergoing statin treatment to reduce effective doses while achieving target lipid values. The aim of the present study is to investigate the occurrence of an enhanced effect of bergamot-derived polyphenolic fraction (BPF) on rosuvastatin-induced hypolipidemic and vasoprotective response in patients with mixed hyperlipidemia. A prospective, open-label, parallel group, placebo-controlled study on 77 patients with elevated serum LDL-C and triglycerides was designed. Patients were randomly assigned to a control group receiving placebo (n=15), two groups receiving orally administered rosuvastatin (10 and 20mg/daily for 30 days; n=16 for each group), a group receiving BPF alone orally (1000 mg/daily for 30 days; n=15) and a group receiving BPF (1000 mg/daily given orally) plus rosuvastatin (10mg/daily for 30 days; n=15). Both doses of rosuvastatin and BPF reduced total cholesterol, LDL-C, the LDL-C/HDL-C ratio and urinary mevalonate in hyperlipidemic patients, compared to control group. The cholesterol lowering effect was accompanied by reductions of malondialdehyde, oxyLDL receptor LOX-1 and phosphoPKB, which are all biomarkers of oxidative vascular damage, in peripheral polymorphonuclear cells. Addition of BPF to rosuvastatin significantly enhanced rosuvastatin-induced effect on serum lipemic profile compared to rosuvastatin alone. This lipid-lowering effect was associated with significant reductions of biomarkers used for detecting oxidative vascular damage, suggesting a multi-action enhanced potential for BPF in patients on statin therapy. © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

Algorithms to Identify Statin Intolerance in Medicare Administrative Claim Data.

PubMed

Colantonio, Lisandro D; Kent, Shia T; Huang, Lei; Chen, Ligong; Monda, Keri L; Serban, Maria-Corina; Manthripragada, Angelika; Kilgore, Meredith L; Rosenson, Robert S; Muntner, Paul

2016-10-01

To compare characteristics of patients with possible statin intolerance identified using different claims-based algorithms versus patients with high adherence to statins. We analyzed 134,863 Medicare beneficiaries initiating statins between 2007 and 2011. Statin intolerance and discontinuation, and high adherence to statins, defined by proportion of days covered ≥80 %, were assessed during the 365 days following statin initiation. Definition 1 of statin intolerance included statin down-titration or discontinuation with ezetimibe initiation, having a claim for a rhabdomyolysis or antihyperlipidemic event followed by statin down-titration or discontinuation, or switching between ≥3 types of statins. Definition 2 included beneficiaries who met Definition 1 and those who down-titrated statin intensity. We also analyzed beneficiaries who met Definition 2 of statin intolerance or discontinued statins. The prevalence of statin intolerance was 1.0 % (n = 1320) and 5.2 % (n = 6985) using Definitions 1 and 2, respectively. Overall, 45,266 (33.6 %) beneficiaries had statin intolerance by Definition 2 or discontinued statins and 55,990 (41.5 %) beneficiaries had high adherence to statins. Compared with beneficiaries with high adherence to statins, those with statin intolerance and who had statin intolerance or discontinued statins were more likely to be female versus male, and black, Hispanic or Asian versus white. The multivariable adjusted odds ratio for statin intolerance by Definitions 1 and 2 comparing patients initiating high versus low/moderate intensity statins were 2.82 (95%CI: 2.42-3.29), and 8.58 (8.07-9.12), respectively, and for statin intolerance or statin discontinuation was 2.35 (2.25-2.45). Definitions of statin intolerance presented herein can be applied to analyses using administrative claims data.

Myoglobin microplate assay to evaluate prevention of protein peroxidation.

PubMed

Marques, Sara S; Magalhães, Luís M; Mota, Ana I P; Soares, Tânia R P; Korsak, Barbara; Reis, Salette; Segundo, Marcela A

2015-10-10

The current therapeutic strategies are based on the design of multifunctional drug candidates able to interact with various disease related targets. Drugs that have the ability to scavenge reactive oxygen species (ROS), beyond their main therapeutic action, may prevent the oxidative damage of biomolecules. Therefore, analytical approaches that monitor in a continuous mode the ability of drugs to counteract peroxidation of physiologically relevant biotargets are required. In the present work, a microplate spectrophotometric assay is proposed to evaluate the ability of selected cardiovascular drugs, including angiotensin-converting enzyme (ACE) inhibitors, β -blockers and statins to prevent protein peroxidation. Myoglobin, which is a heme protein, and peroxyl radicals generated from thermolysis of 2,2'-azo-bis(2-amidinopropane) dihydrochloride at 37 °C, pH 7.4 were selected as protein model and oxidative species, respectively. Myoglobin peroxidation was continuously monitored by the absorbance decrease at 409 nm and the ability of drugs to counteract protein oxidation was determined by the calculation of the area under the curve upon the myoglobin oxidation. Fluvastatin (AUC₅₀=12.5 ± 1.2 μM) and enalapril (AUC₅₀=15.2 ± 1.8 μM) showed high ability to prevent myoglobin peroxidation, providing even better efficiency than endogenous antioxidants such as reduced glutathione. Moreover, labetalol, enalapril and fluvastatin prevent the autoxidation of myoglobin, while glutathione showed a pro-oxidant effect. Copyright © 2015 Elsevier B.V. All rights reserved.

Response to statin therapy in obstructive sleep apnea syndrome: a multicenter randomized controlled trial.

PubMed

Joyeux-Faure, Marie; Tamisier, Renaud; Baguet, Jean-Philippe; Dias-Domingos, Sonia; Perrig, Stephen; Leftheriotis, Georges; Janssens, Jean-Paul; Trzepizur, Wojciech; Launois, Sandrine H; Stanke-Labesque, Françoise; Lévy, Patrick A; Gagnadoux, Frédéric; Pepin, Jean-Louis

2014-01-01

Accumulated evidence implicates sympathetic activation as inducing oxidative stress and systemic inflammation, which in turn lead to hypertension, endothelial dysfunction, and atherosclerosis in obstructive sleep apnea (OSA). Statins through their pleiotropic properties may modify inflammation, lipid profile, and cardiovascular outcomes in OSA. This multicenter, randomized, double-blind study compared the effects of atorvastatin 40 mg/day versus placebo over 12 weeks on endothelial function (the primary endpoint) measured by peripheral arterial tone (PAT). Secondary endpoints included office blood pressure (BP), early carotid atherosclerosis, arterial stiffness measured by pulse wave velocity (PWV), and metabolic parameters. 51 severe OSA patients were randomized. Key demographics for the study population were age 54 ± 11 years, 21.6% female, and BMI 28.5 ± 4.5 kg/m(2). In intention to treat analysis, mean PAT difference between atorvastatin and placebo groups was 0.008 (-0.29; 0.28), P = 0.979. Total and LDL cholesterol significantly improved with atorvastatin. Systolic BP significantly decreased with atorvastatin (mean difference: -6.34 mmHg (-12.68; -0.01), P = 0.050) whereas carotid atherosclerosis and PWV were unchanged compared to the placebo group. In OSA patients, 3 months of atorvastatin neither improved endothelial function nor reduced early signs of atherosclerosis although it lowered blood pressure and improved lipid profile. This trial is registered with NCT00669695.

Dyslipidemia in chronic kidney disease: are statins still indicated in reduction cardiovascular risk in patients on dialysis treatment?

PubMed

Scarpioni, Roberto; Ricardi, Marco; Melfa, Luigi; Cristinelli, Luciano

2010-12-01

Chronic kidney disease (CKD) is an increasingly health disease all around the world with a high burden of mortality and cardiovascular (CV) morbidity rate. Even when renal replacement therapy is reached, more than half patients die, mainly for CV causes due either to uremia-related cardiovascular risk factors (such as anemia, hyperhomocysteinemia, mineral bone disease-CKD with hyperparathyroidism, oxidative stress, hypoalbuminemia, chronic inflammation, prothrombotic factors) or to traditional ones (age, male gender, diabetes, obesity, hypertension, smoking, insulin levels, family history, dyslipidemia). Among the latter causes dyslipidemia represents one of the major, potentially correctable risk factor. Statins have demonstrated to effectively and safely reduce cholesterol levels in CKD patients. Here we will examine the effects of statins on CV risk factors in CKD patients and particularly in patients on dialysis treatment, in the light of the unfavorable results of the large trials 4D and AURORA, recently published, underlining the role of malnutrition/inflammation as confounding factor. Probably it will be that only with a real prevention, starting statins even in the early stages of CKD, as indicated by post hoc analysis of large trials, that we will reach results in reducing the mortality rate in CKD patients. In the meanwhile, all the other remediable CV risk factors have to be at the same time corrected. © 2010 Blackwell Publishing Ltd.

Pharmacologic management of isolated low high-density lipoprotein syndrome.

PubMed

Bermúdez, Valmore; Cano, Raquel; Cano, Clímaco; Bermúdez, Fernando; Arraiz, Nailet; Acosta, Luis; Finol, Freddy; Pabón, María Rebeca; Amell, Anilsa; Reyna, Nadia; Hidalgo, Joaquin; Kendall, Paúl; Manuel, Velasco; Hernández, Rafael

2008-01-01

High-density lipoprotein (HDL) cholesterol is a heterogeneous group of lipoproteins exhibiting a variety of properties like prostacyclin production stimulation, decrease in platelet aggregation, endothelial cell apoptosis inhibition, and low-density lipoprotein oxidation blockade. Epidemiologic studies have shown an inverse relation between HDL cholesterol levels and cardiovascular risk. Low HDL cholesterol is associated with increased risk for myocardial infarction, stroke, sudden death, peripheral artery disease, and postangioplasty restenosis. In contrast, high HDL levels are associated with longevity and protection against atherosclerotic disease development. Given the evolving epidemic of obesity, diabetes mellitus, and metabolic syndrome, the prevalence of low HDL will continue to rise. In the United States, low HDL is present in 35% of men, 15% of women, and approximately 63% of patients with coronary artery disease. Data extracted from the Framingham study highlight that 1-mg increase in HDL levels decreases by 2% to 3% the risk of cardiovascular disease. There is no doubt regarding clinical importance about isolated low HDL, but relatively few clinicians consider a direct therapeutic intervention of this dyslipidemia. In this sense, lifestyle measures should be the first-line strategy to manage low HDL levels. On the other hand, pharmacologic options include niacin, fibrates, and statins. Fibrates appear to reduce risk preferentially in patients with low HDL with metabolic syndrome, whereas statins reduce risk across all levels of HDL. Torcetrapib, a cholesteryl esters transfer protein inhibitor, represented a hope to raise this lipoprotein; however, all clinical trials on this drug had ceased after ILLUMINATE, RADIANCE and ERASE trials had recorded an increase in mortality, rates of myocardial infarction, angina, and heart failure. In the near future, drugs as beta-glucans, Apo-A1 mimetic peptides, and ACAT inhibitors, are the new promises to treat this condition.

SLCO2B1 and SLCO1B3 as New Targets for Enhancing Androgen Deprivation Therapy for Prostate Cancer

DTIC Science & Technology

2015-10-01

that statins block DHEAS uptake by competitively binding to SLCO2B1. We examined the effect of four different statins ( atorvastatin , fluvastatin...300 pmol/mg compared to ~60 pmol/mg protein for LNCaP (Fig. 2B). 100 µM atorvastatin significantly decreased DHEAS influx by ~50% in both cell...or even 100 µM atorvastatin or simvastatin was insufficient to inhibit DHEAS uptake in LNCaP, which has a relatively low level of SLCO2B1 expression

[Organprotection in cardiac risk patients--rational of perioperative beta-adrenoceptor-antagonists and statins].

PubMed

Hanss, Robert; Bein, Berthold

2010-04-01

The number of patients with limited organ function is steadily increasing due to the aging of the population. Consequently, a growing number of patients needing surgery is accompanied by serious comorbidities. These patients are at high risk of perioperative organ dysfunction. In this context cardiac events (e.g. cardiac arrhythmias, angina or myocardial infarction) play a major role with significant impact on postoperative care, long term outcome and economic sequelae. Thus, anaesthesiologists must prevent such events in the perioperative period. Besides general measures such as adequate analgesia, protection from stressful events and sufficient volume replacement, medical intervention with beta-blockers or HMG-CoA-reductase-inhibitors (statins) are necessary to reduce the incidence of perioperative cardiac events. Both beta-blockers and HMG-CoA-reductase-inhibitors are known to exhibit pleiotropic effects (defined as additional cardioprotective effects) besides the primary blockade of the beta-adrenergic receptor or the inhibition of the synthesis of serum cholesterol, respectively. Both groups of drugs improve cardiac function, decrease inflammatory response, decrease activation of blood coagulation and stabilize endothelial plaques. Based on the current literature the following recommendations are published concerning the perioperative administration of beta-blockers: (i) Patients who are on beta-blockers on a regular basis following guidelines concerning chronic treatment of cardiovascular diseases should continue this medication throughout the perioperative period; (ii) a sufficient indicator of an adequate therapy is the baseline heart rate. It should not exceed 60-70bpm at rest; (iii) the Revised Cardiac Risk Index (RCRI) is a widely accepted score to estimate the patient's perioperative cardiac risk; (iv) patients with a RCRI > or =3 should not be scheduled for routine surgery without sufficient beta-adrenergic-receptor blockade; (v) in patients at high cardiac risk based on the RCRI who are scheduled for emergency surgery beta-blocker-therapy should not be initiated de novo perioperatively. However, for perioperative treatment of tachycardia or hypertension beta-blockers are the drug of first choice. Concerning perioperative statin-therapy the following recommendations are suggested: (i) chronic statin-therapy should be continued throughout surgery and the perioperative period; (ii) in patients without chronic statin-therapy scheduled for vascular surgery this treatment should be started perioperativly; (iii) no data is available concerning other patient populations; (iv) if statin-therapy is indicated it should be started independently from baseline serum LDL-C-concentration; (v) side effects of statin-therapy are rare and usually not live threatening, thus treatment is considered to be without serious risks to the patient. Georg Thieme Verlag Stuttgart. New York.

Interaction of clopidogrel and statins in secondary prevention after cerebral ischaemia – a randomized, double-blind, double-dummy crossover study

PubMed Central

Siepmann, Timo; Heinke, Denise; Kepplinger, Jessica; Barlinn, Kristian; Gehrisch, Siegmund; Grählert, Xina; Schwanebeck, Uta; Reichmann, Heinz; Puetz, Volker; Bodechtel, Ulf; Gahn, Georg

2014-01-01

Aims Variability in responsiveness to clopidogrel is a clinical problem in secondary prevention after cerebral ischaemia which has been suggested to be linked to competitive metabolization of clopidogrel and cytochrome P450 (CYP) 3A4-oxidated statins such as simvastatin. We assessed the hypothesis that simvastatin, in contrast to CYP 2C9-metabolized fluvastatin, reduces clopidogrel-mediated platelet inhibition. Methods We performed a randomized, double-blind, double-dummy, two period crossover study in 13 patients with cerebral ischaemia (8F, 5 M), aged 64.1 ± 8.0 years (mean ± SD). After a 14 day period in which all patients received 75 mg clopidogrel day−1, patients additionally received either 20 mg simvastatin day−1 or 80 mg fluvastatin day−1 for 14 days. Regimens were crossed over after a 14 day wash-out period and switched regimens were continued for another 14 days. Platelet aggregation, clopidogrel active metabolite (CAM) plasma concentrations and routine laboratory parameters including prothrombin time (PT) Quick percent value were assessed at baseline and following each treatment phase. Results Clopidogrel reduced platelet aggregation in all patients as expected. Platelet aggregation and CAM plasma concentrations were unaltered when simvastatin or fluvastatin was added to clopidogrel. Simvastatin decreased PT Quick percent value (decrease from 109 ± 10.5% to 103 ± 11%, P < 0.05) when combined with clopidogrel but there was no such change following treatment with fluvastatin and clopidogrel. Conclusions Our data indicate that treatment with CYP 3A4-metabolized simvastatin does not jeopardize clopidogrel-mediated inhibition of platelet aggregation. After co-administration of simvastatin and clopidogrel we observed a decrease in the PT Quick percent value which could be due to simvastatin-induced reduction of activity of prothrombin fragment 1 + 2. PMID:24803100

Statins cause profound effects on gene expression in human cancer cells in vitro: the role of membrane microdomains.

PubMed

Garnett, David John; Greenhough, Trevor James

2012-01-01

There is increasing evidence that statin treatment can be beneficial in certain cancer patients. To determine if these benefits are a direct result of the cholesterol-lowering effects of statins or a result of secondary, protein transcription effects, the impacts of pravastatin and a cholesterol sequestrating agent methyl-beta-cyclodextrin (MbetaCD) on mRNA expression in the breast cancer cell MDA-MB-231 and the lung carcinoma cell Calu-1 have been compared by microarray techniques. The effects of these agents on cholesterol-rich rafts and caveolae, which have significance in cancer signaling, have also been examined. Both treatments caused a general downregulation of not only signal transduction including cancer pathway proteins, but also apoptosis and chemokine pathways, with statins impacting 35 genes by twofold or greater in MDA-MB-231 and > 300 genes in Calu-1. These manifold dysregulations could also explain the various side effects reportedly caused by statins. MbetaCD produced far fewer statistical events than pravastatin in the breast cancer line but many more in the lung cell line. Pravastatin increased expression of CAV1 but caveolae density decreased and overall raft density was unaffected. MbetaCD also caused an increase in CAV1 expression and reduced the prevalence of both rafts and caveolae. It is proposed that sequestration of cholesterol from the membrane by MbetaCD is not equivalent to blockade of the cholesterol pathway and causes different effects on microdomain-mediated signal transduction dependant on the cell line. The profound effects of statins on mRNA expression can be explained by the failure of caveolin-1 to properly complex with cholesterol in an altered sterol environment, with caveolae acting as the main loci for signaling directed towards those transcription processes unaffected by MbetaCD. Targeted inhibition of the postmevalonate pathway could offer an opportunity to specifically reduce caveolae-based signaling in cancer cells. The observed impact of pravastatin on gene expression may explain the pleiotropic effects of statins when they are used as adjuvants in chemotherapy and suggests impact on gene expression as a possible cause of side effects from statin use.

Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression

PubMed Central

Pierno, S; Camerino, GM; Cippone, V; Rolland, J-F; Desaphy, J-F; De Luca, A; Liantonio, A; Bianco, G; Kunic, JD; George, AL; Camerino, D Conte

2009-01-01

Background and purpose: Statins and fibrates can produce mild to life-threatening skeletal muscle damage. Resting chloride channel conductance (gCl), carried by the ClC-1 channel, is reduced in muscles of rats chronically treated with fluvastatin, atorvastatin or fenofibrate, along with increased resting cytosolic calcium in statin-treated rats. A high gCl, controlled by the Ca2+-dependent protein kinase C (PKC), maintains sarcolemma electrical stability and its reduction alters muscle function. Here, we investigated how statins and fenofibrate impaired gCl. Experimental approach: In rats treated with fluvastatin, atorvastatin or fenofibrate, we examined the involvement of PKC in gCl reduction by the two intracellular microelectrodes technique and ClC-1 mRNA level by quantitative real time-polymerase chain reaction. Direct drug effects were tested by patch clamp analysis on human ClC-1 channels expressed in human embryonic kidney (HEK) 293 cells. Key results: Chelerythrine, a PKC inhibitor, applied in vitro on muscle dissected from atorvastatin-treated rats fully restored gCl, suggesting the involvement of this enzyme in statin action. Chelerythrine partially restored gCl in muscles from fluvastatin-treated rats but not in those from fenofibrate-treated rats, implying additional mechanisms for gCl impairment. Accordingly, a decrease of ClC-1 channel mRNA was found in both fluvastatin-and fenofibrate-treated rat muscles. Fenofibric acid, the in vivo metabolite of fenofibrate, but not fluvastatin, rapidly reduced chloride currents in HEK 293 cells. Conclusions and implications: Our data suggest multiple mechanisms underlie the effect of statins and fenofibrate on ClC-1 channel conductance. While statins promote Ca2+-mediated PKC activation, fenofibrate directly inhibits ClC-1 channels and both fluvastatin and fenofibrate impair expression of mRNA for ClC-1. PMID:19220292

Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy).

PubMed

Pezzini, Alessandro; Grassi, Mario; Iacoviello, Licia; Zedde, Marialuisa; Marcheselli, Simona; Silvestrelli, Giorgio; DeLodovici, Maria Luisa; Sessa, Maria; Zini, Andrea; Paciaroni, Maurizio; Azzini, Cristiano; Gamba, Massimo; Del Sette, Massimo; Toriello, Antonella; Gandolfo, Carlo; Bonifati, Domenico Marco; Tassi, Rossana; Cavallini, Anna; Chiti, Alberto; Calabrò, Rocco Salvatore; Musolino, Rossella; Bovi, Paolo; Tomelleri, Giampaolo; Di Castelnuovo, Augusto; Vandelli, Laura; Ritelli, Marco; Agnelli, Giancarlo; De Vito, Alessandro; Pugliese, Nicola; Martini, Giuseppe; Lanari, Alessia; Ciccone, Alfonso; Lodigiani, Corrado; Malferrari, Giovanni; Del Zotto, Elisabetta; Morotti, Andrea; Costa, Paolo; Poli, Loris; De Giuli, Valeria; Bonaiti, Silvia; La Spina, Paolo; Marcello, Norina; Micieli, Giuseppe; de Gaetano, Giovanni; Colombi, Marina; Padovani, Alessandro

2016-09-01

Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated. We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH. A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones. Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A randomised trial of three counselling strategies for lifestyle changes in patients with hypercholesterolemia treated with ezetimibe on top of statin therapy (TWICE).

PubMed

Steg, Philippe Gabriel; Verdier, Jean-Claude; Carré, François; Darne, Bernadette; Ducardonnet, Alain; Jullien, Gérard; Farnier, Michel; Giral, Philippe; Haïat, Robert

2008-01-01

To compare the impact of three patient counselling strategies for lifestyle changes and to assess the safety and efficacy of ezetimibe on top of statin therapy in hypercholesterolemic high risk patients. Open, cluster randomized 3-parallel group trial. Physicians were randomized between patient motivation on: diet or physical exercise or both. Counselling was adapted to the patient's baseline Prochaska stage of change. High cardiovascular risk patients, with LDL-C above or equal to 3 mmol/L despite statin therapy for at least 3 months, were enrolled. Ezetimibe (10mg/day) and patient counselling were started at the same time. Target goal was defined as total cholesterol less than 5 mmol/L and LDL-C above 3 mmol/L. Overall 428 physicians enrolled 1,496 patients. At baseline, LDL-C was 3.9+/-0.9 mmol/L and total cholesterol was 6.1+/-1.1 mmol/L. LDL-C decreased by -30.4+/-19.3% and 869 (62%) patients achieved target goal. No difference was shown between randomisation groups. However, improvements in diet consumption patterns were more easily obtained than improvement in physical activity stage of change in non-active patient at baseline. The marked short-term impact (-30%) on LDL-C, although similar between the three groups, slightly exceeds usual LDL-C reductions achieved by this dose of ezetimibe. Decreasing fat consumption seems easier than increasing physical activity. This study confirms the good efficacy, short-term tolerability and safety of ezetimibe on top of statins.

13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis.

PubMed

Walker, Mary E; Souza, Patricia R; Colas, Romain A; Dalli, Jesmond

2017-08-01

Rheumatoid arthritis is an inflammatory condition characterized by overzealous inflammation that leads to joint damage and is associated with an increased incidence of cardiovascular disease. Statins are frontline therapeutics for patients with cardiovascular disease and exert beneficial actions in rheumatoid arthritis. The mechanism that mediates the beneficial actions of statins in rheumatoid arthritis remains of interest. In the present study, we found that the administration of 2 clinically relevant statins-atorvastatin (0.2 mg/kg) or pravastatin (0.2 mg/kg)-to mice during inflammatory arthritis up-regulated systemic and tissue amounts of a novel family of proresolving mediators, termed 13-series resolvins (RvTs), and significantly reduced joint disease. Of note, administration of simvastatin (0.2 mg/kg) did not significantly up-regulate RvTs or reduce joint inflammation. We also found that atorvastatin and pravastatin each reduced systemic leukocyte activation, including platelet-monocyte aggregates (∼25-60%). These statins decreased neutrophil trafficking to the joint as well as joint monocyte and macrophage numbers. Atorvastatin and pravastatin produced significant reductions (∼30-50%) in expression of CD11b and major histocompatibility complex class II on both monocytes and monocyte-derived macrophages in joints. Administration of an inhibitor to cyclooxygenase-2, the initiating enzyme in the RvT pathway, reversed the protective actions of these statins on both joint and systemic inflammation. Together, these findings provide evidence for the role of RvTs in mediating the protective actions of atorvastatin and pravastatin in reducing local and vascular inflammation, and suggest that RvTs may be useful in measuring the anti-inflammatory actions of statins.-Walker, M. E., Souza, P. R., Colas, R. A., Dalli, J. 13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis. © The Author(s).

On the hypothetical universal use of statins in primary prevention: an observational analysis on low-risk patients and economic consequences of a potential wide prescription rate.

PubMed

Macchia, Alejandro; Mariani, Javier; Romero, Marilena; Robusto, Fabio; Lepore, Vito; Dettorre, Antonio; Tognoni, Gianni

2015-04-01

Recent guidelines expand indications for statins. However, research on practical economic feasibility and cost-effectiveness in low-risk people is lacking. We aimed to describe the incidence of cardiovascular events (CVE), their total direct costs and the hypothetical effects of wide provision of statins on those rates and expenditures. We conducted a population-based cohort study using administrative data among low risk individuals. Estimators of effects of statins were taken from Cholesterol Treatment trialist metaanalysis and from Heart Protection Study trial. Two statin prices were used for analyses: National Italian Health System (€ 0.36) and the International Drug Price Indicator (€ 0.021). Overall, 920,067 persons at low risk were identified and 14,849 CVE were registered (incidence rate 27.3 per 10,000 person-years). Direct costs for hospitalizations for CVE were 143 M €. Universal provision of statins would result in a significant decrease in CVE rates, from 27.3 to 17.5 per 10,000 person-years (PY) (95% confidence interval (CI): 15.8-19.4). Universal prescription of simvastatin 20 mg would cost 802 M €. Otherwise, provision of simvastatin at International Drug Price Indicator's prices would be both clinically effective and cost saving in men older than age 44 (observed expenditures 120 M €, expected 97.4 M €) but not in women (observed expenditures 22.7 M €, expected 36.5 M €). Among a low-risk population, hypothetical universal provision of low-cost simvastatin to men over 44 years could be both clinically effective and a cost-saving strategy.

Potential Molecular Targets of Statins in the Prevention of Hepatocarcinogenesis.

PubMed

Ridruejo, Ezequiel; Romero-Caími, Giselle; Obregón, María J; Kleiman de Pisarev, Diana; Alvarez, Laura

2018-04-09

Hepatocellular carcinoma (HCC) represents 90% of liver tumors. Statins, may reduce the incidence of various tumors, including HCC. Antitumoral activities may be mediated by changes in transforming growth factor-beta (TGF-β1) and thyroid hormones (TH) regulation. The aim of our study is to establish the statins mechanism of action and the potential key molecules involved in an in vivo and in vitro HCC model. We used two models: in vivo (in rats) using diethylnitrosamine (DEN) and hexachlorobenzene (HCB) to develop HCC, we analyzed cell proliferation parameters (proliferating cell nuclear antigen, PCNA) and cholesterol metabolism (hydroxy-methylglutaryl-CoA reductase, HMGCoAR). In vitro (Hep-G2 cells) we evaluated the effects of different doses of Atorvastatin (AT) and Simvastatin (SM) on HCB induced proliferation and analyzed proliferative parameters, colesterol metabolism, TGF-β1 mRNA, c-Src and TH levels. In vivo, we observed that cell proliferation significantly increased as well as cholesterol serum levels in rats treated with HCB. In vitro, we observed the same results on PCNA as in vivo. The statins prevented the increase in HMG-CoAR mRNA levels induced by HCB, reaching levels similar to controls at máximum doses: AT (30 μM), and SM (20 μM). Increases in PCNA, TGF-β1, and pc-Src, and decreases in deiodinase I mRNA levels induced by HCB were not observed when cells were pre-treated with AT and SM at maximum doses. Statins can prevent the proliferative HCB effects on Hep-G2 cells. TGF-β1, c-Src and TH may be the statins molecular targets in hepatocarcinogenesis.

Emotional distress as a predictor of statin non-adherence among Swedish first-time myocardial infarction patients, 2006-2013.

PubMed

Lissåker, C T; Wallert, J; Held, C; Olsson, E

2017-06-01

Emotional distress (depression and anxiety) has been known to affect mortality after a myocardial infarction (MI). One possible mechanism is through medication non-adherence. Few studies have investigated the link between statin adherence and emotional distress, and results are not consistent. We aimed to explore whether emotional distress affects adherence among first-time MI patients younger than 75years old receiving a prescription for the first time. We identified first-MI individuals younger than 75years from the SWEDEHEART national quality registers discharged with a statin prescription. The main exposure was the anxiety/depression portion of the EQ-5D from Interview 1 (6-10weeks post-MI) and Interview 2 (12-14months post-MI). We calculated adherence from the Swedish Prescribed Drugs Register during three observation periods (OP): [1] Interview 1 to Interview 2, [2] one year post Interview 2, and [3] two years post Interview 1. Emotional distress at Interview 1 was not associated with statin adherence for OP1 (RR: 0.99, 95% CI: 0.98, 1.01). Emotional distress at Interview 2 was associated with lower adherence one year later (RR: 0.95, 95% CI: 0.93, 0.98). Emotional distress at Interview 1 was associated with a small decrease in adherence in the complete OP for adherence (RR: 0.98, 95% CI: 0.96, 0.99). Emotional distress was marginally, but independently, associated with lower adherence to statin two years after the MI. Our study suggests that emotional distress may be an important factor for long-term statin adherence, and, thus, may play a clinically important role in long-term outcome. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The apolipoprotein B/A1 ratio is associated with reactive oxygen metabolites and endothelial dysfunction in statin-treated patients with coronary artery disease.

PubMed

Emoto, Takuo; Sawada, Takahiro; Morimoto, Natsumi; Tenjin, Takako; Wakimoto, Taku; Ikeda, Fumie; Sato, Chiaki; Terashita, Daisuke; Mizoguchi, Taiji; Mizuguchi, Takao; Okamoto, Hiroshi; Matsuo, Yosuke; Kim, Sushi-Ku; Takarada, Akira; Yokoyama, Mitsuhiro

2013-01-01

The prognostic significance of the apolipoprotein B/A1 (ApoB/A1) ratio in statintreated patients with coronary artery disease (CAD) is unknown. We aimed to evaluate the association of the ApoB/A1 ratio with oxidative stress and endothelial dysfunction in these patients. We enrolled 62 consecutive statin-treated patients who underwent percutaneous coronary intervention (PCI). Their lipid profiles, diacron-reactive oxygen metabolites (d-ROMs), as a marker of oxidative stress, flow-mediated dilatation (FMD), as a marker of vascular endothelial function, and C-reactive protein (CRP) levels, as a marker of inflammation, were measured. Our study population comprised 44 men and 18 women (mean age, 70.5 ± 2.5 years). The ApoB/A1 ratio was positively correlated with the results of the d-ROMs test (p=0.004, r=0.36) and CRP level (p=0.02, r=0.30) and negatively correlated with the %FMD (p=0.005, r=-0.40). A multivariate logistic regression analysis showed that the most powerful predictive factor for the d-ROMs was the ApoB/A1 ratio (p=0.026). We therefore divided patients into two groups according to the cutoff point reported by the INTERHEART study: a low ApoB/A1 ratio (<0.641, n=26) and a high ApoB/A1 ratio (>0.641, n=36). The patients with a high ApoB/A1 ratio had higher levels of d-ROMs and CRP, and tended to have a lower %FMD. The ApoB/A1 ratio was associated with the d-ROMs, a marker of oxidative stress, endothelial dysfunction and inflammation, and could be useful as a residual atherosclerotic risk marker to help prevent CAD in statin-treated patients.

Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease.

PubMed

Rosenson, Robert S; Kent, Shia T; Brown, Todd M; Farkouh, Michael E; Levitan, Emily B; Yun, Huifeng; Sharma, Pradeep; Safford, Monika M; Kilgore, Meredith; Muntner, Paul; Bittner, Vera

2015-01-27

National guidelines recommend use of high-intensity statins after hospitalization for coronary heart disease (CHD) events. This study sought to estimate the proportion of Medicare beneficiaries filling prescriptions for high-intensity statins after hospital discharge for a CHD event and to analyze whether statin intensity before hospitalization is associated with statin intensity after discharge. We conducted a retrospective cohort study using a 5% random sample of Medicare beneficiaries between 65 and 74 years old. Beneficiaries were included in the analysis if they filled a statin prescription after a CHD event (myocardial infarction or coronary revascularization) in 2007, 2008, or 2009. High-intensity statins included atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg, and simvastatin 80 mg. Among 8,762 Medicare beneficiaries filling a statin prescription after a CHD event, 27% of first post-discharge fills were for a high-intensity statin. The percent filling a high-intensity statin post-discharge was 23.1%, 9.4%, and 80.7%, for beneficiaries not taking statins pre-hospitalization, taking low/moderate-intensity statins, and taking high-intensity statins before their CHD event, respectively. Compared with beneficiaries not on statin therapy pre-hospitalization, multivariable adjusted risk ratios for filling a high-intensity statin were 4.01 (3.58-4.49) and 0.45 (0.40-0.52) for participants taking high-intensity and low/moderate-intensity statins before their CHD event, respectively. Only 11.5% of beneficiaries whose first post-discharge statin fill was for a low/moderate-intensity statin filled a high-intensity statin within 365 days of discharge. The majority of Medicare beneficiaries do not fill high-intensity statins after hospitalization for CHD. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Statin Intolerance: the Clinician's Perspective.

PubMed

Stulc, Tomáš; Ceška, Richard; Gotto, Antonio M

2015-12-01

Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult.

The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells.

PubMed

Chang, Tae Ik; Kang, Hye-Young; Kim, Kyung Sik; Lee, Sun Ha; Nam, Bo Young; Paeng, Jisun; Kim, Seonghun; Park, Jung Tak; Yoo, Tae-Hyun; Kang, Shin-Wook; Han, Seung Hyeok

2014-01-01

Statins have recently been highlighted for their pleiotropic actions distinct from cholesterol-lowering effects. Despite this interest, it is currently unknown whether statin therapy inhibits peritoneal dialysis (PD)-related epithelial-mesenchymal transition (EMT). In vitro, human peritoneal mesothelial cells (HPMCs) were exposed to 5.6 mM glucose (NG) or 100 mM glucose (HG) with or without simvastatin (1 µM). In vivo, PD catheters were inserted into 32 Sprague-Dawley rats, and saline (C, n = 16) or 4.25% peritoneal dialysis fluid (PDF) (PD, n = 16) was infused for 4 weeks. Eight rats from each group were treated with 5 mg/kg/day of simvastatin intraperitoneally. Changes in the protein expression of EMT markers such as E-cadherin, α-SMA, Snail, and fibronectin in HPMCs and the peritoneum were evaluated by Western blot analysis and immunofluorescence or immunohistochemical staining. We also explored whether activation of the mevalonate pathway and its downstream small GTPases were involved in dialysis-related peritoneal EMT and could be inhibited by statin treatment. Compared to NG cells, E-cadherin expression was significantly decreased, while α-SMA, Snail, and fibronectin expression were significantly increased in HPMCs exposed to HG, and these changes were abrogated by simvastatin (p<0.05). In addition, the cobblestone-like appearance of normal HPMCs was converted into a fibroblast-like morphology after HG treatment, which was reversed by simvastatin. These EMT-like changes were also observed in HPMCs treated with geranyl-geranyl pyrophosphate (5 µM). HG significantly increased the protein expression of RhoA and Rac1 in the membrane fractions, and these increases were ameliorated by simvastatin (p<0.05). In PD rats, E-cadherin in the peritoneum was significantly decreased, whereas α-SMA, Snail, and fibronectin expression were significantly increased (p<0.05) compared to C rats. The thickness of the mesothelial layer in the peritoneum were also significantly greater in PD rats than in C rats (p<0.05). These changes of the peritoneum in PD rats were significantly attenuated by simvastatin. This study demonstrated that PD-related EMT was mediated via the mevalonate pathway, and statin treatment inhibited the EMT changes in HG-treated HPMCs and PDF-stimulated PD rats. These findings suggest that statins may be a promising therapeutic strategy for preservation of peritoneal membrane integrity in long-term PD patients.

A short-term statin treatment changes the contractile properties of fast-twitch skeletal muscles.

PubMed

Piette, Antoine Boulanger; Dufresne, Sébastien S; Frenette, Jérôme

2016-10-28

Cumulative evidence indicates that statins induce myotoxicity. However, the lack of understanding of how statins affect skeletal muscles at the structural, functional, and physiological levels hampers proper healthcare management. The purpose of the present study was to investigate the early after-effects of lovastatin on the slow-twitch soleus (Sol) and fast-twitch extensor digitorum longus (EDL) muscles. Adult C57BL/6 mice were orally administrated with placebo or lovastatin [50 mg/kg/d] for 28 days. At the end of the treatment, the isometric ex vivo contractile properties of the Sol and EDL muscles were measured. Subtetanic and tetanic contractions were assessed and contraction kinetics were recorded. The muscles were then frozen for immunohistochemical analyses. Data were analyzed by two-way ANOVA followed by an a posteriori Tukey's test. The short-term lovastatin treatment did not induce muscle mass loss, muscle fiber atrophy, or creatine kinase (CK) release. It had no functional impact on slow-twitch Sol muscles. However, subtetanic stimulations at 10 Hz provoked greater force production in fast-twitch EDL muscles. The treatment also decreased the maximal rate of force development (dP/dT) of twitch contractions and prolonged the half relaxation time (1/2RT) of tetanic contractions of EDL muscles. An early short-term statin treatment induced subtle but significant changes in some parameters of the contractile profile of EDL muscles, providing new insights into the selective initiation of statin-induced myopathy in fast-twitch muscles.

Does the Number of Pharmacies a Patient Frequents Affect Adherence to Statins?

PubMed

Christie, Russell; Sketris, Ingrid; Andreou, Pantalis; Holbrook, Anne; Levy, Adrian; Tamim, Hala

2017-05-06

We hypothesized that medication adherence is affected by the number of pharmacies a patient frequents. The objective was to estimate the strength of association between the number of pharmacies a patient frequents and adherence to statins. Using administrative data from the Nova Scotia Seniors' Pharmacare program, a retrospective cohort study was conducted among subjects aged 65 years and older first dispensed statin between 1998 and 2008. The Usual Provider of Care (UPC), was defined as the number of dispensation days from the most frequented pharmacy divided by the total number of dispensation days. Estimated adherence of over 80% of the Medication Possession Ratio was defined as adherent. Data were analyzed using hierarchical linear regression. The cohort of 25,641 subjects was 59% female with a mean age of 74 years. During follow-up, subjects filled prescriptions in a median of 2 (mean = 2; standard deviation = 0.88) pharmacies and visited pharmacies a median of 28 (mean = 30) times. During that time, 61% of patients used one pharmacy exclusively. Among subjects using 1 pharmacy, 59% were adherent while 58% using more than one pharmacy were adherent. However, upon adjustment for differences in distributions of age, sex, and other confounders, subjects who used more than one pharmacy had 10% decreased odds of statin adherence (odds ratio: 0.90, 95% confidence interval: 0.86-0.96). These results were robust in sensitivity analyses. Among seniors newly starting statin therapy, using a single community pharmacy was modestly associated with adherence.

Genetically Guided Statin Therapy

DTIC Science & Technology

2017-03-01

prevent cardiovascular disease . Long-term adherence is a challenge, due, in part, to statin intolerance due to musculoskeletal side effects. In objective...Statins, cholesterol, LDL, cardiovascular disease , genetic-informed strategy, statin prescription, statin adherence 16. SECURITY CLASSIFICATION OF: 17...28 Mar 2017. 1.0 SUMMARY Statins are well established for lowering cholesterol and preventing cardiovascular disease . High rates of statin

Variability of the LDL-C lowering response to ezetimibe and ezetimibe + statin therapy in hypercholesterolemic patients.

PubMed

Descamps, Olivier; Tomassini, Joanne E; Lin, Jianxin; Polis, Adam B; Shah, Arvind; Brudi, Philippe; Hanson, Mary E; Tershakovec, Andrew M

2015-06-01

We compared the variability of LDL-C-lowering responses to treatment with ezetimibe + statins versus statins in hypercholesterolemic patients. An analysis of patient-level data pooled from 27 double-blind, placebo and/or active-controlled studies in 21,671 patients treated with ezetimibe + statins versus statins on first-line (statin-naïve/wash-out) or second-line (on statin, randomized to ezetimibe versus placebo [add-on] or ezetimibe versus uptitrated statin [uptitrate]) for 6-24 wks. Variances (standard deviation [SD], coefficient of variation [CV], and root mean squared error [RMSE] adjusted for various factors) for % change from baseline in LDL-C were compared. In first-line and second-line add-on studies, the variability (SD, RMSE) of % change from baseline in LDL-C was lower in ezetimibe + statin-treated patients versus statin-treated patients, ±covariates. Differences were small but statistically significant due to the large sample size. In second-line uptitrate studies, ezetimibe + statin treatment resulted in greater unadjusted variability (SD) versus statin therapy, while the adjusted variability (RMSE) was significantly lower. Relative variability (CV=SD/mean) was lower for ezetimibe + statins versus statin therapy for all study types, being more pronounced in second-line add-on and uptitrate studies, attributed to larger mean LDL-C reductions for ezetimibe + statins versus statin groups. When assessed by individual study/type, statin brand, potency or dose, the CVs remained lower for ezetimibe + statins versus statins in second-line studies. The SDs showed no consistent trend for either therapy. In hypercholesterolemic patients, the absolute variability of LDL-C-lowering responses to ezetimibe + statins was not greater versus statins alone and appeared lower when adjusted for other factors. Relative variability was lower in patients treated with statins + ezetimibe. A better understanding of the variability of the LDL-C lowering response may help guide clinicians in making therapeutic decisions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Statin prescription rates and their facility-level variation in patients with peripheral artery disease and ischemic cerebrovascular disease: Insights from the Department of Veterans Affairs.

PubMed

McBride, Cameron L; Akeroyd, Julia M; Ramsey, David J; Nambi, Vijay; Nasir, Khurram; Michos, Erin D; Bush, Ruth L; Jneid, Hani; Morris, Pamela B; Bittner, Vera A; Ballantyne, Christie M; Petersen, Laura A; Virani, Salim S

2018-06-01

The 2013 American College of Cardiology/American Heart Association cholesterol guideline recommends moderate to high-intensity statin therapy in patients with peripheral artery disease (PAD) and ischemic cerebrovascular disease (ICVD). We examined frequency and facility-level variation in any statin prescription and in guideline-concordant statin prescriptions in patients with PAD and ICVD receiving primary care in 130 facilities across the Veterans Affairs (VA) health care system between October 2013 and September 2014. Guideline-concordant statin intensity was defined as the prescription of high-intensity statins in patients with PAD or ICVD ≤75 years and at least moderate-intensity statins in those >75 years. We calculated median rate ratios (MRR) after adjusting for patient demographic factors to assess the magnitude of facility-level variation in statin prescribing patterns independent of patient characteristics. Among 194,151 PAD patients, 153,438 patients (79.0%) were prescribed any statin and 79,435 (40.9%) were prescribed a guideline-concordant intensity of statin. PAD patients without ischemic heart disease were prescribed any statin and a guideline-concordant intensity of statin therapy less frequently (69.1% and 28.9%, respectively). Among 339,771 ICVD patients, 265,491 (78.1%) were prescribed any statin and 136,430 (40.2%) were prescribed a guideline-concordant intensity of statin. ICVD patients without ischemic heart disease were prescribed any statin and a guideline-concordant intensity of statin less frequently (70.9% and 30.5%, respectively). MRRs for both PAD and ICVD patients demonstrated a 20% and 28% variation among two facilities in treating two identical patients with statin therapy and guideline-concordant intensity of statin therapy, respectively. The prescription of statins, especially guideline-recommended intensity of statin therapy, is suboptimal in PAD and ICVD patients, with significant facility-level variation not explained by patient-level factors.

Statins for acute coronary syndrome.

PubMed

Vale, Noah; Nordmann, Alain J; Schwartz, Gregory G; de Lemos, James; Colivicchi, Furio; den Hartog, Frank; Ostadal, Petr; Macin, Stella M; Liem, Anho H; Mills, Edward J; Bhatnagar, Neera; Bucher, Heiner C; Briel, Matthias

2014-09-01

The early period following the onset of acute coronary syndrome (ACS) represents a critical stage of coronary heart disease, with a high risk of recurrent events and deaths. The short-term effects of early treatment with statins on patient-relevant outcomes in patients suffering from ACS are unclear. This is an update of a review previously published in 2011. To assess the effects, both harms and benefits, of early administered statins in patients with ACS, in terms of mortality and cardiovascular events. We updated the searches of CENTRAL (2013, Issue 3), MEDLINE (Ovid) (1946 to April Week 1 2013), EMBASE (Ovid) (1947 to 2013 Week 14), and CINAHL (EBSCO) (1938 to 2013) on 12 April 2013. We applied no language restrictions. We supplemented the search by contacting experts in the field, by reviewing the reference lists of reviews and editorials on the topic, and by searching trial registries. Randomized controlled trials (RCTs) comparing statins with placebo or usual care, with initiation of statin therapy within 14 days following the onset of ACS, follow-up of at least 30 days, and reporting at least one clinical outcome. Two authors independently assessed risk of bias and extracted data. We calculated risk ratios (RRs) for all outcomes in the treatment and control groups and pooled data using random-effects models. Eighteen studies (14,303 patients) compared early statin treatment versus placebo or no treatment in patients with ACS. The new search did not identify any new studies for inclusion. There were some concerns about risk of bias and imprecision of summary estimates. Based on moderate quality evidence, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction, and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) or four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up when compared to placebo or no treatment. There were no statistically significant risk reductions from statins for total death, total myocardial infarction, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month or at four months, although there were favorable trends related to statin use for each of these endpoints. Moderate quality evidence suggests that the incidence of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels more than 10 times the upper limit of normal) in statin-treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg. Based on moderate quality evidence, due to concerns about risk of bias and imprecision, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS. Serious side effects were rare.

Gemfibrozil in Combination with Statins-Is It Really Contraindicated?

PubMed

Wiggins, Barbara S; Saseen, Joseph J; Morris, Pamela B

2016-04-01

Gemfibrozil is a lipid-modifying agent that belongs to the fibric acid derivative class. Fibric acid derivatives activate peroxisome proliferator activated receptor α (PPAR-α). The primary role of these agents in clinical practice is for the management of hypertriglyceridemia. Triglycerides may be reduced by as much as 74 % in some patients. In addition to lowering triglycerides, these agents can also decrease very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) as well as raise high-density lipoprotein cholesterol (HDL-C). Based on the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and the National Lipid Association, pharmacologic therapy to reduce triglycerides should be considered when triglyceride levels are ≥500 mg/dL. While the use of gemfibrozil has decreased over the years for a variety of reasons, muscle-associated adverse effects is the predominant reason and the one that is most clinically relevant. However, despite these concerns, there are situations in which the use of gemfibrozil in combination with a statin may be necessary. Understanding the metabolism of gemfibrozil and the degree of interaction with the various statins will assist health-care providers to optimize safety when this combination is clinically indicated.

Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?

PubMed

Brennan, Emily T; Joy, Tisha R

2017-05-01

Statin-associated muscle symptoms (SAMS) are common. Rechallenge with the same statin (same-statin rechallenge) has recently been included as part of a proposed scoring index for diagnosing SAMS, but data regarding tolerability and efficacy of same-statin rechallenge, compared with other strategies, is minimal. In this study we evaluated the tolerability, percent change in low-density lipoprotein cholesterol (LDL-C), and proportion of patients achieving their LDL-C targets among 3 common management strategies-same-statin rechallenge, switching to a different statin (statin switch), and use of nonstatin medications only. We performed a retrospective analysis of 118 patients referred to our tertiary care centre for management of SAMS, defined as development of muscle-related symptoms with 2 or more statins. Baseline and last follow-up lipid parameters were documented. Patients were classified as tolerant of a strategy if, at their last follow-up, they remained on that strategy. After a median follow-up of 17 months, most (n = 79; 67%) patients were able to tolerate a statin. Tolerability was similar among the 3 treatment strategies (71% same-statin rechallenge vs 53% statin switch vs 57% for nonstatin therapy only; P = 0.11). Those in the same-statin rechallenge and statin switch groups achieved greater LDL-C reductions compared with those who only tolerated nonstatins (-38.8 ± 3.4% vs -36.4 ± 2.9% vs -17.3 ± 4.5%; P = 0.0007). A greater proportion of patients in the same-statin rechallenge group achieved their target LDL-C compared with those in the nonstatin therapy only group (50% vs 15%; odds ratio, 6.8; 95% confidence interval, 1.5-40.7; P = 0.04). Among individuals with a history of SAMS, most will tolerate statin therapy. Same-statin rechallenge was highly tolerable and efficacious. Thus, same-statin rechallenge might warrant increased utilization. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Muscle-related side-effects of statins: from mechanisms to evidence-based solutions.

PubMed

Taylor, Beth A; Thompson, Paul D

2015-06-01

This article highlights the recent findings regarding statin-associated muscle side effects, including mechanisms and treatment as well as the need for more comprehensive clinical trials in statin myalgia. Statin myalgia is difficult to diagnose and treat, as major clinical trials have not routinely assessed muscle side-effects, there are few clinically relevant biomarkers and assessment tools for the symptoms, many apparent statin-related muscle symptoms may be nonspecific and related to other drugs or health conditions, and prevalence estimates vary widely. Data thus suggest that only 30-50% of patients with self-reported statin myalgia actually experience muscle pain on statins during blinded, placebo-controlled trials. In addition, evidence to date involving mechanisms underlying statin myalgia and its range of symptoms and presentations supports the hypothesis that there are multiple, interactive and potentially additive mechanisms underlying statin-associated muscle side-effects. There are likely multiple and interactive mechanisms underlying statin myalgia, and recent studies have produced equivocal data regarding prevalence of statin-associated muscle side-effects, contributing factors and effectiveness of common interventions. Therefore, more clinical trials on statin myalgia are critical to the field, as are systematic resources for quantifying, predicting and reporting statin-associated muscle side-effects.

The impact of statin therapy on long-term cardiovascular outcomes in an outpatient cardiology practice

PubMed Central

Lai, Hoang M.; Aronow, Wilbert S.; Mercando, Anthony D.; Kalen, Phoenix; Desai, Harit V.; Gandhi, Kaushang; Sharma, Mala; Amin, Harshad; Lai, Trung M.

2011-01-01

Summary Background Statins reduce coronary events in patients with coronary artery disease. Material/Methods Chart reviews were performed in 305 patients (217 men and 88 women, mean age 74 years) not treated with statins during the first year of being seen in an outpatient cardiology practice but subsequently treated with statins. Based on the starting date of statins use, the long-term outcomes of myocardial infarction (MI), percutaneous coronary intervention (PCI), and coronary artery bypass graft surgery (CABGS) before and after statin use were compared. Results Mean follow-up was 65 months before statins use and 66 months after statins use. MI occurred in 31 of 305 patients (10%) before statins, and in 13 of 305 patients (4%) after statins (p<0.01). PCI had been performed in 66 of 305 patients (22%) before statins and was performed in 41 of 305 patients (13%) after statins (p<0.01). CABGS had been performed in 56 of 305 patients (18%) before statins and was performed in 20 of 305 patients (7%) after statins (p<0.001). Stepwise logistic regression showed statins use was an independent risk factor for MI (odds ratio=0.0207, 95% CI, 0.0082–0.0522, p<0.0001), PCI (odds ratio=0.0109, 95% CI, 0.0038–0.0315, p<0.0001), and CABGS (odds ratio=0.0177, 95% CI=0.0072–0.0431, p<0.0001) Conclusions Statins use in an outpatient cardiology practice reduces the incidence of MI, PCI, and CABGS. PMID:22129898

A Genetic and Pharmacological Analysis of Isoprenoid Pathway by LC-MS/MS in Fission Yeast

PubMed Central

Takami, Tomonori; Fang, Yue; Zhou, Xin; Jaiseng, Wurentuya; Ma, Yan; Kuno, Takayoshi

2012-01-01

Currently, statins are the only drugs acting on the mammalian isoprenoid pathway. The mammalian genes in this pathway are not easily amenable to genetic manipulation. Thus, it is difficult to study the effects of the inhibition of various enzymes on the intermediate and final products in the isoprenoid pathway. In fission yeast, antifungal compounds such as azoles and terbinafine are available as inhibitors of the pathway in addition to statins, and various isoprenoid pathway mutants are also available. Here in these mutants, treated with statins or antifungals, we quantified the final and intermediate products of the fission yeast isoprenoid pathway using liquid chromatography-mass spectrometry/mass spectrometry. In hmg1-1, a mutant of the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), ergosterol (a final sterol product), and squalene (an intermediate pathway product), were decreased to approximately 80% and 10%, respectively, compared with that of wild-type cells. Consistently in wild-type cells, pravastatin, an HMGR inhibitor decreased ergosterol and squalene, and the effect was more pronounced on squalene. In hmg1-1 mutant and in wild-type cells treated with pravastatin, the decrease in the levels of farnesyl pyrophosphate and geranylgeranyl pyrophosphate respectively was larger than that of ergosterol but was smaller than that of squalene. In Δerg6 or Δsts1 cells, mutants of the genes involved in the last step of the pathway, ergosterol was not detected, and the changes of intermediate product levels were distinct from that of hmg1-1 mutant. Notably, in wild-type cells miconazole and terbinafine only slightly decreased ergosterol level. Altogether, these studies suggest that the pleiotropic phenotypes caused by the hmg1-1 mutation and pravastatin might be due to decreased levels of isoprenoid pyrophosphates or other isoprenoid pathway intermediate products rather than due to a decreased ergosterol level. PMID:23145048

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge

PubMed Central

Majumdar, Gipsy; Mozhui, Khyobeni; Gerling, Ivan C.; Vera, Santiago R.; Fish-Trotter, Hannah; Williams, Robert W.; Childress, Richard D.

2017-01-01

Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myalgia and myositis were observed with increased frequency among patients with statin myalgia. PMID:28771594

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge.

PubMed

Elam, Marshall B; Majumdar, Gipsy; Mozhui, Khyobeni; Gerling, Ivan C; Vera, Santiago R; Fish-Trotter, Hannah; Williams, Robert W; Childress, Richard D; Raghow, Rajendra

2017-01-01

Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myalgia and myositis were observed with increased frequency among patients with statin myalgia.

Risk factors for lack of statin therapy in patients with diabetes and coronary artery disease.

PubMed

Zhang, Huabing; Plutzky, Jorge; Shubina, Maria; Turchin, Alexander

Patients with both diabetes and coronary artery disease (CAD) have exceedingly high cardiovascular risk. Nevertheless, little is known about prevalence of statin therapy in this population and reasons why some patients may not be receiving this potentially life-saving treatment. To investigate prevalence and predictors of statin therapy in patients with combined diabetes and CAD. We conducted a retrospective cohort study of primary care patients with diabetes and CAD followed at 2 academic medical centers between 2000 and 2011. We used multivariable logistic regression to identify patient and provider characteristics associated with (1) statin initiation (any history of statin therapy) and (2) statin persistence (active statin prescription at the study end). Of 8488 study patients, 7427 (87.5%) ever received statins and 6212 (73.2%) had persistent statin therapy. Younger age (odds ratio [OR], 1.26 per decade), smoking (OR, 1.49) and cardiologist evaluation (OR, 2.26) were associated with statin initiation (P < .0001 for all). Younger age (OR, 1.17), family history of CAD (OR, 1.39), no adverse reactions to statins (OR, 1.40; P < .0001 for all), female sex (OR, 1.22; P = .005), history of smoking (OR, 1.22; P = .003), cardiologist evaluation (OR, 1.23; P = .002), and lower HbA1c (OR, 1.04; P = 0.003) were associated with persistent statin therapy. Only 362 (29.8%) of the 1215 patients without persistent statin therapy had tried at least 2 statins, and 58 (4.8%) tried 3 statins. Many patients with combined CAD and diabetes are not treated with statins, although in this very high-risk group, even moderate-intensity statins result in meaningful reductions in cardiovascular events. Higher cardiovascular risk and cardiologist evaluation were associated with higher prevalence of statin therapy. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Statin adherence and risk of acute cardiovascular events among women: a cohort study accounting for time-dependent confounding affected by previous adherence.

PubMed

Lavikainen, Piia; Helin-Salmivaara, Arja; Eerola, Mervi; Fang, Gang; Hartikainen, Juha; Huupponen, Risto; Korhonen, Maarit Jaana

2016-06-03

Previous studies on the effect of statin adherence on cardiovascular events in the primary prevention of cardiovascular disease have adjusted for time-dependent confounding, but potentially introduced bias into their estimates as adherence and confounders were measured simultaneously. We aimed to evaluate the effect when accounting for time-dependent confounding affected by previous adherence as well as time sequence between factors. Retrospective cohort study. Finnish healthcare registers. Women aged 45-64 years initiating statin use for primary prevention of cardiovascular disease in 2001-2004 (n=42 807). Acute cardiovascular event defined as a composite of acute coronary syndrome and acute ischaemic stroke was our primary outcome. Low-energy fractures were used as a negative control outcome to evaluate the healthy-adherer effect. During the 3-year follow-up, 474 women experienced the primary outcome event and 557 suffered a low-energy fracture. The causal HR estimated with marginal structural model for acute cardiovascular events for all the women who remained adherent (proportion of days covered ≥80%) to statin therapy during the previous adherence assessment year was 0.78 (95% CI: 0.65 to 0.94) when compared with everybody remaining non-adherent (proportion of days covered <80%). The result was robust against alternative model specifications. Statin adherers had a potentially reduced risk of experiencing low-energy fractures compared with non-adherers (HR 0.90, 95% CI 0.76 to 1.07). Our study, which took into account the time dependence of adherence and confounders, as well as temporal order between these factors, is support for the concept that adherence to statins in women in primary prevention decreases the risk of acute cardiovascular events by about one-fifth in comparison to non-adherence. However, part of the observed effect of statin adherence on acute cardiovascular events may be due to the healthy-adherer effect. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Statin-Associated Side Effects.

PubMed

Thompson, Paul D; Panza, Gregory; Zaleski, Amanda; Taylor, Beth

2016-05-24

Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins are well tolerated, but associated with various statin-associated symptoms (SAS), including statin-associated muscle symptoms (SAMS), diabetes mellitus (DM), and central nervous system complaints. These are "statin-associated symptoms" because they are rare in clinical trials, making their causative relationship to statins unclear. SAS are, nevertheless, important because they prompt dose reduction or discontinuation of these life-saving mediations. SAMS is the most frequent SAS, and mild myalgia may affect 5% to 10% of statin users. Clinically important muscle symptoms, including rhabdomyolysis and statin-induced necrotizing autoimmune myopathy (SINAM), are rare. Antibodies against HMG-CoA reductase apparently provoke SINAM. Good evidence links statins to DM, but evidence linking statins to other SAS is largely anecdotal. Management of SAS requires making the possible diagnosis, altering or discontinuing the statin treatment, and using alternative lipid-lowering therapy. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Impact of the New ACC/AHA Guidelines on the Treatment of High Blood Cholesterol in a Managed Care Setting.

PubMed

Tran, Josephine N; Caglar, Toros; Stockl, Karen M; Lew, Heidi C; Solow, Brian K; Chan, Paul S

2014-11-01

In November 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) together issued new guidelines for the treatment of patients with high cholesterol, providing a new paradigm for the management of cholesterol in the primary and secondary prevention of coronary artery disease. To examine the impact of the 2013 ACC/AHA cholesterol treatment guidelines on pharmacy utilization of cholesterol-lowering drugs in a real-world managed care setting. Pharmacy claims from OptumRx, a national pharmacy benefit management provider, for the period between January 1, 2013, and December 31, 2013 (baseline period), were used to identify candidates for cholesterol-lowering therapy and to estimate the number of potential patients who will be starting or intensifying statin therapy based on the updated cholesterol treatment guidelines. Potential candidates for cholesterol-lowering treatments included patients with diabetes or hypertension aged 40 to 75 years who were not already receiving a cholesterol-lowering medication, as well as patients receiving cholesterol-lowering therapies during the baseline period. The baseline cholesterol-lowering medication market share was used to project changes in pharmacy utilization over the next 3 years. Based on the 2013 ACC/AHA cholesterol treatment guidelines, there will be a 25% increase in the proportion of the overall population that is treated with statins over the next 3 years, increasing from 3,909,407 (27.7%) patients to 4,892,668 (34.7%) patients. The largest proportion of the increase in statin utilization is projected to be for primary prevention in patients aged 40 to 75 years who were not receiving any cholesterol-lowering treatment at baseline. These projected changes will increase the overall number of statin prescriptions by 25% and will decrease the number of nonstatin cholesterol-lowering medication prescriptions by 68% during the next 3 years. The new 2013 ACC/AHA cholesterol treatment guidelines are projected to have a significant impact on the utilization of cholesterol-lowering drugs by increasing the overall proportion of the population receiving statin therapy and by decreasing the utilization of nonstatin cholesterol-lowering medications.

Effect of rosuvastatin on risk markers for venous thromboembolism in cancer.

PubMed

Ades, S; Douce, D; Holmes, C E; Cory, S; Prior, S; Butenas, S; Callas, P; Cushman, M

2018-06-01

Essentials Statins lower venous thromboembolism risk in general but have not been studied in cancer patients. We completed a randomized trial of rosuvastatin vs. placebo among cancer patients on chemotherapy. Rosuvastatin did not significantly lower prothrombotic biomarkers including D-dimer. The role of statins in venous thrombosis prevention in cancer patients remains unknown. Background Statin therapy is associated with lower risk of venous thromboembolism (VTE) but has not been prospectively evaluated in patients with advanced cancer. Objectives We determined if statin administration in this high-risk population reduces the risk of VTE, based on established and emerging biomarkers. Patients/Methods This double-blind, crossover, randomized controlled trial among patients with advanced cancer receiving systemic therapy allocated participants to rosuvastatin 20 mg daily or placebo for 3-4 weeks prior to crossover to the alternative therapy, with a 3-5-week washout. D-dimer, C-reactive protein (CRP), soluble (s)P-selectin, factor VIII (FVIII), thrombin generation and exploratory biomarkers focusing on endogenous thrombin potential, including tissue factor (TF), activated factor IX (FIXa) and activated factor XI (FXIa), were measured at the start and end of both treatment periods. The primary outcome was change in D-dimer with rosuvastatin compared with placebo. Results Of 38 enrolled participants, 24 (63%) completed the study. Rosuvastatin did not cause statistically significant changes in D-dimer levels or any other biomarker. CRP levels decreased by 40%; 4.3 mg L -1 (95% confidence interval, -11.0 to +2.5 mg L -1 ) compared with placebo. In post-hoc analysis, participants who received rosuvastatin initially during their first line of treatment had a 13% decrease in D-dimer. Circulating TF, FIXa and FXIa were detected in 26%, 68% and 71% of cancer patients despite not being found in healthy individuals. Conclusions Rosuvastatin did not cause favorable changes in biomarkers of VTE risk in advanced cancer patients receiving chemotherapy. The role of statin therapy as thromboprophylaxis in the cancer population remains uncertain. © 2018 International Society on Thrombosis and Haemostasis.

Lipophilic versus hydrophilic statin therapy for heart failure: a protocol for an adjusted indirect comparison meta-analysis

PubMed Central

2013-01-01

Background Statins are known to reduce cardiovascular morbidity and mortality in primary and secondary prevention studies. Subsequently, a number of nonrandomised studies have shown statins improve clinical outcomes in patients with heart failure (HF). Small randomised controlled trials (RCT) also show improved cardiac function, reduced inflammation and mortality with statins in HF. However, the findings of two large RCTs do not support the evidence provided by previous studies and suggest statins lack beneficial effects in HF. Two meta-analyses have shown statins do not improve survival, whereas two others showed improved cardiac function and reduced inflammation in HF. It appears lipophilic statins produce better survival and other outcome benefits compared to hydrophilic statins. But the two types have not been compared in direct comparison trials in HF. Methods/design We will conduct a systematic review and meta-analysis of lipophilic and hydrophilic statin therapy in patients with HF. Our objectives are: 1. To determine the effects of lipophilic statins on (1) mortality, (2) hospitalisation for worsening HF, (3) cardiac function and (4) inflammation. 2. To determine the effects of hydrophilic statins on (1) mortality, (2) hospitalisation for worsening HF, (3) cardiac function and (4) inflammation. 3. To compare the efficacy of lipophilic and hydrophilic statins on HF outcomes with an adjusted indirect comparison meta-analysis. We will conduct an electronic search of databases for RCTs that evaluate statins in patients with HF. The reference lists of all identified studies will be reviewed. Two independent reviewers will conduct the search. The inclusion criteria include: 1. RCTs comparing statins with placebo or no statin in patients with symptomatic HF. 2. RCTs that employed the intention-to-treat (ITT) principle in data analysis. 3. Symptomatic HF patients of all aetiologies and on standard treatment. 4. Statin of any dose as intervention. 5. Placebo or no statin arm as control. The exclusion criteria include: 1. RCTs involving cerivastatin in HF patients. 2. RCTs with less than 4 weeks of follow-up. Discussion We will perform an adjusted indirect comparison meta-analysis of lipophilic versus hydrophilic statins in patients with HF using placebo or no statin arm as common comparator. PMID:23618535

Managing hypercholesterolemia and preventing cardiovascular events in elderly and younger Chinese adults: focus on rosuvastatin.

PubMed

Wang, Zhen; Ge, Junbo

2014-01-01

Coronary heart disease (CHD) is the leading cause of death worldwide. The efficacy and safety of statins in primary and secondary prevention of CHD is confirmed in several large studies, and rosuvastatin is the latest statin on market. We review the published literature on rosuvastatin in Chinese people. The pharmacokinetics of rosuvastatin in Chinese is somewhat different from that in Caucasians, but this does not influence the linear relationship between dosage and efficacy and with no drug accumulation. Rosuvastatin 5-20 mg/day is effective and safe in decreasing low-density lipoprotein cholesterol in both younger and elderly patients with hypercholesterolemia, even in very elderly patients. Rosuvastatin also shows anti-inflammatory and anti-atherosclerosis features, such as reducing carotid intima-media thickness and plaque area. Rosuvastatin can also improve the prognosis of Chinese CHD patients, such as in the case of acute myocardial infarction. Its adverse-event rate is low and comparable to other statins. In conclusion, rosuvastatin is effective and safe for younger or elderly Chinese patients.

Current insights into pathogenesis of Parkinson's disease: Approach to mevalonate pathway and protective role of statins.

PubMed

Saeedi Saravi, Seyed Soheil; Saeedi Saravi, Seyed Sobhan; Khoshbin, Katayoun; Dehpour, Ahmad Reza

2017-06-01

Although Parkinson's disease (PD) is considered as the second most common life threatening age-related neurodegenerative disorder, but the underlying mechanisms for pathogenesis of PD are remained to be fully found. However, a complex relationship between genetic and environmental predisposing factors are involved in progression of PD. Dopaminergic neuronal cell death caused by mutations and accumulation of α-synuclein in Lewy bodies and neurites was suggested as the main strategy for PD, but current studies have paid attention to the role of mevalonate pathway in incidence of neurodegenerative diseases including PD. The discovery may change the therapeutic protocols from symptomatic treatment by dopamine precursors and agonists to neurodegenerative process halting drugs. Moreover, the downstream metabolites of mevalonate pathway may be used as diagnostic biomarkers for early diagnosis of PD. Statins, as cholesterol lowering drugs, may ameliorate the enzyme complex dysfunction, a key step in the progression of the neurodegenerative disorders, oxidative stress-induced damage and neuro-inflammation. Statins exert the neuroprotective effects on striatal dopaminergic neurons through blocking the mevalonate pathway. In the present review, we have focused on the new approaches to pathogenesis of PD regarding to mevalonate pathway, in addition to the previous understood mechanisms for the disease. It tries to elucidate the novel findings about PD for the development of future diagnostic and therapeutic strategies. Moreover, we explain the controversial role of statins in improvement or progression of PD and the position of these drugs in neuroprotection in PD patients. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

CYP109E1 is a novel versatile statin and terpene oxidase from Bacillus megaterium.

PubMed

Putkaradze, Natalia; Litzenburger, Martin; Abdulmughni, Ammar; Milhim, Mohammed; Brill, Elisa; Hannemann, Frank; Bernhardt, Rita

2017-12-01

CYP109E1 is a cytochrome P450 monooxygenase from Bacillus megaterium with a hydroxylation activity for testosterone and vitamin D3. This study reports the screening of a focused library of statins, terpene-derived and steroidal compounds to explore the substrate spectrum of this enzyme. Catalytic activity of CYP109E1 towards the statin drug-precursor compactin and the prodrugs lovastatin and simvastatin as well as biotechnologically relevant terpene compounds including ionones, nootkatone, isolongifolen-9-one, damascones, and β-damascenone was found in vitro. The novel substrates induced a type I spin-shift upon binding to P450 and thus permitted to determine dissociation constants. For the identification of conversion products by NMR spectroscopy, a B. megaterium whole-cell system was applied. NMR analysis revealed for the first time the ability of CYP109E1 to catalyze an industrially highly important reaction, the production of pravastatin from compactin, as well as regioselective oxidations generating drug metabolites (6'β-hydroxy-lovastatin, 3'α-hydroxy-simvastatin, and 4″-hydroxy-simvastatin) and valuable terpene derivatives (3-hydroxy-α-ionone, 4-hydroxy-β-ionone, 11,12-epoxy-nootkatone, 4(R)-hydroxy-isolongifolen-9-one, 3-hydroxy-α-damascone, 4-hydroxy-β-damascone, and 3,4-epoxy-β-damascone). Besides that, a novel compound, 2-hydroxy-β-damascenone, produced by CYP109E1 was identified. Docking calculations using the crystal structure of CYP109E1 rationalized the experimentally observed regioselective hydroxylation and identified important amino acid residues for statin and terpene binding.

Statins are related to impaired exercise capacity in males but not females.

PubMed

Bahls, Martin; Groß, Stefan; Ittermann, Till; Busch, Raila; Gläser, Sven; Ewert, Ralf; Völzke, Henry; Felix, Stephan B; Dörr, Marcus

2017-01-01

Exercise and statins reduce cardiovascular disease (CVD). Exercise capacity may be assessed using cardiopulmonary exercise testing (CPET). Whether statin medication is associated with CPET parameters is unclear. We investigated if statins are related with exercise capacity during CPET in the general population. Cross-sectional data of two independent cohorts of the Study of Health in Pomerania (SHIP) were merged (n = 3,500; 50% males). Oxygen consumption (VO2) at peak exercise (VO2peak) and anaerobic threshold (VO2@AT) was assessed during symptom-limited CPET. Two linear regression models related VO2peak with statin usage were calculated. Model 1 adjusted for age, sex, previous myocardial infarction, and physical inactivity and model 2 additionally for body mass index, smoking, hypertension, diabetes and estimated glomerular filtration rate. Propensity score matching was used for validation. Statin usage was associated with lower VO2peak (no statin: 2336; 95%-confidence interval [CI]: 2287-2,385 vs. statin 2090; 95%-CI: 2,031-2149 ml/min; P < .0001) and VO2@AT (no statin: 1,172; 95%-CI: 1,142-1,202 vs. statin: 1,111; 95%-CI: 1,075-1,147 ml/min; P = .0061) in males but not females (VO2peak: no statin: 1,467; 95%-CI: 1,417-1,517 vs. statin: 1,503; 95%-CI: 1,426-1,579 ml/min; P = 1.00 and VO2@AT: no statin: 854; 95%-CI: 824-885 vs. statin 864; 95%-CI: 817-911 ml/min; P = 1.00). Model 2 revealed similar results. Propensity scores analysis confirmed the results. In the general population present statin medication was related with impaired exercise capacity in males but not females. Sex specific effects of statins on cardiopulmonary exercise capacity deserve further research.

Adherence to Mediterranean Diet Offers an Additive Protection Over the Use of Statin Therapy: Results from the ATTICA Study (2002-2012).

PubMed

Panagiotakos, Demosthenes B; Georgousopoulou, Ekavi N; Georgiopoulos, Georgios A; Pitsavos, Christos; Chrysohoou, Christina; Skoumas, Ioannis; Ntertimani, Maria; Laskaris, Alexandros; Papadimitriou, Lampros; Tousoulis, Dimitrios; Stefanadis, Christodoulos

2015-01-01

The protective role of Mediterranean diet on cardiovascular disease (CVD) risk has been extensively discussed in the literature, but its incremental effect over the use of CVD risk reducing agents (such as hypolipidemic treatment) has rarely been evaluated. The ATTICA study was carried out in the Athens area during 2001-2002 and included 3042 participants free of CVD at baseline (49.8% men, aged 18-89 years). Adherence to Mediterranean diet was assessed using the MedDietScore (range 0-55) and statin use was recorded for all subjects. During 2011-2012, 2583 out of the 3042 baseline participants attended the 10-year follow-up of the ATTICA study (15% lost-to-follow-up) and CVD development was recorded. Adherence to Mediterranean diet (highest tertile) decreased CVD risk by 29.3% (Hazard Ratio (HR): 0.707, 95% Confidence Intervals (CI): 0.537-0.831) as compared with the lowest tertile, independently of statin use. Patients with hyperlipidemia on a statin that adopted unhealthy dietary habits (lowest tertile) had 75% increased CVD risk than normolipidemic subjects with healthy dietary habits (HR=1.75, 95%CI: 1.33-2.29). The addition of Mediterranean diet tertiles in the multivariable model reclassified 46.7% of the participants to CVD risk categories. Adherence to Mediterranean diet confers a considerable reduction in CVD risk, independently of gender, age, family history of CVD, diabetes mellitus, smoking status, hypertension and physical activity status. Therefore, CVD prevention strategies should involve the implementation of a Mediterranean diet in both the general population and patients on a statin.

Statin therapy in patients with community-acquired pneumonia.

PubMed

Grudzinska, Frances S; Dosanjh, Davinder Ps; Parekh, Dhruv; Dancer, Rachel Ca; Patel, Jaimin; Nightingale, Peter; Walton, Georgia M; Sapey, Elizabeth; Thickett, David R

2017-10-01

Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. There is evidence of an association between improved survival from infection and statin use. The possible beneficial effects of statins are complicated by the common use of macrolide antibiotics for pneumonia, with current guidance suggesting that concurrent macrolide and statin use is contraindicated.We conducted an observational study of statin use in patients with CAP. Of 2,067 patients with CAP, 30.4% were on statin therapy at admission. Statin users were more likely to survive the admission (p<0.001). In addition, we conducted a survey of doctors and found that knowledge regarding concurrent macrolide and statin use was lacking.These data suggest a potential role of statins in the management of CAP. Further research using high-dose statins is required to assess their safe use in subjects with mild to moderate infections. © Royal College of Physicians 2017. All rights reserved.

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells*

PubMed Central

Borahay, Mostafa A.; Kilic, Gokhan S.; Yallampalli, Chandrasekha; Snyder, Russell R.; Hankins, Gary D. V.; Al-Hendy, Ayman; Boehning, Darren

2014-01-01

Statins are drugs commonly used for the treatment of high plasma cholesterol levels. Beyond these well known lipid-lowering properties, they possess broad-reaching effects in vivo, including antitumor effects. Statins inhibit the growth of multiple tumors. However, the mechanisms remain incompletely understood. Here we show that simvastatin inhibits the proliferation of human leiomyoma cells. This was associated with decreased mitogen-activated protein kinase signaling and multiple changes in cell cycle progression. Simvastatin potently stimulated leiomyoma cell apoptosis in a manner mechanistically dependent upon apoptotic calcium release from voltage-gated calcium channels. Therefore, simvastatin possesses antitumor effects that are dependent upon the apoptotic calcium release machinery. PMID:25359773

Reduced creatine kinase release with statin use at the time of myocardial infarction.

PubMed

Bybee, Kevin A; Kopecky, Stephen L; Williams, Brent A; Murphy, Joseph G; Scott Wright, R

2004-09-01

Statin pre-treatment has been shown to reduce myocardial infarct size in animal models. We evaluated peak creatine kinase levels in humans based on concomitant or very early statin initiation following myocardial infarction. We identified 66 consecutive patients who received a statin within 24 h of admission to our coronary care unit for myocardial infarction. Each statin patient was matched with three patients who had not received statin therapy (n=198). Statin patients were subgrouped into those receiving statin therapy at the time of infarction (n=44) and those initiated on statin therapy within 24 h of infarction (n=22). Peak total creatine kinase concentrations were compared between groups. A linear regression model was developed to test for differences in peak creatine kinase after adjusting for differences between groups. Patients receiving statin therapy within 24 h of admission had significantly smaller median peak creatine kinase concentrations compared to those not receiving a statin (416 IU/l [258, 992] vs. 699 IU/l [339, 1728]; p=0.020). Subgroup analysis revealed that the lower peak creatine kinase concentrations within the statin group were a result of lower creatine kinase concentrations in those patients on a statin at the time of myocardial infarction (399 IU/l [255, 869] vs. 678 IU/l [276, 1870]; p<0.05). This difference retained statistical significance after adjustment for differences between groups. Statin therapy at the time of myocardial infarction is associated with lower peak creatine kinase concentrations. This suggests that statins may exhibit protective effects in the setting of myocardial ischemia and/or infarction in humans.

Pravastatin reduces steroid-induced osteonecrosis of the femoral head in SHRSP rats

PubMed Central

2012-01-01

Background and purpose Although the definite cause of steroid-induced osteonecrosis of the femoral head (ONFH) is unknown, peripheral circulatory failure, lipid metabolism disturbance, and increased oxidative stress are considered to be possible causes. We investigated whether pravastatin as a statin treatment reduces (1) the incidence of ONFH, (2) the adipocyte area, and (3) bone marrow changes in the femoral head. Methods We divided up 81 thirteen-week-old spontaneously hypertensive stroke-prone (SHRSP)/Izm male rats into 4 groups: a control group (group C), a group given pravastatin (group P), a group given steroid (group S), and a group given both pravastatin and steroid (Group PS). The steroid was administered at 15 weeks of age. Pravastatin, as a statin, was administered in the drinking water for 4 weeks. The rats were killed when 17 weeks old. Osteonecrosis was diagnosed based on histopathological examination. Oxidative stress was assessed from immunostaining. Results The incidence of histological osteonecrosis was lower in the groups given pravastatin. The percentage of adipocyte area in the bone marrow was lower in the PS group than in the S group. Immunohistochemical staining for oxidative stress showed that staining was less in the PS group than in the S group. Pravastatin had no effect on the blood-derived biochemical findings on lipid metabolism. However, it reduced the incidence of steroid-induced ONFH in these SHRSP rats. We presume that this occurred by reducing oxidative stress and by reducing the percentage of adipocyte area in the femoral heads. Interpretation Our data suggest that pravastatin may be effective in reducing steroid-induced ONFH. PMID:22313369

Prevention and management of statin adverse effects: A practical approach for pharmacists.

PubMed

Barry, Arden R; Beach, Jessica E; Pearson, Glen J

2018-01-01

Statin-associated adverse effects, primarily muscle-related symptoms, occur in up to approximately one-third of patients in clinical practice. Recently, a Canadian Consensus Working Group outlined 6 key principles to assess and manage patients with goal-inhibiting statin intolerance, defined as a syndrome characterized by symptoms or biomarker abnormalities that prevent the long-term use of and adherence to indicated statin therapy, which includes a trial of at least 2 statins and precludes reversible causes of statin adverse effects. These principles ensure patients are appropriately receiving a statin and aware of both the benefits and risks of therapy. As well, they address factors that may increase the risk of statin-associated myopathy. A thorough assessment of patients' clinical and laboratory history should be performed in any patient presenting with muscle symptoms on statin therapy, followed by a systematic dechallenge/rechallenge approach. In practice, most patients with statin intolerance due to muscle symptoms will be able to tolerate another statin. This is of particular importance because of the relative paucity of compelling evidence demonstrating a cardiovascular benefit with nonstatin therapies. Pharmacists are ideally situated to provide patient education, recommend changes to therapy and monitor patients with goal-inhibiting statin intolerance.

Early postoperative statin therapy is associated with a lower incidence of acute kidney injury following cardiac surgery

PubMed Central

Billings, Frederic T.; Pretorius, Mias; Siew, Edward D.; Yu, Chang; Brown, Nancy J.

2010-01-01

Objective To test the hypothesis that perioperative statin use reduces acute kidney injury (AKI) following cardiac surgery Design Retrospective analysis of prospectively collected data from an ongoing clinical trial Setting Quaternary-care university hospital Participants Three hundred twenty-four elective adult cardiac surgery patients Interventions None Measurements and Main Results We assessed the association of preoperative statin use, early postoperative statin use, and acute statin withdrawal with the incidence of AKI. Early postoperative statin use was defined as statin treatment within the first postoperative day. Statin withdrawal was defined as discontinuation of preoperative statin treatment prior to surgery until at least postoperative day 2. Logistic regression and propensity score modeling were used to control for AKI risk factors. Sixty-eight of 324 patients (21.0%) developed AKI. AKI patients stayed in the hospital longer (P=0.03) and were more likely to develop pneumonia (P=0.002) or die (P=0.001). Higher body mass index (P=0.003), higher central venous pressure (P=0.03), and statin withdrawal (27.4 vs. 14.7%, P=0.046) were associated with a higher incidence of AKI, while early postoperative statin use was protective (12.5 vs. 23.8%, P=0.03). Preoperative statin use did not affect risk of AKI. In multivariate logistic regression, age (P=0.03), male gender (P=0.02), body mass index (P<0.001), and early postoperative statin use (OR 0.32, 95% CI 0.14–0.72, P=0.006) independently predicted AKI. Propensity score-adjusted risk assessment confirmed the association between early postoperative statin use and reduced AKI (OR 0.30, 95% CI 0.13–0.70, P=0.005). Conclusions Early postoperative statin use is associated with a lower incidence of AKI among both chronic statin users and statin-naïve cardiac surgery patients. PMID:20599398

Efficacy, safety and tolerability of ongoing statin plus ezetimibe versus doubling the ongoing statin dose in hypercholesterolemic Taiwanese patients: an open-label, randomized clinical trial

PubMed Central

2012-01-01

Background Reducing low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia. Methods This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83) to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg) or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg) for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks. Results At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026) and total cholesterol (20.8% vs 12.2%, p = 0.0003). Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6%) vs doubling statin (41.2%), but the difference was not statistically significant (p = 0.1675). The safety and tolerability profiles were similar between treatments. Conclusion Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing. Trial registration Registered at ClinicalTrials.gov: NCT00652327 PMID:22621316

Muscular effects of statins in the elderly female: a review

PubMed Central

Bhardwaj, Shilpa; Selvarajah, Shalini; Schneider, Eric B

2013-01-01

Statins have demonstrated substantial benefits in supporting cardiovascular health. Older individuals are more likely to experience the well-known muscle-related side effects of statins compared with younger individuals. Elderly females may be especially vulnerable to statin-related muscle disorder. This review will collate and discuss statin-related muscular effects, examine their molecular and genetic basis, and how these apply specifically to elderly women. Developing strategies to reduce the incidence of statin-induced myopathy in older adult women could contribute to a significant reduction in the overall incidence of statin-induced muscle disorder in this vulnerable group of patients. Reducing statin-related muscle disorder would likely improve overall patient compliance, thereby leading to an increase in improved short- and long-term outcomes associated with appropriate use of statins. PMID:23355775

[C-reactive protein changes with antihypertensive and statin treatment].

PubMed

Rodilla, Enrique; Gómez-Belda, Ana; Costa, José A; Aragó, Miriam; Miralles, Amparo; González, Carmen; Pascual, José M

2005-10-29

The aim of this study was to evaluate the modifications of high sensitivity C-reactive protein (CRP) with antihypertensive and statin treatment in a hypertensive population with a wide range of coronary risks (CR). Retrospective follow-up study in 665 hypertensive patients: 556 (52% male) without dyslipidemia and CR (Framingham at 10 years) of 8.3 (7.6) as a control group (C) and 109 (61% male) with dyslipidemia and CR of 13.1 (8.8) who were treated with statins (T). Statins treatment was established according to NCEP-ATP-III. In both groups, the antihypertensive treatment was optimized in order to achieve blood pressure (BP) control (< 140/90 mmHg). A lipid profile and high sensitivity CRP (analyzed by nephelometry) was performed at the beginning and at the end of follow up [14.3 (3.6) months]. CRP levels were reduced in the T group -0.17 (0.2) mg/L vs. 0.14 (0.09) mg/L (p = 0.003, Mann-Whitney) in C. The lessening of CRP was not related to the reduction of lipids levels: total cholesterol (r = 0.06; p = 0.49), LDL-C (r = 0.11; p = 0.24), triglycerides (r = -0.02; p = 0.81) (Spearman), or to the reduction of systolic BP (r = -0.07; p = 0.44) and diastolic BP (r = -0.121; p = 0.21). The T group was treated with more antihypertensive drugs than C (2.2 [2.3] vs. 2.5 [1.2]; p = 0.02). Patients treated with ECA inhibitors or angiotensin II antagonist showed a tendency to decreasing the CRP levels more (p = 0.08). In hypertensive populations, statins induce a reduction of CRP levels. The reduction is not related to the lowering of lipids levels or BP values. The effect of statins on the reduction of CRP in hypertensive patients is not related to the lowering of lipids or BP.

Design and Rationale of the LAPLACE-TIMI 57 Trial: A Phase II, Double-Blind, Placebo-Controlled Study of the Efficacy and Tolerability of a Monoclonal Antibody Inhibitor of PCSK9 in Subjects With Hypercholesterolemia on Background Statin Therapy

PubMed Central

Kohli, Payal; Desai, Nihar R.; Giugliano, Robert P.; Kim, Jae B.; Somaratne, Ransi; Huang, Fannie; Knusel, Beat; McDonald, Shannon; Abrahamsen, Timothy; Wasserman, Scott M.; Scott, Robert; Sabatine, Marc S.

2013-01-01

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60–80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein’s role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C–lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy–Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia. PMID:22714699

Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer.

PubMed

Vogel, Tilley Jenkins; Goodman, Marc T; Li, Andrew J; Jeon, Christie Y

2017-08-01

Observational studies suggest that statin therapy for cardio-protection is associated with improved survival in cancer patients. We sought to evaluate the impact of statin treatment on ovarian cancer survival in a nationally representative elderly population. The linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare claims data on patients diagnosed with epithelial ovarian cancer in 2007-2009 were used to extract data on statin prescription fills, population characteristics, primary treatment, comorbidity and survival. Cox regression models were used to examine the association between statin treatment and overall survival. Among the 1431 ovarian cancer patients who underwent surgical resection, 609 (42.6%) filled prescriptions for statin. The majority of statin-users (89%) were prescribed a lipophilic formulation. Mean overall survival among statin-users was 32.3months compared to 28.8months for non-users (p<0.0001). A 34% reduction in death was associated with statin therapy, independent of age, race, neighborhood median household income, stage, platinum therapy and comorbid conditions (HR=0.66, 95% CI 0.55-0.81). Improved overall survival with statin use was observed for both serous (HR=0.69, 95% CI 0.54-0.87) and non-serous (HR=0.63, 95% CI 0.44-0.90) histologies. When statin treatment was categorized by lipophilicity and intensity, a significant survival benefit was limited to lipophilic statin users and those who took statins of moderate intensity. This SEER-Medicare analysis demonstrates improvement in overall survival with lipophilic statin use after surgery in elderly patients with epithelial ovarian cancer. A clinical trial to evaluate the impact of statin treatment in ovarian cancer survival is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

Withdrawal of statins increases event rates in patients with acute coronary syndromes.

PubMed

Heeschen, Christopher; Hamm, Christian W; Laufs, Ulrich; Snapinn, Steven; Böhm, Michael; White, Harvey D

2002-03-26

HMG-CoA Reductase Inhibitors (statins) reduce cardiac event rates in patients with stable coronary heart disease. Withdrawal of chronic statin treatment during acute coronary syndromes may impair vascular function independent of lipid-lowering effects and thus increase cardiac event rate. We investigated the effects of statins on the cardiac event rate in 1616 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study who had coronary artery disease and chest pain in the previous 24 hours. We recorded death and nonfatal myocardial infarction during the 30-day follow-up. Baseline clinical characteristics did not differ among 1249 patients without statin therapy, 379 patients with continued statin therapy, and 86 patients with discontinued statin therapy after hospitalization. Statin therapy was associated with a reduced event rate at 30-day follow-up compared with patients without statins (adjusted hazard ratio, 0.49 [95% CI, 0.21 to 0.86]; P=0.004). If the statin therapy was withdrawn after admission, cardiac risk increased compared with patients who continued to receive statins (2.93 [95% CI, 1.64 to 6.27]; P=0.005) and tended to be higher compared with patients who never received statins (1.69 [95% CI, 0.92 to 3.56]; P=0.15). This was related to an increased event rate during the first week after onset of symptoms and was independent of cholesterol levels. In a multivariate model, troponin T elevation (P=0.005), ST changes (P=0.02), and continuation of statin therapy (P=0.008) were the only independent predictors of patient outcome. Statin pretreatment in patients with acute coronary syndromes is associated with improved clinical outcome. However, discontinuation of statins after onset of symptoms completely abrogates this beneficial effect.

Statin-induced necrotizing myositis - a discrete autoimmune entity within the "statin-induced myopathy spectrum".

PubMed

Hamann, Philip D H; Cooper, Robert G; McHugh, Neil J; Chinoy, Hector

2013-10-01

Statin-induced necrotizing myositis is increasingly being recognised as part of the "statin-induced myopathy spectrum". As in other immune-mediated necrotizing myopathies, statin-induced myositis is characterised by proximal muscle weakness with marked serum creatinine kinase elevations and histological evidence of myonecrosis, with little or no inflammatory cell infiltration. Unlike other necrotizing myopathies, statin-induced myopathy is associated with the presence of autoantibodies directed against 3-hydroxy-3-methylglutaryl- coenzyme A reductase (the enzyme target of statin therapies), and with Human Leukocyte Antigen-DRB1*11. This article summarises the clinical presentation, investigations and management of this rare, but serious complication of statin therapy. © 2013 Elsevier B.V. All rights reserved.

Anticonvulsant and Antioxidant Effects of Pitavastatin Against Pentylenetetrazol-Induced Kindling in Mice.

PubMed

Faghihi, Nastaran; Mohammadi, Mohammad Taghi

2017-06-01

Purpose: The pleiotropic effects of statins (antioxidant and anti-inflammation) have been reported by previous studies. Therefore, we aimed to determine whether pitavastatin has protective effects against pentylenetetrazol (PTZ)-induced kindling in mice and also whether pitavastatin improves the brain antioxidant capacity and attenuates the oxidative injuries in kindled mice. Methods: Twenty-four mice were randomly divided into four groups (each group n=6); control, PTZ-kindling and PTZ-kindled rats treated with pitavastatin (1&4 mg/kg). PTZ kindling seizures were induced by repetitive intraperitoneal injections of PTZ (65 mg/kg) every 48 hours till day twenty-one. Animals received daily oral pitavastatin for twenty-one days. Latency, score and duration of the seizures were recorded. The activities of catalase (CAT) ad superoxide dismutase (SOD), and likewise the contents of malondialdehyde (MDA) and nitrate were assessed in the brains of all rats. Results: There was a progressive reduction in latency of the kindled rats in the next injections of PTZ. Pitavastatin reduced this value (latency) particularly at higher dose. Seizures duration and score also decreased in treatment groups. SOD and CAT activities significantly decreased in PTZ-kindling group by 62% and 64%, respectively, but pitavastatin did not significantly change the SOD and CAT activities. Brain MDA and nitrate significantly increased in PTZ-kindling group by 53% and 30%, respectively. Pitavastatin at higher dose significantly decreased the MDA and nitrate contents of PTZ-kindling rats by 45% and 32%, respectively. Conclusion: Our findings revealed that pitavastatin can improve the behavioral expression of the PTZ-kindling rats and attenuate the seizure-induced oxidative/nitrosative damage.

Successful reintroduction of statin therapy after statin-associated rhabdomyolysis.

PubMed

Simons, Janet E; Holbrook, Anne M; Don-Wauchope, Andrew C

2015-01-01

The case report demonstrates the successful use of an alternative statin after a statin-related episode of rhabdomyolysis. Statin-associated rhabdomyolysis is a serious adverse event with a very low incidence and is considered the most severe of the muscle-related side effects of the statins. Rechallenge with statins is not a recommended practice after rhabdomyolysis. The patient experienced a myocardial infarct 1 y after the episode of rhabdomyolysis. He used alternative lipid-lowering therapy for 2 y. His low-density lipoprotein cholesterol was not meeting typical secondary prevention targets. An alternative statin was introduced and the patient has been followed for 4 years without recurrence of the rhabdomyolysis. This case suggests it may be time to reconsider the accepted practice of permanently avoiding statin therapy after rhabdomyolysis. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

An update on the relationship between statins and physical activity.

PubMed

Panza, Gregory A; Taylor, Beth A; Thompson, Paul D

2016-09-01

This review examined studies published within the last 16 months that investigated the relationship between statins and physical activity. These recent studies suggest that statins do not adversely affect cardiorespiratory fitness, muscle strength, athletic performance, or physical activity adherence. One recent study comparing patients with statin-associated myalgia and nonstatin-using controls did report that statins are associated with a slowing of time to peak power output, increased abdominal adiposity, and insulin resistance. Statin users also had different muscle gene expression than controls, but conclusions are limited by the design of that study. Previous reports suggest that statin-associated muscle symptoms such as myalgia, cramps, and weakness occur more frequently in physically active individuals, but the recent studies we reviewed do not provide additional support for this possibility. Well-designed clinical trials are needed to determine whether different statins or statin doses evoke statin-associated muscle symptoms or muscle damage that may reduce cardiorespiratory fitness and adherence to physical activity.

Statin Intolerance: A Literature Review and Management Strategies.

PubMed

Saxon, David R; Eckel, Robert H

Statin intolerance is a commonly encountered clinical problem for which useful management strategies exist. Although many patients report statin-related muscle symptoms, studies indicate that the majority of these patients can tolerate a statin upon re-challenge. Alternative statin dosing strategies are an effective way to modify and reintroduce statin therapy for patients reporting adverse symptoms. Correction of vitamin D deficiency and hypothyroidism may improve statin tolerability in some patients. CoQ10 supplementation has been found to be of no benefit for statin-related muscle symptoms in most recent clinical trials. PCSK9 inhibitors are a new therapeutic option that if confirmed as safe and effective by outcomes trials may be of substantial benefit to select patients at high ASCVD risk who are unable to achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on maximally tolerated statin therapy. Other available medications to lower LDL-C in statin intolerant patients include ezetimibe, bile acid sequestrants, niacin, and fibrates. Published by Elsevier Inc.

The Relationship between Statins and Prostate Cancer Prevention

DTIC Science & Technology

2011-09-01

jnci.oxfordjournals.org JNCI | Articles 887 any of the following medications: atorvastatin , fluvastatin, lova- statin, pravastatin, or simvastatin. Statin users may...lovastatin and pravastatin doses by 2, dividing the fluvastatin dose by 4, and multiplying the atorvastatin dose by 2. We then determined the hazard...dif- ferent statin agent in the statin user group 1 year after statin initi- ation: simvastatin, 54.6%; lovastatin, 43.9%; atorvastatin , 1.2

Medication non-adherence and uncertainty: Information-seeking and processing in the Danish LIFESTAT survey.

PubMed

Kriegbaum, Margit; Lau, Sofie Rosenlund

2017-09-23

Statins are widely prescribed to lower cardiovascular morbidity and mortality. However, statin non-adherence is very high. The aim of this paper was to investigate reasons for stopping statin treatment in the general population and to study how aspects of information-seeking and processing is associated with statin non-adherence. This study used a population survey on 3050 Danish residents aged 45-65 years. Reasons for statin discontinuation was studied among those who were previous statin users. The association between information seeking and processing and statin discontinuation were analysed using multivariate logistical regression models. Experience of side effects and fear of side effects played an important role in the discontinuation of statin treatment. Feelings of uncertainty and confusion regarding information on statins predicted statin discontinuation. This applied to information from both mass media and from general practitioners. There was no clear pattern of information seeking and statin non-adherence. The article point to the impact of information-seeking on the decision to take cholesterol-lowering medication. This included contributions from information disseminated by media outlets. Side effects and fear of side effects should be addressed in clinical practice. Health care professionals should pay attention to emotional aspects of how information is disseminated and perceived by statin users. Copyright © 2017. Published by Elsevier Inc.

Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement.

PubMed

Banach, Maciej; Stulc, Tomas; Dent, Ricardo; Toth, Peter P

2016-12-15

Although statin therapy has proven to be the cornerstone for prevention and treatment of cardiovascular disease (CVD), there are many patients for whom long-term therapy remains suboptimal. The aims of this article are to review the current complex issues associated with statin use and to explore when novel treatment approaches should be considered. Statin discontinuation as well as adherence to statin therapy remain two of the greatest challenges for lipidologists. Evidence suggests that between 40 and 75% of patients discontinue their statin therapy within one year after initiation. Furthermore, whilst the reasons for persistence with statin therapy are complex, evidence shows that low-adherence to statins negatively impacts clinical outcomes and residual CV risk remains a major concern. Non-adherence or lack of persistence with long-term statin therapy in real-life may be the main cause of inadequate low density lipoprotein cholesterol lowering with statins. There is a large need for the improvement of the use of statins, which have good safety profiles and are inexpensive. On the other hand, in a non-cost-constrained environment, proprotein convertase subtilisin/kexin type 9 inhibitors should arguably be used more often in those patients in whom treatment with statins remains unsatisfactory. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Clinical review: impact of statin substitution policies on patient outcomes.

PubMed

Atar, Dan; Carmena, Rafael; Clemmensen, Peter; K-Laflamme, Annik; Wassmann, Sven; Lansberg, Peter; Hobbs, Richard

2009-01-01

The increasing awareness of cost issues in health care has led to the increasing use of policy-driven substitution of branded for generic medications, particularly relative to statin treatment for cardiovascular diseases. While there are potential short-term health care savings, the consequences for primary care are under-researched. Our objective was to review data on intensive statin therapy and generic substitution in patients at high cardiovascular risk. Current treatment guidelines for the prevention of cardiovascular disease are consistent in their recommendations regarding statin therapy and treatment targets. Clinical trials demonstrate that to reduce cardiovascular events, a statin is more effective than placebo, intensive statin therapy is more effective than moderate statin therapy in patients with established coronary disease, and in patients receiving intensive statin therapy the lowest risk is associated with the lowest low-density lipoprotein levels. However, in clinical practice, patients at high cardiovascular risk are prone to be undertreated. Observational studies suggest that mandatory statin substitution may increase the gap between achieved and recommended therapeutic targets. Substitution of generic statins may be cost-saving, particularly at the primary prevention level. However, statin substitution policies have not been adequately studied on a population level. Data raise concern that mandated statin substitution may lead to unfavourable treatment choices at the level of the individual high-risk patient.

Statin and NSAID Use and Prostate Cancer Risk

PubMed Central

Coogan, Patricia F.; Kelly, Judith Parsells; Strom, Brian L.; Rosenberg, Lynn

2010-01-01

Purpose Some studies have reported reduced risks of advanced, but not early, prostate cancer among statin users, and one study found a reduced risk only among statin users who had also used nonsteroidal anti-inflammatory drugs (NSAIDs). We have previously reported no association between statin use and prostate cancer in our hospital-based Case Control Surveillance Study. The purpose of the present analyses was to update the findings by cancer stage and to evaluate the joint use of statins and NSAIDs. Methods Cases were 1367 men with prostate cancer and controls were 2007 men with diagnoses unrelated to statin or NSAID use. We used multivariable logistic regression analyses to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for statin use compared with no use, and joint use of statin and NSAIDs compared with use of neither. Results The odds ratio among regular statin users was 1.1 (95% CI 0.9–1.5), and odds ratios were similar among early and late stage cancers. The odds ratio among joint statin and NSAID users was 1.1 (95% CI 0.7–1.6). Conclusion The present results do not support a protective effect of statin use, or statin and NSAID use, on the risk of advanced prostate cancer. PMID:20582910

Statin Therapy: Review of Safety and Potential Side Effects.

PubMed

Ramkumar, Satish; Raghunath, Ajay; Raghunath, Sudhakshini

2016-11-01

Hydroxymethyl glutaryl coenzyme A reductase inhibitors, commonly called statins, are some of the most commonly prescribed medications worldwide. Evidence suggests that statin therapy has significant mortality and morbidity benefit for both primary and secondary prevention from cardiovascular disease. Nonetheless, concern has been expressed regarding the adverse effects of long term statin use. The purpose of this article was to review the current medical literature regarding the safety of statins. Major trials and review articles on the safety of statins were identified in a search of the MEDLINE database from 1980 to 2016, which was limited to English articles. Myalgia is the most common side effect of statin use, with documented rates from 1-10%. Rhabdomyolysis is the most serious adverse effect from statin use, though it occurs quite rarely (less than 0.1%). The most common risk factors for statin-related myopathy include hypothyroidism, polypharmacy and alcohol abuse. Derangement in liver function tests is common, affecting up to 1% of patients; however, the clinical significance of this is unknown. Some statin drugs are potentially diabetogenic and the risk appears to increase in those patients on higher doses. Pitavastatin has not been associated with increased risk of diabetes. Statins have not been proven to increase the risk of malignancy, dementia, mood disorders or acute interstitial nephritis. However, statins do have multiple drug interactions, primarily those which interact with the cytochrome p450 enzyme group. Overall, statin drugs appear to be safe for use in the vast majority of patients. However, patients with multiple medical co-morbidities are at increased risk of adverse effects from long-term statin use.

Current treatment of dyslipidaemia: PCSK9 inhibitors and statin intolerance.

PubMed

Koskinas, Konstantinos; Wilhelm, Matthias; Windecker, Stephan

2016-01-01

Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients.

The association between achieving low-density lipoprotein cholesterol (LDL-C) goal and statin treatment in an employee population.

PubMed

Burton, Wayne N; Chen, Chin-Yu; Schultz, Alyssa B; Edington, Dee W

2010-02-01

Statin medications are recommended for patients who have not achieved low-density lipoprotein cholesterol (LDL-C) goals through lifestyle modifications. The objective of this retrospective observational study was to examine statin medication usage patterns and the relationship with LDL-C goal levels (according to Adult Treatment Panel III guidelines) among a cohort of employees of a major financial services corporation. From 1995 to 2004, a total of 1607 executives participated in a periodic health examination program. An index date was assigned for each study participant (date of their exam) and statin medication usage was determined from the pharmacy claims database for 365 days before the index date. Patients were identified as adherent to statins if the medication possession ratio was > or =80%. In all, 150 (9.3%) executives filled at least 1 statin prescription in the 365 days prior to their exam. A total of 102 statin users (68%) were adherent to statin medication. Among all executives who received statin treatment, 70% (odds ratio [OR] = 2.30, 95% confidence interval [CI] = 1.82, 2.90) achieved near-optimal (<130 mg/dL) and 30% (OR = 1.78, 95% CI = 1.15, 2.76) achieved optimal (<100 mg/dL) LDL-C goals, which is significantly higher than the rates among statin nonusers (55% and 21%). Adherent statin users were more likely to achieve recommended near-optimal LDL-C goals compared to statin nonusers (overall P = 0.002; adherent: OR = 2.75, 95% CI = 1.662, 4.550), while nonadherent statin users were more likely to achieve the optimal goal compared to statin nonusers (OR = 2.223; CI = 1.145, 4.313). Statin usage was associated with improvements in LDL-C goal attainment among executives who participated in a periodic health examination. Appropriate statin medication adherence should be encouraged in working populations in order to achieve LDL-C goals.

Investigating the prevalence, predictors, and prognosis of suboptimal statin use early after a non-ST elevation acute coronary syndrome.

PubMed

Turner, Richard M; Yin, Peng; Hanson, Anita; FitzGerald, Richard; Morris, Andrew P; Stables, Rod H; Jorgensen, Andrea L; Pirmohamed, Munir

High-potency statin therapy is recommended in the secondary prevention of cardiovascular disease but discontinuation, dose reduction, statin switching, and/or nonadherence occur in practice. To determine the prevalence and predictors of deviation from high-potency statin use early after a non-ST elevation acute coronary syndrome (NSTE-ACS) and its association with subsequent major adverse cardiovascular events (MACE) and all-cause mortality (ACM). A total of 1005 patients from a UK-based prospective NSTE-ACS cohort study discharged on high-potency statin therapy (atorvastatin 80 mg, rosuvastatin 20 mg, or 40 mg daily) were included. At 1 month, patients were divided into constant high-potency statin users, and suboptimal users incorporating statin discontinuation, dose reduction, switching statin to a lower equivalent potency, and/or statin nonadherence. Follow-up was a median of 16 months. There were 156 suboptimal (∼15.5%) and 849 constant statin users. Factors associated in multivariable analysis with suboptimal statin occurrence included female sex (odds ratio 1.75, 95% confidence interval [CI] 1.14-2.68) and muscular symptoms (odds ratio 4.28, 95% CI 1.30-14.08). Suboptimal statin use was associated with increased adjusted risks of time to MACE (hazard ratio 2.10, 95% CI 1.25-3.53, P = .005) and ACM (hazard ratio 2.46, 95% CI 1.38-4.39, P = .003). Subgroup analysis confirmed that the increased MACE/ACM risks were principally attributable to statin discontinuation or nonadherence. Conversion to suboptimal statin use is common early after NSTE-ACS and is partly related to muscular symptoms. Statin discontinuation or non-adherence carries an adverse prognosis. Interventions that preserve and enhance statin utilization could improve post NSTE-ACS outcomes. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

[THE SPIRIT CHOLESTEROL, BIOLOGICA L ROLE AT STAGES OF PHYLOGENESIS, MECHANISMS OF INHIBITION OF SYNTHESIS OF STEROL BY STATINS, FACTORS OF PHARMACOGENOMICS AND DIAGNOSTIC SIGNIFICANCE OF CHOLESTEROL OF LIPOPROTEINS OF LOW DENSITY].

PubMed

Titov, V N; Kotlovskii, M Yu; Pokrovskii, A A; Kotlovskaia, O S; Osedko, A V; Titova, N M; Kotlovskii, Yu V; Digaii, A M

2015-04-01

The hypolipidemic effect of statins is realized by inhibition of synthesis of local pool of cholesterol spirit in endoplasmic net of hepatocytes. The cholesterol spirit covers all hydrophobic medium of triglycerides with polar mono layer of phosphatidylcholines and cholesterol spirit prior to secretion of lipoproteins of very low density into hydrophilic medium. The lesser mono layer between lipase enzyme and triglycerides substrate contains of cholesterol spirit the higher are the parameters of hydrolysis of palmitic and oleic lipoproteins of very low density. The sequence of effect of statins is as follows: blocking of synthesis in hepatocytes and decreasing of content of unesterified cholesterol spirit in blood plasma; activation of hydrolysis of triglycerides in palmitic and oleic lipoproteins of very low density; formation of ligand lipoproteins of very low density and their absorption by cells by force of apoB-100 endocytosis; decreasing in blood of content of polyenoic fatty acids, equimolar esterified by cholesterol spirit, polyethers of cholesterol spirit and decreasing of level of cholesterol spirit-lipoproteins of very low density. There is no way to eliminate aphysiological effect of disordered biological function of trophology (nutrition) on metabolism of fatty acids in population by means of pharmaceuticals intake. It is necessary to eliminate aphysiological effect of environment. To decrease rate of diseases of cardiovascular system one has to decrease in food content of saturated fatty acids and in the first instance palmitic saturated fatty acid, trans-form fatty acid, palmitoleic fatty acids up to physiological values and increase to the same degree the content of polyenoic fatty acids. The saturated fatty acids block absorption of polyenoic fatty acids by cells. The atherosclerosis is a deficiency of polyenoic fatty acids under surplus of palmitic saturated fatty acid.

The new dyslipidemia guidelines: what is the debate?

PubMed

Anderson, Todd J; Mancini, G B John; Genest, Jacques; Grégoire, Jean; Lonn, Eva M; Hegele, Robert A

2015-05-01

Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Therefore, lifestyle interventions and pharmacological approaches to decrease cholesterol are widely used in cardiovascular disease prevention. The introduction and widespread use of 3-hydroxy-3 methylglutaryl coenzyme A inhibitors (statins) for individuals at risk of atherosclerotic disease has been an important advance in cardiovascular care. There can be no doubt that better control of dyslipidemia, even in subjects whose low-density lipoprotein cholesterol level is not particularly high, has reduced overall event rates. On a background of lifestyle interventions, statins are routinely used to decrease risk along with aspirin and interventions to control hypertension and diabetes. More than other risk factors, the approach to the identification and treatment of dyslipidemia has been heterogeneous and widely debated. The recent release of the 2013 American College of Cardiology/American Heart Association dyslipidemia guidelines has reignited the controversy over the best approach for risk stratification and treatment. In this article we review the importance of statin therapy for global cardiovascular risk reduction, compare the Canadian Cardiovascular Society dyslipidemia guidelines with other standards, and discuss the points of debate. Despite the seeming variety of recommendations, their common link is a systematic approach to risk stratification and treatment, which will continue to benefit our patients at risk. Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Weakness and pain in arms and legs · dark urine · history of vertebral osteomyelitis · Dx?

PubMed

Charokopos, Antonios; Muhammad, Tariq; Surbhi, Sidana; Brateanu, Andrei

2017-03-01

Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious usclerelated syndrome. Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold. The trigger for our patient's statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.

Management of statin-intolerant high-risk patients.

PubMed

Tziomalos, Konstantinos; Athyros, Vasilios G; Karagiannis, Asterios; Mikhailidis, Dimitri P

2010-09-01

Statins are an essential part of the management of patients at high vascular risk and are generally well-tolerated. However, statin intolerance will be observed more frequently as more stringent low density lipoprotein cholesterol (LDL-C) targets are pursued in an ever increasing number of patients. We review the management options for high-risk patients intolerant to statin treatment. Potential strategies include switching to a different statin, reducing the frequency of statin administration, substituting statins with other LDL-C-lowering agents (e.g. ezetimibe, colesevelam or nicotinic acid) and combining low-dose statin treatment with other lipid-modifying drugs. A limited number of studies specifically assessed statin-intolerant patients and most were small and of short duration. It is therefore difficult to make evidence-based recommendations for the management of this population. In addition, all treatment options have limitations in terms of safety and/or efficacy.

Statin intolerance - a question of definition.

PubMed

Algharably, Engi Abdel-Hady; Filler, Iris; Rosenfeld, Stephanie; Grabowski, Katja; Kreutz, Reinhold

2017-01-01

Statin therapy is the backbone of pharmacologic therapy for low-density lipoproteins cholesterol lowering and plays a pivotal role in cardiovascular disease prevention. Statin intolerance is understood as the inability to continue using a statin to reduce individual cardiovascular risk sufficiently, due to the development of symptoms or laboratory abnormalities attributable to the initiation or dose escalation of a statin. Muscle symptoms are the most common side effects observed. Areas covered: The main aim of this article is to present a review on published definitions of statin intolerance. In addition, a brief review on clinical aspects and risk factors of statin intolerance is provided and features for a common definition for statin intolerance are suggested. Expert opinion: A definition of statin intolerance by major drug regulatory agencies is not available. In clinical studies, different definitions are chosen and results are not comparable; different medical associations do not agree on one common definition. There is an unmet need to establish a common definition of statin intolerance to ensure an appropriate clinical use of this important drug class. Further work is required to develop a consensus definition on statin intolerance that could have significant positive impact on both research and clinical management.

Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that is enhanced in combination with a statin.

PubMed

Mason, R Preston; Dawoud, Hazem; Jacob, Robert F; Sherratt, Samuel C R; Malinski, Tadeusz

2018-07-01

The endothelium exerts many vasoprotective effects that are largely mediated by release of nitric oxide (NO). Endothelial dysfunction represents an early but reversible step in atherosclerosis and is characterized by a reduction in the bioavailability of NO. Previous studies have shown that eicosapentaenoic acid (EPA), an omega-3 fatty acid (O3FA), and statins individually improve endothelial cell function, but their effects in combination have not been tested. Through a series of in vitro experiments, this study evaluated the effects of a combined treatment of EPA and the active metabolite of atorvastatin (ATM) on endothelial cell function under conditions of oxidative stress. Specifically, the comparative and time-dependent effects of these agents on endothelial dysfunction were examined by measuring the levels of NO and peroxynitrite (ONOO - ) released from human umbilical vein endothelial cells (HUVECs). The data suggest that combined treatment with EPA and ATM is beneficial to endothelial function and was unique to EPA and ATM since similar improvements could not be recapitulated by substituting another O3FA docosahexaenoic acid (DHA) or other TG-lowering agents such as fenofibrate, niacin, or gemfibrozil. Comparable beneficial effects were observed when HUVECs were pretreated with EPA and ATM before exposure to oxidative stress. Interestingly, the kinetics of EPA-based protection of endothelial function in response to oxidation were found to be significantly different than those of DHA. Lastly, the beneficial effects on endothelial function generated by combined treatment of EPA and ATM were reproduced when this study was expanded to an ex vivo model utilizing rat glomerular endothelial cells. Taken together, these findings suggest that a combined treatment of EPA and ATM can inhibit endothelial dysfunction that occurs in response to conditions such as hyperglycemia, oxidative stress, and dyslipidemia. Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Statin Use and Musculoskeletal Pain Among Adults with and without Arthritis

PubMed Central

Buettner, Catherine; Rippberger, Matthew J.; Smith, Julie K.; Leveille, Suzanne G.; Davis, Roger B.; Mittleman, Murray A.

2011-01-01

BACKGROUND Musculoskeletal symptoms are common adverse effects of statins, yet little is known about the prevalence of musculoskeletal pain and statin use in the general population. METHODS We conducted a cross sectional study of the National Health and Nutrition Examination Survey (NHANES) 1999–2004. We estimated the prevalence of self-reported musculoskeletal pain according to statin use and calculated prevalence ratio estimates of musculoskeletal pain obtained from adjusted multiple logistic regression modeling. RESULTS Among 5,170 participants without arthritis, the unadjusted prevalence of musculoskeletal pain was significantly higher for statin users reporting pain in any region (23% among statin users, 95%CI: 19–27% compared to 18% among those not using statins, 95%CI: 17–20%; p=0.02) and in the lower extremities (12% among statin users, 95%CI: 8–16% compared to 8% among those not using statins, 95%CI: 7–9%; p=0.02). Conversely, among 3,058 participants with arthritis, statin use was not associated with higher musculoskeletal pain in any region. After controlling for confounders, among those without arthritis, statin use was associated with a significantly higher prevalence of musculoskeletal pain in any region, the lower back, and the lower extremities (adjusted prevalence ratios: 1.33 [1.06, 1.67]; 1.47 [1.02, 2.13]; 1.59 [1.12, 2.22], respectively). Among participants with arthritis, no association was observed between musculoskeletal pain and statin use on adjusted analyses. CONCLUSIONS In this population-based study, statin use was associated with a higher prevalence of musculoskeletal pain, particularly in the lower extremities, among individuals without arthritis. Evidence that statin use was associated with musculoskeletal pain among those with arthritis was lacking. PMID:22269621

Patients' Perspectives on Nonadherence to Statin Therapy: A Focus-Group Study

PubMed Central

Vicki, Fung; Sinclair, Fiona; Wang, Huihui; Dailey, Diane; Hsu, John; Shaber, Ruth

2010-01-01

Context: Nonadherence to statin therapy is associated with poor cardiovascular outcomes. Objective: We explored factors and perceptions that contribute to statin therapy nonadherence. Design: We conducted a qualitative study that was based on three patient focus groups using a structured discussion guide to explore factors related to statin therapy nonadherence, information sources, perceptions of statins and cardiovascular risks factors, and suggestions for improving adherence. Participants: We enrolled 18 adult patients of an integrated delivery system who had been newly prescribed a statin between November 2006 and August 2007, with a subsequent one- to six-month gap in drug supply as documented by automated pharmacy data. Measures: We performed content analysis of verbatim focus-group transcripts to assess themes within each domain. Results: Study participants identified many factors that contributed to their statin therapy nonadherence, including concerns or experiences with adverse effects, uncertainty about the benefits or importance of statins for their overall health, and lack of convenience. Concerns about the adverse effects of statins were a dominant theme. Although most participants believed that having a high cholesterol level is unsafe, many were unsure about their personal need for statins if they were making other lifestyle changes or had only borderline high cholesterol levels. Participants suggested that systematic follow-up, as well as greater information about the risks and benefits of statins and the merits of alternative approaches for lowering cholesterol, could have improved their adherence to therapy. Conclusions: Many patients reduced statin use because of concerns about adverse effects and desire for more information about statins. Effective interventions that address patients' underlying concerns and perceptions are needed to improve statin therapy adherence. PMID:20740125

Effect of Prescription Drug Coupons on Statin Utilization and Expenditures: A Retrospective Cohort Study.

PubMed

Daubresse, Matthew; Andersen, Martin; Riggs, Kevin R; Alexander, G Caleb

2017-01-01

Drug coupons are widely used, but their effects are not well understood. To quantify the effect of coupons on statin use and expenditures. Retrospective cohort analysis of IMS Health LRx LifeLink database. U.S. retail pharmacy transactions. Incident statin users who initiated branded atorvastatin or rosuvastatin between June 2006 and February 2013. Monthly statin utilization (pill-days of therapy), switching (filling a different statin), termination (failure to refill statin for 6 mo), and out-of-pocket and total costs. Of 1.1 million incident atorvastatin and rosuvastatin users, 2% used a coupon for at least one statin fill. At 1 year, compared with noncoupon users, those who used a statin coupon on their first fill were dispensed an equal number of monthly pill-days (23.7 vs 23.8), were less likely to switch statins (14.4% vs 16.3%), and were less likely to have terminated statin therapy (31.3% vs 39.2%). At 4 years, coupon users were more likely to have switched (45.5% vs 40.8%) and less likely to have terminated statin therapy (50.6% vs 61.1%) compared with noncoupon users. Those who used greater numbers of coupons were substantially less likely to switch and terminate statin therapies. Monthly out-of-pocket costs were lower among coupon than noncoupon users at 1 year ($9.7 vs $15.1), but total monthly costs were qualitatively similar ($115.5 vs $116.9). At 4 years, monthly out-of-pocket costs among coupon users remained lower ($14.3 vs $16.6) compared with noncoupon users. Sensitivity analyses supported the main results. Coupons for branded statins are associated with higher utilization and lower rates of discontinuation and short-term switching to other statin products. © 2016 Pharmacotherapy Publications, Inc.

Statin use and risk for type 2 diabetes: what clinicians should know.

PubMed

Maki, Kevin C; Diwadkar-Navsariwala, Veda; Kramer, Melvyn W

2018-03-01

Statins are the first line of pharmacologic treatment for the management of hypercholesterolemia in patients at risk for atherosclerotic cardiovascular (CV) disease. In recent years, several randomized, controlled trials (RCTs) and observational studies have reported increased risk for new-onset type 2 diabetes mellitus (T2D) with statin treatment, particularly with use of high-intensity statins that reduce low-density lipoprotein cholesterol (LDL-C) by 50% or more. This paper summarizes the data from RCTs and observational studies for statin-associated T2D risk, and puts into perspective this evidence, weighed against the established benefits of statin therapy for CV risk reduction. In RCTs, the increase in T2D risk with statin therapy appears to be attributable mainly to those with major T2D risk factors. The increase in incidence of T2D in those with major risk is approximately 25% for statin use, compared to placebo, and for intensive statin therapy compared to moderate-intensity statin therapy. However, in those with major T2D risk factors, the number of CV disease events prevented for each excess case of T2D is close to or greater than one, indicating that the risk-benefit ratio still strongly favors use of statin therapy, or intensive statin therapy, for patients with sufficient CV disease risk to warrant cholesterol-lowering drug therapy. Recommendations are summarized for evaluation of the T2D risk factor profile before initiation of and during statin therapy. In addition, the importance of lifestyle management and other preventive measures is emphasized for management of risks for both T2D and CV disease events in patients receiving statin therapy.

Statins and physical activity in older men: the osteoporotic fractures in men study.

PubMed

Lee, David S H; Markwardt, Sheila; Goeres, Leah; Lee, Christine G; Eckstrom, Elizabeth; Williams, Craig; Fu, Rongwei; Orwoll, Eric; Cawthon, Peggy M; Stefanick, Marcia L; Mackey, Dawn; Bauer, Douglas C; Nielson, Carrie M

2014-08-01

Muscle pain, fatigue, and weakness are common adverse effects of statin medications and may decrease physical activity in older men. To determine whether statin use is associated with physical activity, longitudinally and cross-sectionally. Men participating in the Osteoporotic Fractures in Men Study (N = 5994), a multicenter prospective cohort study of community-living men 65 years and older, enrolled between March 2000 and April 2002. Follow-up was conducted through 2009. Statin use as determined by an inventory of medications (taken within the last 30 days). In cross-sectional analyses (n = 4137), statin use categories were users and nonusers. In longitudinal analyses (n = 3039), categories were prevalent users (baseline use and throughout the study), new users (initiated use during the study), and nonusers (never used). Self-reported physical activity at baseline and 2 follow-up visits using the Physical Activity Scale for the Elderly (PASE). At the third visit, an accelerometer measured metabolic equivalents (METs [kilocalories per kilogram per hour]) and minutes of moderate activity (METs ≥3.0), vigorous activity (METs ≥6.0), and sedentary behavior (METs ≤1.5). At baseline, 989 men (24%) were users and 3148 (76%) were nonusers. The adjusted difference in baseline PASE between users and nonusers was -5.8 points (95% CI, -10.9 to -0.7 points). A total of 3039 men met the inclusion criteria for longitudinal analysis: 727 (24%) prevalent users, 845 (28%) new users, and 1467 (48%) nonusers. PASE score declined by a mean (95% CI) of 2.5 (2.0 to 3.0) points per year for nonusers and 2.8 (2.1 to 3.5) points per year for prevalent users, a nonstatistical difference (0.3 [-0.5 to 1.0] points). For new users, annual PASE score declined at a faster rate than nonusers (difference of 0.9 [95% CI, 0.1 to 1.7] points). A total of 3071 men had adequate accelerometry data, 1542 (50%) were statin users. Statin users expended less METs (0.03 [95% CI, 0.02-0.04] METs less) and engaged in less moderate physical activity (5.4 [95% CI, 1.9-8.8] fewer minutes per day), less vigorous activity (0.6 [95% CI, 0.1-1.1] fewer minutes per day), and more sedentary behavior (7.6 [95% CI, 2.6-12.4] greater minutes per day). Statin use was associated with modestly lower physical activity among community-living men, even after accounting for medical history and other potentially confounding factors. The clinical significance of these findings deserves further investigation.

Statin-associated immune-mediated myopathy: biology and clinical implications.

PubMed

Christopher-Stine, Lisa; Basharat, Pari

2017-04-01

In the last 6 years, our understanding of statin-associated myopathy expanded to include not only a toxic myopathy with limited and reversible side-effects but also an autoimmune variety in which statins likely induce an autoimmune myopathy that is both associated with a specific autoantibody and responsive to immunosuppression and immune modulation. This review widens the reader's understanding of statin myopathy to include an autoimmune process. Statin-associated immune-mediated myopathy provides an example of an environmental trigger (statins) directly implicated in an autoimmune disease associated with a genetic predisposition as well as potential risk factors including concomitant diseases and specific statins. Given a median exposure to statins of 38 months, providers should be aware that anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy may occur even after several years of statin exposure. It is important for the reader to understand the clinical presentation of statin-associated immune-mediated myopathy and the difference in its clinical presentation to that of statins as direct myotoxins. Prompt recognition of such an entity allows the clinician to immediately stop the offending agent if it has not already been discontinued as well as to recognize that statin rechallenge is not a likely option, and that prompt treatment with immunosuppression and/or immunomodulation is usually of enormous benefit to the patient in restoring muscle strength and physical function. VIDEO ABSTRACT.

Does Googling lead to statin intolerance?

PubMed

Khan, Sarah; Holbrook, Anne; Shah, Baiju R

2018-07-01

The nocebo effect, where patients with expectations of adverse effects are more likely to experience them, may contribute to the high rate of statin intolerance found in observational studies. Information that patients read on the internet may be a precipitant of this effect. The objective of the study was to establish whether the number of websites about statin side effects found using Google is associated with the prevalence of statin intolerance. The prevalence of statin intolerance in 13 countries across 5 continents was established in a recent study via a web-based survey of primary care physicians and specialists. Using the Google search engine for each country, the number of websites about statin side effects was determined, and standardized to the number of websites about statins overall. Searches were restricted to pages in the native language, and were conducted after connecting to each country using a virtual private network (VPN). English-speaking countries (Australia, Canada, UK, USA) had the highest prevalence of statin intolerance and also had the largest standardized number of websites about statin side effects. The sample Pearson correlation coefficient between these two variables was 0.868. Countries where patients using Google are more likely to find websites about statin side effects have greater levels of statin intolerance. The nocebo effect driven by online information may be contributing to statin intolerance. Copyright © 2018 Elsevier B.V. All rights reserved.

The Effect of Ezetimibe/Statin Combination and High-Dose Statin Therapy on Thyroid Autoimmunity in Women with Hashimoto's Thyroiditis and Cardiovascular Disease: A Pilot Study.

PubMed

Krysiak, R; Szkróbka, W; Okopień, B

2016-10-01

Background: Intensive statin therapy was found to reduce thyroid autoimmunity in women with Hashimoto's thyroiditis. No similar data are available for other hypolipidemic agents. Methods: The participants of the study were 16 women with Hashimoto's thyroiditis and coronary artery disease. On the basis of statin tolerance, they were divided into 2 groups. 8 patients who did not tolerate high-dose statin therapy were treated with a statin, the dose of which was reduced by half, together with ezetimibe. The remaining 8 patients tolerating the treatment continued high-dose statin therapy. Plasma lipids, serum levels of thyrotropin, free thyroxine and free triiodothyronine, as well as titers of thyroid peroxidase and thyroglobulin antibodies were measured at the beginning of the study and 6 months later. Results: Replacing high-dose statin therapy with ezetimibe/statin combination therapy increased serum titers of thyroid peroxidase as well as led to an insignificant increase in serum titers of thyroglobulin antibodies. At the end of the study, thyroid peroxidase and thyroglobulin antibody titers were higher in patients receiving the combination therapy than in those treated only with high-dose statin. Conclusions: Our study shows that high-dose statin therapy produces a stronger effect on thyroid autoimmunity than ezetimibe/statin combination therapy. © Georg Thieme Verlag KG Stuttgart · New York.

Different time trends of caloric and fat intake between statin users and nonusers among US adults: gluttony in the time of statins?

PubMed

Sugiyama, Takehiro; Tsugawa, Yusuke; Tseng, Chi-Hong; Kobayashi, Yasuki; Shapiro, Martin F

2014-07-01

Both dietary modification and use of statins can lower blood cholesterol. The increase in caloric intake among the general population is reported to have plateaued in the last decade, but no study has examined the relationship between the time trends of caloric intake and statin use. To examine the difference in the temporal trends of caloric and fat intake between statin users and nonusers among US adults. A repeated cross-sectional study in a nationally representative sample of 27,886 US adults, 20 years or older, from the National Health and Nutrition Examination Survey, 1999 through 2010. Statin use. Caloric and fat intake measured through 24-hour dietary recall. Generalized linear models with interaction term between survey cycle and statin use were constructed to investigate the time trends of dietary intake for statin users and nonusers after adjustment for possible confounders. We calculated model-adjusted caloric and fat intake using these models and examined if the time trends differed by statin use. Body mass index (BMI) changes were also compared between statin users and nonusers. In the 1999-2000 period, the caloric intake was significantly less for statin users compared with nonusers (2000 vs 2179 kcal/d; P = .007). The difference between the groups became smaller as time went by, and there was no statistical difference after the 2005-2006 period. Among statin users, caloric intake in the 2009-2010 period was 9.6% higher (95% CI, 1.8-18.1; P = .02) than that in the 1999-2000 period. In contrast, no significant change was observed among nonusers during the same study period. Statin users also consumed significantly less fat in the 1999-2000 period (71.7 vs 81.2 g/d; P = .003). Fat intake increased 14.4% among statin users (95% CI, 3.8-26.1; P = .007) while not changing significantly among nonusers. Also, BMI increased more among statin users (+1.3) than among nonusers (+0.4) in the adjusted model (P = .02). Caloric and fat intake have increased among statin users over time, which was not true for nonusers. The increase in BMI was faster for statin users than for nonusers. Efforts aimed at dietary control among statin users may be becoming less intensive. The importance of dietary composition may need to be reemphasized for statin users.

Green analytical method development for statin analysis.

PubMed

Assassi, Amira Louiza; Roy, Claude-Eric; Perovitch, Philippe; Auzerie, Jack; Hamon, Tiphaine; Gaudin, Karen

2015-02-06

Green analytical chemistry method was developed for pravastatin, fluvastatin and atorvastatin analysis. HPLC/DAD method using ethanol-based mobile phase with octadecyl-grafted silica with various grafting and related-column parameters such as particle sizes, core-shell and monolith was studied. Retention, efficiency and detector linearity were optimized. Even for column with particle size under 2 μm, the benefit of keeping efficiency within a large range of flow rate was not obtained with ethanol based mobile phase compared to acetonitrile one. Therefore the strategy to shorten analysis by increasing the flow rate induced decrease of efficiency with ethanol based mobile phase. An ODS-AQ YMC column, 50 mm × 4.6 mm, 3 μm was selected which showed the best compromise between analysis time, statin separation, and efficiency. HPLC conditions were at 1 mL/min, ethanol/formic acid (pH 2.5, 25 mM) (50:50, v/v) and thermostated at 40°C. To reduce solvent consumption for sample preparation, 0.5mg/mL concentration of each statin was found the highest which respected detector linearity. These conditions were validated for each statin for content determination in high concentrated hydro-alcoholic solutions. Solubility higher than 100mg/mL was found for pravastatin and fluvastatin, whereas for atorvastatin calcium salt the maximum concentration was 2mg/mL for hydro-alcoholic binary mixtures between 35% and 55% of ethanol in water. Using atorvastatin instead of its calcium salt, solubility was improved. Highly concentrated solution of statins offered potential fluid for per Buccal Per-Mucous(®) administration with the advantages of rapid and easy passage of drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Comparison of the low-density lipoprotein cholesterol target value and the preventive effect of statins in elderly patients and younger patients.

PubMed

Endo, Akihiro; Okada, Taiji; Pak, Misun; Kagawa, Yuzo; Ito, Shimpei; Sato, Hirotomo; Kageshima, Kenji; Yoshida, Yasuyuki; Tanabe, Kazuaki

2017-06-01

To assess whether the low-density lipoprotein cholesterol (LDL-C) target value and preventive effect of statins are different between elderly and younger patients. We investigated 304 patients with previous percutaneous coronary intervention who underwent coronary angiography from January 2007 to December 2016 for examination of recurrent ischemia beyond the early restenosis. Patients were classified into two groups: age ≥ 75 years (elderly group: n = 140) and < 75 years (younger group: n = 164). Relationships between the achieved LDL-C level, incidence of late coronary events, and the effectiveness of statins were evaluated. During follow-up, 179 patients underwent late coronary revascularization. Recurrent ischemia presenting as acute coronary syndrome (ACS) occurred in 83 cases. Kaplan-Meier curve analysis revealed that in the younger group, recurrent ACS was significantly lower in patients with LDL-C < 70 mg/dL than in those with LDL-C ranging from 70 to < 100 mg/dL ( P = 0.035); however, there was no difference between these in the elderly group ( P = 0.863). Instead, recurrent ACS was less frequent in patients with LDL-C ranging from 70 mg/dL to < 100 mg/dL than in those with LDL-C ≥ 100 mg/dL in the elderly group ( P = 0.033). Statin use was associated with decreased recurrent ACS ( P = 0.005); moreover, only using statins was an independent predictor in the elderly group (HR: 0.375; P = 0.007). Strict control of LDL-C to < 70 mg/dL was effective for reducing the incidence of recurrent ACS in younger patients. However, LDL-C < 100 mg/dL might be sufficient as the target value of LDL-C-lowering therapy for secondary prevention of ischemic events in Japanese elderly patients.

Effects of a diet rich in arabinoxylan and resistant starch compared with a diet rich in refined carbohydrates on postprandial metabolism and features of the metabolic syndrome.

PubMed

Schioldan, Anne Grethe; Gregersen, Søren; Hald, Stine; Bjørnshave, Ann; Bohl, Mette; Hartmann, Bolette; Holst, Jens Juul; Stødkilde-Jørgensen, Hans; Hermansen, Kjeld

2018-03-01

Low intake of dietary fibre is associated with the development of type 2 diabetes. Dyslipidaemia plays a key role in the pathogenesis of type 2 diabetes. Knowledge of the impact of dietary fibres on postprandial lipaemia is, however, sparse. This study aimed in subjects with metabolic syndrome to assess the impact on postprandial lipaemia and features of the metabolic syndrome of a healthy carbohydrate diet (HCD) rich in cereal fibre, arabinoxylan and resistant starch compared to a refined-carbohydrate western-style diet (WSD). Nineteen subjects completed the randomised, crossover study with HCD and WCD for 4-week. Postprandial metabolism was evaluated by a meal-challenge test and insulin sensitivity was assessed by HOMA-IR and Matsuda index. Furthermore, fasting cholesterols, serum-fructosamine, circulating inflammatory markers, ambulatory blood pressure and intrahepatic lipid content were measured. We found no diet effects on postprandial lipaemia. However, there was a significant diet × statin interaction on total cholesterol (P = 0.02) and LDL cholesterol (P = 0.002). HCD decreased total cholesterol (-0.72 mmol/l, 95% CI (-1.29; -0.14) P = 0.03) and LDL cholesterol (-0.61 mmol/l, 95% CI (-0.86; -0.36) P = 0.002) compared with WSD in subjects on but not without statin treatment. We detected no other significant diet effects. In subjects with metabolic syndrome on statins a 4-week diet rich in arabinoxylan and resistant starch improved fasting LDL and total cholesterol compared to subjects not being on statins. However, we observed no diet related impact on postprandial lipaemia or features of the metabolic syndrome. The dietary fibre x statin interaction deserves further elucidation.

Age-Related Differences in Non-Persistence with Statin Treatment in Patients after a Transient Ischaemic Attack.

PubMed

Wawruch, Martin; Zatko, Dusan; Wimmer, Gejza; Luha, Jan; Wimmerova, Sona; Matalova, Petra; Kukumberg, Peter; Murin, Jan; Tesar, Tomas; Havelkova, Beata; Shah, Rashmi

2017-11-01

Non-persistence with secondary preventive measures, including medications such as statins, adversely affects the prospects of successful outcomes. This study was aimed at evaluating non-persistence with statin therapy in cohorts of young and elderly patients after a transient ischaemic attack (TIA) and identifying patient-associated characteristics that influence the risk for non-persistence. The study cohorts included 797 adult patients who were initiated on statin therapy following a TIA diagnosis between 1 January 2010 and 31 December 2010. Patients were followed up for 3 years and those with a treatment gap of at least a 6-month period were considered 'non-persistent'. In order to identify any age-related differences, all analyses were conducted in the entire study cohort (n = 797) as well as separately in the 'younger' (aged <65 years, n = 267) and the 'older' (aged ≥65 years, n = 530) patients. Non-persistence was significantly more common in younger patients compared to older patients (67.8% vs. 49.1%; p < 0.001). Factors that decreased the probability of non-persistence in younger and older patients included diabetes mellitus (hazard ratio [HR] = 0.72 and HR = 0.64, respectively) and hypercholesterolaemia (HR = 0.43 and HR = 0.62, respectively). Female gender (HR = 1.42) was associated with a higher and increasing number of medications taken (HR = 0.93), with lower probability for non-persistence in younger patients but not in the older patients. Our results indicate that certain patients with TIA require special counselling to improve persistence with statin therapy. These include younger patients, especially females and those not on polypharmacy, and both younger and older patients without diabetes mellitus or hypercholesterolaemia.

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors improve myocardial high-energy phosphate metabolism in men.

PubMed

Schocke, Michael F; Martinek, Martin; Kremser, Christian; Wolf, Christian; Steinboeck, Peter; Lechleitner, Monika; Jaschke, Werner; Pachinger, Otmar; Metzler, Bernhard

2003-01-01

We intended to prove that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins have a beneficial impact on the human myocardial, high-energy, phosphate metabolism. The present study included 18 male patients (mean age 49.8 +/- 10.3) with statin-treated, familiar hypercholesterolemia (FH) and 13 male patients with untreated FH (mean age 44.6 +/- 9.5). Twenty-six healthy male volunteers served as controls (mean age 44.2 +/- 12.1). Phosphorus-31, two-dimensional chemical shift imaging (31P 2D CSI) of the heart was performed in all subjects using a 1.5 Tesla whole-body magnetic resonance (MR) scanner. The ratios between phosphocreatine (PCr) and beta-adenosine-triphosphate (beta-ATP) were calculated for the left ventricular myocardium. Furthermore, echocardiographic evaluation and stress tests were performed in all individuals. The untreated patients with FH exhibited a significant decrease in left ventricular PCr to beta-ATP ratios (1.78 +/- 0.34) compared with statin-treated FH patients (2.15 +/- 0.26, p < 0.001) and healthy controls (2.04 +/- 0.26, p = 0.009). The left ventricular PCr-to-beta-ATP ratios of the treated FH patients were in the range of the healthy controls. Our study shows for the first time an-improvement of the high-energy, phosphate metabolism in the left ventricular myocardium of patients with statin-treated FH compared with untreated FH patients.

Patient adherence to generic versus brand statin therapy after acute myocardial infarction: Insights from the Can Rapid Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines Registry.

PubMed

O'Brien, Emily C; McCoy, Lisa A; Thomas, Laine; Peterson, Eric D; Wang, Tracy Y

2015-07-01

Statins reduce mortality after acute myocardial infarction, but up to half of patients discontinue statin use within 1 year of therapy initiation. Although cost may influence medication adherence, it is unknown whether use of generic versus brand statins influences adherence. We linked detailed inhospital clinical data for 1421 non-ST-segment elevation myocardial infarction patients discharged on a statin in 2006 to Medicare Part D medication claims records to examine postdischarge medication use. One-year statin adherence was defined using the proportion of days covered with optimal adherence ≥80%. We examined the association of brand versus generic statin prescription and 1-year adherence after adjusting for demographics, clinical factors, predischarge lipid values, prior statin use, and socioeconomic status. Overall, 65.5% of statin fills were for brand-name statins. There were few baseline differences in demographics and clinical factors among generic versus brand users. Patient copay amounts were higher for brand versus generic statins (median = $25 vs $5, P < .001), yet the mean proportion of days covered over 1 year was similar (71.5% vs 68.9%; P = .97; unadjusted odds ratio 1.15 [95% CI 0.96-1.37]). Proportion of days covered ≥80% was low for both generic (56.2%) and brand statins (55.9%; P = .93). Statin adherence rates remained similar between generic and brand users after adjusting for demographics, clinical risk factors, lipid value, prior statin use, and socioeconomic status. In a cohort of older non-ST-segment elevation myocardial infarction patients, we found no evidence that use of generic versus brand drug was associated with higher adherence to statins at 1 year after hospital discharge. Copyright © 2015 Elsevier Inc. All rights reserved.

Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study.

PubMed

Zhang, Huabing; Plutzky, Jorge; Shubina, Maria; Turchin, Alexander

2017-08-15

Many patients discontinue statin treatment, often after having a possible adverse reaction. The risks and benefits of continued statin therapy after an adverse reaction are not known. To examine the relationship between continuation of statin therapy (any prescription within 12 months after an adverse reaction) and clinical outcomes. Retrospective cohort study. Primary care practices affiliated with 2 academic medical centers. Patients with a presumed adverse reaction to a statin between 2000 and 2011. Information on adverse reactions to statins was obtained from structured electronic medical record data or natural-language processing of narrative provider notes. The primary composite outcome was time to a cardiovascular event (myocardial infarction or stroke) or death. Most (81%) of the adverse reactions to statins were identified from the text of electronic provider notes. Among 28 266 study patients, 19 989 (70.7%) continued receiving statin prescriptions after the adverse reaction. Four years after the presumed adverse event, the cumulative incidence of the composite primary outcome was 12.2% for patients with continued statin prescriptions, compared with 13.9% for those without them (difference, 1.7% [95% CI, 0.8% to 2.7%]; P < 0.001). In a secondary analysis of 7604 patients for whom a different statin was prescribed after the adverse reaction, 2014 (26.5%) had a documented adverse reaction to the second statin, but 1696 (84.2%) of those patients continued receiving statin prescriptions. The risk for recurrent adverse reactions to statins could not be established for the entire sample. It was also not possible to determine whether patients actually took the statins. Continued statin prescriptions after an adverse reaction were associated with a lower incidence of death and cardiovascular events. Chinese National Key Program of Clinical Science, National Natural Science Foundation of China, and Young Scientific Research Fund of Peking Union Medical College Hospital.

Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis.

PubMed

Kunutsor, Setor K; Seidu, Samuel; Khunti, Kamlesh

2017-02-01

Statins have been suggested to have a protective effect on venous thromboembolism (which includes deep vein thrombosis and pulmonary embolism), but the evidence is uncertain. We sought to evaluate the extent to which statins are associated with first venous thromboembolism events. We did a systematic review and meta-analysis of observational cohort studies and randomised controlled trials (RCTs). Relevant studies that reported associations between statins and first venous thromboembolism outcomes were identified from MEDLINE, Embase, Web of Science, Cochrane Library, and a manual search of bibliographies for studies published up until July 18, 2016, and from email correspondence with investigators. Observational cohorts that assessed the association of statin use with venous thromboembolism, deep vein thrombosis, or pulmonary embolism in adults were included, as were intervention studies that assessed the effects of statin therapy compared with a placebo or no treatment and collected data on venous thromboembolism, deep vein thrombosis, or pulmonary embolism outcomes. Studies that compared statins with another statin or lipid-lowering agent were excluded. Study specific relative risks (RRs) were aggregated using random-effects models and were grouped by study-level characteristics. The review has been registered with PROSPERO, number CRD42016035622. 36 eligible studies (13 cohort studies comprising 3 148 259 participants and 23 RCTs of statins vs placebo or no treatment comprising 118 464 participants) were included. In observational studies, the pooled RR for venous thromboembolism was 0·75 (95% CI 0·65-0·87; p<0·0001) when statin use was compared with no statin use. This association remained consistent when grouped by various study-level characteristics. In RCTs, the RR for venous thromboembolism was 0·85 (0·73-0·99; p=0·038) when statin therapy was compared with placebo or no treatment. Subgroup analyses suggested significant differences in the effect of statins by type of statin, with rosuvastatin having the lowest risk on venous thromboembolism compared with other statins 0·57 (0·42-0·75; p=0·015). There was no evidence of an effect of statin use on pulmonary embolism. Statin use was associated with a significant reduction in risk of the specific endpoint of deep vein thrombosis compared with no statin use (RR 0·77, 95% CI 0·69-0·86; p<0·0001). Available evidence from observational and intervention studies suggest a beneficial effect of statin use on venous thromboembolism. In intervention studies, therapy with rosuvastatin significantly reduced venous thromboembolism compared with other statins. Further evidence is however needed to validate these findings. None. Copyright © 2017 Elsevier Ltd. All rights reserved.

Consequences of succinylcholine administration to patients using statins.

PubMed

Turan, Alparslan; Mendoza, Maria L; Gupta, Shipra; You, Jing; Gottlieb, Alexandru; Chu, Weihan; Saager, Leif; Sessler, Daniel I

2011-07-01

Statins cause structural changes in myocytes and provoke myotoxicity, myopathy, and myalgias. Thus, patients taking statins may be especially susceptible to succinylcholine-induced muscle injury. The authors tested the hypothesis that succinylcholine increases plasma concentrations of myoglobin, potassium, and creatine kinase more in patients who take statins than in those who do not and that succinylcholine-induced postoperative muscle pain is aggravated in statin users. Patients who took statins for at least 3 months and those who had never used statins were enrolled. General anesthesia was induced and included 1.5 mg/kg succinylcholine for intubation. The incidence and degree of fasciculation after succinylcholine administration were recorded. Blood samples were obtained before induction and 5 and 20 min and 24 h after succinylcholine administration. Patients were interviewed 2 and 24 h after surgery to determine the degree of myalgia. The authors enrolled 38 patients who used statins and 32 who did not. At 20 min, myoglobin was higher in statin users versus nonusers (ratio of medians 1.34 [95% CI: 1.1, 1.7], P = 0.018). Fasciculations in statin users were more intense than in nonusers (P = 0.047). However, plasma potassium and creatine kinase concentrations were similar in statin users and nonusers, as was muscle pain. The plasma myoglobin concentration at 20 min was significantly greater in statin users than nonusers, although the difference seems unlikely to be clinically important. The study results suggest that the effect of succinylcholine given to patients taking statins is likely to be small and probably of limited clinical consequence.

Management of statin-intolerant patient.

PubMed

Arca, M; Pigna, G; Favoccia, C

2012-06-01

Large scale clinical trials have undoubtedly demonstrated that statins are effective in reducing cardiovascular events and all-cause mortality in almost all patient populations. Also the short and long-term safety of statin therapy has been well established in the majority of treated patients. Nevertheless, intolerance to statins must be frequently faced in the clinical practice. The most commonly observed adverse effects of statins are muscle symptoms and elevation of hepatic aminotransferase and creatinine kinase (CK) levels. Overall, myalgia (muscle pain with or without plasma CK elevations) and a single abnormally elevated liver function test constitute approximately two-thirds of reported adverse events during statin therapy. These side effects raise concerns in the patients and are likely to reduce patient's adherence and, consequently, the cardiovascular benefit. Therefore, it is mandatory that clinicians improve knowledge on the clinical aspects of side effects of statins and the ability to manage patients with intolerance to statins. Numerous different approaches to statin-intolerant patients have been suggested, but an evidence-based consensus is difficult to be reached due to the lack of controlled trials. Therefore, it might be useful to review protocols and procedures to control statin intolerance. The first step in managing intolerant patients is to determine whether the adverse events are indeed related to statin therapy. Then, the switching to another statin or lower dosage, the alternate dosing options and the use of non-statin compounds may be practical strategies. However, the cardiovascular benefit of these approaches has not been established, so that their use has to be employed after a careful clinical assessment of each patient.

Prevalence of statin-drug interactions in older people: a systematic review.

PubMed

Thai, Michele; Reeve, Emily; Hilmer, Sarah N; Qi, Katie; Pearson, Sallie-Anne; Gnjidic, Danijela

2016-05-01

Statins are among the most frequently prescribed medications internationally. Older people are commonly prescribed multiple medications and are at an increased risk of drug-drug interactions, including statin-drug interactions. The aim of this study was to conduct a systematic review of current evidence on the prevalence of statin-drug interactions in older people. A systematic search of observational studies in Embase, Medline, and PubMed was conducted. Articles were included if they were published in English during the period July 2000-July 2014 and reported on the prevalence of statin-drug interactions in people over 65 years of age. Two reviewers independently assessed the articles for eligibility and extracted the data. The search returned 1556 eligible articles. A total of 19 articles met the inclusion criteria. In studies (n = 7) that focused on statin users only, the prevalence of potential statin-drug interactions assessed using different measures ranged from 0.19 to 33.0 %. In studies that examined drug interactions across a population of both statin users and non-users (n = 12), the prevalence of potential statin-drug interactions ranged from 0.1 to 7.1 % (n = 8), and the prevalence of clinically relevant statin-drug interactions ranged from 1.5 to 4 % (n = 4). Current published evidence suggests substantial variations in the prevalence of statin-drug interactions and their clinical relevance. Further studies are necessary to provide a better understanding of the prevalence of clinically significant statin-drug interactions, the medications most frequently contributing to statin-drug interactions, and impact on relevant clinical outcomes in older people.

Effect of pretreatment with statins on ischemic stroke outcomes.

PubMed

Reeves, Mathew J; Gargano, Julia Warner; Luo, Zhehui; Mullard, Andrew J; Jacobs, Bradley S; Majid, Arshad

2008-06-01

Statins reduce the risk of stroke in at-risk populations and may improve outcomes in patients taking statins before an ischemic stroke (IS). Our objectives were to examine the effects of pretreatment with statins on poor outcome in IS patients. Over a 6-month period all acute IS admissions were prospectively identified in 15 hospitals participating in a statewide acute stroke registry. Poor stroke outcome was defined as modified Rankin score >/=4 at discharge (ie, moderate-severe disability or death). Multivariable logistic regression models and matched propensity score analyses were used to quantify the effect of statin pretreatment on poor outcome. Of 1360 IS patients, 23% were using statins before their stroke event and 42% had a poor stroke outcome. After multivariable adjustment, pretreatment with statins was associated with lower odds of poor outcome (OR=0.74, 95% CI 0.52, 1.02). A significant interaction (P<0.01) was found between statin use and race. In whites, statins were associated with statistically significantly lower odds of poor outcome (OR=0.61, 95% CI 0.42, 0.86), but in blacks statins were associated with a nonstatistically significant increase in poor outcome (OR=1.82, 95% CI 0.98, 3.39). Matched propensity score analyses were consistent with the multivariable model results. Pretreatment with statins was associated with better stroke outcomes in whites, but we found no evidence of a beneficial effect of statins in blacks. These findings indicate the need for further studies, including randomized trials, to examine differential effects of statins on ischemic stroke outcomes among whites and blacks.

Nitric oxide-donating statin improves multiple functions of circulating angiogenic cells

PubMed Central

Mangialardi, G; Monopoli, A; Ongini, E; Spinetti, G; Fortunato, O; Emanueli, C; Madeddu, P

2011-01-01

BACKGROUND AND PURPOSE Statins, a major component of the prevention of cardiovascular disease, aid progenitor cell functions in vivo and in vitro. Statins bearing a NO-releasing moiety were developed for their enhanced anti-inflammatory/anti-thrombotic properties. Here, we investigated if the NO-donating atorvastatin (NCX 547) improved the functions of circulating angiogenic cells (CACs). EXPERIMENTAL APPROACH Circulating angiogenic cells (CACs) were prepared from peripheral blood monocytes of healthy volunteers and type-2 diabetic patients and were cultured in low (LG) or high glucose (HG) conditions, in presence of atorvastatin or NCX 547 (both at 0.1 µM) or vehicle. Functional assays (outgrowth, proliferation, viability, senescence and apoptosis) were performed in presence of the endothelial NOS inhibitor L-NIO, the NO scavenger c-PTIO or vehicle. KEY RESULTS Culturing in HG conditions lowered NO in CACs, inhibited outgrowth, proliferation, viability and migration, and induced cell senescence and apoptosis. NCX 547 fully restored NO levels and functions of HG-cultured CACs, while atorvastatin prevented only apoptosis in CACs. The activity of Akt, a pro-survival kinase, was increased by atorvastatin in LG-cultured but not in HG-cultured CACs, whereas NCX 547 increased Akt activity in both conditions. L-NIO partially blunted and c-PTIO prevented NCX 547-induced improvements in CAC functions. Finally, NCX 547 improved outgrowth and migration of CACs prepared from patients with type 2 diabetes. CONCLUSIONS AND IMPLICATIONS NCX 547 was more effective than atorvastatin in preserving functions of CACs. This property adds to the spectrum of favourable actions that would make NO-releasing statins more effective agents for treating cardiovascular disease. PMID:21486281

Risk identification and possible countermeasures for muscle adverse effects during statin therapy.

PubMed

Magni, Paolo; Macchi, Chiara; Morlotti, Beatrice; Sirtori, Cesare R; Ruscica, Massimiliano

2015-03-01

The use of statins for cardiovascular disease prevention is clearly supported by clinical evidence. However, in January 2014 the U.S. Food and Drug Administration released an advice on statin risk reporting that "statin benefit is indisputable, but they need to be taken with care and knowledge of their side effects". Among them the by far most common complication is myopathy, ranging from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. This class side effect appears to be dose dependent, with more lipophilic statin (i.e., simvastatin) carrying a higher overall risk. Hence, to minimize statin-associated myopathy, clinicians should take into consideration a series of factors that potentially increase this risk (i.e., drug-drug interactions, female gender, advanced age, diabetes mellitus, hypothyroidism and vitamin D deficiency). Whenever it is appropriate to stop statin treatment, the recommendations are to stay off statin until resolution of symptoms or normalization of creatine kinase values. Afterwards, clinicians have several options to treat dyslipidemia, including the use of a lower dose of the same statin, intermittent non-daily dosing of statin, initiation of a different statin, alone or in combination with nonstatin lipid-lowering agents, and substitution with red yeast rice. Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Statin intolerance: diagnosis and remedies.

PubMed

Pirillo, Angela; Catapano, Alberico Luigi

2015-05-01

Despite the efficacy of statins in reducing cardiovascular events in both primary and secondary prevention, the adherence to statin therapy is not optimal, mainly due to the occurrence of muscular adverse effects. Several risk factors may concur to the development of statin-induced myotoxicity, including patient-related factors (age, sex, and race), statin properties (dose, lipophilicity, and type of metabolism), and the concomitant administration of other drugs. Thus, the management of patients intolerant to statins, particularly those at high or very high cardiovascular risk, involves alternative therapies, including the switch to another statin or the use of intermittent dosage statin regimens, as well as nonstatin lipid lowering drugs (ezetimibe and fibrates) or new hypolipidemic drugs such as PCSK9 monoclonal antibodies, the antisense oligonucleotide against the coding region of human apolipoprotein B mRNA (mipomersen), and microsomal triglyceride transfer protein inhibitor lomitapide. Ongoing clinical trials will reveal whether the lipid-lowering effects of alternative therapies to statins can also translate into a cardiovascular benefit.

Rhabdomyolysis from Statins: What's the Risk?

MedlinePlus

... do you know if you have rhabdomyolysis from statin use, and how likely is it? Answers from ... pain is a relatively common side effect of statins, some people who take statin medications to lower ...

Endothelial progenitor cell mobilization and increased intravascular nitric oxide in patients undergoing cardiac rehabilitation.

PubMed

Paul, Jonathan D; Powell, Tiffany M; Thompson, Michael; Benjamin, Moshe; Rodrigo, Maria; Carlow, Andrea; Annavajjhala, Vidhya; Shiva, Sruti; Dejam, Andre; Gladwin, Mark T; McCoy, J Philip; Zalos, Gloria; Press, Beverly; Murphy, Mandy; Hill, Jonathan M; Csako, Gyorgy; Waclawiw, Myron A; Cannon, Richard O

2007-01-01

We investigated whether cardiac rehabilitation participation increases circulating endothelial progenitor cells (EPCs) and benefits vasculature in patients already on stable therapy previously shown to augment EPCs and improve endothelial function. Forty-six of 50 patients with coronary artery disease completed a 36-session cardiac rehabilitation program: 45 were treated with HMG-CoA reductase inhibitor (statin) therapy > or = 1 month (average baseline low-density lipoprotein cholesterol = 81 mg/dL). Mononuclear cells isolated from blood were quantified for EPCs by flow cytometry (CD133/VEGFR-2 cells) and assayed in culture for EPC colony-forming units (CFUs). In 23 patients, EPCs were stained for annexin-V as a marker of apoptosis, and nitrite was measured in blood as an indicator of intravascular nitric oxide. Endothelial progenitor cells increased from 35 +/- 5 to 63 +/- 10 cells/mL, and EPC-CFUs increased from 0.9 +/- 0.2 to 3.1 +/- 0.6 per well (both P < .01), but 11 patients had no increase in either measure. Those patients whose EPCs increased from baseline showed significant increases in nitrite and reduction in annexin-V staining (both P < .01) versus no change in patients without increase in EPCs. Over the course of the program, EPCs increased prior to increase in nitrite in the blood. Cardiac rehabilitation in patients receiving stable statin therapy and with low-density lipoprotein cholesterol at goal increases EPC number, EPC survival, and endothelial differentiation potential, associated with increased nitric oxide in the blood. Although this response was observed in most patients, a significant minority showed neither EPC mobilization nor increased nitric oxide in the blood.

Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis.

PubMed

Wang, L W; Jabbour, A; Hayward, C S; Furlong, T J; Girgis, L; Macdonald, P S; Keogh, A M

2015-04-01

Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin-induced rhabdomyolysis. © 2015 Royal Australasian College of Physicians.

Perspectives and challenges of antioxidant therapy for atrial fibrillation.

PubMed

Gasparova, Iveta; Kubatka, Peter; Opatrilova, Radka; Caprnda, Martin; Filipova, Slavomira; Rodrigo, Luis; Malan, Leone; Mozos, Ioana; Rabajdova, Miroslava; Nosal, Vladimir; Kobyliak, Nazarii; Valentova, Vanda; Petrovic, Daniel; Adamek, Mariusz; Kruzliak, Peter

2017-01-01

Atrial fibrillation (AF) is the most common sustained arrhythmia associated with significant morbidity and mortality. The mechanisms underlying the pathogenesis of AF are poorly understood, although electrophysiological remodeling has been described as an important initiating step. There is growing evidence that oxidative stress is involved in the pathogenesis of AF. Many known triggers of oxidative stress, such as age, diabetes, smoking, and inflammation, are linked with an increased risk of arrhythmia. Numerous preclinical studies and clinical trials reported the importance of antioxidant therapy in the prevention of AF, using vitamins C and E, polyunsaturated fatty acids, statins, or nitric oxide donors. The aim of our work is to give a current overview and analysis of opportunities, challenges, and benefits of antioxidant therapy in AF.

Effects of Statins on Skeletal Muscle: A Perspective for Physical Therapists

PubMed Central

Di Stasi, Stephanie L.; MacLeod, Toran D.; Winters, Joshua D.

2010-01-01

Hyperlipidemia, also known as high blood cholesterol, is a cardiovascular health risk that affects more than one third of adults in the United States. Statins are commonly prescribed and successful lipid-lowering medications that reduce the risks associated with cardiovascular disease. The side effects most commonly associated with statin use involve muscle cramping, soreness, fatigue, weakness, and, in rare cases, rapid muscle breakdown that can lead to death. Often, these side effects can become apparent during or after strenuous bouts of exercise. Although the mechanisms by which statins affect muscle performance are not entirely understood, recent research has identified some common causative factors. As musculoskeletal and exercise specialists, physical therapists have a unique opportunity to identify adverse effects related to statin use. The purposes of this perspective article are: (1) to review the metabolism and mechanisms of actions of statins, (2) to discuss the effects of statins on skeletal muscle function, (3) to detail the clinical presentation of statin-induced myopathies, (4) to outline the testing used to diagnose statin-induced myopathies, and (5) to introduce a role for the physical therapist for the screening and detection of suspected statin-induced skeletal muscle myopathy. PMID:20688875

Statin use and risk of diabetes mellitus

PubMed Central

Chogtu, Bharti; Magazine, Rahul; Bairy, KL

2015-01-01

The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, statins, are widely used in the primary and secondary prevention of cardiovascular diseases to lower serum cholesterol levels. As type 2 diabetes mellitus is accompanied by dyslipidemia, statins have a major role in preventing the long term complications in diabetes and are recommended for diabetics with normal low density lipoprotein levels as well. In 2012, United States Food and Drug Administration released changes to statin safety label to include that statins have been found to increase glycosylated haemoglobin and fasting serum glucose levels. Many studies done on patients with cardiovascular risk factors have shown that statins have diabetogenic potential and the effect varies as per the dosage and type used. The various mechanisms for this effect have been proposed and one of them is downregulation of glucose transporters by the statins. The recommendations by the investigators are that though statins can have diabetogenic risk, they have more long term benefits which can outweigh the risk. In elderly patients and those with metabolic syndrome, as the risk of diabetes increase, the statins should be used cautiously. Other than a subset of population with risk for diabetes; statins still have long term survival benefits in most of the patients. PMID:25789118

Inhibition of Interferon-beta Responses in Multiple Sclerosis Immune Cells Associated With High-Dose Statins

PubMed Central

Feng, Xuan; Han, Diana; Kilaru, Bharat K.; Franek, Beverly S.; Niewold, Timothy B.; Reder, Anthony T.

2014-01-01

Objective To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). Design Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. Patients The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. Interventions Statin effects on in vitro and in vivo interferon-beta–induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. Results In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P< .001), interferon regulatory factor 1 protein by 30% (P= .006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy–induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. Conclusions High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease. PMID:22801747

Achieving Guideline-Driven High-Intensity Statin Dose in Cardiac Rehabilitation Patients With Coronary Artery Disease.

PubMed

Lin, Jonathan; Banathy, Alexandra; Winters, Carla; Andersen, Lars; Hudson, Cindy; Testa, Heidi; Reardon, Joy; Alagona, Peter

2018-05-12

The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends high-intensity statin therapy in patients aged ≤75 y with clinical coronary artery disease (CAD). The effectiveness of cardiac rehabilitation (CR) in lipid management and guideline adherence is unknown. The purpose of this study is to determine whether CR participation affects guideline-driven achievement for statin use. This multicenter retrospective study evaluated statin utilization in patients pre- and post-CR between January 1, 2014, and August 31, 2015. Records for patients with known CAD who completed 18 or more CR sessions were reviewed for statin-drug use and dose before and after CR and documented statin intolerance. Of the total 468 patients, 76% were male with mean age ± SD = 66.0 ± 10.8 y and range of 32 to 89 y. Patients aged ≤75 y (n = 375) showed a modest but statistically significant increase (P = .0006) in high-intensity statin use post-CR (56.3%-61.1%). Males demonstrated a significant increase in high-intensity statin use (P = .0005). Of the 146 patients aged ≤75 y not on high-intensity statins post-CR, only 21 had history of statin intolerance. Of the subjects aged >75 y (n = 93), 91% were already on high- or moderate-intensity statins with no significant change during CR. Patients aged ≤75 y following CR completion increased high-intensity statin use but only by 4.8% and 33% of subjects were inadequately treated. The updated 2013 treatment recommendations simplified statin use, yet substantial data continue to reveal that guideline achievement even post-CR remains limited.

The efficiency of cardiovascular risk assessment: do the right patients get statin treatment?

PubMed Central

van Staa, Tjeerd-Pieter; Smeeth, Liam; Ng, Edmond S-W; Goldacre, Ben; Gulliford, Martin

2013-01-01

Objective To evaluate targeting of statin prescribing for primary prevention to those with high cardiovascular disease (CVD) risk. Design Two cohort studies including the general population and initiators of statins aged 35–74 years. Setting UK primary care records in the Clinical Practice Research Datalink. Patients 3.8 million general population patients and 300 914 statin users. Intervention Statin prescribing. Main outcome measures Statin prescribing by CVD risk; observed 5-year CVD risks; variability between practices. Results Statin prescribing increased substantially over time to patients with high 10-year CVD risk (≥20%): 7.0% of these received a statin prior to 2007, and 30.4% in 2007 onwards. Prescribing to patients with low risk (<15%) also increased (from 1.9% to 5.0%). Only about half the patients initiating statin treatment were high risk according to CVD risk score. The 5-year CVD risks, as observed during statin treatment, reduced over calendar time (from 17.0% to 7.1%). There was a large variation between general practices in the percentage of high-risk patients prescribed a statin in 2007 onwards, ranging from 8.2% to 61.5%. For low-risk patients, these varied from 2.1% to 29.1%. Conclusions There appeared to be substantive overuse in low CVD risk and underuse in high CVD risk (600 000 and 850 000 patients, respectively, in the UK since 2007). There is wide variation between practices in statin prescribing to patients at high CVD risk. There is a clear need for randomised trials for the best strategy to target statin treatment and manage CVD risk for primary prevention. PMID:23735939

Impact of statin guidelines on statin utilization and costs in an employer-based primary care clinic.

PubMed

Gurgle, Holly E; Schauerhamer, Marisa B; Rodriguez, Simón A; McAdam-Marx, Carrie

2017-12-01

The purpose of this study was to describe statin utilization and costs in an employer-based patient cohort by comparing actual practice and assumed adoption of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) or 2016 US Preventive Services Task Force (USPSTF) statin recommendations versus the guidelines described in 2001 (and supplemented in 2004) in the Third Report of the National Cholesterol Education Program's Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATPIII). Descriptive cohort analysis included patients treated in an employer-based primary care clinic between January 2012 and April 2014. ATPIII, ACC/AHA, and USPSTF recommendations were retrospectively applied at the patient level based on lipid levels and statin prescribing data collected from a health risk assessment and electronic health record. Actual statin prescribing was compared with prescribing predicted by guideline recommendations. Costs for each strategy were estimated using employer pharmacy claims data. The study included 555 patients, of whom 112 (20.2%) were treated with a statin at baseline. ATPIII and ACC/AHA recommended statin use in 284 (51.2%) and 279 (50.3%) patients, respectively. Within the subgroup of 479 primary prevention patients, ACC/AHA recommended statin use in 203 (42.4%) versus USPSTF, which recommended statin use in 91 (19.0%). The 90-day cost per patient was similar to baseline with implementation of ATPIII or ACC/AHA recommendations, excluding use of brand name-only high-intensity statins, and costs could be reduced slightly with implementation of USPSTF guidelines. Despite differences in ATPIII, ACC/AHA, and USPSTF guidelines, application of any of these statin recommendations would result in optimized statin utilization and fairly neutral effects on cost in this real-world employer-based population.

Estimating the extent of reporting to FDA: a case study of statin-associated rhabdomyolysis.

PubMed

McAdams, Mara; Staffa, Judy; Dal Pan, Gerald

2008-03-01

To estimate the extent of reporting to FDA through statin-associated rhabdomyolysis data. Data included incidence rates (IRs) of hospitalized rhabdomyolysis among statin users from a population-based study, and comparable reported AERS cases and national estimates of statin use from an AERS analysis. Using IRs, national estimates of statin use and average days supply per prescription, we estimated the number of US statin-associated cases of hospitalized rhabdomyolysis. We compared this estimate to the observed number of cases reported to FDA to evaluate the extent of reporting. We repeated this method for atorvastatin, cerivastatin, pravastatin, and simvastatin and statin combinations. We performed sensitivity analyses to check for biases such as misclassification of statin use and cohort selection bias. We evaluated potential time-dependent cerivastatin reporting by a "Dear Health Care Provider (DHCP)" letter. The estimated extent of reporting to FDA varied by statin (atorvastatin, 5.0%; cerivastatin, 31.2%; simvastatin, 14.2%; all four combined, 17.7%; and non-cerivastatin statins combined, 9.9%). No pravastatin-associated cohort cases occurred. Across a reasonable value range, sensitivity analyses did not significantly alter the results; overall the cohort was similar to national statin-users. There was a large increase in AERS reports after the cerivastatin DHCP letter and the estimated extent of reporting increased from 14.8 to 35.0%. The extent of reporting of adverse events to FDA varied by statin and may be influenced by publicity. For statins-associated rhabdomyolysis, the estimated extent of reporting appears to range from 5 to 30% but in the absence of stimulated reporting appears to be 5-15%. Copyright 2008 John Wiley & Sons, Ltd.

Statin use and risk of prostate cancer: a Danish population-based case-control study, 1997-2010.

PubMed

Jespersen, Christina G; Nørgaard, Mette; Friis, Søren; Skriver, Charlotte; Borre, Michael

2014-02-01

Conflicting evidence has suggested that statins possess chemopreventive properties against prostate cancer (PCa). Therefore, we examined the association between statin use and risk of PCa in a Denmark-based case-control study. We identified 42,480 patients diagnosed with incident PCa during 1997-2010 from a national cancer registry. Five age-matched population controls (n=212,400) were selected for each case using risk-set sampling. Statin use from 1996 to the index date was obtained from the National Prescription Registry. Odds ratios (ORs) adjusted for age, comorbidity, non-steroidal anti-inflammatory drug use, and educational level for PCa associated with statin use, were computed using conditional logistic regression. Analyses were stratified by duration of statin use (0-1, 2-4, 5-9, or ≥10 years), stage of PCa (localized or advanced), and type of statin used (lipophilic or hydrophilic). In total, 7915 patients (19%) and 39,384 controls (19%) redeemed statin prescriptions prior to the index date. Overall, statin users had a 6% lower risk of PCa compared with non-users [adjusted OR (ORa), 0.94; 95% confidence interval (CI), 0.91-0.97]. Risk estimates did not differ substantially by duration or type of statin used. Slightly larger statin use-associated risk reductions were observed for advanced PCa (ORa, 0.90; 95% CI, 0.85-0.96) and with statin use ≥10 years (ORa, 0.78; 95% CI, 0.65-0.95). Statin use was associated with a risk reduction overall (6%) and, specifically with advanced PCa (10%). Differences in diagnostic measures and residual confounding by socioeconomic parameters may have influenced our results. Copyright © 2013 Elsevier Ltd. All rights reserved.

Clinical Profile of Statin Intolerance in the Phase 3 GAUSS-2 Study.

PubMed

Cho, Leslie; Rocco, Michael; Colquhoun, David; Sullivan, David; Rosenson, Robert S; Dent, Ricardo; Xue, Allen; Scott, Rob; Wasserman, Scott M; Stroes, Erik

2016-06-01

Recent evidence suggests that statin intolerance may be more common than reported in randomized trials. However, the statin-intolerant population is not well characterized. The goal of this report is to characterize the population enrolled in the phase 3 Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects Study (GAUSS-2; NCT 01763905). GAUSS-2 compared evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) to ezetimibe in hypercholesterolemic patients who discontinued statin therapy due to statin-associated muscle symptoms (SAMS). GAUSS-2 was a 12-week, double-blind, placebo-controlled, randomized study that enrolled patients with elevated LDL-C who were either not on a statin or able to tolerate only a low-dose due to SAMS. Patients had received ≥2 statins and were unable to tolerate any statin dose or increase in dose above a specified weekly dose due to SAMS. Three hundred seven patients (mean [SD] age, 62 [10] years; 54 % males) were randomized 2:1 (evolocumab:ezetimibe). Mean (SD) LDL-C was 4.99 (1.51) mmol/L. Patients had used ≥2 (100 %), ≥3 (55 %), or ≥4 (21 %) statins. Coronary artery disease was present in 29 % of patients. Statin-intolerant symptoms were myalgia in 80 % of patients, weakness in 39 %, and more serious complications in 20 %. In 98 % of patients, SAMS interfered with normal daily activity; in 52 %, symptoms precluded moderate exertion. Evaluation of the GAUSS-2 trial population of statin-intolerant patients demonstrates that most patients were high risk with severely elevated LDL-C and many had statin-associated muscle symptoms that interfered with their quality of life.

Statin Use and Hospital Length of Stay Among Adults Hospitalized With Community-acquired Pneumonia.

PubMed

Havers, Fiona; Bramley, Anna M; Finelli, Lyn; Reed, Carrie; Self, Wesley H; Trabue, Christopher; Fakhran, Sherene; Balk, Robert; Courtney, D Mark; Girard, Timothy D; Anderson, Evan J; Grijalva, Carlos G; Edwards, Kathryn M; Wunderink, Richard G; Jain, Seema

2016-06-15

Prior retrospective studies suggest that statins may benefit patients with community-acquired pneumonia (CAP) due to antiinflammatory and immunomodulatory effects. However, prospective studies of the impact of statins on CAP outcomes are needed. We determined whether statin use was associated with improved outcomes in adults hospitalized with CAP. Adults aged ≥18 years hospitalized with CAP were prospectively enrolled at 3 hospitals in Chicago, Illinois, and 2 hospitals in Nashville, Tennessee, from January 2010-June 2012. Adults receiving statins before and throughout hospitalization (statin users) were compared with those who did not receive statins (nonusers). Proportional subdistribution hazards models were used to examine the association between statin use and hospital length of stay (LOS). In-hospital mortality was a secondary outcome. We also compared groups matched on propensity score. Of 2016 adults enrolled, 483 (24%) were statin users; 1533 (76%) were nonusers. Statin users were significantly older, had more comorbidities, had more years of education, and were more likely to have health insurance than nonusers. Multivariable regression demonstrated that statin users and nonusers had similar LOS (adjusted hazard ratio [HR], 0.99; 95% confidence interval [CI], .88-1.12), as did those in the propensity-matched groups (HR, 1.03; 95% CI, .88-1.21). No significant associations were found between statin use and LOS or in-hospital mortality, even when stratified by pneumonia severity. In a large prospective study of adults hospitalized with CAP, we found no evidence to suggest that statin use before and during hospitalization improved LOS or in-hospital mortality. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Effect of statins on intracerebral hemorrhage outcome and recurrence.

PubMed

FitzMaurice, Emilie; Wendell, Lauren; Snider, Ryan; Schwab, Kristin; Chanderraj, Rishi; Kinnecom, Cathrine; Nandigam, Kaveer; Rost, Natalia S; Viswanathan, Anand; Rosand, Jonathan; Greenberg, Steven M; Smith, Eric E

2008-07-01

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence. We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months. Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P=0.84) or mortality (46% versus 45%, P=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm(3) in pre-ICH statin users compared to 22 cm(3) in nonusers, P=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10, P=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99, P=0.66). Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.

The effect of ezetimibe-statin combination on steroid hormone production in men with coronary artery disease and low cholesterol levels.

PubMed

Krysiak, Robert; Kowalska, Beata; Żmuda, Witold; Okopień, Bogusław

2015-04-01

Aggressive statin treatment was found to slightly reduce testosterone production. The aim of this study was to compare the effects of ezetimibe-statin combination and high-dose statin therapy on testicular and adrenal cortex function in men with LDL cholesterol levels below 70 mg/dL. The study included 26 adult men with coronary artery disease. Twelve of these patients did not tolerate high-dose statin therapy and were treated with lower doses of a statin plus ezetimibe. Fourteen patients tolerating high-dose simvastatin or rosuvastatin treatment continued high-dose statin therapy throughout the study period. Plasma lipids, glucose homeostasis markers and plasma levels of testosterone, cortisol, dehydroepiandrosterone sulphate, sex hormone-binding globulin, gonadotropins and ACTH, as well as urine free cortisol were assessed at baseline and after 16 weeks of treatment. Replacing high-dose statin therapy with ezetimibe/statin combination therapy reduced plasma levels of LH by 32% (p=0.043), as well as increased plasma levels of testosterone by 20% (p=0.038). Ezetimibe/statin combination did not induce any significant changes in plasma levels or urine excretion of the remaining hormones. At the end of the study, plasma LH levels were higher, while plasma testosterone levels were lower in patients receiving the combination therapy than in those treated only with high-dose statin. Our results indicate that ezetimibe combined with moderate statin dose exerts a less pronounced effect on testicular function in comparison with high-dose statin therapy. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

[Help me--I do not tolerate my statin].

PubMed

Nater, Harald; Perger, Ludwig; Suter, Paolo M

2015-05-06

Statins represent the most widely prescribed drugs. Accordingly, in daily practice statin-related muscle pain and other myopathic sensations are frequently seen. In this practice review the clinical approach to statin myopathy is discussed.

Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia.

PubMed

Khine, Htet; Yuet, Wei Cheng; Adams-Huet, Beverley; Ahmad, Zahid

2016-09-01

Patients with familial hypercholesterolemia (FH) may be at increased risk for statin-associated muscle symptoms because they require long-term treatment with high-intensity statin therapy. We sought to determine (1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms-solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056-also increase the risk of statin-associated muscle symptoms in FH patients, and (2) the natural history and management for FH patients with statin-associated muscle symptoms. We queried electronic records (2004-2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment low-density lipoprotein cholesterol [LDL-C] 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX, area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy. The risk of muscle symptoms was associated with age (odds ratio 1.6 [95% CI 1.2-2.2]), body mass index in non-African Americans (0.90 [0.83-0.97]), and hypertension (0.4 [0.2-0.9]). Simvastatin was the most commonly used statin, and it was the statin most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy ("eventually tolerant") and 29% (n = 28) never reestablished statin therapy ("never tolerant"). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually tolerated statins, and eventually tolerant patients achieved lower treated LDL-C levels (eventually tolerant 127 vs never tolerant 192 mg/dL, P < .001). Never tolerant patients also developed muscle symptoms on nonstatins (16% vs 50%, P = .003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (odds ratio 1.40 [95% CI 0.74-2.64]). Age, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never reestablished statin therapy. Such patients developed muscle symptoms even on nonstatin lipid-lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship between FH and statin-associated muscle symptoms so all FH patients can be adequately treated. Copyright © 2016 Elsevier Inc. All rights reserved.

Statin-associated Muscle Symptoms and SLCO1B1 rs4149056 Genotype in Patients with Familial Hypercholesterolemia

PubMed Central

Khine, Htet; Yuet, Wei Cheng; Adams-Huet, Beverley; Ahmad, Zahid

2016-01-01

Background and Aims Patients with familial hypercholesterolemia (FH) may be at increased risk of statin-associated muscle symptoms since they require long-term treatment with high-intensity statin therapy. We sought to determine 1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms - solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056 – also increase the risk of statin-associated muscle symptoms in FH patients, and 2) the natural history and management for FH patients with statin-associated muscle symptoms. Methods We queried electronic records (2004–2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment LDL-C 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy. Results The risk of muscle symptoms was associated with age (OR 1.6, [95% CI 1.2, 2.2]), BMI in non-African-Americans (0.90 [0.83, 0.97]), and hypertension (0.4, [0.2, 0.9]). Simvastatin most commonly employed and most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy (“eventually tolerant”) and 29% (n = 28) never reestablished statin therapy (“never tolerant”). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually-tolerated statins, and “eventually tolerant” patients achieved lower treated LDL-C levels (“eventually tolerant” 127 vs “never tolerant” 192 mg/dL, p < 0.001). “Never tolerant” patients also developed muscle symptoms on non-statins (16% vs. 50%, p = 0.003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (OR 1.40, [95% CI 0.74–2.64]). Conclusion Age, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never re-established statin therapy. Such patients developed muscle symptoms even on non-statin lipid lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship of FH and statin-associated muscle symptoms so all FH patients can be adequately treated. PMID:27595674

Understanding Patient Adherence and Concerns with STatins and MedicatION Discussions with Physicians (ACTION): A Survey on the Patient Perspective of Dialogue with Healthcare Providers Regarding Statin Therapy.

PubMed

Brinton, Eliot A

2018-05-10

Statin therapy is used first-line for cholesterol lowering and prevention of atherosclerotic cardiovascular disease (CVD), but side effects and the potential for drug-drug interactions may complicate its use. Provider-patient communication is essential for shared decision-making, which, in turn, is recommended by guidelines to reduce or overcome these challenges. Unfortunately, relatively little is known about provider-patient communication surrounding statin use. We conducted an online survey of 5,014 patients, U.S. residents over age 45 years, who had been prescribed a statin for hypercholesterolemia, to learn their perspectives on their disease state, medication use, side effects and, most importantly, recall of communication with their provider, especially at the time they were first diagnosed with hypercholesterolemia. Results were weighted to reflect the racial/ethnic composition of the general U.S. Ninety-four percent of patients said they were currently taking a statin and 6% said they had stopped. Past users vs current users were more likely to be female (64% vs 47%), younger than age 65 (57% vs 49%), and to have fewer CVD-related comorbidities (hypertension 58% vs 69%, Type 2 diabetes 17% vs 27%, and coronary heart disease 4% vs 9%, respectively; all p<0.05). Although 93% of current statin users were taking one or more other prescription medications (median of 4), 76% were "not at all"/"not very concerned" about the possibility of a drug-drug interaction with their statin, only 25% recalled having been told that "some statins might be more likely than others to interact with other medications," and only 18% (and only 20% of past users) were told that "their particular statin could potentially interact with other medications." Ninety-five percent and 94% of current and past users, respectively, said it was "extremely"/"somewhat" important that their healthcare provider take "an individualized approach to selecting the right statin," but 73% and 76%, respectively, said the choice of their statin was made with little or no input from them. Further, among current users, only 45% said that they communicate "openly" with their provider about statin-related challenges, and 39% said they usually don't ask questions about their statin. Forty-three percent of current users had switched a statin at least once and 47% of past statin users had switched statins at least once before stopping. Current users were more likely than past users to switch due to "it was recommended" (27% vs 8%), medication costs (14 vs 7%), lack of insurance coverage (10% vs 2%), desire for a generic statin (14 vs 2%), lack of cholesterol efficacy (13% vs 6%), or lack of triglyceride efficacy (11% vs 5%) (all p<0.05). Past users were more likely than current users to switch because of muscle and/or joint pain (42% vs 17%), other symptoms (29% vs 9%), and risk of medication interference (9% vs 3%) (all p<0.05). Patient-provider communication regarding statin use is suboptimal in that patients usually desire but often do not recall instructions customizing or explaining the selection of a given statin, even in the context of potential drug-drug interactions, and patients report a lack of shared input and open communication regarding statin choice and/or challenges on a statin. Current users cite issues surrounding cost and coverage of statin expenses and lipid efficacy as their most common reasons for switching statin agents while past users cite side effects and risk of drug-drug interactions as their main reasons for quitting statin therapy. Efforts toward more open communication and shared decision-making between providers and patients appear warranted. This article is protected by copyright. All rights reserved.

Managing hypercholesterolemia and preventing cardiovascular events in elderly and younger Chinese adults: focus on rosuvastatin

PubMed Central

Wang, Zhen; Ge, Junbo

2014-01-01

Coronary heart disease (CHD) is the leading cause of death worldwide. The efficacy and safety of statins in primary and secondary prevention of CHD is confirmed in several large studies, and rosuvastatin is the latest statin on market. We review the published literature on rosuvastatin in Chinese people. The pharmacokinetics of rosuvastatin in Chinese is somewhat different from that in Caucasians, but this does not influence the linear relationship between dosage and efficacy and with no drug accumulation. Rosuvastatin 5–20 mg/day is effective and safe in decreasing low-density lipoprotein cholesterol in both younger and elderly patients with hypercholesterolemia, even in very elderly patients. Rosuvastatin also shows anti-inflammatory and antiatherosclerosis features, such as reducing carotid intima-media thickness and plaque area. Rosuvastatin can also improve the prognosis of Chinese CHD patients, such as in the case of acute myocardial infarction. Its adverse-event rate is low and comparable to other statins. In conclusion, rosuvastatin is effective and safe for younger or elderly Chinese patients. PMID:24353409

A novel use of oxidative coupling reactions for determination of some statins (cholesterol-lowering drugs) in pharmaceutical formulations

NASA Astrophysics Data System (ADS)

Ashour, Safwan; Bahbouh, Mahmoud; Khateeb, Mouhammed

2011-03-01

New, accurate and reliable spectrophotometric methods for the assay of three statin drugs, atorvastatin calcium (AVS), fluvastatin sodium (FVS) and pravastatin sodium (PVS) in pure form and pharmaceutical formulations have been described. All methods involve the oxidative coupling reaction of AVS, FVS and PVS with 3-methyl-2-benzothiazolinone hydrazone hydrochloride monohydrate (MBTH) in the presence of Ce(IV) in an acidic medium to form colored products with λmax at 566, 615 and 664 nm, respectively. Beer's law was obeyed in the ranges of 2.0-20.0, 4.9-35.4 and 7.0-30.0 μg mL -1 for AVS-MBTH, FVS-MBTH and PVS-MBTH, respectively. Molar absorptivities for the above three methods were found to be 3.24 × 10 4, 1.05 × 10 4 and 0.68 × 10 4 L mol -1 cm -1, respectively. Statistical treatment of the experimental results indicates that the methods are precise and accurate. The proposed methods have been applied to the determination of the components in commercial forms with no interference from the excipients. A comparative study between the suggested procedures and the official methods for these compounds in the commercial forms showed no significant difference between the two methods.

Influence of statins on distinct circulating microRNAs during prolonged aerobic exercise

PubMed Central

Min, Pil-Ki; Park, Joseph; Isaacs, Stephanie; Taylor, Beth A.; Thompson, Paul D.; Troyanos, Chris; D'Hemecourt, Pierre; Dyer, Sophia; Baggish, Aaron L.

2015-01-01

Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) increase in plasma after prolonged exercise, but the patterns of myomiRs release after statin-associated muscle injury have not been examined. We examined the relationships between statin exposure, in vitro and in vivo muscle contraction, and expression of candidate circulating myomiRs. We measured plasma levels of myomiRs, circulating microRNA-1 (c-miR-1), c-miR-133a, c-miR-206, and c-miR-499-5p from 28 statin-using and 28 nonstatin-using runners before (PRE), immediately after (FINISH), and 24 h after they ran a 42-km footrace (the 2011 Boston marathon) (POST-24). To examine these cellular-regulation myomiRs, we used contracting mouse C2C12 myotubes in culture with and without statin exposure to compare intracellular and extracellular expression of these molecules. In marathoners, c-miR-1, c-miR-133a, and c-miR-206 increased at FINISH, returned to baseline at POST-24, and were unaffected by statin use. In contrast, c-miR-499-5p was unchanged at FINISH but increased at POST-24 among statin users compared with PRE and runners who did not take statins. In cultured C2C12 myotubes, extracellular c-miR-1, c-miR-133a, and c-miR-206 were significantly increased by muscle contraction regardless of statin use. In contrast, extracellular miR-499-5p was unaffected by either isolated statin exposure or isolated carbachol exposure but it was increased when muscle contraction was combined with statin exposure. In summary, we found that statin-potentiated muscle injury during exercise is accompanied by augmented extracellular release of miR-499-5p. Thus c-miR-499-5p may serve as a biomarker of statin-potentiated muscle damage. PMID:26472872

Ezetimibe-Statin Combination Therapy.

PubMed

Nußbaumer, Barbara; Glechner, Anna; Kaminski-Hartenthaler, Angela; Mahlknecht, Peter; Gartlehner, Gerald

2016-07-01

To date, most clinical comparisons of ezetimibe-statin combination therapy versus statin monotherapy have relied entirely on surrogate variables. In this systematic review, we study the efficacy and safety of ezetimibe-statin combination therapy in comparison to statin monotherapy in terms of the prevention of cardiovascular events in hyperlipidemic patients with atherosclerosis and/or diabetes mellitus. This review is based on a systematic literature search (1995 to July 2015) in PubMed, the Excerpta Medica Database (EMBASE), the Cochrane Library, and the ClinicalTrials.gov registry. Nine randomized, controlled trials with data from a total of 19 461 patients were included. Ezetimibe-statin combination therapy was associated with a lower risk of cardiovascular events than statin monotherapy: 33% of the patients treated with ezetimibe and a statin, and 35% of those treated with a statin alone, had a cardiovascular event within seven years (number needed to treat [NNT]: 50 over 7 years). Combination therapy was also significantly more effective in preventing a composite endpoint consisting of death due to cardiovascular disease, nonfatal myocardial infarction, unstable angina pectoris, coronary revascularization, and nonfatal stroke (hazard ratio [HR] 0.94, 95% confidence interval [0,89; 0,99]; p = 0.016). Diabetic patients benefited from combination therapy rather than monotherapy with respect to cardiovascular morbidity (HR 0.87 [0.78; 0.94]). On the other hand, the addition of ezetimibe to statin therapy did not lessen either cardiovascular or overall mortality. Serious undesired events occurred in 38% of the patients taking ezetimibe and a statin nd in 39% of the patients taking a statin alone (relative risk 1.09 [0.77; 1.55]). In high-risk patients with an acute coronary syndrome, combination therapy with ezetimibe and a statin lowered the risk of cardiovascular events in comparison to statin monotherapy. The risk of dying or suffering an adverse drug effect was similar in the two treatment groups.

Effect of Early Statin Treatment in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction

PubMed Central

Sim, Doo Sun; Cho, Kyung Hoon; Ahn, Youngkeun; Kim, Young Jo; Chae, Shung Chull; Hong, Taek Jong; Seong, In Whan; Chae, Jei Keon; Kim, Chong Jin; Cho, Myeong Chan; Rha, Seung-Woon; Bae, Jang Ho; Seung, Ki Bae; Park, Seung Jung

2013-01-01

Background and Objectives The benefit of early statin treatment following acute myocardial infarction (MI) complicated with cardiogenic shock (CS) has not been well studied. We sought to assess the effect of early statin therapy in patients with CS complicating acute MI. Subjects and Methods We studied 553 statin-naive patients with acute MI and CS (Killip class IV) who underwent revascularization therapy between November 2005 and January 2008 at 51 hospitals in the Korea Acute Myocardial Infarction Registry. Patients were divided into 2 groups: those who received statins during hospitalization (n=280) and those who did not (n=273). The influence of statin treatment on a 12-month clinical outcome was examined using a matched-pairs analysis (n=200 in each group) based on the propensity for receiving statin therapy during hospitalization. Results Before adjustment, patients receiving statin, compared to those not receiving statin, had a more favorable clinical profile, were less likely to suffer procedural complications, and more likely to receive adequate medical therapy. Patients receiving statin had lower unadjusted in-hospital mortality and composite rate of mortality, MI, and repeat revascularization at 12 months, which remained significantly lower after adjustment for patient risk, procedural characteristics, and treatment propensity. Conclusion In CS patients with acute MI undergoing revascularization therapy, early statin treatment initiated during hospitalization was associated with lower rates of in-hospital death and 12-month adverse cardiac events. PMID:23508129

Role of Statin Drugs for Polycystic Ovary Syndrome.

PubMed

Cassidy-Vu, Lisa; Joe, Edwina; Kirk, Julienne K

2016-12-01

Objective: To review the potential role and specific impact of statin drugs in women with PCOS. The evidence for this use of statins in PCOS is limited and still under further investigation. Materials and methods: A search was conducted using PubMed, DynaMed and PubMedHealth databases through October 16, 2016 using the terms polycystic ovary syndrome, PCOS, hydroxymethylglutaryl-CoA reductase inhibitors, hydroxymethylglutaryl-CoA, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin . English-language trials evaluating statins in PCOS were obtained and incorporated if they provided relevant data for providers. Results: We summarize twelve trials involving statins in PCOS. The trials were predominantly 12 weeks to 3 months in length (8 of the 12 trials) and low to moderate dose of statin drugs were used. The majority (10 of 12) of the trials show that statins reduce testosterone levels or other androgen hormones (DHEA-S and androstenedione), half of the trials evaluating LH/FSH ratio show an improvement, and all had positive effects on lipid profiles. Conclusion: Statins show promising improvements in serum levels of androgens and LH/FSH ratios translating to improved cardiovascular risk factors above and beyond simply lowering LDL levels. More investigation is needed to determine if statins can clinically impact women with PCOS long term, particularly those who are young and are not yet candidates for traditional preventative treatment with a statin medication.

Effect of statin use on pain relief by transforaminal epidural steroid injection

PubMed Central

Aydın, Osman Nuri; Tasdemir, Banu; Galimberti, Fabrizio; Turan, Alparslan

2016-01-01

Aim To investigate the impact of statin use on response to fluoroscopy-assisted transforaminal anterior epidural steroid injection (TAESI). Methods Patients undergoing TAESI for low back pain were recruited and stratified according to statin use. Pain was evaluated with a visual analogue scale (VAS) before and at 1, 3, and 6 months after TAESI. Health-related quality-of-life was evaluated using the Short Form 36 (SF-36) questionnaire 6 months after TAESI. Results There were no significant differences in VAS scores after TAESI between statin users (n = 40) and statin nonusers (n = 253). The SF-36 subgroup: role limitations due to emotional problems score was significantly lower in statin users than statin nonusers. There were no significant between-group differences in any other SF-36 parameter. Conclusion Statin use had no effect on pain scores after TAESI. PMID:26912508

PCSK9 inhibitors in the current management of atherosclerosis.

PubMed

Whayne, Thomas F

The history of proprotein convertase subtilisin/kexin type 9 (PCSK9) in medical science is fascinating and the evolution of knowledge of its function has resulted in new medications of major importance for the cardiovascular (CV) patient. PCSK9 functions as a negative control or feedback for the cell surface receptors for low-density lipoprotein including its component of cholesterol (LDL-C). The initial and key findings were that different abnormalities of PCSK9 can result in an increase or a decrease of LDL-C because of more or less suppression of cell surface receptors. These observations gave hints and awoke interest that it might be possible to prepare monoclonal antibodies to PCSK9 and decrease its activity, after which there should be more active LDL-C cell receptors. The rest is a fascinating story that currently has resulted in two PCSK9 inhibitors, alirocumab and evolocumab, which, on average, decrease LDL-C approximately 50%. Nevertheless, if there are no contraindications, statins remain the standard of prevention for the high-risk CV patient and this includes both secondary and primary prevention. The new inhibitors are for the patient that does not attain the desired target for LDL-C reduction while taking a maximum statin dose or who does not tolerate any statin dose whatsoever. Atherosclerosis can be considered a metabolic disease and the clinician needs to realize this and think more and more of CV prevention. These inhibitors can contribute to both the stabilization and regression of atherosclerotic plaques and thereby avoid or delay major adverse cardiac events. (United States). Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects.

PubMed

Sakamoto, Kentaro; Kawamura, Mitsunobu; Watanabe, Takayuki; Ashidate, Keiko; Kohro, Takahide; Tanaka, Akira; Mori, Yasumichi; Tagami, Motoki; Hirano, Tsutomu; Yamazaki, Tsutomu; Shiba, Teruo

2017-06-24

Lowering cholesterol levels decreases the risk of atherosclerotic diseases. Effective ways to stably reduce LDL-C level are warranted in type 2 diabetic patients, a high-risk population for CVD, with various anti-diabetic therapeutic background. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles. We evaluated long-term ezetimibe add-on therapy in T2DM patients with hypercholesterolemia. In a randomized, multicenter, open-label, prospective study, a total of 109 T2DM patients not attaining LDL-C target value despite first-line dose statin (10 mg of atorvastatin or 1 mg of pitavastatin) therapy in Japan were recruited. We investigated the difference in cholesterol lowering effect between ezetimibe (10 mg) add-on statin (EAT) group and double-dose statin (DST) group. Changes of parameters related to atherosclerotic event risks were assessed. The reduction of LDL-C was larger in the EAT group (28.3%) than in the DST group (9.2%) at 52 weeks as well as the primary endpoint of 12 weeks. EAT achieved significant lower levels of TC and apo B, respectively. Both treatments attained significant reduction in sd-LDL-C or hsCRP on this long-term basis. Notably, sd-LDL-C in EAT reduced as low as 36.1 ± 14.9 mg/dl to reach near the threshold (35.0 mg/dl) for atherosclerosis with significantly higher achievement rate (55.6%) than DST treatment. Simultaneously, hsCRP reduction by EAT attained as low value as 0.52 ± 0.43 mg/l. In the present 52-week long-term period, ezetimibe add-on therapy showed a robust advantage in lowering LDL-C and in attaining target LDL-C values compared with the doubling of statin dose. Moreover, it's meaningful that sd-LDL, powerfully atherogenic lipoprotein, exhibited prominent decrease consistently prominently by ezetimibe add-on therapy. DM patients with hypercholesterolemia are at high risk for CAD, and adding ezetimibe onto usual-dose statin treatment in Japan has been suggested as the first-line therapy for those DM patients who failed to attain the target LDL-C value (UMIN000002593).

Statins and musculoskeletal conditions, arthropathies, and injuries.

PubMed

Mansi, Ishak; Frei, Christopher R; Pugh, Mary Jo; Makris, Una; Mortensen, Eric M

2013-07-22

Statin use may be associated with increased musculoskeletal adverse events, especially in physically active individuals. To determine whether statin use is associated with musculoskeletal conditions, including arthropathy and injury, in a military health care system. A retrospective cohort study with propensity score matching. San Antonio Military Multi-Market. Tricare Prime/Plus beneficiaries evaluated from October 1, 2003, to March 1, 2010. Statin use during fiscal year 2005. On the basis of medication fills, patients were divided into 2 groups: statin users (received a statin for at least 90 days) and nonusers (never received a statin throughout the study period). Using patients' baseline characteristics, we generated a propensity score that was used to match statin users and nonusers; odds ratios (ORs) were determined for each outcome measure. Secondary analyses determined adjusted ORs for all patients who met study criteria and a subgroup of patients with no comorbidities identified using the Charlson Comorbidity Index. Sensitivity analysis further determined adjusted ORs for a subgroup of patients with no musculoskeletal diseases at baseline and a subgroup of patients who continued statin therapy for 2 years or more. The occurrence of musculoskeletal conditions was determined using prespecified groups of International Classification of Diseases, Ninth Revision, ClinicalModification codes: Msk1, all musculoskeletal diseases; Msk1a, arthropathies and related diseases; Msk1b, injury-related diseases (dislocation, sprain, strain); and Msk2, drug-associated musculoskeletal pain. A total of 46 249 individuals met study criteria (13 626 statin users and 32 623 nonusers). Of these, we propensity score-matched 6967 statin users with 6967 nonusers. Among matched pairs, statin users had a higher OR for Msk1 (OR, 1.19; 95% CI, 1.08-1.30), Msk1b (1.13; 1.05-1.21), and Msk2 (1.09; 1.02-1.18); the OR for Msk1a was 1.07 (0.99-1.16; P = .07). Secondary and sensitivity analyses revealed higher adjusted ORs for statin users in all outcome groups. Musculoskeletal conditions, arthropathies, injuries, and pain are more common among statin users than among similar nonusers. The full spectrum of statins' musculoskeletal adverse events may not be fully explored, and further studies are warranted, especially in physically active individuals.

Drug-drug Interactions of Statins Potentially Leading to Muscle-Related Side Effects in Hospitalized Patients.

PubMed

Bucsa, Camelia; Farcas, Andreea; Leucuta, D; Mogosan, Cristina; Bojita, M; Dumitrascu, D L

2015-01-01

The associations of drugs that may interact with the statins resulting in elevated serum concentration of the statins are an important risk factor for statin induced muscle disorders. We aimed to determine the prevalence of these associations in all hospitalized patients that had been prescribed statins before/during hospitalization and to find out how often they are associated with muscle-related side effects. This prospective, non-interventional study performed in two internal medicine departments included patients with statin therapy before/during hospitalization. Data on each patient demographic characteristics, co-morbidities and treatment was collected from medical charts and interviews. We evaluated patients' therapy for the targeted associations using Thomson Micromedex Drug Interactions checker and we ranked the identified drug-drug interactions (DDIs) accordingly. Each patient with statin treatment before admission was additionally interviewed in order to identify muscular symptoms. In 109 patients on statin treatment we found 35 potential (p) DDIs of statins in 30 (27.5%) patients, most of which were in the therapy before admission (27 pDDIs). The pDDIs were moderate (20 pDDIs) and major (15 pDDIs). Of the total number of pDDIs, 24 were targeting the muscular system. The drugs most frequently involved in the statins' pDDIs were amiodarone and fenofibrate. Two of the patients with pDDIs reported muscle pain, both having additional risk factors for statin induced muscular effects. The prevalence of statins' pDDIs was high in our study, mostly in the therapy before admission, with only a small number of pDDIs resulting in clinical outcome.

Identification and Management of Statin-Associated Symptoms in Clinical Practice: Extension of a Clinician Survey to 12 Further Countries.

PubMed

Rosenson, Robert S; Gandra, Shravanthi R; McKendrick, Jan; Dent, Ricardo; Wieffer, Heather; Cheng, Lung-I; Catapano, Alberico L; Oh, Paul; Kees Hovingh, G; Stroes, Erik S

2017-04-01

Statins are the first-choice pharmacological treatment for patients with hypercholesterolemia and at risk for cardiovascular disease; however, a minority of patients experience statin-associated symptoms (SAS) and are considered to have reduced statin tolerance. The objective of this study was to establish how patients with SAS are identified and managed in clinical practice in Austria, Belgium, Colombia, Croatia, the Czech Republic, Denmark, Portugal, Switzerland, Russia, Saudi Arabia, Turkey, and the United Arab Emirates. A cross-sectional survey was conducted (2015-2016) among clinicians (n = 60 per country; Croatia: n = 30) who are specialized/experienced in the treatment of hypercholesterolemia. Participants were asked about their experience of patients presenting with potential SAS and how such patients were identified and treated. Muscle-related symptoms were the most common presentation of potential SAS (average: 51%; range across countries [RAC] 17-74%); other signs/symptoms included persistent elevation in transaminases. To establish whether symptoms are due to statins, clinicians required rechallenge after discontinuation of statin treatment (average: 77%; RAC 40-90%); other requirements included trying at least one alternative statin. Clinicians reported that half of high-risk patients with confirmed SAS receive a lower-dose statin (average: 53%; RAC 43-72%), and that most receive another non-statin lipid-lowering therapy with or without a concomitant statin (average: 65%; RAC 52-83%). The specialists and GPs surveyed use stringent criteria to establish causality between statin use and signs or symptoms, and persevere with statin treatment where possible.

Evaluation of anti-inflammatory effect of statins in chronic periodontitis.

PubMed

Suresh, Snophia; Narayana, Satya; Jayakumar, P; Sudhakar, Uma; Pramod, V

2013-01-01

Statins are the group of lipid-lowering drugs commonly used to control cardiovascular and cerebrovascular diseases. Statins have potential anti-inflammatory effect by blocking the intermediate metabolites of the mevalonate pathway. The objective of this study was to evaluate the anti-inflammatory effect of statin medication in chronic periodontitis patients. Thirty patients of age group between 40 and 60 years were selected from the outpatient pool of Department of Periodontics, Thaimoogambigai Dental College and Hospital, Chennai. Thirty patients selected were grouped into two groups, Group-I consists of patients with generalized chronic periodontitis and on statin medication and Group-II consists of patients with generalized chronic periodontitis. Clinical parameters were recorded and gingival crevicular fluid (GCF) samples were analyzed for interleukin (IL)-1β using commercially available enzyme-linked immunosorbent assay. The mean GCF IL-1β levels in generalized chronic periodontitis patients who are on statin medication (Group-I) were lower than the generalized chronic periodontitis patients without statin medication (Group-II). Reduction of GCF IL-1β levels in statin users indicate that statins have anti-inflammatory effect on periodontal disease.

Statin Lactonization by Uridine 5'-Diphospho-glucuronosyltransferases (UGTs).

PubMed

Schirris, Tom J J; Ritschel, Tina; Bilos, Albert; Smeitink, Jan A M; Russel, Frans G M

2015-11-02

Statins are cholesterol-lowering drugs that have proven to be effective in lowering the risk of major cardiovascular events. Although well tolerated, statin-induced myopathies are the most common side effects. Compared to their pharmacologically active acid form, statin lactones are more potent inducers of toxicity. They can be formed by glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferases (UGTs), but a systematic characterization of subtype specificity and kinetics of lactonization is lacking. Here, we demonstrate for six clinically relevant statins that only UGT1A1, 1A3, and 2B7 contribute significantly to their lactonization. UGT1A3 appeared to have the highest lactonization capacity with marked differences in statin conversion rates: pitavastatin ≫ atorvastatin > cerivastatin > lovastatin > rosuvastatin (simvastatin not converted). Using in silico modeling we could identify a probable statin interaction region in the UGT binding pocket. Polymorphisms in these regions of UGT1A1, 1A3, and 2B7 may be a contributing factor in statin-induced myopathies, which could be used in personalization of statin therapy with improved safety.

Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sirvent, P., E-mail: pascal.sirvent@univ-bpclermont.fr; CHRU Montpellier, 34295 Montpellier; Clermont Université, Université Blaise Pascal, EA 3533, Laboratoire des Adaptations Métaboliques à l'Exercice en conditions Physiologiques et Pathologiques

2012-03-01

The most common and problematic side effect of statins is myopathy. To date, the patho-physiological mechanisms of statin myotoxicity are still not clearly understood. In previous studies, we showed that acute application in vitro of simvastatin caused impairment of mitochondrial function and dysfunction of calcium homeostasis in human and rat healthy muscle samples. We thus evaluated in the present study, mitochondrial function and calcium signaling in muscles of patients treated with statins, who present or not muscle symptoms, by oxygraphy and recording of calcium sparks, respectively. Patients treated with statins showed impairment of mitochondrial respiration that involved mainly the complexmore » I of the respiratory chain and altered frequency and amplitude of calcium sparks. The muscle problems observed in statin-treated patients appear thus to be related to impairment of mitochondrial function and muscle calcium homeostasis, confirming the results we previously reported in vitro. -- Highlights: ► The most common and problematic side effect of statins is myopathy. ► Patients treated with statins showed impairment of mitochondrial respiration. ► Statins-treated patients showed altered frequency and amplitude of calcium sparks.« less

Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galtier, F., E-mail: f-galtier@chu-montpellier.fr; INSERM, CIC 1001, 80 Avenue Augustin Fliche, 34295 Montpellier Cedex 5; CPID, Faculté de Pharmacie, 15 Av. Charles Flahault, BP 14491, 34093 Montpellier Cedex 5, Montpellier

Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca{sup 2+} homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca{sup 2+} spark properties were evaluated on a muscle biopsy 4 days before the second stress test. Simvastatin-treated subjects were separated according to theirmore » median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38 ± 5.68 vs − 1.15 ± 4.32 UI/L, P < 0.001) and CK (− 24.3 ± 99.1 ± 189.3vs 48.3 UI/L, P = 0.01) and a trend to an elevation of isoprostanes (193 ± 408 vs12 ± 53 pmol/mmol creatinine, P = 0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca{sup 2+} sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca{sup 2+} spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca{sup 2+} spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r = 0.71, P = 0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication. -- Highlights: ► Statin use may be limited by side effects, particularly myopathy. ► Statins might impair mitochondrial function and muscle Ca2+ signaling in muscle. ► This was tested among healthy volunteers receiving simvastatin 80 mg daily for 8 weeks. ► CK increase was associated with alterations in Ca2+ sparks and mitochondrial function.« less

Impact of statins on cognitive deficits in adult male rodents after traumatic brain injury: a systematic review.

PubMed

Peng, Weijun; Yang, Jingjing; Yang, Bo; Wang, Lexing; Xiong, Xin-gui; Liang, Qinghua

2014-01-01

The efficacy of statin treatment on cognitive decline is controversial, and the effect of statins on cognitive deficits in individuals with traumatic brain injury (TBI) has yet to be investigated. Therefore, we systematically reviewed the effect of statins on cognitive deficits in adult male rodents after TBI. After identifying eligible studies by searching four electronic databases on February 28, 2014, we assessed study quality, evaluated the efficacy of statin treatment, and performed stratified metaregression and metaregression to assess the influence of study design on statin efficacy. Eleven studies fulfilled our inclusion criteria from a total of 183 publications. The overall methodological quality of these studies was poor. Meta-analysis showed that statins exert statistically significant positive effects on cognitive performance after TBI. Stratified analysis showed that atorvastatin has the greatest effect on acquisition memory, simvastatin has the greatest effect on retention memory, and statin effects on acquisition memory are higher in closed head injury models. Metaregression analysis further showed that that animal species, study quality, and anesthetic agent impact statin effects on retention memory. We conclude that statins might reduce cognitive deficits after TBI. However, additional well-designed and well-reported animal studies are needed to inform further clinical study.

Preventable statin adverse reactions and therapy discontinuation. What can we learn from the spontaneous reporting system?

PubMed

Sessa, Maurizio; Rafaniello, Concetta; Scavone, Cristina; Mascolo, Annamaria; di Mauro, Gabriella; Fucile, Annamaria; Rossi, Francesco; Sportiello, Liberata; Capuano, Annalisa

2018-05-01

Statin treatment is often associated with poor adherence, which may be due to the onset of adverse drug reactions (ADRs). We investigated on potential risk factors related to preventable cases of statin-induced ADRs and to the discontinuation of statin therapy. We performed a study using the database of Italian spontaneous reporting. The target population for the preventability assessment was all patients with suspected statin-induced ADRs deriving from Campania Region (a territory of Southern Italy) between 2012 and 2017. Additionally, a local sentinel surveillance site involving General Practitioners was selected to countercheck in routine clinical practice the role of ADRs for statin discontinuation. In total, 34 of 655 (5.19%) regional cases were preventable and among detected risk factors 90.0% was related to healthcare professionals' practices and 10.0% to patient behaviour. In 81.4% (533/655) of cases, statin therapy was discontinued due to ADRs, mainly classified as not serious and associated with a positive prognosis. These results were also confirmed in the active sentinel site. Our findings suggest an inappropriate use of statins among the identified preventable cases and a potential inappropriate statin discontinuation due to ADRs. These factors may be useful for targeting interventions to improve statin adherence.

Progression of kidney disease in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

PubMed

Rahman, Mahboob; Baimbridge, Charles; Davis, Barry R; Barzilay, Joshua; Basile, Jan N; Henriquez, Mario A; Huml, Anne; Kopyt, Nelson; Louis, Gail T; Pressel, Sara L; Rosendorff, Clive; Sastrasinh, Sithiporn; Stanford, Carol

2008-09-01

Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy in the progression of kidney disease is unclear. Prospective randomized clinical trial, post hoc analyses. 10,060 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) stratified by baseline estimated glomerular filtration rate (eGFR): less than 60, 60 to 89, and 90 or greater mL/min/1.73 m(2). Mean follow-up was 4.8 years. Randomized; pravastatin, 40 mg/d, or usual care. Total, high-density lipoprotein, and low-density lipoprotein cholesterol; end-stage renal disease (ESRD), eGFR. Through year 6, total cholesterol levels decreased in the pravastatin (-20.7%) and usual-care groups (-11.2%). No significant differences were seen between groups for rates of ESRD (1.36 v 1.45/100 patient-years; P = 0.9), composite end points of ESRD and 50% or 25% decrease in eGFR, or rate of change in eGFR. Findings were consistent across eGFR strata. In patients with eGFR of 90 mL/min/1.73 m(2) or greater, the pravastatin arm tended to have a higher eGFR. Proteinuria data unavailable, post hoc analyses, unconfirmed validity of the Modification of Diet in Renal Disease Study equation in normal eGFR range, statin drop-in rate in usual-care group with small cholesterol differential between groups. In hypertensive patients with moderate dyslipidemia and decreased eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR. However, benefit from statin therapy may depend on the degree of the cholesterol level decrease achieved.

Toward "pain-free" statin prescribing: clinical algorithm for diagnosis and management of myalgia.

PubMed

Jacobson, Terry A

2008-06-01

Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and post-marketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins.

Cognitive and Physical Function by Statin Exposure in Elderly Individuals Following Acute Myocardial Infarction.

PubMed

Swiger, Kristopher J; Martin, Seth S; Tang, Fengming; Blaha, Michael J; Blumenthal, Roger S; Alexander, Karen P; Arnold, Suzanne V; Spertus, John A

2015-08-01

Despite beneficial effects on morbidity and mortality after acute myocardial infarction (AMI), concerns remain about the safety of statin therapy, particularly their potential effects on cognitive and physical function, in elderly individuals. Among statin-naive AMI patients age ≥ 65 years in a multicenter US registry, we examined the association between statin prescription at discharge and change in cognition (via Modified Telephone Interview for Cognitive Status [TICS-M]) assessed at 1 and 6 months after AMI. Short Form-12 Physical Component score, hand grip, walk time, and chair-rise tests were used to assess physical function. We conducted noninferiority testing to evaluate the hypothesis that the mean change in cognitive function was no worse among patients recently started on statins compared with those who were not. Among 317 elderly AMI patients, 262 patients (83%) were prescribed a statin at discharge and 55 were not. After matching for propensity to be discharged on statin after AMI, the effect of statin treatment on change in TICS-M from 1 to 6 months (estimated difference, 0.11 points; 95% confidence interval: -2.11 to 2.32, P = 0.92) showed noninferiority (inferiority threshold 3 points). There were no significant differences in any physical function measure. Among statin-naive elderly individuals recovering from AMI, initiation of statin therapy was not associated with detectable changes in short-term cognitive or physical function. These findings support the general safety of statin therapy for secondary prevention in this population. © 2015 Wiley Periodicals, Inc.

Do statin users adhere to a healthy diet and lifestyle? The Australian Diabetes, Obesity and Lifestyle Study.

PubMed

Johal, Simran; Jamsen, Kris M; Bell, J Simon; Mc Namara, Kevin P; Magliano, Dianna J; Liew, Danny; Ryan-Atwood, Taliesin E; Anderson, Claire; Ilomäki, Jenni

2017-04-01

Background Lifestyle and dietary advice typically precedes or accompanies the prescription of statin medications. However, evidence for adherence to this advice is sparse. The objective was to compare saturated fat intake, exercise, alcohol consumption and smoking between statin users and non-users in Australia. Methods Data were analysed for 4614 participants aged ≥37 years in the Australian Diabetes, Obesity and Lifestyle study in 2011-2012. Statin use, smoking status and physical activity were self-reported. Saturated fat and alcohol intake were measured via a food frequency questionnaire. Multinomial logistic regression was used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between statin use and the four lifestyle factors. All models were adjusted for age, sex, education, number of general practitioner visits, body mass index, hypertension, diabetes and prior cardiovascular diseases. Results In total 1108 (24%) participants used a statin. Statin users were 29% less likely to be within the highest quartile versus the lowest quartile of daily saturated fat intake compared to non-users (OR 0.71, 95% CI 0.54-0.94). There were no statistically significant associations between statin use and smoking, physical activity or alcohol consumption. Conclusions Smoking status, alcohol consumption and exercise level did not differ between users and non-users of statins. However, statin users were less likely to consume high levels of saturated fat than non-users. We found no evidence that people took statins to compensate for a poor diet or lifestyle.

Differential response of endothelial cells to simvastatin when conditioned with steady, non-reversing pulsatile or oscillating shear stress.

PubMed

Rossi, Joanna; Jonak, Paul; Rouleau, Leonie; Danielczak, Lisa; Tardif, Jean-Claude; Leask, Richard L

2011-01-01

Few studies have investigated whether fluid mechanics can impair or enhance endothelial cell response to pharmacological agents such as statin drugs. We evaluated and compared Kruppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and thrombomodulin (TM) expression in human abdominal aortic endothelial cells (HAAEC) treated with increasing simvastatin concentrations (0.1, 1 or 10 μM) under static culture and shear stress (steady, non-reversing pulsatile, and oscillating). Simvastatin, steady flow, and non-reversing pulsatile flow each separately upregulated KLF2, eNOS, and TM mRNA. At lower simvastatin concentrations (0.1 and 1 μM), the combination of statin and unidirectional steady or pulsatile flow produced an overall additive increase in mRNA levels. At higher simvastatin concentration (10 μM), a synergistic increase in eNOS and TM mRNA expression was observed. In contrast, oscillating flow impaired KLF2 and TM, but not eNOS expression by simvastatin at 1 μM. A higher simvastatin concentration of 10 μM overcame the inhibitory effect of oscillating flow. Our findings suggest that oscillating shear stress renders the endothelial cells less responsive to simvastatin than cells exposed to unidirectional steady or pulsatile flow. Consequently, the pleiotropic effects of statins in vivo may be less effective in endothelial cells exposed to atheroprone hemodynamics.

Managing statin-induced muscle toxicity in a lipid clinic.

PubMed

Blaier, O; Lishner, M; Elis, A

2011-06-01

Muscle toxicity is the most significant adverse effect related to statins. The aim of the study was to analyse the clinical course and achievement of LDL-C target levels in patients with statin-induced muscle toxicity. All patients who were referred to the lipid clinic because of statin-induced muscle toxicity, or developed it during follow-up, or did not reach LDL-C target levels because of its previous occurrence, and attended the clinic for at least three follow-up visits, were eligible. Files were reviewed for demographic and clinical parameters, coronary heart disease risk level, the severity of muscle injury, the type of statin and dose that caused the adverse effects, the clinical approach and outcome, and whether the LDL-C target level was achieved. The study group consisted of 54 patients. Twenty-three (43%) patients complained of myalgia, 23 (43%) had asymptomatic serum creatine kinase (CK) level elevation, five (9%) had myopathy and three (5%) had rhabdomyolysis. Fifty of the patients (93%) continued statin therapy and 43 (80%) achieved the LDL-C target level. We show that for the majority of patients with statin-induced muscle toxicity, statin therapy can be safely and effectively continued. In cases of asymptomatic CK levels <3-5 upper limit of normal (ULN), statin treatment should not be interrupted. When CK levels >3-5 ULN or when various symptomatic muscle adverse reactions are present, statins rechallenge, after a recovery period, should be individualized either by a low dose of a potent statin or by a less potent statin. An additional lipid medication is advised if the target levels are not achieved. © 2011 Blackwell Publishing Ltd.

Muscle symptoms in statin users, associations with cytochrome P450, and membrane transporter inhibitor use: a subanalysis of the USAGE study.

PubMed

Ito, Matthew K; Maki, Kevin C; Brinton, Eliot A; Cohen, Jerome D; Jacobson, Terry A

2014-01-01

Drug interactions have been identified as a risk factor for muscle-related side effects in statin users. The aim was to assess whether use of medications that inhibit cytochrome P450 (CYP450) isozymes, organic anion transporting polypeptide 1B1 (OATP1B1), or P-glycoprotein (P-gp) are associated with muscle-related symptoms among current and former statin users. Persons (n = 10,138) from the Understanding Statin Use in America and Gaps in Education (USAGE) internet survey were categorized about whether they ever reported new or worsening muscle pain while taking a statin (n = 2935) or ever stopped a statin because of muscle pain (n = 1516). Univariate and multivariate logistic regression models were used to assess associations between use of concomitant therapies that inhibit CYP450 isozymes, OATP1B1, P-gp, or a combination and muscle-related outcomes. In multivariate analyses, concomitant use of a CYP450 inhibitor was associated with increased odds for new or worse muscle pain (odds ratio [OR] = 1.42; P < .001) or ever having stopped a statin because of muscle pain (OR = 1.28; P = .037). Concomitant use of medication known to inhibit both OATP1B1 and P-gp was also associated with increased odds (OR = 1.80; P = .030) of ever having stopped a statin because of muscle pain. Concomitant use of medication(s) that inhibit statin metabolism was associated with increased odds of new or worse muscle pain while taking a statin and having previously stopped a statin because of muscle symptoms. These data emphasize the importance of enhancing the capabilities of clinicians and health systems for identifying and reducing statin drug interactions. Copyright © 2014 National Lipid Association. All rights reserved.

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

PubMed Central

Golomb, Beatrice A.; Evans, Marcella A.

2009-01-01

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 (CYP)3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many non-muscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity. PMID:19159124

Statin therapy is not associated with improved outcomes after heart transplantation in children and adolescents.

PubMed

Greenway, Steven C; Butts, Ryan; Naftel, David C; Pruitt, Elizabeth; Kirklin, James K; Larsen, Ingrid; Urschel, Simon; Knecht, Kenneth; Law, Yuk

2016-04-01

Although used routinely, the pleiotropic benefits of statins remain understudied in children after heart transplantation. We hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD). This study was a retrospective review of 964 pediatric (ages 5 to 18 years) heart transplant recipients in the multicenter Pediatric Heart Transplant Study registry from 2001 to 2012. Patients were excluded if they were undergoing re-transplantation, survived <1 year post-transplant, or had missing data regarding statin use. The effects of statins beyond the first year were estimated by Kaplan-Meier and Cox regression multivariable analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival. Statin use was variable among participating centers with only 30% to 35% of patients ≥10 years of age started on a statin at <1 year post-transplant. After the first year post-transplant, statin-treated children (average age at transplant 13.24 ± 3.29 years) had significantly earlier rejection (HR 1.42, 95% CI 1.11 to 1.82, p = 0.006) compared with untreated children (transplanted at 12 ± 3.64 years) after adjusting for conventional risk factors for rejection. Freedom from PTLD, CAV and overall survival up to 5 years post-transplant were not affected by statin use, although the number of events was small. Statin therapy did not confer a survival benefit and was not associated with delayed onset of PTLD or CAV. Early (<1 year post-transplant) statin therapy was associated with increased later frequency of rejection. These findings suggest that a prospective trial evaluating statin therapy in pediatric heart transplant recipients is warranted. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.

PubMed

Mitchell, Dominic; Guertin, Jason R; Dubois, Anick; Dubé, Marie-Pierre; Tardif, Jean-Claude; Iliza, Ange Christelle; Fanton-Aita, Fiorella; Matteau, Alexis; LeLorier, Jacques

2018-04-01

Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown. We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters. Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations. We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.

Direct-to-consumer television advertising exposure, diagnosis with high cholesterol, and statin use.

PubMed

Niederdeppe, Jeff; Byrne, Sahara; Avery, Rosemary J; Cantor, Jonathan

2013-07-01

While statin drugs are recommended for secondary prevention of coronary heart disease (CHD), there is no medical consensus on whether or not a statin should be added to lifestyle change efforts for primary prevention of CHD. Previous research suggests that exposure to direct-to-consumer advertising (DTCA) increases drug demand among those at comparatively low risk. Research has yet to examine whether individual-level DTCA exposure may influence statin use among men and women at high, moderate, or low risk for future cardiac events. To determine the relationship between estimated exposure to DTCA for statin drugs and two clinical variables: diagnosis with high cholesterol and statin use. We used logistic regression to analyze repeated cross-sectional surveys of the United States population, merged with data on the frequency of DTCA appearances on national, cable, and local television, between 2001 and 2007. American adults (n=106,685) aged 18 and older. Levels of exposure to statin DTCA, based on ad appearances and TV viewing patterns; self-reports of whether or not a respondent has been diagnosed with high cholesterol, and whether or not a respondent took a statin in the past year. Adjusting for potential confounders, we estimate that exposure to statin ads increased the odds of being diagnosed with high cholesterol by 16 to 20 %, and increased statin use by 16 to 22 %, among both men and women (p<0.05). These associations were driven almost exclusively by men and women at low risk for future cardiac events. There was also evidence of a negative association between DTCA exposure and statin use among high-risk women (p<0.05) CONCLUSIONS: This study provides new evidence that DTCA may promote over-diagnosis of high cholesterol and over-treatment for populations where risks of statin use may outweigh potential benefits.

Reduced Risk of Barrett's Esophagus in Statin Users: Case-Control Study and Meta-Analysis.

PubMed

Beales, Ian L P; Dearman, Leanne; Vardi, Inna; Loke, Yoon

2016-01-01

Use of statins has been associated with a reduced incidence of esophageal adenocarcinoma in population-based studies. However there are few studies examining statin use and the development of Barrett's esophagus. The purpose of this study was to examine the association between statin use and the presence of Barrett's esophagus in patients having their first gastroscopy. We have performed a case-control study comparing statin use between patients with, and without, an incident diagnosis of non-dysplastic Barrett's esophagus. Male Barrett's cases (134) were compared to 268 male age-matched controls in each of two control groups (erosive gastro-esophageal reflux and dyspepsia without significant upper gastrointestinal disease). Risk factor and drug exposure were established using standardised interviews. Logistic regression was used to compare statin exposure and correct for confounding factors. We performed a meta-analysis pooling our results with three other case-control studies. Regular statin use was associated with a significantly lower incidence of Barrett's esophagus compared to the combined control groups [adjusted OR 0.62 (95 % confidence intervals 0.37-0.93)]. This effect was more marked in combined statin plus aspirin users [adjusted OR 0.43 (95 % CI 0.21-0.89)]. The inverse association between statin or statin plus aspirin use and risk of Barrett's was significantly greater with longer duration of use. Meta-analysis of pooled data (1098 Barrett's, 2085 controls) showed that statin use was significantly associated with a reduced risk of Barrett's esophagus [pooled adjusted OR 0.63 (95 % CI 0.51-0.77)]. Statin use is associated with a reduced incidence of a new diagnosis of Barrett's esophagus.

Statins and Risk of Bleeding: An Analysis to Evaluate Possible Bias Due to Prevalent Users and Healthy User Aspects.

PubMed

van Rein, Nienke; Cannegieter, Suzanne C; le Cessie, Saskia; Rosendaal, Frits R; Reitsma, Pieter H; van der Meer, Felix J M; Lijfering, Willem M

2016-05-15

Statins are said to protect against a wide range of diseases. We studied to what extent potential bias influences the results of studies on beneficial side effects of statins. We selected 8,188 atrial fibrillation patients who started treatment with anticoagulants at the Leiden Anticoagulation Clinic in the Netherlands between 2003 and 2009 and experienced 1,683 minor and 451 major bleeds during 18,105 person-years of follow-up. Statins were associated with a risk reduction of 9% for bleeds (hazard ratio = 0.91, 95% confidence interval: 0.82, 1.00). Additionally, analyses were stratified by age, incident users (patients who started statins during follow-up, i.e., an inception cohort), and prevalent statin users (statin users at baseline), as restriction to incident users avoids overoptimistic risk estimates. After stratification, the protective associations disappeared or reversed (range of hazard ratios = 0.99-3.22), except for patients aged 75 years or older. This remaining association could be due to another bias as, according to guidelines, in the elderly, statins should be prescribed only to those with a reasonable life expectancy. This could have resulted in a comparison of fit statin users with less fit nonstatin users (healthy user effect). The apparent protective association of statins on bleeds may be due to bias. We recommend stratification by age and incident and prevalent statin use when studying associations of statins with disease outcomes to avoid overoptimistic risk estimates. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Statins and risk of poststroke hemorrhagic complications

PubMed Central

MacIsaac, Rachael L.; Abdul-Rahim, Azmil H.; Siegerink, Bob; Bath, Philip M.; Endres, Matthias; Lees, Kennedy R.; Nolte, Christian H.

2016-01-01

Objective: To assess whether statin treatment before or after acute ischemic stroke (AIS) affects the risk of acute intracerebral hemorrhage (ICH), postacute ICH, and mortality within 90 days. Methods: Data were sought from the Virtual International Stroke Trials Archive, an international repository of clinical trials data. Using propensity score matching, we retrospectively compared patients with prior statin treatment and newly initiated statin within 3 days after AIS to patients without statin exposure. Outcomes of interest were acute symptomatic ICH (sICH), any acute ICH, postacute ICH, and mortality during follow-up of 3 months. Results: A total of 8,535 patients (mean age 70 years, 54% male, median baseline NIH Stroke Scale score 13) were analyzed. After propensity score matching, prior statin use was not strongly associated with sICH (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.83–2.14) or any ICH (adjusted OR 1.35, 95% CI 0.92–1.98). There was no evidence of an interaction between prior statin use and thrombolysis. New initiation of statins was not associated with postacute ICH (adjusted hazard ratio [HR] 1.60, 95% CI 0.70–3.65). There was a signal towards lower 90-day mortality in patients with prior statin use (adjusted HR 0.84, 95% CI 0.70–1.00) and especially early initiation of statins (adjusted HR 0.67, 95% CI 0.46–0.97). Conclusions: Statin use prior to AIS was not associated with early hemorrhagic complications, irrespective of treatment with thrombolysis. New initiation of statin treatment early after AIS did not affect risk of postacute ICH, but might be associated with reduced mortality. PMID:27016519

Prevalence of Potential and Clinically Relevant Statin-Drug Interactions in Frail and Robust Older Inpatients.

PubMed

Thai, Michele; Hilmer, Sarah; Pearson, Sallie-Anne; Reeve, Emily; Gnjidic, Danijela

2015-10-01

A significant proportion of older people are prescribed statins and are also exposed to polypharmacy, placing them at increased risk of statin-drug interactions. To describe the prevalence rates of potential and clinically relevant statin-drug interactions in older inpatients according to frailty status. A cross-sectional study of patients aged ≥65 years who were prescribed a statin and were admitted to a teaching hospital between 30 July and 10 October 2014 in Sydney, Australia, was conducted. Data on socio-demographics, comorbidities and medications were collected using a standardized questionnaire. Potential statin-drug interactions were defined if listed in the Australian Medicines Handbook and three international drug information sources: the British National Formulary, Drug Interaction Facts and Drug-Reax(®). Clinically relevant statin-drug interactions were defined as interactions with the highest severity rating in at least two of the three international drug information sources. Frailty was assessed using the Reported Edmonton Frail Scale. A total of 180 participants were recruited (median age 78 years, interquartile range 14), 35.0% frail and 65.0% robust. Potential statin-drug interactions were identified in 10% of participants, 12.7% of frail participants and 8.5% of robust participants. Clinically relevant statin-drug interactions were identified in 7.8% of participants, 9.5% of frail participants and 6.8% of robust participants. Depending on the drug information source used, the prevalence rates of potential and clinically relevant statin-drug interactions ranged between 14.4 and 35.6% and between 14.4 and 20.6%, respectively. In our study of frail and robust older inpatients taking statins, the overall prevalence of potential statin-drug interactions was low and varied significantly according to the drug information source used.

Comparison of the efficacy and safety of intensive-dose and standard-dose statin treatment for stroke prevention: A meta-analysis.

PubMed

Wang, Juan; Chen, Dan; Li, Da-Bing; Yu, Xin; Shi, Guo-Bing

2016-09-01

Previous study indicated that high-dose statin treatment might increase the risk of hemorrhagic stroke and adverse reactions. We aim to compare the efficacy and safety of intensive-dose and standard-dose statin treatment for preventing stroke in high-risk patients. A thorough search was performed of multiple databases for publications from 1990 to June 2015. We selected the randomized clinical trials comparing standard-dose statin with placebo and intensive-dose statin with standard-dose statin or placebo for the prevention of stroke events in patients. Duplicate independent data extraction and bias assessments were performed. Data were pooled using a fixed-effects model or a random-effects model if significant heterogeneity was present. For the all stroke incidences, intensive-dose statin treatment compared with placebo treatment and standard-dose statin treatment compared with placebo treatment showed a significant 21% reduction in relative risk (RR) (RR 0.79, 95% confidence interval (CI) [0.71, 0.87], P < 0.00001) and an 18% reduction in RR (RR 0.82, 95% CI [0.73, 0.93], P = 0.002) in the subgroup without renal transplant recipients and patients undergoing regular hemodialysis separately. For the fatal stroke incidences, intensive-dose statin treatment compared with standard dose or placebo was effective reducing fatal stroke (RR 0.61, 95% CI [0.39, 0.96], P = 0.03) and the RR was 1.01 (95% CI [0.85, 1.20], P = 0.90) in standard-dose statin treatment compared with placebo. The results of this meta-analysis suggest that intensive-dose statin treatment might be more favorable for reducing the incidences of all strokes than standard-dose statin treatment, especially for patients older than 65 years in reducing the incidences of all stroke incidences.

Association of statins with aortic, peripheral, and visceral artery aneurysm development.

PubMed

Mansi, Ishak A; Frei, Christopher R; Halm, Ethan A; Mortensen, Eric M

2017-08-01

Objectives Prior studies examining the effects of statins on arterial aneurysm development and progression yielded conflicting results due to their smaller size and presence of residual confounders. The objective of this study is to examine the association of statins with risk of being diagnosed with aortic, peripheral, and visceral artery aneurysm. Methods This was a retrospective cohort study of Tricare enrollees (from 1 October 2003 to 31 March 2012). Main outcomes were diagnosis of aortic, peripheral, or visceral artery aneurysm and undergoing aortic aneurysm repair procedure during follow-up period. Using 115 baseline characteristics, we generated a propensity score to match statin users and nonusers and examine the odds of outcomes (primary analysis). Secondary analysis examined outcomes at various subcohorts. Results Out of 10,910 statin users and 49,545 nonusers, we propensity score-matched 6728 pairs of statin users and nonusers. Statin users and nonusers had similar odds of being diagnosed with aortic, peripheral, and visceral artery aneurysms (odds ratio [OR]: 1.06, 95% confidence interval [95% CI]: 0.85-1.33) and of undergoing aortic aneurysm repair procedures (OR: 0.54, 95% CI: 0.22-1.35). Secondary analysis showed a tendency toward fewer aortic aneurysm procedures among statin users that did not reach statistical significance. However, high-intensity statin users in comparison to non-intensive statin users had higher adjusted odds of aortic, peripheral, and visceral artery aneurysms (OR: 1.76, 95% CI: 1.37-2.25, p < .0001). Conclusions This study does not support a clinically significant benefit or harm from statins regarding development of arterial aneurysm. However, secondary analyses may support the hypothesis proposed by previous research proposing a bidirectional role for statins.

Summary of clinical and laboratory data of study subjects with and without DCE-MRI plaque measurements in the AIM-HIGH clinical trial.

PubMed

O'Brien, Kevin D; Hippe, Daniel S; Chen, Huijun; Neradilek, Moni B; Probstfield, Jeffrey L; Peck, Suzanne; Isquith, Daniel A; Canton, Gador; Yuan, Chun; Polissar, Nayak L; Zhao, Xue-Qiao; Kerwin, William S

2016-03-01

This brief data article summarizes the clinical risk factors and laboratory data of a group of subjects recruited for the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) and an associated magnetic resonance imaging (MRI) substudy. The sample is restricted to those on statin therapy at the time of enrollment and data are presented stratified by whether dynamic contrast enhanced MRI (DCE-MRI) markers of carotid plaque vascularity and inflammation were available or not. The data provided herein are directly related to the article "Longer Duration of Statin Therapy is Associated with Decreased Carotid Plaque Vascularity by Magnetic Resonance Imaging" [2].

Association between statin use, the vaginal microbiome, and Gardnerella vaginalis vaginolysin-mediated cytotoxicity.

PubMed

Abdelmaksoud, Abdallah A; Girerd, Philippe H; Garcia, Erin M; Brooks, J Paul; Leftwich, Lauren M; Sheth, Nihar U; Bradley, Steven P; Serrano, Myrna G; Fettweis, Jennifer M; Huang, Bernice; Strauss, Jerome F; Buck, Gregory A; Jefferson, Kimberly K

2017-01-01

Bacterial vaginosis (BV) is the leading dysbiosis of the vaginal microbiome. The pathways leading towards the development of BV are not well understood. Gardnerella vaginalis is frequently associated with BV. G. vaginalis produces the cholesterol-dependent cytolysin (CDC), vaginolysin, which can lyse a variety of human cells and is thought to play a role in pathogenesis. Because membrane cholesterol is required for vaginolysin to function, and because HMG-CoA reductase inhibitors (statins) affect not only serum levels of cholesterol but membrane levels as well, we hypothesized that statins might affect the vaginal microbiome. To investigate the relationship between use of the statins and the vaginal microbiome, we analyzed 16S rRNA gene taxonomic surveys performed on vaginal samples from 133 women who participated in the Vaginal Human Microbiome Project and who were taking statins at the time of sampling, 152 women who reported high cholesterol levels but were not taking statins, and 316 women who did not report high cholesterol. To examine the effect of statins on the cytolytic effect of vaginolysin, the cholesterol-dependent cytolysin (CDC) produced by Gardnerella vaginalis, we assessed the effect of simvastatin pretreatment of VK2E6/E7 vaginal epithelial cells on vaginolysin-mediated cytotoxicity. The mean proportion of G. vaginalis among women taking statins was significantly lower relative to women not using statins. Women using statins had higher mean proportions of Lactobacillus crispatus relative to women with normal cholesterol levels, and higher levels of Lactobacillus jensenii relative to women with high cholesterol but not taking statins. In vitro, vaginal epithelial cells pretreated with simvastatin were relatively resistant to vaginolysin and this effect was inhibited by cholesterol. In this cross-sectional study, statin use was associated with reduced proportions of G. vaginalis and greater proportions of beneficial lactobacilli within the vaginal microbiome. The negative association between statin use and G. vaginalis may be related to inhibition of vaginolysin function.

Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study

PubMed Central

Pedersen, Lars; Tarp, Maja; Cronin-Fenton, Deirdre P.; Garne, Jens Peter; Silliman, Rebecca A.; Sørensen, Henrik Toft; Lash, Timothy L.

2011-01-01

Background Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied. Methods We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I–III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18 769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided. Results Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = −0.10, 95% confidence interval = −0.11 to −0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = −0.01 to 0.11). Conclusions Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I–III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed. PMID:21813413

Efficacy of Short-Term Statin Treatment for the Prevention of Contrast-Induced Acute Kidney Injury in Patients Undergoing Coronary Angiography/Percutaneous Coronary Intervention: A Meta-Analysis of 21 Randomized Controlled Trials.

PubMed

Li, Haixia; Wang, Cailian; Liu, Chuanzhi; Li, Ruifei; Zou, Meijuan; Cheng, Gang

2016-06-01

The results of previous studies have been contradictory in terms of the efficacy of statin treatment in preventing contrast-induced acute kidney injury (CI-AKI) and clinical adverse events (AEs). This meta-analysis was undertaken to assess the role of short-term statin treatment in the prevention of CI-AKI and clinical AEs. We searched the Cochrane Library, EMBASE, and PubMed databases for randomized controlled trials (RCTs) with the development of CI-AKI as a primary outcome. Secondary outcomes were the post-procedural serum creatinine (SCr) level, estimated glomerular filtration rate (eGFR), and development of AEs. We also performed prespecified subgroup analyses. A total of 21 RCTs involving 7746 patients were included. Short-term statin treatment significantly reduced the risk of CI-AKI [risk ratio (RR) 0.57; 95 % confident interval (CI) 0.47-0.69; p < 0.00001) and was associated with a lower post-procedural SCr level and a higher eGFR. High-dose statins resulted in a lower incidence of CI-AKI than the lower-dose statins. In addition, the benefit was seen across various subgroups for patients at risk of CI-AKI, statin-naïve patients, and East Asians, regardless of statin type, definition of CI-AKI, use of N-acetylcysteine (NAC) and hydration, and osmolality of contrast. However, there was no significant difference between the two groups in terms of the incidence of AEs. The meta-analysis suggests that short-term statin treatment can effectively prevent CI-AKI, and the benefit is also observed in high-risk patients, statin-naïve patients, and an East Asian population. However, the effect of simvastatin for the prevention of CI-AKI, of statins for the prevention of AEs, and whether high-dose statins have a better effect than lower-dose statins are all still uncertain.

Impact of the 2013 American College of Cardiology/American Heart Association cholesterol guidelines on the prescription of high-intensity statins in patients hospitalized for acute coronary syndrome or stroke.

PubMed

Valentino, Michael; Al Danaf, Jad; Panakos, Andrew; Ragupathi, Loheetha; Duffy, Danielle; Whellan, David

2016-11-01

The 2013 American College of Cardiology/American Heart Association cholesterol management guidelines represented a paradigm shift from the National Cholesterol Education Program Adult Treatment Panel III guidelines, replacing low-density lipoprotein cholesterol targets with a risk assessment model to guide statin therapy. Our objectives are to compare provider prescription of high-intensity statin therapy in patients hospitalized with acute coronary syndrome (ACS) or cerebrovascular accident (CVA) before and after the publication of the 2013 cholesterol guidelines, determine potential predictors of high-intensity statin utilization, and identify targets for improvement in cardiovascular risk reduction among these high-risk populations. A single-center retrospective cohort study of 695 patients discharged with a diagnosis of ACS or CVA in the 6months before (n=359) and after (n=336) the release of the 2013 American College of Cardiology/American Heart Association cholesterol guidelines. Patient characteristics were compared using analysis of variance and χ 2 tests. Multivariable logistic regression models were used to assess clinical predictors of provider utilization of high-intensity statins. After the 2013 cholesterol guidelines, the rate of prescribing high-intensity statins was greater for statin-naïve patients compared with those already on statin therapy (odds ratio [OR]0.51, P=.02). Prescription of high-intensity statins was higher for patients with ACS compared with CVA (OR 8.4, P<.001-pre-2013 guidelines; OR 4.5, P<.001-post-2013 guidelines). Prescription of high-intensity statins steadily improved over the study period, significantly among patients with CVA (P<.001). Physicians were more likely to prescribe high-intensity statins in statin-naïve patients as compared with intensifying existing statin therapy, and their prescription pattern was lower after CVA vs ACS. Copyright © 2016 Elsevier Inc. All rights reserved.

Statin Selection in Qatar Based on Multi-indication Pharmacotherapeutic Multi-criteria Scoring Model, and Clinician Preference.

PubMed

Al-Badriyeh, Daoud; Fahey, Michael; Alabbadi, Ibrahim; Al-Khal, Abdullatif; Zaidan, Manal

2015-12-01

Statin selection for the largest hospital formulary in Qatar is not systematic, not comparative, and does not consider the multi-indication nature of statins. There are no reports in the literature of multi-indication-based comparative scoring models of statins or of statin selection criteria weights that are based primarily on local clinicians' preferences and experiences. This study sought to comparatively evaluate statins for first-line therapy in Qatar, and to quantify the economic impact of this. An evidence-based, multi-indication, multi-criteria pharmacotherapeutic model was developed for the scoring of statins from the perspective of the main health care provider in Qatar. The literature and an expert panel informed the selection criteria of statins. Relative weighting of selection criteria was based on the input of the relevant local clinician population. Statins were comparatively scored based on literature evidence, with those exceeding a defined scoring threshold being recommended for use. With 95% CI and 5% margin of error, the scoring model was successfully developed. Selection criteria comprised 28 subcriteria under the following main criteria: clinical efficacy, best publish evidence and experience, adverse effects, drug interaction, dosing time, and fixed dose combination availability. Outcome measures for multiple indications were related to effects on LDL cholesterol, HDL cholesterol, triglyceride, total cholesterol, and C-reactive protein. Atorvastatin, pravastatin, and rosuvastatin exceeded defined pharmacotherapeutic thresholds. Atorvastatin and pravastatin were recommended as first-line use and rosuvastatin as a nonformulary alternative. It was estimated that this would produce a 17.6% cost savings in statins expenditure. Sensitivity analyses confirmed the robustness of the evaluation's outcomes against input uncertainties. Incorporating a comparative evaluation of statins in Qatari practices based on a locally developed, transparent, multi-indication, multi-criteria scoring model has the potential to considerably reduce expenditures on statins. Atorvastatin and pravastatin should be the first-line statin therapies in the main Qatari health care provider, with rosuvastatin as an alternative. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

The Variation of Statin Use Among Nursing Home Residents and Physicians: A Cross-Sectional Analysis.

PubMed

Campitelli, Michael A; Maxwell, Colleen J; Giannakeas, Vasily; Bell, Chaim M; Daneman, Nick; Jeffs, Lianne; Morris, Andrew M; Austin, Peter C; Hogan, David B; Ko, Dennis T; Lapane, Kate L; Maclagan, Laura C; Seitz, Dallas P; Bronskill, Susan E

2017-09-01

To examine the variability of statin use among nursing home residents and prescribing physicians, and to assess statin use by resident frailty. Population-based, cross-sectional analysis. All nursing home facilities (N = 631) in Ontario, Canada between April 1, 2013 and March 31, 2014. All adults aged 66 years and older who received a full clinical assessment while residing in a nursing home facility and their assigned, most responsible, physician. Statin use on date of clinical assessment. Resident- and physician-level characteristics ascertained through clinical assessment and health administrative data. Resident frailty was derived using a previously validated index. Among 76,226 nursing home residents assigned to 1,919 physicians, 25,648 (33.6%) were statin users. There were 13,331 (30.1%) statin users among the 44,290 residents categorized as frail. In an adjusted mixed-effects logistic regression model, frail residents (adjusted odds ratio = 0.62, 95% confidence interval 0.58-0.65) were significantly less likely to be statin users compared with non-frail residents. After adjustment for resident characteristics, the intraclass correlation coefficient indicated that between-physician variability accounted for 9.1% of the residual unexplained variation in statin use (P < .001). Among the 894 physicians assigned 20 or more residents, funnel plots confirmed there were more low-outlying (17.4%) and high-outlying (12.0%) prescribers of statins than expected by chance. Physicians who were high-outlying prescribers had higher historical rates of statin prescribing. Statin prescribing was substantial within nursing homes, even among frail residents. After controlling for resident characteristics, the likelihood of statin prescribing varied significantly across physicians. Further studies are required to evaluate the risks and benefits of statin use, and discontinuation, among nursing home residents to better inform clinical practice in this setting. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Effects of Statin Treatment on Inflammation and Cardiac Function in Heart Failure: An Adjusted Indirect Comparison Meta-Analysis of Randomized Trials.

PubMed

Bonsu, Kwadwo Osei; Reidpath, Daniel Diamond; Kadirvelu, Amudha

2015-12-01

Statins are known to prevent heart failure (HF). However, it is unclear whether statins as class or type (lipophilic or hydrophilic) improve outcomes of established HF. The current meta-analysis was performed to compare the treatment effects of lipophilic and hydrophilic statins on inflammation and cardiac function in HF. Outcomes were indicators of cardiac function [changes in left ventricular ejection fraction (LVEF) and B-type natriuretic peptide (BNP)] and inflammation [changes in highly sensitive C-reactive protein (hsCRP) and interluekin-6 (IL-6)]. We conducted a search of PubMed, EMBASE, and the Cochrane databases until December 31, 2014 for randomized control trials (RCTs) of statin versus placebo in patients with HF. RCTs with their respective extracted information were dichotomized into statin type evaluated and analyzed separately. Outcomes were pooled with random effect approach, producing standardized mean differences (SMD) for each statin type. Using these pooled estimates, we performed adjusted indirect comparisons for each outcome. Data from 6214 patients from 19 trials were analyzed. Lipophilic statin was superior to hydrophilic statin treatment regarding follow-up LVEF (SMD, 4.54; 95% CI, 4.16-4.91; P < 0.001), BNP (SMD, -1.60; 95% CI, -2.56 to -0.65; P < 0.001), hsCRP (SMD, -1.13; 95% CI, -1.54 to -0.72; P < 0.001), and IL-6 (SMD, -3.75; 95% CI, -4.77 to -0.72; P < 0.001) in HF. Lipophilic statin produces greater treatment effects on cardiac function and inflammation compared with hydrophilic statin in patients with HF. Until data from adequately powered head-to-head trial of the statin types are available, our meta-analysis brings clinicians and researchers a step closer to the quest on which statin--lipophilic or hydrophilic--is associated with better outcomes in HF. © 2015 John Wiley & Sons Ltd.

Statin therapy with or without ezetimibe and the progression to diabetes.

PubMed

Barkas, Fotios; Elisaf, Moses; Liberopoulos, Evangelos; Klouras, Eleftherios; Liamis, George; Rizos, Evangelos C

2016-01-01

To assess the risk of progression from normoglycemia or prediabetes to overt diabetes among individuals treated with statins alone or in combination with ezetimibe. This was a retrospective study conducted in Greece including 877 subjects treated for dyslipidemia. We included individuals without overt diabetes at baseline and divided them in 2 subgroups according to their baseline fasting glucose: <100 (normal glucose) and 100 to 125 mg/dL (prediabetes). High and moderate-intensity statin therapy was defined according to the expected low-density lipoprotein cholesterol reduction (≥50% and 30 to <50%, respectively). We identified the predictors of incident diabetes and assessed the risk of new-onset diabetes among subgroups on various intensity statin or no statin treatment at all. Similar analyses were performed across different potency of statin monotherapy or combination of statin plus ezetimibe treatment. A total of 877 subjects were eligible and followed-up for a median of 7 years. There were no differences between statins regarding diabetes development. However, a higher risk of incident diabetes was observed in prediabetic individuals receiving high-intensity statin therapy compared with those on moderate intensity (adjusted odds ratio [OR] = 2.12, 95% confidence interval [CI] = 1.06-4.24, P < .05) and those not taking a statin (adjusted OR = 4.90; 95% CI = 1.16-20.66, P < .05). The addition of ezetimibe to statin treatment did not increase the risk of incident diabetes in prediabetic individuals (adjusted OR = 0.89; 95% CI = 0.36-2.22, P > .05). Baseline fasting glucose, presence of metabolic syndrome, family history of diabetes, and follow-up duration were independent predictors of new-onset diabetes. High-intensity statin treatment is associated with a higher risk of incident diabetes in prediabetic individuals, whereas the addition of ezetimibe to statin therapy has a neutral effect on glucose metabolism. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.

PubMed

Gotoh, Saki; Negishi, Masahiko

2015-09-22

Statin therapy is known to increase blood glucose levels in humans. Statins utilize pregnane X receptor (PXR) and serum/glucocorticoid regulated kinase 2 (SGK2) to activate phosphoenolpyruvate carboxykinase 1 (PEPCK1) and glucose-6-phosphatase (G6Pase) genes, thereby increasing glucose production in human liver cells. Here, the novel statin/PXR/SGK2-mediated signaling pathway has now been characterized for hepatic gluconeogenesis. Statin-activated PXR scaffolds the protein phosphatase 2C (PP2C) and SGK2 to stimulate PP2C to dephosphorylate SGK2 at threonine 193. Non-phosphorylated SGK2 co-activates PXR-mediated trans-activation of promoters of gluconeogenic genes in human liver cells, thereby enhancing gluconeogenesis. This gluconeogenic statin-PXR-SGK2 signal is not present in mice, in which statin treatment suppresses hepatic gluconeogenesis. These findings provide the basis for statin-associated side effects such as an increased risk for Type 2 diabetes.

The Risk of Hepatotoxicity, New Onset Diabetes and Rhabdomyolysis in the Era of High-Intensity Statin Therapy: Does Statin Type Matter?

PubMed

Benes, Lane B; Bassi, Nikhil S; Davidson, Michael H

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management have placed greater emphasis on high-intensity statin dosing for those with known cardiovascular disease or diabetes mellitus. Differences in risk of hepatotoxicity, new onset diabetes and rhabdomyolysis specifically between the high-intensity statins and the most common moderate-intensity statin, simvastatin, were not found to a significant degree in this review. Rather, baseline characteristics and drug-drug interactions (DDIs) appear to be more important regarding the risk of these adverse effects. Pharmacogenetic differences in statin metabolism may explain individual susceptibility, however genetic testing is not felt to be cost effective at this time. More importantly, statin choice should consider concomitant use of the many prevalent CYP3A4 inhibitors or inducers, and when present, rosuvastatin selection is recommended to reduce DDIs and risk of statin-induced adverse effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of 6 genetic variants on the efficacy of statins in patients with dyslipidemia.

PubMed

Cano-Corres, Ruth; Candás-Estébanez, Beatriz; Padró-Miquel, Ariadna; Fanlo-Maresma, Marta; Pintó, Xavier; Alía-Ramos, Pedro

2018-05-07

Patients with dyslipidemia are often treated with statins to reduce lipids and hence cardiovascular risk, but treatment response is variable, partly due to genetic factors. We studied the influence of 6 gene variants (APOE c.526C > T (APOE2), APOE c.388T > C (APOE4), SLCO1B1 c.521T > C, CYP3A4 c.-392G > A, HMGCR c.1564-106A > G, and LPA c.3947 + 467T > C) on statin efficacy assessing 2 indicators: the percent reduction in total cholesterol (TC) and non-HDL cholesterol (non-HDL), as well as the achievement of therapeutic goals. The study was performed in a group of patients (n = 100) without previous pharmacological treatment. Multiple regression models were used to calculate the percentage of explanation in response variability added by every variant to a basal model constructed with significant nongenetic control variables. The most influential variant was HMGCR c.1564-106A > G (rs3846662), and carriers showed a significantly lower reduction in TC and non-HDL. This variant is related to an alternative splicing involving exon 13, which is also regulated by lipid concentrations in patients without the variant. Concerning therapeutic goals, HMGCR c.1564-106A > G hindered the achievement of TC targets on patients. The HMGCR c.1564-106A > G variant was associated with less statin efficacy to decrease cholesterol. © 2018 Wiley Periodicals, Inc.

Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology Position Statement on Dyslipidemia Management: differences between the European and American Guidelines.

PubMed

Lobos Bejarano, José María; Galve, Enrique; Royo-Bordonada, Miguel Ángel; Alegría Ezquerra, Eduardo; Armario, Pedro; Brotons Cuixart, Carlos; Camafort Babkowski, Miguel; Cordero Fort, Alberto; Maiques Galán, Antonio; Mantilla Morató, Teresa; Pérez Pérez, Antonio; Pedro-Botet, Juan; Villar Álvarez, Fernando; González-Juanatey, José Ramón

2015-01-01

The publication of the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of high blood cholesterol has had a strong impact due to the paradigm shift in its recommendations. The Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology reviewed this guideline and compared it with current European guidelines on cardiovascular prevention and dyslipidemia management. The most striking aspect of the American guideline is the elimination of the low-density lipoprotein cholesterol treat-to-target strategy and the adoption of a risk reduction strategy in 4 major statin benefit groups. In patients with established cardiovascular disease, both guidelines recommend a similar therapeutic strategy (high-dose potent statins). However, in primary prevention, the application of the American guidelines would substantially increase the number of persons, particularly older people, receiving statin therapy. The elimination of the cholesterol treat-to-target strategy, so strongly rooted in the scientific community, could have a negative impact on clinical practice, create a certain amount of confusion and uncertainty among professionals, and decrease follow-up and patient adherence. Thus, this article reaffirms the recommendations of the European guidelines. Although both guidelines have positive aspects, doubt remains regarding the concerns outlined above. In addition to using risk charts based on the native population, the messages of the European guideline are more appropriate to the Spanish setting and avoid the possible risk of overtreatment with statins in primary prevention.

Early Statin Use and the Progression of Alzheimer Disease: A Total Population-Based Case-Control Study.

PubMed

Lin, Feng-Cheng; Chuang, Yun-Shiuan; Hsieh, Hui-Min; Lee, Tzu-Chi; Chiu, Kuei-Fen; Liu, Ching-Kuan; Wu, Ming-Tsang

2015-11-01

The protective effect of statin on Alzheimer disease (AD) is still controversial, probably due to the debate about when to start the use of statin and the lack of any large-scale randomized evidence that actually supports the hypothesis. The purpose of this study was to examine the protective effect of early statin use on mild-to-moderate AD in the total Taiwanese population.This was a total population-based case-control study, using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The study patients were those with newly diagnosed dementia (ICD-9 290.x) and prescribed any acetylcholinesterase inhibitors (AChEI) from the Taiwan National Health Insurance dataset in 1997 to 2008. The newly diagnosed eligible mild-to-moderate AD patients were traced from the dates of their index dates, which was defined as the first day to receive any AChEI treatment, back to 1 year (exposure period) to categorize them into AD with early statin use and without early statin use. Early statin use was defined as patients using statin before AChEI treatment. Alzheimer disease patients with early statin use were those receiving any statin treatment during the exposure period. Then, we used propensity-score-matched strategy to match these 2 groups as 1:1. The matched study patients were followed-up from their index dates. The primary outcome was the discontinuation of AChEI treatment, indicating AD progression.There were 719 mild-to-moderate AD-paired patients with early statin use and without early statin use for analyses. Alzheimer disease progression was statistically lower in AD patients with early statin use than those without (P = 0.00054). After adjusting for other covariates, mild-to-moderate AD patients with early stain use exhibited a 0.85-risk (95% CI = 0.76-0.95, P = 0.0066) to have AD progression than those without.Early statin use was significantly associated with a reduction in AD progression in mild-to-moderate AD patients. The future randomized trial studies can confirm our findings.

Impact of Statin Therapy on the Blood Pressure-Lowering Efficacy of a Single-Pill Perindopril/Amlodipine Combination in Hypertensive Patients with Hypercholesterolemia.

PubMed

Sirenko, Yuriy; Radchenko, Ganna

2017-03-01

Several lines of research indicate that statins can lower blood pressure (BP) independently of their lipid-lowering effects when used as monotherapy and in combination with antihypertensive agents. This short-term, open-label study examined whether statin therapy had a synergistic effect on the BP-lowering efficacy of perindopril/amlodipine in a subgroup of patients in the PERSPECTIVA study with concomitant hypertension and hypercholesterolemia, with or without statin at baseline. The PERSPECTIVA study recruited 732 adults with untreated or uncontrolled hypertension. This subgroup analysis of PERSPECTIVA included 587 patients with concomitant hypertension and hypercholesterolemia (mean age 56.7 years) of whom 226 were receiving a statin at baseline (statin [+] group) and 361 were not (statin [-] group). All patients received treatment with single-pill combination perindopril/amlodipine at a dose of 5/5, 10/5 or 10/10 mg/day. The study duration was 60 days with follow-up visits for BP monitoring at 7, 15, 30 and 60 days. At day 60, BP control (<140/90 mmHg) was significantly greater in the statin [+] vs statin [-] group: 73 vs 64% respectively (+14%, P < 0.05). In the statin [+] group, the single-pill perindopril/amlodipine combination significantly reduced BP in patients previously untreated (n = 18), or treated with monotherapy (n = 97), dual therapy (n = 93), or triple therapy (n = 18): -38.8/-20.0, -39.1/-20.1, -38.0/-19.4, -39.9/-18.3 mmHg respectively (P < 0.001 vs baseline BP). The greatest BP reductions were observed in the first 7 days. Treatment was well tolerated with a similar rate of adverse events in the statin [+] group (0.9%) vs the statin [-] group (2.5%). BP control rates in patients with uncontrolled hypertension and concomitant hypercholesterolemia are significantly improved with a treatment regimen that combines perindopril/amlodipine with statin therapy, regardless of previous antihypertensive therapy. This subanalysis of the PERSPECTIVA study supports the synergistic BP-lowering effect of statins and perindopril/amlodipine.

Statin Therapy as Primary Prevention in Exercising Adults: Best Evidence for Avoiding Myalgia.

PubMed

Bosomworth, N John

This review aims to determine whether active adults who begin statins and develop myalgia reduce or stop activity to become less symptomatic. If this occurs, strategies to mitigate symptoms are explored. Should these strategies fail, the question of whether exercise is an adequate alternative to statin therapy is addressed. PubMed, Google Scholar, and the Cochrane Database were searched with keywords designed to retrieve information on statin myopathy in exercising adults. Statins are well tolerated by most people who exercise; however, caution is warranted in those who exercise at high levels, in the elderly, and in those receiving high-dose therapy. Several strategies improve statin tolerance while maintaining exercise levels, based on low-quality evidence. If statins are not tolerated, a continuing physical activity program can provide equivalent or superior cardiometabolic protection. Statins may occasionally present a barrier to physical activity. A number of strategies exist that can reduce the risk of myopathy. If a choice between exercise and statins becomes necessary, exercise provides equal benefit in terms of cardiovascular protection and superior mortality reduction, with improved quality of life. © Copyright 2016 by the American Board of Family Medicine.

Price and utilisation differences for statins between four countries.

PubMed

Thai, Loc Phuoc; Vitry, Agnes Isabelle; Moss, John Robert

2018-02-01

Australia, England, France and New Zealand use different policies to regulate their medicines market, which can impact on utilisation and price. To compare the prices and utilisation of statins in Australia, England, France and New Zealand from 2011 to 2013. Utilisation of statins in the four countries was compared using Defined Daily Doses (DDD) per 1000 inhabitants per year. Pairwise Laspeyres and Paasche index comparisons were conducted comparing the price and utilisation of statins. The results showed that the price of statins in New Zealand was the cheapest. The price of statins in Australia was most expensive in 2011 and 2012 but France was more expensive in 2013. There were large differences between the Laspeyres index and Paasche index when comparing the price and utilisation of England with Australia and France. The policies that regulate the New Zealand and England medicines markets were more effective in reducing the price of expensive statins. The relative utilisation of cheaper statins was greatest in England and had a large effect on the differences between the two index results. The pricing policies in Australia have been only partly effective in reducing the price of statins compared to other countries.

Interplay between statins and PPARs in improving cardiovascular outcomes: a double-edged sword?

PubMed Central

Balakumar, Pitchai; Mahadevan, Nanjaian

2012-01-01

Statins are best-selling medications in the management of high cholesterol and associated cardiovascular complications. They inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase in order to prevent disproportionate cholesterol synthesis. Statins slow the progression of atherosclerosis, prevent the secondary cardiovascular events and improve the cardiovascular outcomes in patients with elevated cholesterol levels. The underlying mechanisms pertaining to the cardioprotective role of statins are linked with numerous pleiotropic actions including inhibition of inflammatory events and improvement of endothelial function, besides an effective cholesterol-lowering ability. Intriguingly, recent studies suggest possible interplay between statins and nuclear transcription factors like PPARs, which should also be taken into consideration while analysing the potential of statins in the management of cardiovascular complications. It could be suggested that statins have two major roles: (i) a well-established cholesterol-lowering effect through inhibition of HMG-CoA-reductase; (ii) a newly explored PPAR-activating property, which could mediate most of cardiovascular protective pleiotropic effects of statins including anti-inflammatory, antioxidant and anti-fibrotic properties. The present review addressed the underlying principles pertaining to the modulatory role of statins on PPARs. PMID:21790534

Statin Therapy and Outcomes in Trials of Nintedanib in Idiopathic Pulmonary Fibrosis.

PubMed

Kreuter, Michael; Costabel, Ulrich; Richeldi, Luca; Cottin, Vincent; Wijsenbeek, Marlies; Bonella, Francesco; Bendstrup, Elisabeth; Maher, Toby M; Wachtlin, Daniel; Stowasser, Susanne; Kolb, Martin

Cardiovascular comorbidities are frequent in patients with idiopathic pulmonary fibrosis (IPF), and many patients with IPF receive treatment with statins to reduce cardiovascular risk. We investigated whether statin use at baseline was associated with differences in disease progression in placebo-treated patients or influenced the treatment effect of nintedanib in the INPULSIS® trials. Post-hoc subgroup analyses of patients receiving versus not receiving statins at baseline using pooled data from the INPULSIS® trials. At baseline, 312 patients received statins and 749 did not. The annual rates of decline in forced vital capacity (FVC) in patients treated with nintedanib and placebo, respectively, were -78.9 and -187.6 mL/year in patients who received statins at baseline, and -127.9 and -237.9 mL/year in patients who did not. The effect of nintedanib was consistent across subgroups (p = 0.9590). In the INPULSIS® trials, there was a numerically lower FVC decline in placebo-treated patients with IPF who received statins at baseline versus those who did not. Use of statins at baseline did not influence the treatment effect of nintedanib. Prospective data are needed to assess the impact of statins on the course of IPF. © 2018 S. Karger AG, Basel.

Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update.

PubMed

Mancini, G B John; Tashakkor, A Yashar; Baker, Steven; Bergeron, Jean; Fitchett, David; Frohlich, Jiri; Genest, Jacques; Gupta, Milan; Hegele, Robert A; Ng, Dominic S; Pearson, Glen J; Pope, Janet

2013-12-01

The Proceedings of a Canadian Working Group Consensus Conference, first published in 2011, provided a summary of statin-associated adverse effects and intolerance and management suggestions. In this update, new clinical studies identified since then that provide further insight into effects on muscle, cognition, cataracts, diabetes, kidney disease, and cancer are discussed. Of these, the arenas of greatest controversy pertain to purported effects on cognition and the emergence of diabetes during long-term therapy. Regarding cognition, the available evidence is not strongly supportive of a major adverse effect of statins. In contrast, the linkage between statin therapy and incident diabetes is more firm. However, this risk is more strongly associated with traditional risk factors for new-onset diabetes than with statin itself and any possible negative effect of new-onset diabetes during statin treatment is far outweighed by the cardiovascular risk reduction benefits. Additional studies are also discussed, which support the principle that systematic statin rechallenge, and lower or intermittent statin dosing strategies are the main methods for dealing with suspected statin intolerance at this time. Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Association of Cognitive Impairment in Patients on 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitors.

PubMed

Roy, Satyajeet; Weinstock, Joshua Louis; Ishino, Allyse Sachiko; Benites, Jefferson Felix; Pop, Samantha Rachel; Perez, Christopher David; Gumbs, Edvard Adrian; Rosenbaum, Jennifer Ann; Roccato, Mary Kate; Shah, Hely; Contino, Gabriela; Hunter, Krystal

2017-07-01

Atherosclerotic cardiovascular diseases are the leading cause of death in the United States. A reduction in cholesterol with 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statin) significantly reduces mortality and morbidity. Statins may be associated with cognitive impairment or dementia. Our aim was to study the association of cognitive impairment or dementia in patients who were on a statin. Electronic medical records of 3,500 adult patients in our suburban internal medicine office were reviewed. There were 720 (20.6%) patients in the statin treatment group. Dementia or cognitive impairment was an associated comorbid condition in 7.9% patients in the statin treatment group compared to 3.1% patients in the non-statin group (P < 0.001). Analysis of all of the patients with cognitive impairment or dementia showed that among the age ranges of 51 years through 100 years, the patients in the statin treatment group had a higher prevalence of cognitive impairment or dementia compared to the non-statin group. In the statin treatment group, we found significantly higher prevalence of hyperlipidemia (86.3%), hypertension (69.6%), diabetes mellitus (36.0%), osteoarthritis (31.5%), coronary artery disease (26.1%), hypothyroidism (21.5%) and depression (19.3%) compared to the non-statin group (P < 0.001). About 39.9% of the patients with dementia or cognitive impairment were on statin therapy compared to 18.9% patients who had no dementia or cognitive impairment and were on statin therapy (P < 0.001). Among the patients with cognitive deficit or dementia in the statin treatment group, the majority of the patients were either on atorvastatin (43.9%) or simvastatin (35.1%), followed by rosuvastatin (12.2%) and pravastatin (8.8%). We found greater odds of dementia or cognitive impairment with each year increase in age (1.3 times), in women (2.2 times), African American race (2.7 times), non-consumption of moderate amount of alcohol (two times), diabetes mellitus (1.6 times), hypothyroidism (1.7 times), cerebrovascular accident (3.2 times), and other rheumatological diseases (1.8 times). The association of dementia or cognitive impairment was significantly higher in the patients who were on statin therapy compared to the patients who were not on a statin.

Exclusive and Combined Use of Statins and Aspirin and the Risk of Pancreatic Cancer: a Case-Control Study.

PubMed

Archibugi, Livia; Piciucchi, Matteo; Stigliano, Serena; Valente, Roberto; Zerboni, Giulia; Barucca, Viola; Milella, Michele; Maisonneuve, Patrick; Delle Fave, Gianfranco; Capurso, Gabriele

2017-10-12

Data on the association between aspirin and statin use and Pancreatic Ductal AdenoCarcinoma (PDAC) risk are conflicting. These drugs are often co-prescribed, but no studies evaluated the potential combined or confounding effect of the two at the same time. We aimed to investigate the association between aspirin and statin exclusive and combined use and PDAC occurrence. Data on environmental factors, family and medical history were screened in a case-control study. PDAC cases were matched to controls for age and gender. Power calculation performed ahead. Odds ratios (OR) and 95% confidence intervals(CI) were obtained from multivariable logistic regression analysis. In 408 PDAC patients and 816 matched controls, overall statin (OR 0.61; 95%CI,0.43-0.88), but not aspirin use was associated to reduced PDAC risk. Compared to non-users, exclusive statin (OR 0.51; 95%CI,0.32-0.80) and exclusive aspirin users (OR 0.64; 95%CI,0.40-1.01) had reduced PDAC risk. Concomitant statin and aspirin use did not further reduce the risk compared with statin use alone and no interaction was evident. Statin protective association was dose-dependent, and consistent in most subgroups, being stronger in smokers, elderly, obese and non-diabetic patients. The present study suggests that statin use is associated to reduced PDAC risk, supporting a chemopreventive action of statins on PDAC.

High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statin therapy

PubMed Central

Dietrich, Sascha; Okun, Jürgen G.; Schmidt, Kathrin; Falk, Christine S.; Wagner, Andreas H.; Karamustafa, Suzan; Radujkovic, Aleksandar; Hegenbart, Ute; Ho, Anthony D.; Dreger, Peter; Luft, Thomas

2014-01-01

Steroid-refractory graft-versus-host disease is a life-threatening complication after allogeneic stem cell transplantation. Evidence is accumulating that steroid-refractory graft-versus-host disease is associated with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigated whether quantification of serum nitrates could predict steroid-refractory graft-versus-host disease. Elevated pre-transplant levels of serum nitrates (>26.5 μM) predicted steroid-refractory graft-versus-host disease (P=0.026) and non-relapse mortality (P=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (P=0.0007 and P=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory graft-versus-host disease and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of inducible nitric oxide synthase in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (P=0.031) when pravastatin was taken. In summary, patients at high risk of developing steroid-refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort. PMID:24142995

Human skeletal muscle drug transporters determine local exposure and toxicity of statins.

PubMed

Knauer, Michael J; Urquhart, Bradley L; Meyer zu Schwabedissen, Henriette E; Schwarz, Ute I; Lemke, Christopher J; Leake, Brenda F; Kim, Richard B; Tirona, Rommel G

2010-02-05

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. Interindividual differences in the activities of hepatic membrane drug transporters and metabolic enzymes are known to influence statin plasma pharmacokinetics and risk for myopathy. Interestingly, little is known regarding the molecular determinants of statin distribution into skeletal muscle and its relevance to toxicity. We sought to identify statin transporters in human skeletal muscle and determine their impact on statin toxicity in vitro. We demonstrate that the uptake transporter OATP2B1 (human organic anion transporting polypeptide 2B1) and the efflux transporters, multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 are expressed on the sarcolemmal membrane of human skeletal muscle fibers and that atorvastatin and rosuvastatin are substrates of these transporters when assessed using a heterologous expression system. In an in vitro model of differentiated, primary human skeletal muscle myoblast cells, we demonstrate basal membrane expression and drug efflux activity of MRP1, which contributes to reducing intracellular statin accumulation. Furthermore, we show that expression of human OATP2B1 in human skeletal muscle myoblast cells by adenoviral vectors increases intracellular accumulation and toxicity of statins and such effects were abrogated when cells overexpressed MRP1. These results identify key membrane transporters as modulators of skeletal muscle statin exposure and toxicity.

Statins and morbidity and mortality in COPD in the COMIC study: a prospective COPD cohort study

PubMed Central

Citgez, Emanuel; van der Palen, Job; Koehorst-ter Huurne, Kirsten; Movig, Kris; van der Valk, Paul; Brusse-Keizer, Marjolein

2016-01-01

Background Both chronic inflammation and cardiovascular comorbidity play an important role in the morbidity and mortality of patients with chronic obstructive pulmonary disease (COPD). Statins could be a potential adjunct therapy. The additional effects of statins in COPD are, however, still under discussion. The aim of this study is to further investigate the association of statin use with clinical outcomes in a well-described COPD cohort. Methods 795 patients of the Cohort of Mortality and Inflammation in COPD (COMIC) study were divided into statin users or not. Statin use was defined as having a statin for at least 90 consecutive days after inclusion. Outcome parameters were 3-year survival, based on all-cause mortality, time until first hospitalisation for an acute exacerbation of COPD (AECOPD) and time until first community-acquired pneumonia (CAP). A sensitivity analysis was performed without patients who started a statin 3 months or more after inclusion to exclude immortal time bias. Results Statin use resulted in a better overall survival (corrected HR 0.70 (95% CI 0.51 to 0.96) in multivariate analysis), but in the sensitivity analysis this association disappeared. Statin use was not associated with time until first hospitalisation for an AECOPD (cHR 0.95, 95% CI 0.74 to 1.22) or time until first CAP (cHR 1.1, 95% CI 0.83 to 1.47). Conclusions In the COMIC study, statin use is not associated with a reduced risk of all-cause mortality, time until first hospitalisation for an AECOPD or time until first CAP in patients with COPD. PMID:27403321

Statins and morbidity and mortality in COPD in the COMIC study: a prospective COPD cohort study.

PubMed

Citgez, Emanuel; van der Palen, Job; Koehorst-Ter Huurne, Kirsten; Movig, Kris; van der Valk, Paul; Brusse-Keizer, Marjolein

2016-01-01

Both chronic inflammation and cardiovascular comorbidity play an important role in the morbidity and mortality of patients with chronic obstructive pulmonary disease (COPD). Statins could be a potential adjunct therapy. The additional effects of statins in COPD are, however, still under discussion. The aim of this study is to further investigate the association of statin use with clinical outcomes in a well-described COPD cohort. 795 patients of the Cohort of Mortality and Inflammation in COPD (COMIC) study were divided into statin users or not. Statin use was defined as having a statin for at least 90 consecutive days after inclusion. Outcome parameters were 3-year survival, based on all-cause mortality, time until first hospitalisation for an acute exacerbation of COPD (AECOPD) and time until first community-acquired pneumonia (CAP). A sensitivity analysis was performed without patients who started a statin 3 months or more after inclusion to exclude immortal time bias. Statin use resulted in a better overall survival (corrected HR 0.70 (95% CI 0.51 to 0.96) in multivariate analysis), but in the sensitivity analysis this association disappeared. Statin use was not associated with time until first hospitalisation for an AECOPD (cHR 0.95, 95% CI 0.74 to 1.22) or time until first CAP (cHR 1.1, 95% CI 0.83 to 1.47). In the COMIC study, statin use is not associated with a reduced risk of all-cause mortality, time until first hospitalisation for an AECOPD or time until first CAP in patients with COPD.

Generic atorvastatin, the Belgian statin market and the cost-effectiveness of statin therapy.

PubMed

Simoens, Steven; Sinnaeve, Peter R

2013-02-01

This study examines how the market entry of generic atorvastatin influences the Belgian statin market and the cost-effectiveness of statin therapy. Using IMS Health data, the Belgian 2000-2011 statin market was analyzed in terms of total expenditure, annual price of statin treatment, and patient numbers. A simulation analysis projected statin market shares from 2012 to 2015 following market entry of generic atorvastatin. This analysis was based on three scenarios regarding the number of patients taking specific statins. Savings associated with an atorvastatin price reduction of 50-70 % were calculated. A literature review of economic evaluations assessed the cost-effectiveness of generic atorvastatin. Statin expenditure increased from €113 million in 2000 to €285 million in 2011 due to higher expenditure on atorvastatin and rosuvastatin. Although the number of patients treated with simvastatin increased by nearly 800 %, the resulting increase in expenditure was partially offset by price reductions. Atorvastatin is projected to become the dominant product in the Belgian statin market (market share of 47-66 % by 2015). Annual savings would attain €108.6-€153.7 million for a 50 % reduction in the atorvastatin price and €152.0-€215.2 million for a 70 % price reduction. The literature suggests that generic atorvastatin is cost-effective as compared to simvastatin. The limited evidence about the cost-effectiveness of rosuvastatin as compared with generic atorvastatin is inconclusive. Generic atorvastatin is cost-effective as compared to simvastatin, is projected to become the dominant product in the Belgian statin market and is expected to generate substantial savings to health care payers.

Guideline concordance of new statin prescriptions: who got a statin?

PubMed

Cascino, Thomas; Vali, Marzieh; Redberg, Rita; Bravata, Dawn M; Boscardin, John; Eilkhani, Elnaz; Keyhani, Salomeh

2017-09-01

Statins are recommended to reduce serum cholesterol in patients at risk for atherosclerotic cardiovascular disease. Despite the prevalence of statin use, little is known about the indications for new prescriptions. We assessed the concordance of new statin prescriptions in the Veterans Health Administration (VHA) compared with the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) guidelines (the guidelines in force in 2012) and the American College of Cardiology (ACC)-American Heart Association (AHA) 2013 guidelines. Cross-sectional study. We identified every patient who received a new prescription (no statin use in the prior year) in the VHA in 2012. Patients were excluded if they had incomplete data, triglycerides greater than 400 mg/dL, or fewer than 2 primary care visits to ensure adequate baseline data to calculate Framingham and ACC-AHA 2013 risk scores. We identified 250,243 new statin prescriptions in 2012 in the VHA, with 121,081 meeting inclusion criteria. Among new prescriptions, 68% were prescribed for primary prevention and 32% were prescribed for secondary prevention. Among patients receiving new statins for primary prevention, 48% did not have an indication supported by the ATP III guideline and 20% did not have an indication supported by the ACC/AHA guideline. Overall, approximately 19% of patients may have received a statin for an indication not supported by either guideline. Veterans are commonly prescribed statins for indications not supported by professional society guidelines. The finding of common use of statins outside established guidelines represents an opportunity to improve the quality and value of the healthcare delivery.

Correlation of compliance to statin therapy with lipid profile and serum HMGCoA reductase levels in dyslipidemic patients.

PubMed

Grover, Abhinav; Rehan, Harmeet Singh; Gupta, Lalit Kumar; Yadav, Madhur

The efficacy of statin therapy may be lost or vary with reduction in compliance and intensity of statin therapy. To study and correlate the quantitative effect of compliance on lipid profile and 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMGCoA-R) levels in dyslipidemic patients. Compliance to different intensity of statin therapy assessed by pill count was correlated with serum levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and HMGCoA-R. Out of 200 patients, 160 received moderate intensity statin therapy whereas 40 were on high intensity statin therapy. The overall mean compliance of patients was 56.7%. The compliance of patients on moderate intensity statin therapy was higher (56.8%) than those on high intensity (56.4%) (p=0.92). There was significant inverse correlation (p<0.05) between compliance and TC, TG, LDL-C and HMGCoA-R levels and positive correlation (p<0.05) with HDL-C levels. The mean serum HMGCoA-R levels did not fall below 9-10ng/mL when compliance to either moderate or high intensity statin therapy was increased above 60%. It is appropriate to improve the compliance to existing statin therapy than switching over to higher intensity statin therapy. Estimation of HMGCoA-R levels may be explored as a surrogate marker to monitor and assess the compliance of patients to statin therapy. Copyright © 2016. Published by Elsevier B.V.

[Medication adherence to secondary prevention for coronary artery disease].

PubMed

Rossi, Emiliano; Perman, Gastón; Michelangelo, Hernán; Alonzo, Claudia B; Brescacin, Laura; Kopitowski, Karin S; Navarro Estrada, José L

2014-01-01

We compared the use of evidence-based secondary prevention drugs for coronary artery disease at hospital discharge and 3 years of follow-up in a group of patients associated to an integrated network of health services. We conducted a retrospective group study that included 125 patients under 80 years of age who were hospitalized for acute coronary syndrome. McNemar's test was used to compare values at baseline and 3 years. The mean age of of participants was 63.7 years (SD ± 10.08) and 65.6% (95% CI 56.6-73.9) of male sex. The average follow-up time was 2.94 years (SD ± 0.25). The use of secondary prevention drugs for coronary heart disease decreased at 3 years of follow-up: anti-platelet 97.6 to 88.0% (p = 0.012), beta-blockers 94.4 to 84.8% (p = 0.021) and statins 83.7 to 91.2% (p = 0.035). Patients medicated with a combination of anti-platelet, beta blockers and statins showed a decrease from 86.4 to 66.3% (p < 0.0001). It is necessary to study the causes for the decreased adherence to long-term cardio-protective drugs.

Removal of emerging contaminants in sewage water subjected to advanced oxidation with ozone.

PubMed

Ibáñez, M; Gracia-Lor, E; Bijlsma, L; Morales, E; Pastor, L; Hernández, F

2013-09-15

Advanced oxidation processes (AOP) based on ozone treatments, assisted by ultrasounds, have been investigated at a pilot-plant scale in order to evaluate the removal of emerging contaminants in sewage water. Around 60 emerging contaminants, mainly pharmaceuticals from different therapeutically classes and drugs of abuse, have been determined in urban wastewater samples (treated and untreated) by LC-MS/MS. In a first step, the removal efficiency of these contaminants in conventional sewage water treatment plants was evaluated. Our results indicate that most of the compounds were totally or partially removed during the treatment process of influent wastewater. Up to 30 contaminants were quantified in the influent and effluent samples analysed, being antibiotics, anti-inflammatories, cholesterol lowering statin drugs and angiotensin II receptor antagonists the most frequently detected. Regarding drugs of abuse, cocaine and its metabolite benzoylecgonine were the most frequent. In a second step, the effectiveness of AOP in the removal of emerging contaminants remaining in the effluent was evaluated. Ozone treatments have been proven to be highly efficient in the removal, notably decreasing the concentrations for most of the emerging contaminants present in the water samples. The use of ultrasounds, alone or assisting ozone treatments, has been shown less effective, being practically unnecessary. Copyright © 2013 Elsevier B.V. All rights reserved.

Cytochrome P450 drug interactions with statin therapy.

PubMed

Goh, Ivanna Xin Wei; How, Choon How; Tavintharan, Subramaniam

2013-03-01

Statins are commonly used in the treatment of hyperlipidaemia. Although the benefits of statins are well-documented, they have the potential to cause myopathy and rhabdomyolysis due to the complex interactions of drugs, comorbidities and genetics. The cytochrome P450 family consists of major enzymes involved in drug metabolism and bioactivation. This article aims to highlight drug interactions involving statins, as well as provide updated recommendations and approaches regarding the safe and appropriate use of statins in the primary care setting.

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

PubMed Central

Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A.; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, Daniel I.; Zhou, Kaixin; Arsenault, Benoit J.; Donnelly, Louise A.; Wiggins, Kerri L.; Avery, Christy L.; Griffin, Paula; Feng, QiPing; Taylor, Kent D.; Li, Guo; Evans, Daniel S.; Smith, Albert V.; de Keyser, Catherine E.; Johnson, Andrew D.; de Craen, Anton J. M.; Stott, David J.; Buckley, Brendan M.; Ford, Ian; Westendorp, Rudi G. J.; Eline Slagboom, P.; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C.; O’Brien, Eoin; Shaw-Hawkins, Sue; Ida Chen, Y.-D.; Nickerson, Deborah A.; Smith, Joshua D.; Pierre Dubé, Marie; Matthijs Boekholdt, S.; Kees Hovingh, G.; Kastelein, John J. P.; McKeigue, Paul M.; Betteridge, John; Neil, Andrew; Durrington, Paul N.; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C.; Rice, Kenneth; Smith, Nicholas L.; Lumley, Thomas; Whitsel, Eric A.; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S.; O’Donnell, Christopher J.; Vasan, Ramachandran S.; Wei, Wei-Qi; Wilke, Russell A.; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M.; Stafford, Jeanette M.; Ding, Jingzhong; Herrington, David M.; Kritchevsky, Stephen B.; Eiriksdottir, Gudny; Launer, Leonore J.; Harris, Tamara B.; Chu, Audrey Y.; Giulianini, Franco; MacFadyen, Jean G.; Barratt, Bryan J.; Nyberg, Fredrik; Stricker, Bruno H.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H.; Ridker, Paul M.; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C.; Ballantyne, Christie M.; Rotter, Jerome I.; Adrienne Cupples, L.; Psaty, Bruce M.; Palmer, Colin N. A.; Tardif, Jean-Claude; Colhoun, Helen M.; Hitman, Graham; Krauss, Ronald M.; Wouter Jukema, J; Caulfield, Mark J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; McCarthy, Mark I.; Spencer, Chris C. A.

2014-01-01

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response. PMID:25350695

Immune-mediated statin myopathy.

PubMed

Loganathan, Priyadarshini; Oddis, Chester V; Aggarwal, Rohit

2016-01-01

Statin-induced necrotizing autoimmune myopathy (SINAM) is associated with a unique clinical 5 phenotype of severe proximal muscle weakness during or after exposure to statins in patients with high creatine kinase (CK) levels. Electromyography (EMG) and muscle biopsy reveal features of a necrotizing myopathy and the anti-HMGCR autoantibody is frequently detected. Treatment requires a combination of statin discontinuation as well as immunomodulatory or immunosuppressive therapy. HLA typing (HLADRB1*1101) is strongly associated with anti-10 HMGCR autoantibody positivity in statin-exposed patients. It is well documented that statin triggers autoimmune disease in those with a genetic susceptibility. With the commercial availability of an accurate ELISA test, the natural history of the disease and its phenotypic features are becoming increasingly understood.

Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism.

PubMed

Fiorillo, Marco; Peiris-Pagès, Maria; Sanchez-Alvarez, Rosa; Bartella, Lucia; Di Donna, Leonardo; Dolce, Vincenza; Sindona, Giovanni; Sotgia, Federica; Cappello, Anna Rita; Lisanti, Michael P

2018-04-04

Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed "BMF", has a statin-like properties, which blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration (OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion diagnostic for BMF-directed personalized therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Statin therapy and the risk for diabetes among adult women: do the benefits outweigh the risk?

PubMed

Ma, Yunsheng; Culver, Annie; Rossouw, Jacques; Olendzki, Barbara; Merriam, Philip; Lian, Bill; Ockene, Ira

2013-02-01

The purpose of this review was to examine statin therapy and the risk for diabetes among adult women using a selective review. The literature contains reports of new-onset diabetes associated with statin use. While many studies do not report sex-specific results, there is evidence indicating the risk to benefit ratio may vary by gender. However, the absolute effects are not clear because women have historically been under-represented in clinical trials. A review of the literature indicates that the cardiovascular benefits of statins appear to outweigh the risk for statin-related diabetes. However, the effect may depend upon baseline diabetes risk, dose, and statin potency. Rigorous, long-term studies focused on the risks and benefits of statins in women are unavailable to sort for gender-specific differences. Until this changes, individualized attention to risk assessment, and strong prevention with lifestyle changes must prevail.

'Muscle-sparing' statins: preclinical profiles and future clinical use.

PubMed

Pfefferkorn, Jeffrey A

2009-03-01

Coronary heart disease (CHD) is a leading cause of death in the US, and hypercholesterolemia is a key risk factor for this disease. The current standard of care for treating hypercholesterolemia is the use of HMG-CoA reductase inhibitors, also known as statins, which block the rate-limiting step of cholesterol biosynthesis. In widespread clinical use, statins have proven safe and effective for both primary prevention of CHD and secondary prevention of coronary events. Results from several recent clinical trials have demonstrated that increasingly aggressive cholesterol-lowering therapy might offer additional protection against CHD compared with less aggressive treatment standards. While higher doses of current statin therapies are capable of achieving these more aggressive treatment goals, in certain cases statin-induced myalgia, the muscle pain or weakness that sometimes accompanies high-dose statin therapy, limits patient compliance with a treatment regimen. To address this limitation, efforts have been undertaken to develop highly hepatoselective statins that are capable of delivering best-in-class efficacy with minimized risk of dose-limiting myalgia. In this review, the preclinical and early clinical data for these next generation statins are discussed.

The safety of statins in clinical practice.

PubMed

Armitage, Jane

2007-11-24

Statins are effective cholesterol-lowering drugs that reduce the risk of cardiovascular disease events (heart attacks, strokes, and the need for arterial revascularisation). Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual. Myopathy--muscle pain or weakness with blood creatine kinase levels more than ten times the upper limit of the normal range--typically occurs in fewer than one in 10,000 patients on standard statin doses. However, this risk varies between statins, and increases with use of higher doses and interacting drugs. Rhabdomyolysis is a rarer and more severe form of myopathy, with myoglobin release into the circulation and risk of renal failure. Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease. For most people, statins are safe and well-tolerated, and their widespread use has the potential to have a major effect on the global burden of cardiovascular disease.

Relationships between HMG-CoA reductase inhibitors (statin) use and strength, balance and falls in older people.

PubMed

Haerer, W; Delbaere, K; Bartlett, H; Lord, S R; Rowland, J

2012-12-01

To investigate associations between HMG-CoA reductase inhibitor (statin) use and muscle strength, balance, mobility and falls in older people. Five hundred community-dwelling people aged 70-90 years provided information about their medication use and undertook tests of lower limb strength, postural sway, leaning balance (maximal balance range and coordinated stability tests) and functional mobility. Participants were then followed up for 12 months with respect to falls. After adjusting for general health in analyses of covariance procedures, statin users had poorer maximal balance range than non-statin users (P = 0.017). Statin and non-statin users did not differ with respect to strength, postural sway, mobility or falls experienced in the follow-up year. In a sample of healthy older people, statin use was not associated with muscle weakness, postural sway, reduced mobility or falls. Statin users, however, had poorer leaning balance which may potentially increase fall risk in this group. © 2011 The Authors; Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect

PubMed Central

Cao, Peirang; Hanai, Jun-ichi; Tanksale, Preeti; Imamura, Shintaro; Sukhatme, Vikas P.; Lecker, Stewart H.

2009-01-01

Statins are widely used to treat hypercholesterolemia but can lead to a number of side effects in muscle, including rhabdomyolysis. Our recent findings implicated the induction of atrogin-1, a gene required for the development of muscle atrophy, in statin-induced muscle damage. Since statins inhibit many biochemical reactions besides cholesterol synthesis, we sought to define the statin-inhibited pathways responsible for atrogin-1 expression and muscle damage. We report here that lovastatin-induced atrogin-1 expression and muscle damage in cultured mouse myotubes and zebrafish can be prevented in the presence of geranylgeranol but not farnesol. Further, inhibitors of the transfer of geranylgeranyl isoprene units to protein targets cause statin muscle damage and atrogin-1 induction in cultured cells and in fish. These findings support the concept that dysfunction of small GTP-binding proteins lead to statin-induced muscle damage since these molecules require modification by geranylgeranyl moieties for their cellular localization and activity. Collectively, our animal and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be regulated by novel signaling pathways.—Cao, P., Hanai, J., Tanksale, P., Imamura, S., Sukhatme, V. P., Lecker, S. H. Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect. PMID:19406843

Amyotrophic Lateral Sclerosis Associated with Statin Use: A Disproportionality Analysis of the FDA's Adverse Event Reporting System.

PubMed

Golomb, Beatrice A; Verden, Abril; Messner, Alexis K; Koslik, Hayley J; Hoffman, Keith B

2018-04-01

Apparent elevations in reporting of amyotrophic lateral sclerosis (ALS)-like conditions associated with statin use have been previously described from data obtained via US and European databases. The aim of this study was to examine US FDA Adverse Event Reporting System (FAERS) data to compare reporting odds ratios (RORs) of ALS and ALS-like conditions between statins and other drugs, for each statin agent. We assessed for disproportional rates of reported ALS and ALS-related conditions for each statin agent separately by using the ROR formula. FAERS data were analyzed through September 2015. RORs for ALS were elevated for all statins, with elevations possibly stronger for lipophilic statins. RORs ranged from 9.09 (6.57-12.6) and 16.2 (9.56-27.5) for rosuvastatin and pravastatin (hydrophilic) to 17.0 (14.1-20.4), 23.0 (18.3-29.1), and 107 (68.5-167) for atorvastatin, simvastatin, and lovastatin (lipophilic), respectively. For simvastatin, an ROR of 57.1 (39.5-82.7) was separately present for motor neuron disease. These findings extend previous evidence showing that significantly elevated ALS reporting extends to individual statin agents, and add to concerns about potential elevated occurrence of ALS-like conditions in association with statin usage.

Rosuvastatin and atorvastatin: comparative effects on glucose metabolism in non-diabetic patients with dyslipidaemia.

PubMed

Abbas, Ahmed; Milles, John; Ramachandran, Sudarshan

2012-01-01

The ever increasing interventional CVD outcome studies have resulted in statins being an essential factor of cardiovascular prevention strategies. The JUPITER study in 2008, despite reducing CVD and overall mortality, highlighted an increase in new onset diabetes in the rosuvastatin treated arm. Since then there have been many meta-analyses of the RCTs and the largest carried out by Sattar et al showed a significant increase in the incidence of diabetes during the trials. The findings from the individual studies when comparing the different statins were less clear. A higher statin dosage and risk factors associated with diabetes appeared to predict this phenomenon. There have been many studies investigating the effects of statins on glycaemic control, but again no clear conclusion is apparent. Despite the increase in new onset diabetes observed, the risk is clearly out-weighed by the CVD benefits observed in nearly all the statin trials. Thus, no change is required to any of the prevention guidelines regarding statins. However, it may be prudent to monitor glycaemic control after commencing statin therapy. This review will focus on atorvastatin which is the most widely used statin worldwide and rosuvastatin which is the most efficacious. This will be against a background of the effects of other statins on glucose metabolism in non-diabetic patients.

Rosuvastatin and Atorvastatin: Comparative Effects on Glucose Metabolism in Non-Diabetic Patients with Dyslipidaemia

PubMed Central

Abbas, Ahmed; Milles, John; Ramachandran, Sudarshan

2012-01-01

The ever increasing interventional CVD outcome studies have resulted in statins being an essential factor of cardiovascular prevention strategies. The JUPITER study in 2008, despite reducing CVD and overall mortality, highlighted an increase in new onset diabetes in the rosuvastatin treated arm. Since then there have been many meta-analyses of the RCTs and the largest carried out by Sattar et al showed a significant increase in the incidence of diabetes during the trials. The findings from the individual studies when comparing the different statins were less clear. A higher statin dosage and risk factors associated with diabetes appeared to predict this phenomenon. There have been many studies investigating the effects of statins on glycaemic control, but again no clear conclusion is apparent. Despite the increase in new onset diabetes observed, the risk is clearly out-weighed by the CVD benefits observed in nearly all the statin trials. Thus, no change is required to any of the prevention guidelines regarding statins. However, it may be prudent to monitor glycaemic control after commencing statin therapy. This review will focus on atorvastatin which is the most widely used statin worldwide and rosuvastatin which is the most efficacious. This will be against a background of the effects of other statins on glucose metabolism in non-diabetic patients. PMID:22879796

Association between statin therapy and tendon rupture: a case-control study.

PubMed

Beri, Abhimanyu; Dwamena, Francesca C; Dwamena, Ben A

2009-05-01

Although case reports of a possible association between statin therapy and tendon rupture have been published, no analytical studies exploring this relationship have been reported. We conducted a case-control study using the electronic medical records at Michigan State University from 2002 to 2007 to assess whether statin use is a risk factor for tendon rupture. We compared exposure to statins in 93 cases of tendon rupture with similar exposure in 279 sex- and age-matched controls. Exposure to statins was defined as documentation in the electronic medical record of statin use in the 12 months preceding tendon rupture. For controls, the exposure period was defined as 1 year preceding the last office visit. We used a multivariate logistic regression model, controlling for diabetes, renal disease, rheumatologic disease, and steroid use, to calculate the adjusted odds ratios (ORs). There was no significant difference between cases and controls in the rates of statin use, with either univariate [OR = 1.0, 95% confidence interval (CI) 0.54-1.84] or multivariate analyses (OR = 1.10, 95% CI 0.57-2.13). Based on predetermined subgroup analyses, statin exposure was found to be a significant risk factor for tendon rupture in women (adjusted OR = 3.76, 95% CI 1.11-12.75) but not in men (adjusted OR = 0.66, 95% CI 0.29-1.51). In conclusion, we found no overall association between statin use and tendon rupture, but subgroup analysis suggested that women with tendon rupture were more likely to be on statins.

Pleiotropic effects of statins: new therapeutic targets in drug design.

PubMed

Bedi, Onkar; Dhawan, Veena; Sharma, P L; Kumar, Puneet

2016-07-01

The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.

[Incremental effect and mechanism of cyclosporine on blood concentration of statins and statin package insert information in Japan].

PubMed

Hirata-Koizumi, Mutsuko; Saito, Mitsuo; Miyake, Shinji; Hasegawa, Ryuichi

2005-01-01

Cyclosporine is an indispensable immunosuppressant used in organ transplant patients, who frequently manifest hyperlipidemia. Statins, which are cholesterol-lowering agents, are often combined with cyclosporine in the treatment of hyperlipidemia of organ transplant patients. Since cyclosporine is a substrate and inhibitor of CYP3A4, researchers suspect that the immunosuppressant inhibits CYP3A4-mediated metabolism of statins, leading to an increase in statin plasma concentration and infrequently resulting in rhabdomyolysis. However, a number of clinical trials have shown cyclosporine to increase the plasma concentration of all developed statins, including those not metabolized by CYP3A4. Furthemore, recent mechanistic studies have shown organic anion transporting peptides (OATP) C to mediate the uptake of some statins and cyclosporine has been shown to inhibit the uptake via OATP-C in cultured cells. Therefore, the inhibition of hepatic uptake of statins is considered to be one of the mechanisms by which cyclosporine incrementally increases statin blood concentration. However, most current Japanese package inserts of statins give no information on change in pharmacokinetic parameters such as AUC and Cmax in the combined medication with cyclosporine. Furthermore, in the Japanese package inserts, it is either stated that cyclosporine inhibits CYP3A4-mediated metabolism or no comment is made on the mechanism. The package insert should properly provide available quantitative information on the change of pharmacokinetic parameters and the probable mechanism of action.

Prognostic impact of preoperative statin use after radical nephroureterectomy for upper urinary tract urothelial carcinoma

PubMed Central

Lim, Ju Hyun; Jeong, In Gab; Park, Jong Yeon; You, Dalsan; Hong, Bumsik; Hong, Jun Hyuk; Ahn, Hanjong

2015-01-01

Purpose The objective was to investigate the impact of statin use on prognosis after radical nephroureterectomy for upper urinary tract urothelial carcinoma (UTUC). Materials and Methods A retrospective review of medical records identified 277 patients who underwent radical nephroureterectomy for primary UTUC at Asan Medical Center between January 2006 and December 2011. Information on preoperative statin use was obtained from patient charts in an electronic database. We assessed the impact of statin use on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results Of these 277 patients, 62 (22.4%) were taking statin medications. Compared to the statin nonusers, the statin users were older, had a higher body mass index, and had higher rates of cardiovascular disease and diabetes. The 5-year RFS rates of statin users and nonusers were 78.5% and 72.5%, respectively (p=0.528); the 5-year CSS rates were 85.6% and 77.7%, respectively (p=0.516); and the 5-year OS rates were 74.5% and 71.4%, respectively (p=0.945). In the multivariate analysis, statin use was not an independent prognostic factor for RFS (hazard ratio, 0.47; p=0.056), CSS (hazard ratio, 0.46; p=0.093), or OS (hazard ratio, 0.59; p=0.144) in patients who underwent radical nephroureterectomy for UTUC. Conclusions Statin use was not associated with improved RFS, CSS, or OS in the sample population of patients with UTUC. PMID:26175868

Prognostic impact of preoperative statin use after radical nephroureterectomy for upper urinary tract urothelial carcinoma.

PubMed

Lim, Ju Hyun; Jeong, In Gab; Park, Jong Yeon; You, Dalsan; Hong, Bumsik; Hong, Jun Hyuk; Ahn, Hanjong; Kim, Choung-Soo

2015-07-01

The objective was to investigate the impact of statin use on prognosis after radical nephroureterectomy for upper urinary tract urothelial carcinoma (UTUC). A retrospective review of medical records identified 277 patients who underwent radical nephroureterectomy for primary UTUC at Asan Medical Center between January 2006 and December 2011. Information on preoperative statin use was obtained from patient charts in an electronic database. We assessed the impact of statin use on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Of these 277 patients, 62 (22.4%) were taking statin medications. Compared to the statin nonusers, the statin users were older, had a higher body mass index, and had higher rates of cardiovascular disease and diabetes. The 5-year RFS rates of statin users and nonusers were 78.5% and 72.5%, respectively (p=0.528); the 5-year CSS rates were 85.6% and 77.7%, respectively (p=0.516); and the 5-year OS rates were 74.5% and 71.4%, respectively (p=0.945). In the multivariate analysis, statin use was not an independent prognostic factor for RFS (hazard ratio, 0.47; p=0.056), CSS (hazard ratio, 0.46; p=0.093), or OS (hazard ratio, 0.59; p=0.144) in patients who underwent radical nephroureterectomy for UTUC. Statin use was not associated with improved RFS, CSS, or OS in the sample population of patients with UTUC.

LIFESTAT - Living with statins: An interdisciplinary project on the use of statins as a cholesterol-lowering treatment and for cardiovascular risk reduction.

PubMed

Christensen, Christa Lykke; Wulff Helge, Jørn; Krasnik, Allan; Kriegbaum, Margit; Rasmussen, Lene Juel; Hickson, Ian D; Liisberg, Kasper Bering; Oxlund, Bjarke; Bruun, Birgitte; Lau, Sofie Rosenlund; Olsen, Maria Nathalie Angleys; Andersen, John Sahl; Heltberg, Andreas Søndergaard; Kuhlman, Anja Birk; Morville, Thomas Hoffmann; Dohlmann, Tine Lovsø; Larsen, Steen; Dela, Flemming

2016-07-01

LIFESTAT is an interdisciplinary project that leverages approaches and knowledge from medicine, the humanities and the social sciences to analyze the impact of statin use on health, lifestyle and well-being in cohorts of Danish citizens. The impetus for the study is the fact that 10% of the population in the Scandinavian countries are treated with statins in order to maintain good health and to avoid cardiovascular disease by counteracting high blood levels of cholesterol. The potential benefit of treatment with statins should be considered in light of evidence that statin use has prevalent and unintended side effects (e.g. myalgia, and glucose and exercise intolerance). The LIFESTAT project combines invasive human experiments, biomedical analyses, nationwide surveys, epidemiological studies, qualitative interviews, media content analyses, and ethnographic participant observations. The study investigates the biological consequences of statin treatment; determines the mechanism(s) by which statin use causes muscle and mitochondrial dysfunction; and analyzes achievement of treatment goals, people's perception of disease risk, media influence on people's risk and health perception, and the way people manage to live with the risk (personally, socially and technologically). CONCLUSIONS THE ORIGINALITY AND SUCCESS OF LIFESTAT DEPEND ON AND DERIVE FROM ITS INTERDISCIPLINARY APPROACH, IN WHICH THE DISCIPLINES CONVERGE INTO THOROUGH AND HOLISTIC STUDY AND DESCRIBE THE IMPACT OF STATIN USE ON THE EVERYDAY LIFE OF STATIN USERS THIS HAS THE POTENTIAL FOR MUCH GREATER BENEFIT THAN ANY ONE OF THE DISCIPLINES ALONE INTEGRATING TRADITIONAL DISCIPLINES PROVIDES NOVEL PERSPECTIVES ON POTENTIAL CURRENT AND FUTURE SOCIAL, MEDICAL AND PERSONAL BENEFITS OF STATIN USE. © 2016 the Nordic Societies of Public Health.

The Cost-Benefit Balance of Statins in Hawai'i: A Moving Target.

PubMed

Lum, Corey J; Nakagawa, Kazuma; Shohet, Ralph V; Seto, Todd B; Taira, Deborah A

2017-04-01

Statins are lipid-lowering medications used for primary and secondary prevention of atherosclerotic disease and represent a substantial portion of drug costs in the United States. A better understanding of prescribing patterns and drug costs should lead to more rational utilization and help constrain health care expenditures in the United States. The 2013 Medicare Provider Utilization and Payment Data: Part D Prescriber Public Use File for the State of Hawai'i was analyzed. The number of prescriptions for statins, total annual cost, and daily cost were calculated by prescriber specialty and drug. Potential savings from substituting the highest-cost statin with lower-cost statins were calculated. Over 421,000 prescriptions for statins were provided to Medicare Part D beneficiaries in Hawai'i in 2013, which cost $17.6M. The three most commonly prescribed statins were simvastatin (33.4%), atorvastatin (33.4%), and lovastatin (13.9%). Although rosuvastatin comprised 5.4% of the total statin prescriptions, it represented 30.1% of the total cost of statins due to a higher daily cost ($5.53/day) compared to simvastatin ($0.25/day) and atorvastatin ($1.10/day). Cardiologists and general practitioners prescribed the highest percentage of rosuvastatin (8% each). Hypothetical substitution of rosuvastatin would have resulted in substantial annual cost savings (Simvastatin would have saved $1.3M for 25% substitution and $5.1M for 100% substitution, while atorvastatin would have saved $1.1M for 25% substitution and $4.3M for 100% substitution). Among Medicare Part D beneficiaries in Hawai'i, prescribing variation for statins between specialties were observed. Substitution of higher-cost with lower-cost statins may lead to substantial cost savings.

C-C4-01: Statin Use and Risk of Basal Cell Carcinoma

PubMed Central

Asgari, Maryam M; Tang, Jean; Epstein, Ervin; Chren, Mary-Margaret; Warton, Margaret; Quesenberry, Charles P; Go, Alan S; Friedman, Gary D

2010-01-01

Background: Limited data exist about the association between statin use and skin cancer risk. We examined the independent relation between statin use and basal cell carcinoma (BCC) risk. Methods: We identified all members of a large integrated healthcare delivery system diagnosed with a histologically proven BCC in 1997. Subsequent BCCs were identified through 2006 from health plan electronic pathology records. Longitudinal exposure to statins and other lipid lowering agents was determined from automated pharmacy records. We used extended Cox regression to examine the independent association between receipt of statin therapy (ever vs. never, cumulative duration) and risk of subsequent BCC. To minimize confounding by indication, we conducted sensitivity analyses in the subset of individuals considered eligible for lipid lowering therapy based on national guidelines. Results: Among 12,123 members diagnosed with BCC who had no prior statin exposure, 6,381 developed a subsequent BCC during follow-up. Neither ever use of statins (adjusted hazard ratio [aHR] 1.02, 95% CI: 0.92–1.12) or cumulative duration of statin (aHR 1.02 per year, 95% CI: 0.99–1.11) was associated with subsequent BCC after adjustment for age, sex, and healthcare utilization. Risk estimates did not change appreciably when the analysis was limited to the subset of individuals who met eligibility criteria for initiating statin therapy. There was also no significant association between use of non-statin anti-lipemics and subsequent BCC (aHR 1.10, 95% CI: 0.76–1.58). Conclusions: Among a large cohort of individuals with BCC, statin therapy was not significantly associated with risk of subsequent BCC.

The Association of Statin Use and Statin Type on Cognitive Performance: Analysis of The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study

PubMed Central

Glasser, Stephen P; Wadley, Virginia; Judd, Suzanne; Kana, Bhumika; Prince, Valerie; Jenny, Nancy Swords; Kissela, Brett; Safford, Monika; Prineas, Ronald; Howard, George

2010-01-01

SUMMARY Context Statin use and type has been variably associated with impaired or improved cognitive performance. Objective To assess the association of statin use and type (lipophilic vs hydrophilic) and cognitive impairment Design Cross-sectional analysis of 24595 (7191 statin users and 17404 non-users) participants (age >45), from a population-based national cohort study (REasons for Geographic And Racial Differences in Stroke) enrolled from January 2003-October 2008 with over-sampling from the southeastern Stroke Belt, and African Americans. Main Outcomes Statin use and type were documented in participants’ homes by a trained health professional. Cognitive performance was assessed with a prior validated instrument of global cognitive status (Six-Item Screener). Cognitive impairment was defined as a score of < 4. . Results Overall, an association of cognitive impairment and statin use was observed (8.6% of users vs 7.7% or non-users had cognitive impairment p=.014) but, after adjusting for variables known to be associated with cognition (age, gender, race, income, levels of education, and cardiovascular disease) the association was attenuated (OR 0.98, CI; 0.87;1.10). No association was observed between statin type (lipophilic vs hydrophilic) and cognition (OR 1.03, CI; 0.86;1.24), and there were no regional differences in cognitive impairment in statin users (8% in the stroke belt and 7.9% other regions p=0.63). Conclusions Statin use and type was marginally associated with cognitive impairment. After adjusting for known variables that affect cognition, no association was observed. No regional differences were observed. This large study found no evidence to support an association between statins and cognitive performance. PMID:20513066

Statins in Acute Ischemic Stroke: A Systematic Review

PubMed Central

Hong, Keun-Sik; Lee, Ji Sung

2015-01-01

Background and Purpose Statins have pleiotropic effects of potential neuroprotection. However, because of lack of large randomized clinical trials, current guidelines do not provide specific recommendations on statin initiation in acute ischemic stroke (AIS). The current study aims to systematically review the statin effect in AIS. Methods From literature review, we identified articles exploring prestroke and immediate post-stroke statin effect on imaging surrogate markers, initial stroke severity, functional outcome, and short-term mortality in human AIS. We summarized descriptive overview. In addition, for subjects with available data from publications, we conducted meta-analysis to provide pooled estimates. Results In total, we identified 70 relevant articles including 6 meta-analyses. Surrogate imaging marker studies suggested that statin might enhance collaterals and reperfusion. Our updated meta-analysis indicated that prestroke statin use was associated with milder initial stroke severity (odds ratio [OR] [95% confidence interval], 1.24 [1.05-1.48]; P=0.013), good functional outcome (1.50 [1.29-1.75]; P<0.001), and lower mortality (0.42 [0.21-0.82]; P=0.0108). In-hospital statin use was associated with good functional outcome (1.31 [1.12-1.53]; P=0.001), and lower mortality (0.41 [0.29-0.58]; P<0.001). In contrast, statin withdrawal was associated with poor functional outcome (1.83 [1.01-3.30]; P=0.045). In patients treated with thrombolysis, statin was associated with good functional outcome (1.44 [1.10-1.89]; P=0.001), despite an increased risk of symptomatic hemorrhagic transformation (1.63 [1.04-2.56]; P=0.035). Conclusions The current study findings support the use of statin in AIS. However, the findings were mostly driven by observational studies at risk of bias, and thereby large randomized clinical trials would provide confirmatory evidence. PMID:26437994

The Impact of Statin Use on Lipid Levels in Statin-Naive Patients with Rheumatoid Arthritis (RA) vs. non-RA Subjects: Results from a Population-Based Study

PubMed Central

Myasoedova, Elena; Gabriel, Sherine E.; Green, Abigail B.; Matteson, Eric L.; Crowson, Cynthia S.

2013-01-01

Objectives To examine lipid profiles among statin-naive patients with rheumatoid arthritis (RA) and those without RA before and after the initiation of statins. Methods Information regarding lipid measures and statin use was gathered in a population-based incident cohort of patients with RA (1987 ACR criteria first met between 1/1/1988 and 1/1/2008) and in a cohort of non-RA subjects from the same underlying population. Only patients with no prior history of statin use were included. Results The study included 161 patients with RA (mean age 56.3 years, 57% female) and 221 non-RA subjects (mean age 56.0 years, 66% female). Prior to the start of statins, the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) were lower in RA vs non-RA cohort (p<0.001 and p=0.003, respectively). The absolute and percent change in LDL after at least 90 days of statin use tended to be smaller in RA vs non-RA cohort (p=0.03 and p=0.09). After at least 90 days of statin use patients with RA were less likely to achieve therapeutic goals for LDL than the non-RA subjects (p=0.046). Increased erythrocyte sedimentation rate (ESR) at baseline (OR 0.47; 95% CI 0.26, 0.85) was associated with lower likelihood of achieving therapeutic LDL goals. Conclusion Patients with RA had lower TC and LDL levels before statin initiation and lower likelihood of achieving therapeutic LDL goals following statin use than the non-RA subjects. Some RA disease characteristics, in particular ESR at baseline, may have an adverse impact on achieving therapeutic LDL goals. PMID:23592565

Harnessing the trophic and modulatory potential of statins in a dopaminergic cell line.

PubMed

Schmitt, Mathieu; Dehay, Benjamin; Bezard, Erwan; Garcia-Ladona, F Javier

2016-03-01

The identification of an effective disease-modifying treatment for the neurodegenerative progression in Parkinson's disease (PD) remains a major challenge. Epidemiological studies have reported that intake of statins, cholesterol lowering drugs, could be associated to a reduced risk of developing PD. In-vivo studies suggest that statins may reduce the severity of dopaminergic neurodegeneration. The trophic potential of statins and their impact on the expression of dopaminergic synaptic markers and dopamine (DA) transport function in SH-SY5Y cells has been investigated. The findings showed that statin treatment induces neurite outgrowth involving a specific effect on the complexity of the neurite branching pattern. Statins increased the levels of presynaptic dopaminergic biomarkers such as vesicular monoamine transporter 2 (VMAT2), synaptic vesicle glycoproteins 2A and 2C (SV2C), and synaptogyrin-3 (SYNGR3). Gene expression analysis confirmed a rapid statin-induced up-regulation of VMAT2-, SV2C-, and SYNGR3-mRNA levels. Assessment of [(3) H]DA transport in statin-treated cells showed a reduction in DA uptake concomitant to a modification of VMAT2 pharmacological properties. It was also observed that a nuclear translocation of the sterol regulatory element-binding protein 1 (SREBP-1). The results suggested that statins induced phenotypic changes in dopaminergic cells characterized by an increase of growth, complexity of structural synaptic elements, and expression of key presynaptic proteins with functional impact on the DA transport capacity. Statin-induced changes are likely the result of a downstream modulation of SREBP-1 pathway. Overall, these mechanisms may contribute to the neuroprotective or neurorestorative effects observed in the dopaminergic system and strengthen the therapeutic potential of statins for PD. © 2016 Wiley Periodicals, Inc.

Statin Treatment and Clinical Outcomes of Heart Failure Among Africans: An Inverse Probability Treatment Weighted Analysis.

PubMed

Bonsu, Kwadwo Osei; Owusu, Isaac Kofi; Buabeng, Kwame Ohene; Reidpath, Daniel D; Kadirvelu, Amudha

2017-04-01

Randomized control trials of statins have not demonstrated significant benefits in outcomes of heart failure (HF). However, randomized control trials may not always be generalizable. The aim was to determine whether statin and statin type-lipophilic or -hydrophilic improve long-term outcomes in Africans with HF. This was a retrospective longitudinal study of HF patients aged ≥18 years hospitalized at a tertiary healthcare center between January 1, 2009 and December 31, 2013 in Ghana. Patients were eligible if they were discharged from first admission for HF (index admission) and followed up to time of all-cause, cardiovascular, and HF mortality or end of study. Multivariable time-dependent Cox model and inverse-probability-of-treatment weighting of marginal structural model were used to estimate associations between statin treatment and outcomes. Adjusted hazard ratios were also estimated for lipophilic and hydrophilic statin compared with no statin use. The study included 1488 patients (mean age 60.3±14.2 years) with 9306 person-years of observation. Using the time-dependent Cox model, the 5-year adjusted hazard ratios with 95% CI for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55-0.83), 0.67 (0.54-0.82), and 0.63 (0.51-0.79), respectively. Use of inverse-probability-of-treatment weighting resulted in estimates of 0.79 (0.65-0.96), 0.77 (0.63-0.96), and 0.77 (0.61-0.95) for statin treatment on all-cause, cardiovascular, and HF mortality, respectively, compared with no statin use. Among Africans with HF, statin treatment was associated with significant reduction in mortality. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Effects of statins on bone mineral density: a meta-analysis of clinical studies.

PubMed

Uzzan, Bernard; Cohen, Régis; Nicolas, Patrick; Cucherat, Michel; Perret, Gérard-Yves

2007-06-01

Statins inhibit HMG-CoA reductase, preventing synthesis of mevalonate but also of isoprenoids, which affect osteoclast activity. Amino-bisphosphonates share this effect. In vitro and in vivo, statins show convincing anabolic and anti-resorptive bone effects. However, in a clinical meta-analysis (MA), they did not prevent hip fractures. Our meta-analysis studied the impact of statins on bone mineral density (BMD) at various sites and compared the effects of lipophilic and more hydrophilic statins. Our PubMed and Embase queries using two keywords (statins, BMD) were updated to October 2006. Two readers independently collected BMDs from studies. Twenty-one studies, mostly observational (three randomized controlled trials and one pseudo-randomized study), were assessed. Two studies were excluded (no control groups). Three studies could not be analyzed. The sixteen studies analyzed mainly included postmenopausal osteopenic women (2971 patients under statins). Statins significantly increased BMD at total hip (TH) and femoral neck (FN). Effect sizes (ESs) were modest: 0.21 at TH (95% confidence interval [CI]: 0.16-0.25) and 0.20 at FN (CI: 0.08-0.28). Among women, statins acted similarly (ES: 0.20 for TH and 0.18 for FN; CI: 0.14-0.25 and 0.06-0.31 respectively); lipophilic statins (simvastatin, lovastatin) almost entirely caused this effect, at both TH (ES: 0.20; CI: 0.15-0.26) and FN (ES: 0.22; CI: 0.06-0.37). Our findings of modest but statistically significant beneficial effects of statins on hip BMD should promote large double-blind randomized controlled trials on their bone effects, in view of their major beneficial cardiovascular effects with excellent safety profile.

Clinical outcome of statin plus ezetimibe versus high-intensity statin therapy in patients with acute myocardial infarction propensity-score matching analysis.

PubMed

Ji, Mi Seon; Jeong, Myung Ho; Ahn, Young Keun; Kim, Sang Hyung; Kim, Young Jo; Chae, Shung Chull; Hong, Taek Jong; Seong, In Whan; Chae, Jei Keon; Kim, Chong Jin; Cho, Myeong Chan; Rha, Seung-Woon; Bae, Jang Ho; Seung, Ki Bae; Park, Seung Jung

2016-12-15

It is unclear whether simvastatin-ezetimibe could be an alternative therapy to high-intensity statin therapy in high-risk patients. The aim of this study was to compare the clinical outcomes of simvastatin-ezetimibe and high-intensity statin therapy in patients with acute myocardial infarction (AMI), and especially in those with high-risk factor. A total of 3520 AMI patients in the KAMIR (Korea Acute Myocardial Infarction Registry) were classified into simvastatin-ezetimibe group (n=1249) and high-intensity statin group (n=2271). Multivariate analysis and propensity-score matching analysis were performed. The primary endpoint was major adverse cardiac events (MACE) at 12-months follow-up. In overall AMI patients, MACE occurred in 116 patients (9.3%) in simvastatin-ezetimibe group and 116 patients (5.1%) in high-intensity statin group. The difference in MACE between groups was driven by repeat revascularization (5.9% vs. 2.2%). After propensity matching analysis, simvastatin-ezetimibe was associated with a higher incidence of MACE than high-intensity statin therapy (adjusted hazard ratio: 3.090, 95% confidence interval: 1.715 to 5.566, p<0.001). However, in patients with high-risk factors, such as diabetes, old age, or heart failure, simvastatin-ezetimibe had similar incidence of MACE compared with high-intensity statin therapy in further adjusted analysis. In overall AMI patients, high-intensity statin therapy had better clinical outcomes than simvastatin-ezetimibe. However, in patients with high-risk factor, simvastatin-ezetimibe had comparable clinical outcomes to high-intensity statin therapy. Therefore, simvastatin-ezetimibe could be used as an alternative to high-intensity statin therapy in such patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Impact of the JUPITER trial on statin prescribing for primary prevention.

PubMed

Teng, Jennifer F T; Gomes, Tara; Camacho, Ximena; Grundy, Scott; Juurlink, David N; Mamdani, Muhammad M

2014-01-01

As the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial identified a new population of individuals with cholesterol levels below traditional treatment thresholds but with elevated high-sensitivity C-reactive protein (hs-CRP) levels who may benefit from primary prevention with statin therapy, we sought to evaluate the impact of this trial on the incident prescription rates of rosuvastatin alone as well as all statins in a primary prevention population. Population-based, cross-sectional time-series analysis. Administrative health care databases in Ontario, Canada. A total of 299,809 incident statin users 66 years or older were identified during the study period, from January 1, 2003, to March 31, 2011, who were prescribed statin therapy for primary prevention. We evaluated the incident rate of rosuvastatin and all statin use during each quarter of the study period. Overall, no significant trends in all incident statin use were observed (p=0.99). Furthermore, no significant differences were observed in incident rates of rosuvastatin (p=0.21) or all statin (p=0.41) use after the publication of the JUPITER trial. Despite the lack of impact of the JUPITER trial on rosuvastatin or all statin utilization, the relative market share of rosuvastatin increased from 9% to 65% over the study period. The publication of the JUPITER trial did not significantly affect trends in overall statin and rosuvastatin prescribing patterns for primary prevention in this study. Increases in the relative market share of rosuvastatin may be attributed to the impact of the pharmaceutical industry on prescribing patterns. Our results highlight the need to further improve the integration of evidence-based prescribing into cost-effective clinical practice. © 2013 Pharmacotherapy Publications, Inc.

Statin Use and Self-Reported Hindering Muscle Complaints in Older Persons: A Population Based Study.

PubMed

van der Ploeg, Milly A; Poortvliet, Rosalinde K E; van Blijswijk, Sophie C E; den Elzen, Wendy P J; van Peet, Petra G; de Ruijter, Wouter; Blom, Jeanet W; Gussekloo, Jacobijn

2016-01-01

Statins are widely used by older persons in primary and secondary prevention of cardiovascular disease. Although serious adverse events are rare, many statin users report mild muscle pain and/or muscle weakness. It's unclear what impact statins exert on a patient's daily life. Research on statin related side effects in older persons is relatively scarce. We therefore investigated the relation between statin use and self-reported hindering muscle complaints in older persons in the general population. The present research was performed within the Integrated Systematic Care for Older Persons (ISCOPE) study in the Netherlands (Netherlands trial register, NTR1946). All registered adults aged ≥ 75 years from 59 participating practices (n = 12,066) were targeted. Information about the medical history and statin use at baseline and after 9 months was available for 4355 participants from the Electronic Patient Records of the general practitioners. In the screening questionnaire at baseline we asked participants: 'At the moment, which health complaints limit you the most in your day-to-day life?' Answers indicating muscle or musculoskeletal complaints were coded as such. No specific questions about muscle complaints were asked. The participants had a median age of 80.3 (IQR 77.6-84.4) years, 60.8% were female and 28.5% had a history of CVD. At baseline 29% used a statin. At follow-up, no difference was found in the prevalence of self-reported hindering muscle complaints in statin users compared to non-statin users (3.3% vs. 2.5%, OR 1.39, 95% CI 0.94-2.05; P = 0.98). Discontinuation of statin use during follow-up was independent of self-reported hindering muscle complaints. Based on the present findings, prevalent statin use in this community-dwelling older population is not associated with self-reported hindering muscle complaints; however, the results might be different for incident users.

Trends in Use of High-Intensity Statin Therapy After Myocardial Infarction, 2011 to 2014.

PubMed

Rosenson, Robert S; Farkouh, Michael E; Mefford, Matthew; Bittner, Vera; Brown, Todd M; Taylor, Ben; Monda, Keri L; Zhao, Hong; Dai, Yuling; Muntner, Paul

2017-06-06

Data prior to 2011 suggest that a low percentage of patients hospitalized for acute coronary syndromes filled high-intensity statin prescriptions upon discharge. Black-box warnings, generic availability of atorvastatin, and updated guidelines may have resulted in a change in high-intensity statin use. The aim of this study was to examine trends and predictors of high-intensity statin use following hospital discharge for myocardial infarction (MI) between 2011 and 2014. Secular trends in high-intensity statin use following hospital discharge for MI were analyzed among patients 19 to 64 years of age with commercial health insurance in the MarketScan database (n = 42,893) and 66 to 75 years of age with U.S. government health insurance through Medicare (n = 75,096). Patients filling statin prescriptions within 30 days of discharge were included. High-intensity statins included atorvastatin 40 or 80 mg and rosuvastatin 20 or 40 mg. The percentage of beneficiaries whose first statin prescriptions filled following hospital discharge for MI were for high-intensity doses increased from 33.5% in January through March 2011 to 71.7% in October through November 2014 in MarketScan and from 24.8% to 57.5% in Medicare. Increases in high-intensity statin use following hospital discharge occurred over this period among patients initiating treatment (30.6% to 72.0% in MarketScan and 21.1% to 58.8% in Medicare) and those taking low- or moderate-intensity statins prior to hospitalization (from 27.8% to 62.3% in MarketScan and from 12.6% to 45.1% in Medicare). In 2014, factors associated with filling high-intensity statin prescriptions included male sex, filling beta-blocker and antiplatelet agent prescriptions, and attending cardiac rehabilitation within 30 days following discharge. The use of high-intensity statins following hospitalization for MI increased progressively from 2011 through 2014. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Comparison of the efficacy and safety of intensive-dose and standard-dose statin treatment for stroke prevention

PubMed Central

Wang, Juan; Chen, Dan; Li, Da-Bing; Yu, Xin; Shi, Guo-Bing

2016-01-01

Abstract Background: Previous study indicated that high-dose statin treatment might increase the risk of hemorrhagic stroke and adverse reactions. We aim to compare the efficacy and safety of intensive-dose and standard-dose statin treatment for preventing stroke in high-risk patients. Methods: A thorough search was performed of multiple databases for publications from 1990 to June 2015. We selected the randomized clinical trials comparing standard-dose statin with placebo and intensive-dose statin with standard-dose statin or placebo for the prevention of stroke events in patients. Duplicate independent data extraction and bias assessments were performed. Data were pooled using a fixed-effects model or a random-effects model if significant heterogeneity was present. Results: For the all stroke incidences, intensive-dose statin treatment compared with placebo treatment and standard-dose statin treatment compared with placebo treatment showed a significant 21% reduction in relative risk (RR) (RR 0.79, 95% confidence interval (CI) [0.71, 0.87], P < 0.00001) and an 18% reduction in RR (RR 0.82, 95% CI [0.73, 0.93], P = 0.002) in the subgroup without renal transplant recipients and patients undergoing regular hemodialysis separately. For the fatal stroke incidences, intensive-dose statin treatment compared with standard dose or placebo was effective reducing fatal stroke (RR 0.61, 95% CI [0.39, 0.96], P = 0.03) and the RR was 1.01 (95% CI [0.85, 1.20], P = 0.90) in standard-dose statin treatment compared with placebo. Conclusion: The results of this meta-analysis suggest that intensive-dose statin treatment might be more favorable for reducing the incidences of all strokes than standard-dose statin treatment, especially for patients older than 65 years in reducing the incidences of all stroke incidences. PMID:27684837

Statin Eligibility in Primary Prevention: From a Risk-Based Strategy to a Personalized Approach Based on the Predicted Benefit.

PubMed

Cesena, Fernando H Y; Laurinavicius, Antonio G; Valente, Viviane A; Conceição, Raquel D; Nasir, Khurram; Santos, Raul D; Bittencourt, Marcio S

2018-06-01

Guidelines have recommended statin initiation based on the absolute cardiovascular risk. We tested the hypothesis that a strategy based on the predicted cardiovascular benefit, compared with the risk-based approach, modifies statin eligibility and the estimated benefit in a population in primary cardiovascular prevention. The study included 16,008 subjects (48 ± 6 years, 73% men) with low-density lipoprotein cholesterol levels of 70 to <190 mg/dl, not on lipid-lowering drugs, who underwent a routine health screening in a single center. For the risk-based strategy, criterion for statin eligibility was defined as a 10-year atherosclerotic cardiovascular disease (ASCVD) risk of ≥7.5%. In the benefit-based strategy, subjects were considered for statin according to the predicted absolute cardiovascular risk reduction, so that the number of statin candidates would be the same as in the risk-based strategy. The benefit-based strategy would replace 11% of statin candidates allocated in the risk-based approach with younger, lower risk subjects with higher low-density lipoprotein cholesterol. Using the benefit-based strategy, 13% of subjects with 5.0% to < 7.5% ASCVD risk would shift from a statin-ineligible to a statin-eligible status, whereas 24% of those with 7.5% to <10.0% ASCVD risk would become statin ineligible. These effects would transfer the benefit from higher to lower risk subjects. In the entire population, no clinically meaningful change in the benefit would be expected. In conclusion, switching from a risk-based strategy to a benefit-based approach, while keeping the same rate of statin use in the population, is expected to promote substantial changes in statin eligibility in subjects at intermediate cardiovascular risk, modifying the subpopulation to be benefited by the treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.

PubMed

Cohen, Jerome D; Brinton, Eliot A; Ito, Matthew K; Jacobson, Terry A

2012-01-01

Statins substantially reduce the risk of cardiovascular disease and are generally well-tolerated. Despite this, many patients discontinue therapy. A better understanding of the characteristics of current and former statin users may be helpful for formulating strategies to improve long-term adherence. The Understanding Statin Use in America and Gaps in Education (USAGE) survey assessed the attitudes, beliefs, practices, and behavior of current and former statin users. Individuals 18 years or older who reported a history of high cholesterol and current or former statin use were identified within a registered consumer panel cohort in the United States and invited to participate in an Internet survey. Of the 10,138 respondents, 8918 (88%) were current statin users and 1220 (12%) were former users. Participants (mean age 61 years) were predominantly white (92%), female (61%), of middle income (median $44,504/yr), and had health insurance (93%). Among current users, 95% took a statin alone, and 70% had not missed a dose in the past month. Although ∼70% reported that their physicians had explained the importance of cholesterol levels for their heart health former users were less satisfied with the discussions (65% vs. 83%, P < .05). Muscle-related side effects were reported by 60% and 25% of former and current users, respectively (P < .05). Nearly half of all respondents switched statins at least once. The primary reason for switching by current users was cost (32%) and the primary reason for discontinuation was side effects (62%). This survey provides important insights into behavior and attitudes among current and former statin users and the results suggest that more effective dialogue between healthcare providers and patients may increase persistence of statin use, particularly when the patient has concerns about side effects and drug costs. Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Statin adherence and the risk of Parkinson's disease: A population-based cohort study.

PubMed

Rozani, Violetta; Giladi, Nir; El-Ad, Baruch; Gurevich, Tanya; Tsamir, Judith; Hemo, Beatriz; Peretz, Chava

2017-01-01

While experimental data provided some compelling evidence on the benefits of statins on dopaminergic neurons, observational studies reported conflicting results regarding the potential of statins to effect the risk of Parkinson's disease (PD). To evaluate the association between changes in statin adherence over time and PD risk. A population-based cohort of new statin users (ages 40-79, years 1999-2012) was derived from a large Israeli healthcare services organization. Data included history of statin purchases and low density lipoprotein cholesterol (LDL-C) levels. Personal statin adherence was measured annually by the proportion of days covered (PDC). PD was detected employing a drug-tracer approach. Stratified (by sex, LDL-C levels at baseline and age) Cox proportional hazards models with time-dependent covariates were used to compute adjusted Hazard Ratio (HR) with 95%CI. The cohort included 232,877 individuals, 49.3% men. Mean age at first statin purchase was 56.5 (±9.8) years for men and 58.7 (±9.2) years for women. PDC distribution for the whole follow up period differed between men and women: medians 58.3% and 54.1% respectively. During a mean follow up of 7.6 (±3.4) years, 2,550 (1.1%) PD cases were identified. In a 1-year lagged analysis, we found no association between annual statin adherence and PD risk in all age-groups regardless of statin type and potency. Age-pooled HR (95%CI) for men and women with LDL-C levels at baseline ≤160mg/dL were: 0.99 (0.99-1.01), 1.01 (1.00-1.02); and for men and women with LDL-C >160mg/dL levels: 0.99 (0.98-1.01), 0.97 (0.98-1.01). Our findings suggest that statin adherence over time does not affect PD risk. Future studies should use large-scale cohorts and refining assessments of long-term profiles in statin adherence.

Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis.

PubMed

Awad, Kamal; Serban, Maria-Corina; Penson, Peter; Mikhailidis, Dimitri P; Toth, Peter P; Jones, Steven R; Rizzo, Manfredi; Howard, George; Lip, Gregory Y H; Banach, Maciej

Evidence about the optimal time of day at which to administer statins is lacking. The objective of this study is to synthesize evidence about effects of morning vs evening statin administration on lipid profile. We searched PubMed, SCOPUS, Web of Science, and Embase databases (from inception up to July 24, 2016) to identify the relevant studies. Mean differences (MDs) between the change scores in lipid parameters were pooled using a fixed-effect model. Eleven articles with 1034 participants were eligible for the analysis. The pooled analysis comparing effects of morning vs evening administration of statins on plasma total cholesterol (TC; P = .10), high-density lipoprotein cholesterol (P = .90), and triglycerides (P = .45) was not statistically significant. Low-density lipoprotein cholesterol (LDL-C) lowering was statistically greater in the evening-dose group (MD: 3.24 mg/dL, 95% CI: 1.23-5.25, P = .002). Subgroup analysis according to statin half-lives showed that evening dose of statins was significantly superior to morning dose for lowering LDL-C in case of both short and long half-life statins (MD: 9.68 mg/dL, 95% CI: 3.32-16.03, P = .003 and MD: 2.53 mg/dL, 95% CI: 0.41-4.64, P = .02, respectively) and also for TC reduction in case of short half-life statins only (P = .0005). LDL-C and TC lowering was significantly greater in the evening dose than in the morning dose in case of short-acting statins. Besides slight but significant effect on LDL-C, the efficacy of long-acting statins was equivalent for both regimens. Therefore, long-acting statins should be given at a time that will best aid compliance. Short-acting statins should be given in the evening. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Individualized Statin Benefit for Determining Statin Eligibility in the Primary Prevention of Cardiovascular Disease.

PubMed

Thanassoulis, George; Williams, Ken; Altobelli, Kathleen Kimler; Pencina, Michael J; Cannon, Christopher P; Sniderman, Allan D

2016-04-19

Current guidelines recommend statins in the primary prevention of cardiovascular disease on the basis of predicted cardiovascular risk without directly considering the expected benefits of statin therapy based on the available randomized, controlled trial evidence. We included 2134 participants representing 71.8 million American residents potentially eligible for statins in primary prevention from the National Health and Nutrition Examination Survey for the years 2005 to 2010. We compared statin eligibilities using 2 separate approaches: a 10-year risk-based approach (≥7.5% 10-year risk) and an individualized benefit approach (ie, based on predicted absolute risk reduction over 10 years [ARR10] ≥2.3% from randomized, controlled trial data). A risk-based approach led to the eligibility of 15.0 million (95% confidence interval, 12.7-17.3 million) Americans, whereas a benefit-based approach identified 24.6 million (95% confidence interval, 21.0-28.1 million). The corresponding numbers needed to treat over 10 years were 21 (range, 9-44) and 25 (range, 9-44). The benefit-based approach identified 9.5 million lower-risk (<7.5% 10-year risk) Americans not currently eligible for statin treatment who had the same or greater expected benefit from statins (≥2.3% ARR10) compared with higher-risk individuals. This lower-risk/acceptable-benefit group includes younger individuals (mean age, 55.2 versus 62.5 years; P<0.001 for benefit based versus risk based) with higher low-density lipoprotein cholesterol (140 versus133 mg/dL; P=0.01). Statin treatment in this group would be expected to prevent an additional 266 508 cardiovascular events over 10 years. An individualized statin benefit approach can identify lower-risk individuals who have equal or greater expected benefit from statins in primary prevention compared with higher-risk individuals. This approach may help develop guideline recommendations that better identify individuals who meaningfully benefit from statin therapy. © 2016 American Heart Association, Inc.

American College of Cardiology/American Heart Association (ACC/AHA) Class I Guidelines for the Treatment of Cholesterol to Reduce Atherosclerotic Cardiovascular Risk: Implications for US Hispanics/Latinos Based on Findings From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

PubMed

Qureshi, Waqas T; Kaplan, Robert C; Swett, Katrina; Burke, Gregory; Daviglus, Martha; Jung, Molly; Talavera, Gregory A; Chirinos, Diana A; Reina, Samantha A; Davis, Sonia; Rodriguez, Carlos J

2017-05-11

The prevalence estimates of statin eligibility among Hispanic/Latinos living in the United States under the new 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol treatment guidelines are not known. We estimated prevalence of statin eligibility under 2013 ACC/AHA and 3rd National Cholesterol Education Program Adult Treatment Panel (NCEP/ATP III) guidelines among Hispanic Community Health Study/Study of Latinos (n=16 415; mean age 41 years, 40% males) by using sampling weights calibrated to the 2010 US census. We examined the characteristics of Hispanic/Latinos treated and not treated with statins under both guidelines. We also redetermined the statin-therapy eligibility by using black risk estimates for Dominicans, Cubans, Puerto Ricans, and Central Americans. Compared with NCEP/ATP III guidelines, statin eligibility increased from 15.9% (95% CI 15.0-16.7%) to 26.9% (95% CI 25.7-28.0%) under the 2013 ACC/AHA guidelines. This was mainly driven by the ≥7.5% atherosclerotic cardiovascular disease risk criteria (prevalence 13.9% [95% CI 13.0-14.7%]). Of the participants eligible for statin eligibility under NCEP/ATP III and ACC/AHA guidelines, only 28.2% (95% CI 26.3-30.0%) and 20.6% (95% CI 19.4-21.9%) were taking statins, respectively. Statin-eligible participants who were not taking statins had a higher prevalence of cardiovascular risk factors compared with statin-eligible participants who were taking statins. There was no significant increase in statin eligibility when atherosclerotic cardiovascular disease risk was calculated by using black estimates instead of recommended white estimates (increase by 1.4%, P =0.12) for Hispanic/Latinos. The eligibility of statin therapy increased consistently across all Hispanic/Latinos subgroups under the 2013 ACC/AHA guidelines and therefore will potentially increase the number of undertreated Hispanic/Latinos in the United States. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Clinical Effectiveness of Statin Therapy After Ischemic Stroke: Primary Results From the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study.

PubMed

O'Brien, Emily C; Greiner, Melissa A; Xian, Ying; Fonarow, Gregg C; Olson, DaiWai M; Schwamm, Lee H; Bhatt, Deepak L; Smith, Eric E; Maisch, Lesley; Hannah, Deidre; Lindholm, Brianna; Peterson, Eric D; Pencina, Michael J; Hernandez, Adrian F

2015-10-13

In patients with ischemic stroke, data on the real-world effectiveness of statin therapy for clinical and patient-centered outcomes are needed to better inform shared decision making. Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) is a Patient-Centered Outcomes Research Institute-funded research program designed with stroke survivors to evaluate the effectiveness of poststroke therapies. We linked data on patients ≥65 years of age enrolled in the Get With The Guidelines-Stroke Registry to Medicare claims. Two-year to postdischarge outcomes of those discharged on a statin versus not on a statin were adjusted through inverse probability weighting. Our coprimary outcomes were major adverse cardiovascular events and home time (days alive and out of a hospital or skilled nursing facility). Secondary outcomes included all-cause mortality, all-cause readmission, cardiovascular readmission, and hemorrhagic stroke. From 2007 to 2011, 77 468 patients who were not taking statins at the time of admission were hospitalized with ischemic stroke; of these, 71% were discharged on statin therapy. After adjustment, statin therapy at discharge was associated with a lower hazard of major adverse cardiovascular events (hazard ratio, 0.91; 95% confidence interval, 0.87-0.94), 28 more home-time days after discharge (P<0.001), and lower all-cause mortality and readmission. Statin therapy at discharge was not associated with increased risk of hemorrhagic stroke (hazard ratio, 0.94; 95% confidence interval, 0.72-1.23). Among statin-treated patients, 31% received a high-intensity dose; after risk adjustment, these patients had outcomes similar to those of recipients of moderate-intensity statin. In older ischemic stroke patients who were not taking statins at the time of admission, discharge statin therapy was associated with lower risk of major adverse cardiovascular events and nearly 1 month more home time during the 2-year period after hospitalization. © 2015 American Heart Association, Inc.

The association of statin therapy with the risk of recurrent venous thrombosis.

PubMed

Smith, N L; Harrington, L B; Blondon, M; Wiggins, K L; Floyd, J S; Sitlani, C M; McKnight, B; Larson, E B; Rosendaal, F R; Heckbert, S R; Psaty, B M

2016-07-01

Essentials A lowered risk of recurrent venous thrombosis (VT) with statin treatment is controversial. Among observational inception cohort of 2,798 adults with incident VT, 457 had recurrent VT. Time-to-event models with time-varying statin use and adjustment for potential confounders was used for analysis. Compared to nonuse, current statin use was associated with 26% lower risk of recurrent VT. Click to hear Prof. Büller's perspective on Anticoagulant Therapy in the Treatment of Venous Thromboembolism Background Meta-analyses of randomized controlled trials suggest that treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lowers the risk of incident venous thrombosis (VT), particularly among those without prevalent clinical cardiovascular disease (CVD). Whether this is true for the prevention of recurrent VT is debated. We used an observational inception cohort to estimate the association of current statin use with the risk of recurrent VT. Methods and Results The study setting was a large healthcare organization with detailed medical record and pharmacy information at cohort entry and throughout follow-up. We followed 2798 subjects 18-89 years of age who experienced a validated incident VT between January 1, 2002, and December 31, 2010, for a first recurrent VT, validated by medical record review. During follow-up, 457 (16%) developed a first recurrent VT. In time-to-event models incorporating time-varying statin use and adjusting for potential confounders, current statin use was associated with a 26% lower risk of recurrent VT: hazard ratio 0.74, 95% confidence interval 0.59-0.94. Among cohort members free of CVD (n = 2134), current statin use was also associated with a lower risk (38%) of recurrent VT: hazard ratio 0.62, 95% confidence interval 0.45-0.85. We found similar results when restricting to new users of statins and in subgroups of different statin types and doses. Conclusions In a population-based cohort of subjects who had experienced an incident VT, statin use, compared with nonuse, was associated with a clinically relevant lower risk of recurrent VT. These findings suggest a potential secondary benefit of statins among patients who have experienced an incident VT. © 2016 International Society on Thrombosis and Haemostasis.

Statins and cancer.

PubMed

Vallianou, Natalia G; Kostantinou, Alexandra; Kougias, Marios; Kazazis, Christos

2014-06-01

Statins have pleiotropic properties and might exert an effect even in the field of cancer. Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid. Specifically, inhibition of HMG-CoA reductase by statins has been proved to prevent the synthesis of mevalonic acid, a precursor of non-steroidal isoprenoids, which are lipid attachment molecules for small G proteins, such as Ras, Rho and Rac. Thus, statins may inhibit the synthesis of isoprenoids and thereby suppress the activation of small G proteins. In addition, statins exert pro-apoptotic, anti-angiogenic, and immunomodulatory effects, which may prevent cancer growth. Statins may inhibit the growth of a variety of cancer cell types, including breast, gastric, pancreatic, and prostate carcinoma, neuroblastoma, melanoma, mesothelioma and acute myeloid leukemia cells. They exert pro-apoptotic effects in a wide range of cancer cell lines, but with many differences in the sensitivity to statin-induced cell death among different cancer cell types. Regarding anti-angiogenic effects, multiple statin effects on blood vessel formation by inhibition of angiogenesis through down-regulation of pro-angiogenic factors, such as vascular endothelial growth factor, inhibition of endothelial cell proliferation and inhibition of adhesion to extracellular matrix by blocking intercellular adhesion molecules have been suggested. The molecular mechanisms of statin immunomodulation often implicate multiple pathways, regarding the regulation of genes encoding key molecules, which are involved in antigen presentation and subsequent immunomodulation. Another mechanism involves the down-regulation of the nuclear factor-kappa-B, which is responsible for the transcription of many genes involved in immunologic mechanisms, such as interferon-inducible protein-10, monocyte chemo-attractant protein 1 and cyclooxygenase-2. Statins have been associated with a significantly lower risk of breast, colorectal, ovarian, pancreatic, lung cancers and lymphoma in several observational studies. On the other hand, other studies, including meta-analyses have raised concerns about the safety of statins among elderly patients. A recent study upon the relationship between statin use (prior to cancer diagnosis) and cancer-related mortality in the entire Danish population from 1995-2009 in adults > 40 years of age has been conducted. As compared to statin non-users, patients using statins prior to cancer diagnosis were 15% less likely to die from any cause or cancer specifically. Further investigation is needed to elaborate on their mode of action as well as their true significance on cancer prevention and perhaps as an adjuvant to cancer chemotherapy.

Statins use and risk of new-onset diabetes in hypertensive patients: a population-based retrospective cohort study in Yinzhou district, Ningbo city, People's Republic of China.

PubMed

Li, Hailong; Lin, Hongbo; Zhao, Houyu; Xu, Yang; Cheng, Yinchu; Shen, Peng; Zhan, Siyan

2018-01-01

Reports have suggested that statin use is associated with an increased incidence of type 2 diabetes mellitus (T2DM). Guidelines suggested that statins should be prescribed in hypertensive patients for primary prevention. However, there were very few studies on the risk of T2DM associated with statin use among patients with hypertension in mainland People's Republic of China. To determine the association between statin use and new-onset diabetes mellitus among patients with hypertension in mainland People's Republic of China. We performed a retrospective cohort study of hypertensive patients using the Yinzhou regional health care database from January 1, 2010, to August 31, 2016. Patients aged 30-90 years old without T2DM were eligible for inclusion. We identified new statin initiators and nonusers by using prescription records of inpatients and outpatients. Multivariate Cox model and propensity score methods were used to adjust potential confounders, including age, sex, body mass index, comorbidities, lifestyle characteristics, and baseline antihypertensive drug use. The risk of incident T2DM among statin initiators compared to nonusers was estimated by the Cox proportional hazards model. Propensity scores for statin use were then developed using logistic regression, statin initiators were matched 1:1 with nonusers according to propensity scores with the nearest neighbor matching method within 0.2 caliper width, and Cox regression was again conducted. Among 67,993 patients (21,551 statin initiators; 46,442 nonusers), the unadjusted incidence rate of incident T2DM was higher in statin initiators than nonusers (25.68 versus 14.19 events/1,000 person-years; adjusted hazard ratio: 1.55; 95% confidence interval: 1.44-1.66). After propensity score 1:1 matching (19,818 statin initiators; 19,818 nonusers), baseline characteristics between 2 groups were balanced except that the nonusers group was 0.53 years older on average ( P <0.001). Then statin use was still associated with a significant increased risk for T2DM in the matched cohort (adjusted hazard ratio: 1.54; 95% confidence interval: 1.41-1.67). Subgroup analyses also demonstrated similar findings. Our study indicated an association between statin use and an increased risk of new-onset diabetes mellitus. It provides better understanding of statin and new-onset diabetes mellitus association among hypertensive patients in real-word setting. As an observational study, our findings were prone to unmeasured confounding and bias.

Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials.

PubMed

Banach, Maciej; Serban, Corina; Sahebkar, Amirhossein; Ursoniu, Sorin; Rysz, Jacek; Muntner, Paul; Toth, Peter P; Jones, Steven R; Rizzo, Manfredi; Glasser, Stephen P; Lip, Gregory Y H; Dragan, Simona; Mikhailidis, Dimitri P

2015-01-01

To evaluate the efficacy of coenzyme Q10 (CoQ10) supplementation on statin-induced myopathy. We searched the MEDLINE, Cochrane Library, Scopus, and EMBASE databases (November 1, 1987, to May 1, 2014) to identify randomized controlled trials investigating the impact of CoQ10 on muscle pain and plasma creatine kinase (CK) activity as 2 measures of statin-induced myalgia. Two independent reviewers extracted data on study characteristics, methods, and outcomes. We included 6 studies with 302 patients receiving statin therapy: 5 studies with 226 participants evaluated the effect of CoQ10 supplementation on plasma CK activity, and 5 studies (4 used in the CK analysis and 1 other study) with 253 participants were included to assess the effect of CoQ10 supplementation on muscle pain. Compared with the control group, plasma CK activity was increased after CoQ10 supplementation, but this change was not significant (mean difference, 11.69 U/L [to convert to μkat/L, multiply by 0.0167]; 95% CI, -14.25 to 37.63 U/L; P=.38). Likewise, CoQ10 supplementation had no significant effect on muscle pain despite a trend toward a decrease (standardized mean difference, -0.53; 95% CI, -1.33 to 0.28; P=.20). No dose-effect association between changes in plasma CK activity (slope, -0.001; 95% CI, -0.004 to 0.001; P=.33) or in the indices of muscle pain (slope, 0.002; 95% CI, -0.005 to 0.010; P=.67) and administered doses of CoQ10 were observed. The results of this meta-analysis of available randomized controlled trials do not suggest any significant benefit of CoQ10 supplementation in improving statin-induced myopathy. Larger, well-designed trials are necessary to confirm the findings from this meta-analysis. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis

PubMed Central

Walker, Mary E.; Souza, Patricia R.; Colas, Romain A.; Dalli, Jesmond

2017-01-01

Rheumatoid arthritis is an inflammatory condition characterized by overzealous inflammation that leads to joint damage and is associated with an increased incidence of cardiovascular disease. Statins are frontline therapeutics for patients with cardiovascular disease and exert beneficial actions in rheumatoid arthritis. The mechanism that mediates the beneficial actions of statins in rheumatoid arthritis remains of interest. In the present study, we found that the administration of 2 clinically relevant statins—atorvastatin (0.2 mg/kg) or pravastatin (0.2 mg/kg)—to mice during inflammatory arthritis up-regulated systemic and tissue amounts of a novel family of proresolving mediators, termed 13-series resolvins (RvTs), and significantly reduced joint disease. Of note, administration of simvastatin (0.2 mg/kg) did not significantly up-regulate RvTs or reduce joint inflammation. We also found that atorvastatin and pravastatin each reduced systemic leukocyte activation, including platelet-monocyte aggregates (∼25–60%). These statins decreased neutrophil trafficking to the joint as well as joint monocyte and macrophage numbers. Atorvastatin and pravastatin produced significant reductions (∼30–50%) in expression of CD11b and major histocompatibility complex class II on both monocytes and monocyte-derived macrophages in joints. Administration of an inhibitor to cyclooxygenase-2, the initiating enzyme in the RvT pathway, reversed the protective actions of these statins on both joint and systemic inflammation. Together, these findings provide evidence for the role of RvTs in mediating the protective actions of atorvastatin and pravastatin in reducing local and vascular inflammation, and suggest that RvTs may be useful in measuring the anti-inflammatory actions of statins.—Walker, M. E., Souza, P. R., Colas, R. A., Dalli, J. 13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis. PMID:28465323

Lipid-lowering therapy in older persons

PubMed Central

2015-01-01

Numerous randomized, double-blind, placebo-controlled studies and observational studies have shown that statins reduce mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia. The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program III guidelines state that in very high-risk persons, a serum low-density lipoprotein (LDL) cholesterol level of < 70 mg/dl (1.8 mmol/l) is a reasonable clinical strategy for moderately high-risk persons (2 or more risk factors and a 10-year risk for coronary artery disease of 10% to 20%), and the serum LDL cholesterol should be reduced to < 100 mg/dl (2.6 mmol/l). When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be reduced by at least 30% to 40%. The serum LDL cholesterol should be decreased to less than 160 mg/dl in persons at low risk for cardiovascular disease. Addition of other lipid-lowering drugs to statin therapy has not been demonstrated to further reduce cardiovascular events and mortality. PMID:25861289

Simvastatin as an Adjunct to Conventional Therapy of Non-infectious Uveitis: A Randomized, Open-Label Pilot Study.

PubMed

Shirinsky, Ivan V; Biryukova, Anastasia A; Shirinsky, Valery S

2017-12-01

Statins have been shown to reduce ocular inflammation in animal models of uveitis and to prevent development of uveitis in observational studies. There have been no experimental human studies evaluating statins' efficacy and safety in uveitis. In this study, we aimed to investigate efficacy and safety of simvastatin in patients with uveitis. For this single-center, open-label, randomized study, we enrolled patients with acute non-infectious uveitis. The patients were randomized to receive 40 mg simvastatin per day for 2 months in addition to conventional treatment or conventional treatment alone. The studied outcomes were the rate of steroid-sparing control of ocular inflammation, measures of ocular inflammation, intraocular pressure, and visual acuity. Fifty patients were enrolled in the study. Twenty-five patients were randomly assigned to receive simvastatin with conventional treatment and 25 to conventional treatment alone. Simvastatin was associated with significantly higher rates of steroid-sparing ocular inflammation control, decrease in anterior chamber inflammation, and improvement in visual acuity. The treatment was well tolerated, no serious adverse effects were observed. Our findings suggest that statins may have therapeutic potential in uveitis. These results need to be confirmed in double-blind, randomized, controlled studies.

Acute lipophilicity-dependent effect of intravascular simvastatin in the early phase of focal cerebral ischemia.

PubMed

Beretta, S; Pastori, C; Sala, G; Piazza, F; Ferrarese, C; Cattalini, A; de Curtis, M; Librizzi, L

2011-05-01

The acute effects of simvastatin lactone (lipophilic) and simvastatin acid (hydrophilic) on transient focal ischemia were assessed using the isolated guinea pig brain maintained in vitro by arterial perfusion. This new model of cerebral ischemia allows the assessment of the very early phase of the ischemic process, with the functional preservation of the vascular and neuronal compartments and the blood-brain barrier (bbb). The middle cerebral artery was transiently tied for 30 min followed by reperfusion for 60 min. Statins (nanomolar doses) were administered by intravascular continuous infusion starting 60 min before ischemia induction. Brain cortical activity and arterial vascular tone were continuously recorded. At the end of the experiment immunoreactivity for microtubule-associated protein 2 (MAP-2), expression of survival kinases (ERK and Akt) and total anti-oxidant capacity were assayed. Brains treated with simvastatin lactone showed i) reduced amplitude and delayed onset of ischemic depressions, ii) preservation of MAP-2 immunoreactivity, iii) activation of ERK signaling in the ischemic hemisphere and iv) increase in whole-brain anti-oxidant capacity. Treatment with the bbb-impermeable simvastatin acid was ineffective on the above-mentioned parameters. Vascular resistance recordings and Akt signaling were unchanged by any statin treatment. Our findings suggest that intravascular-delivered simvastatin exerts an acute lipophilicity-dependent protective effect in the early phase of cerebral ischemia. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a.

PubMed

Rudick, R A; Pace, A; Rani, M R S; Hyde, R; Panzara, M; Appachi, S; Shrock, J; Maurer, S L; Calabresi, P A; Confavreux, C; Galetta, S L; Lublin, F D; Radue, E-W; Ransohoff, R M

2009-06-09

Findings from a small clinical study suggested that statins may counteract the therapeutic effects of interferon beta (IFNbeta) in patients with relapsing-remitting multiple sclerosis (RRMS). We conducted a post hoc analysis of data from the Safety and Efficacy of Natalizumab in Combination With IFNbeta-1a in Patients With Relapsing-Remitting Multiple Sclerosis (SENTINEL) study to determine the effects of statins on efficacy of IFNbeta. SENTINEL was a prospective trial of patients with RRMS treated with natalizumab (Tysabri, Biogen Idec, Inc., Cambridge, MA) plus IM IFNbeta-1a (Avonex, Biogen Idec, Inc.) 30 microg compared with placebo plus IM IFNbeta-1a 30 microg. Clinical and MRI outcomes in patients treated with IM IFNbeta-1a only (no-statins group, n = 542) were compared with those of patients taking IM IFNbeta-1a and statins at doses used to treat hyperlipidemia (statins group, n = 40). No significant differences were observed between treatment groups in adjusted annualized relapse rate (p = 0.937), disability progression (p = 0.438), number of gadolinium-enhancing lesions (p = 0.604), or number of new or enlarging T2-hyperintense lesions (p = 0.802) at 2 years. More patients in the statins group reported fatigue, extremity pain, muscle aches, and increases in hepatic transaminases compared with patients in the no-statins group. Statin treatment had no ex vivo or in vitro effect on induction of IFN-stimulated genes. Statin therapy does not appear to affect clinical effects of IM interferon beta-1a in patients with relapsing-remitting multiple sclerosis or the primary molecular response to interferon beta treatment.

Statins in hypercholesterolaemia: A dose-specific meta-analysis of lipid changes in randomised, double blind trials

PubMed Central

Edwards, Jayne E; Moore, R Andrew

2003-01-01

Background Statins alter lipid concentrations. This systematic review determined the efficacy of particular statins, in terms of their ability to alter cholesterol. Review methods PubMed, the Cochrane Library, references lists of reports, and reviews were searched (September 2001) for randomised, double blind trials of statins for cholesterol in trials of 12 weeks or longer. Mean change in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides was calculated using pooled data for particular statins, and for particular doses of a statin. Pre-planned sensitivity analyses were used to determine the effects of initial concentration of total cholesterol, study duration, the effects of major trials, and effects in placebo versus active controlled trials. Information was not collected on adverse events. Results Different statins at a range of doses reduced total cholesterol by 17–35% and LDL-cholesterol by 24–49% from baseline. Lower doses of statins generally produced less cholesterol lowering, though for most statins in trials of 12 weeks or longer there was at best only a weak relationship between dose and cholesterol reduction. Duration of treatment and baseline total cholesterol concentration did not alter the amount of the benefit attained. Conclusions Statins are effective medicines and confer benefit to patients in terms of primary and secondary prevention of coronary heart disease. Reductions in total cholesterol of 25% or more and LDL cholesterol of more than 30% were recorded for fixed doses of simvastatin 40 mg, atorvastatin 10 mg, and rosuvastatin 5 mg and 10 mg. PMID:14969594

Patient beliefs and attitudes to taking statins: systematic review of qualitative studies.

PubMed

Ju, Angela; Hanson, Camilla S; Banks, Emily; Korda, Rosemary; Craig, Jonathan C; Usherwood, Tim; MacDonald, Peter; Tong, Allison

2018-06-01

Statins are effective in preventing cardiovascular disease (CVD) events and are recommended for at-risk individuals but estimated adherence rates are low. To describe patients' perspectives, experiences, and attitudes towards taking statins. Systematic review of qualitative studies reporting perspectives of patients on statins. PsycINFO, CINAHL, Embase, MEDLINE, and PhD dissertations from inception to 6 October 2016 were searched for qualitative studies on adult patients' perspectives on statins. All text and participant quotations were extracted from each article and analysed by thematic synthesis. Thirty-two studies involving 888 participants aged 22-93 years across eight countries were included. Seven themes were identified: confidence in prevention (trust in efficacy, minimising long-term catastrophic CVD, taking control, easing anxiety about high cholesterol); routinising into daily life; questioning utility (imperceptible benefits, uncertainties about pharmacological mechanisms); medical distrust (scepticism about overprescribing, pressure to start therapy); threatening health (competing priorities and risks, debilitating side effects, toxicity to body); signifying sickness (fear of perpetual dependence, losing the battle); and financial strain. An expectation that statins could prevent CVD and being able to integrate the statin regimen in daily life facilitated acceptance of statins among patients. However, avoiding the 'sick' identity and prolonged dependence on medications, uncertainties about the pharmacological mechanisms, risks to health, side effects, costs, and scepticism about clinicians' motives for prescribing statins were barriers to uptake. Shared decision making that addresses the risks, reasons for prescribing, patient priorities, and implementing strategies to minimise lifestyle intrusion and manage side effects may improve patient satisfaction and continuation of statins. © British Journal of General Practice 2018.

Effects of Statin Intensity and Adherence on the Long-Term Prognosis After Acute Ischemic Stroke.

PubMed

Kim, Jinkwon; Lee, Hye Sun; Nam, Chung Mo; Heo, Ji Hoe

2017-10-01

Statin is an established treatment for secondary prevention after ischemic stroke. However, the effects of statin intensity and adherence on the long-term prognosis after acute stroke are not well known. This retrospective cohort study using a nationwide health insurance claim data in South Korea included patients admitted with acute ischemic stroke between 2002 and 2012. Statin adherence and intensity were determined from the prescription data for a period of 1 year after the index stroke. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. We performed multivariate Cox proportional regression analyses. We included 8001 patients with acute ischemic stroke. During the mean follow-up period of 4.69±2.72 years, 2284 patients developed a primary outcome. Compared with patients with no statin, adjusted hazard ratios (95% confidence interval) were 0.74 (0.64-0.84) for good adherence, 0.93 (0.79-1.09) for intermediate adherence, and 1.07 (0.95-1.20) for poor adherence to statin. Among the 1712 patients with good adherence, risk of adverse events was lower in patients with high-intensity statin (adjusted hazard ratio [95% confidence interval], 0.48 [0.24-0.96]) compared with those with low-intensity statin. Neither good adherence nor high intensity of statin was associated with an increased risk of hemorrhagic stroke. After acute ischemic stroke, high-intensity statin therapy with good adherence was significantly associated with a lower risk of adverse events. © 2017 American Heart Association, Inc.

Pleiotropic effects of statins on the treatment of chronic periodontitis--a systematic review.

PubMed

Estanislau, Ilanna Mara Gomes; Terceiro, Icrólio Ribeiro Colares; Lisboa, Mario Roberto Pontes; Teles, Patrícia de Barros; Carvalho, Rosimary de Sousa; Martins, Ricardo Souza; Moreira, Maria Mônica Studart Mendes

2015-06-01

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are an important group of hypolipidaemic drugs, widely used in the treatment of hypercholesterolaemia and cardiovascular disease. Some studies have shown that statins are able to modulate inflammation and alveolar bone loss. In order to evaluate whether statins could influence periodontal treatment, improving the clinical and radiographic parameters in chronic periodontitis, a systematic review was conducted in the databases PUBMED and BIREME, searching for articles in English and Portuguese, published between the years 2004 and 2014, using the combined keywords statin, periodontal disease, periodontitis and alveolar bone. Studies regarding the treatment of chronic periodontitis in humans, blind or double-blind, retrospective cohort or randomized controlled trials that used statins topically or systemically were selected. Statins have important anti-inflammatory and immune effects, reducing levels of C-reactive protein and matrix metalloproteinases and their intermediate products, such as tumour necrosis factor-α, and are also able to inhibit the adhesion and extravasation of leukocytes, which block the co-stimulation of T cells. Statins reduce bone resorption by inhibiting osteoclast formation and lead to increased apoptosis of these cells. The effect of statins on bone formation is related to the increased gene expression of bone morphogenetic protein in osteoblasts. Although we found biological mechanisms and clinical results that show lower alveolar bone loss and reduction of clinical signs of inflammation, further studies are needed to evaluate the clinical applicability of statins in the routine treatment of chronic periodontitis. © 2014 The British Pharmacological Society.

Consumer behavior in the setting of over-the-counter statin availability: lessons from the consumer use study of OTC Mevacor.

PubMed

Brass, Eric P

2004-11-04

Despite the proven benefits of statins, large numbers of patients meeting guideline criteria for therapy are not receiving these drugs. It has been suggested that over-the-counter (OTC) availability of statins would allow more consumers to use statins and achieve cardiovascular risk reduction. However, concerns have been raised as to the consumers' ability to self-manage hyperlipidemia and use statins safely. The Consumer Use Study of OTC Mevacor (CUSTOM) was designed to define consumer behaviors in the setting of OTC statin availability. The study was conducted in a simulated OTC setting and allowed consumers to purchase once-daily lovastatin 20 mg. The CUSTOM dataset includes >3,300 consumers who evaluated OTC lovastatin for potential purchase at study sites and follow-up information on purchasers for up to 6 months of self-managed therapy. These data have been analyzed to address consumers' knowledge of their cholesterol concentrations as well as their ability to make OTC use decisions based on their cardiovascular risk, avoid drug-drug interactions, self-manage their cholesterol treatment after deciding to use the OTC product, and maintain interactions with physicians while using lovastatin OTC. The results showed that most study participants appropriately self-selected OTC statin therapy and managed their treatment. Use of OTC statins by consumers needing more intensive statin therapy or facing the risk of potential drug-drug interactions remains an area of concern but occurred infrequently in CUSTOM. These data are important for making an informed risk-benefit decision concerning OTC statin availability.

Statins and New-Onset Diabetes in Cardiovascular and Kidney Disease Cohorts: A Meta-Analysis.

PubMed

Kamran, Haroon; Kupferstein, Eric; Sharma, Navneet; Karam, Jocelyne G; Myers, Alyson K; Youssef, Irini; Sowers, James R; Gustafson, Deborah R; Salifu, Moro O; McFarlane, Samy I

2018-01-01

Statins have long been prescribed for the primary and secondary prevention of cardiovascular disease (CVD) and kidney disease. Their benefits and efficacy are widely accepted in current clinical practice, but like any other therapeutic agents, they have adverse effects. One of the emerging concerns with statin therapy is the development of new-onset diabetes mellitus (NODM), a dreaded risk factor for CVD and kidney disease and widely viewed as CVD equivalent. Accumulating evidence indicates that NODM is a consequence of statin use. We conducted a meta-analysis of studies reporting on associations between NODM and statin use. Based on strict exclusion criteria, a total of 11 studies were selected. Their data were analyzed using Comprehensive Meta-Analysis® statistical software and reported as odds ratios (OR) with 95% confidence intervals (CI). The cumulative fixed effect for use of statin therapy and incident NODM was an OR of 1.61 (95% CI 1.55-1.68, p < 0.001). Our results suggest that statin therapy is associated with NODM, such that there is a small but significant risk of NODM among patients receiving statin for CVD prevention therapy. However, this high-risk population also has other diabetes risk factors (such as obesity and hypertension) contributing to the development of NODM. It is imperative that patients on statin therapy be monitored carefully for NODM. However, it can be argued that the risk of statin therapy is offset by the multitude of cardiovascular and kidney-protective effects provided by such an important and highly effective therapeutic agent. © 2018 S. Karger AG, Basel.

Improving long-term adherence to statin therapy: a qualitative study of GPs' experiences in primary care.

PubMed

Krüger, Karen; Leppkes, Niklas; Gehrke-Beck, Sabine; Herrmann, Wolfram; Algharably, Engi A; Kreutz, Reinhold; Heintze, Christoph; Filler, Iris

2018-06-01

Statins substantially reduce the risk of cardiovascular disease when taken regularly. Though statins are generally well tolerated, current studies show that one-third of patients discontinue use of statins within 2 years. A qualitative approach may improve the understanding of attitudes and behaviours towards statins, the mechanisms related to discontinuation, and how they are managed in primary care. To identify factors related to statin discontinuation and approaches for long-term statin adherence. A qualitative study of German GPs' experiences with statin therapy in rural and urban settings in primary care. Semi-structured interviews ( n = 16) with purposefully recruited GPs were recorded, transcribed, and analysed using qualitative content analysis. Sociodemographic patient factors, the nocebo effect, patient attitudes towards primary prevention, and negative media coverage had significant impacts on statin therapy according to GPs. To overcome these barriers, GPs described useful strategies combining patient motivation and education with person-centred care. GPs used computer programs for individual risk-benefit analyses in the context of shared decision making. They encouraged patients with strong concerns or perceived side effects to continue therapy with a modified medication regimen combined with individual therapy goals. GPs should be aware of barriers to statin therapy and useful approaches to overcome them. They could be supported by guideline recommendations that are more closely aligned to primary care as well as comprehensible patient information about lipid-lowering therapy. Future studies, exploring patients' specific needs and involving them in improving adherence behaviour, are recommended. © British Journal of General Practice 2018.

Society already achieves economic benefits from generic substitution but fails to do the same for therapeutic substitution.

PubMed

Gumbs, Pearl D; Verschuren, W M Monique; Souverein, Patrick C; Mantel-Teeuwisse, Aukje K; de Wit, G Ardine; de Boer, Anthonius; Klungel, Olaf H

2007-11-01

To assess the potential annual savings due to generic and therapeutic substitution of statin therapy for the general Dutch population, taking the patients medical history into account. We conducted a population-based costing study using the PHARMO Record Linkage System (RLS). PHARMO RLS contains drug dispensing records from a representative sample of pharmacies located in more than 50 regions in the Netherlands. We selected all statin users in the database since 2003. The cost-savings of generic substitution of statin therapy for all simvastatin and pravastatin users, and of therapeutic substitution of statin therapy for other statin users were calculated. Substituting current users and new users of statins were considered separately. Therapeutic substitution was based on the medical history of the individual patient. Patients were only substituted if there was an appropriate substitute available. The appropriateness of substitution was based on drug-drug interactions between statins and possible comedication and the availability of an equipotent alternative. Substituting (generic and therapeutic) statin therapy for all current users would lead to potential annual savings of approximately 87 million euros. Substituting (generic and therapeutic) all starters on statin therapy would lead to potential annual savings of around 51 million euros. In the case of generic substitution only, the potential annual savings for all current simvastatin and pravastatin users would be 2.4 million euros and for the new users about 1.8 million euros. From an economic point of view, society could gain a lot from substituting statin therapy, especially from therapeutic substitution.

Statin treatment and functional outcome after ischemic stroke: case-control and meta-analysis.

PubMed

Biffi, Alessandro; Devan, William J; Anderson, Christopher D; Cortellini, Lynelle; Furie, Karen L; Rosand, Jonathan; Rost, Natalia S

2011-05-01

Multiple studies suggest that statin use before acute ischemic stroke is associated with improved functional outcome. However, available evidence is conflicting, and several published reports are limited by small sample sizes. We therefore investigated the effect of antecedent use of statins on stroke outcome by performing a meta-analysis of all results from published studies as well as our own unpublished data. We performed a systematic literature search and meta-analysis of studies investigating the association between prestroke statin use and clinical outcome and included additional data from 126 prestroke statin users and 767 nonusers enrolled at our institution. A total of 12 studies, comprising 2013 statin users and 9682 nonusers, was meta-analyzed using a random effects model. We also meta-analyzed results for individual Trial of ORG 10172 in Acute Stroke Treatment stroke subtypes to determine whether the effect of statin use differed across subtypes using the Breslow-Day test. Meta-analysis of all available data identified an association between prestroke statin use and improved functional outcome (OR, 1.62; 95% CI, 1.39 to 1.88), but we uncovered evidence of publication bias. The effect of statin use on functional outcome was found to be larger for small vessel strokes compared with other subtypes (Breslow-Day P=0.008). Antecedent use of statins is associated with improved outcome in patients with acute ischemic stroke. This association appears to be stronger in patients with small vessel stroke subtype. However, evidence of publication bias in the existing literature suggests these findings should be interpreted with caution.

Statin Treatment and Functional Outcome after Ischemic Stroke: Case-control and Meta-analysis

PubMed Central

Biffi, A; Devan, WJ; Anderson, CD; Cortellini, L; Furie, KL; Rosand, J; Rost, NS

2011-01-01

Background and Purpose Multiple studies suggest that statin use prior to acute ischemic stroke (AIS) is associated with improved functional outcome. However, available evidence is conflicting, and several published reports are limited by small sample sizes. We therefore investigated the effect of antecedent use of statins on stroke outcome by performing a meta-analysis of all results from published studies as well as our own unpublished data. Methods We performed a systematic literature search and meta-analysis of studies investigating the association between pre-stroke statin use and clinical outcome, and included additional data from 126 pre-stroke statin users and 767 non-users enrolled at our Institution. A total of 12 studies, comprising 2013 statin users and 9682 non- users were meta-analyzed using a random effects model. We also meta-analyzed results for individual TOAST stroke subtypes to determine whether the effect of statin use differed across subtypes, using the Breslow-Day (BD) test. Results Meta-analysis of all available data identified an association between pre-stroke statin use and improved functional outcome (Odds Ratio = 1.62, 95% Confidence Interval: 1.39 -1.88), but we uncovered evidence of publication bias. The effect of statin use on functional outcome was found to be larger for small vessel strokes compared to other subtypes (BD p = 0.008). Conclusions Antecedent use of statins is associated with improved outcome in AIS patients. This association appears to be stronger in patients with small vessel stroke subtype. However, evidence of publication bias in the existing literature suggests these findings should be interpreted with caution. PMID:21415396

ATVB Council Statement: Non-statin LDL-lowering Therapy and Cardiovascular Risk Reduction

PubMed Central

Hegele, Robert A.; Gidding, Samuel S.; Ginsberg, Henry N.; McPherson, Ruth; Raal, Frederick J.; Rader, Daniel J.; Robinson, Jennifer G.; Welty, Francine K.

2015-01-01

Pharmacologic reduction of low-density lipoprotein (LDL) cholesterol using statin drugs is foundational therapy to reduce cardiovascular disease (CVD) risk. Here we consider the place of non-statin therapies that also reduce LDL cholesterol in prevention of CVD. Among conventional non-statins, placebo-controlled randomized clinical trials showed that bile acid sequestrants, niacin and fibrates given as monotherapy each reduce CVD end points. From trials in which patients’ LDL cholesterol was already well-controlled on a statin, adding ezetimibe incrementally reduced CVD end points, while adding a fibrate or niacin showed no incremental benefit. Among emerging non-statins, monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9) added to a statin and given for up to 78 weeks showed preliminary evidence of reductions in CVD outcomes. While these promising early findings contributed to the recent approval of these agents in Europe and the US, much larger and longer duration outcomes studies are ongoing for definitive proof of CVD benefits. Other non-statin agents recently approved in the US include lomitapide and mipomersen, which both act via distinctive LDL-receptor independent mechanisms to substantially reduce LDL cholesterol in homozygous familial hypercholesterolemia. We also address some unanswered questions, including measuring alternative biochemical variables to LDL cholesterol, evidence for treating children with monitoring of subclinical atherosclerosis, and potential risks of extremely low LDL cholesterol. As evidence for benefit in CVD prevention accumulates, we anticipate that clinical practice will shift towards more assertive LDL-lowering treatment, using both statins and non-statins initiated earlier in appropriately selected patients. PMID:26376908

Preprocedural statin therapy reduces the risk and extent of cardiac biomarker release following percutaneous coronary intervention.

PubMed

Veselka, Josef; Procházková, Sárka; Duchonová, Radka; Homolová, Ingrid; Tesar, David; Bybee, Kevin A

2006-05-01

This study evaluates the association between statin therapy in patients treated by percutaneous coronary intervention (PCI) for stable angina pectoris and postinterventional myocardial injury with subsequent long-term clinical outcome. Prospectively collected data on 400 consecutive patients with stable angina pectoris or evidence of inducible myocardial ischemia were analyzed. The incidence of myocardial infarction based on postinterventional release of troponin I>1.5 ng/ml was 12% in the statin pretreated patients and 20% in those not pretreated with statin therapy (P=0.04, odds ratio 1.84, 95% confidence interval 1.06-3.21). Of the patients experiencing a post-PCI troponin elevation>1.5 ng/ml, those pretreated with a statin pre-PCI had a lesser troponin elevation compared with those not receiving a statin pre-PCI (median: 2.9 ng/ml [1.9-11.5] vs 5.0 ng/ml [3.1-8.8]; P<0.001). In the multivariate model, preprocedural statin therapy was identified as the only independent negative predictor of procedure-related myocardial necrosis based on postprocedural troponin elevation. In the 21-month follow-up period, statin pretreated patients were observed to have fewer deaths, revascularizations, or myocardial infarction; however, this difference was not statistically significant. These results suggest that pretreatment with statins in patients undergoing PCI for stable angina pectoris reduces the risk and extent of procedure-related myocardial injury measured by troponin release.

Statins and Thyroid Carcinoma: a Meta-Analysis.

PubMed

Zhao, Junyu; Xu, Chunmei; Yao, Jinming; Yu, Changzhen; Liao, Lin; Dong, Jianjun

2018-06-19

Experimental studies have reported the antineoplastic effects of statins in thyroid carcinoma; however, observational studies suggested that statins might increase the risk of thyroid carcinoma. Therefore, this study evaluated the antineoplastic effects of statins in both in vitro studies and animal models, as well as the epidemiological evidence. Databases-PubMed, Cochrane Library, SinoMed, CNKI, Wanfang, and clinical trial registries- were searched. A meta-analysis was performed with sufficiently homogeneous studies. Eighteen articles were involved. In in vitro studies, statins showed a concentration-dependent inhibition of cell line growth (weighted mean difference -34.68, 95% confidence interval -36.53 to -32.83). A significant efficacy of statin-induced apoptosis was observed (weighted mean difference [95% confidence interval]: 24 h, 57.50 [55.98-59.03]; 48 h, 23.43 [22.19-24.66]; 72 h, 51.29 [47.52-55.07]). Early apoptosis was increased in a dose- and time-dependent manner. In in vivo antitumor studies, lovastatin inhibited tumor growth, as shown by a reduction in tumor volume. However, two clinical studies showed discordant results from the experimental studies. Experimental studies revealed the antineoplastic efficacy of statins but statins were associated with thyroid carcinoma in clinical studies. This discrepancy may be due to the different concentrations of statins used and the effects of hyperlipidemia interventions, and thus further study is required. © 2018 The Author(s). Published by S. Karger AG, Basel.

Statin use increases the risk of depressive disorder in stroke patients: a population-based study.

PubMed

Kang, Jiunn-Horng; Kao, Li-Ting; Lin, Herng-Ching; Tsai, Ming-Chieh; Chung, Shiu-Dong

2015-01-15

This study aimed to explore the risk for depressive disorder (DD) among stroke patients with statin use. Totally, 11,218 patients who had a first-time acute hospitalization for stroke were identified from Taiwan's Longitudinal Health Insurance Database 2000. We individually followed each study subject for a 1-year period to identify those patients who were subsequently diagnosed with DD during the follow-up period. We found that the incidence rate of DD during the 1-year follow-up period was 5.52 (95% CI: 4.70-6.43) and 3.46 (95% CI: 3.08-3.88) per 100 person-years for stroke patients who were statin users and nonusers, respectively. Cox proportional hazards regressions revealed that the adjusted hazard ratio (HR) for DD during the 1-year follow-up period was 1.59 for stroke patients who were statin users compared to those who were non-statin users. We further found that the adjusted HR for DD for stroke patients who were regular statin users was 1.65 compared to stroke patients who had never been prescribed statin. However, there was no increased hazard of DD for stroke patients who were irregular statin users compared to stroke patients who had never been prescribed statin (HR: 1.22, 95% CI: 0.70-2.11). Copyright © 2014. Published by Elsevier B.V.

Statins Reduce the Risks of Relapse to Addiction in Rats

PubMed Central

Chauvet, Claudia; Nicolas, Celine; Lafay-Chebassier, Claire; Jaber, Mohamed; Thiriet, Nathalie; Solinas, Marcello

2016-01-01

Statins are drugs that have been used for decades in humans for the treatment of hypercholesterolemia. More recently, several lines of evidence demonstrate that statins, in addition to their peripheral effects, produce a wide variety of effects in the brain and may be beneficial in neurological and psychiatric conditions. In this study, we allowed rats to self-administer cocaine for several weeks and, at the end of self-administration training, we treated them with low doses of statins daily for a 21-day period of abstinence. Chronic administration of brain-penetrating statins, simvastatin (1 mg/kg) and atorvastatin (1 mg/kg), reduced cocaine seeking compared with vehicle, whereas administration of pravastatin (2 mg/kg), a statin with low brain penetrability, did not. Importantly, the effects of brain-penetrating statins persisted even after discontinuation of the treatment and were specific for drug seeking because drug taking was not altered by simvastatin treatment. Finally, the effects of simvastatin were found to generalize to another drug of abuse such as nicotine, but not to food reward, and to reinstatement of cocaine seeking induced by stress. These results demonstrate that brain-penetrating statins can reduce risks of relapse to addiction. Given their well-known safety profile in humans, statins could be a novel effective treatment for relapse to cocaine and nicotine addiction and their use could be implemented in clinical settings without major health risks. PMID:26466819

The association between statin use and risk of age-related macular degeneration

PubMed Central

Ma, Le; Wang, Yafeng; Du, Junhui; Wang, Mingxu; Zhang, Rui; Fu, Yihao

2015-01-01

The aim of the present study was to evaluate the association between statin use and the risk of age-related macular degeneration (AMD). A systematic search of the PubMed, EMBASE and ISI web of science databases was used to identify eligible published literatures without language restrictions up to April 2015. Summary relative ratios (RRs) and 95% CIs were estimated using a fixed-effect or random-effects model. A total of 14 studies met the inclusion criteria and were included in this meta-analysis. No significant association was observed between statin use and the risk of any AMD (RR, 0.95; 95% CI, 0.74–1.15); and stratified analysis showed that statins had a significantly different effects on early and late stages of AMD. For early AMD, statin use significantly reduced the risk approximately 17% (RR, 0.83; 95% CI, 0.66–0.99). At the late stage, we observed a significant protective association of statin use with exudative AMD (RR, 0.90; 95% CI, 0.80–0.99), in contrast with the absent association between statins and geographic atrophy (RR, 1.16; 95% CI, 0.77–1.56). These results demonstrated that statin use was protective for early and exudative AMD. Additional large prospective cohort studies and RCTs are required to determine the potential effect of statins on AMD prevention. PMID:26658620

Uremic toxins enhance statin-induced cytotoxicity in differentiated human rhabdomyosarcoma cells.

PubMed

Uchiyama, Hitoshi; Tsujimoto, Masayuki; Shinmoto, Tadakazu; Ogino, Hitomi; Oda, Tomoko; Yoshida, Takuya; Furukubo, Taku; Izumi, Satoshi; Yamakawa, Tomoyuki; Tachiki, Hidehisa; Minegaki, Tetsuya; Nishiguchi, Kohshi

2014-09-03

The risk of myopathy and rhabdomyolysis is considerably increased in statin users with end-stage renal failure (ESRF). Uremic toxins, which accumulate in patients with ESRF, exert cytotoxic effects that are mediated by various mechanisms. Therefore, accumulation of uremic toxins might increase statin-induced cytotoxicity. The purpose of this study was to determine the effect of four uremic toxins-hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indole-3-acetic acid, and 3-indoxyl sulfate-on statin-induced myopathy. Differentiated rhabdomyosarcoma cells were pre-treated with the uremic toxins for seven days, and then the cells were treated with pravastatin or simvastatin. Cell viability and apoptosis were assessed by viability assays and flow cytometry. Pre-treatment with uremic toxins increased statin- but not cisplatin-induced cytotoxicity (p < 0.05 vs. untreated). In addition, the pre-treatment increased statin-induced apoptosis, which is one of the cytotoxic factors (p < 0.05 vs. untreated). However, mevalonate, farnesol, and geranylgeraniol reversed the effects of uremic toxins and lowered statin-induced cytotoxicity (p < 0.05 vs. untreated). These results demonstrate that uremic toxins enhance statin-induced apoptosis and cytotoxicity. The mechanism underlying this effect might be associated with small G-protein geranylgeranylation. In conclusion, the increased severity of statin-induced rhabdomyolysis in patients with ESRF is likely due to the accumulation of uremic toxins.

Safety of statins.

PubMed

Brown, William Virgil

2008-12-01

To examine the evidence for the adverse effects that have been reported during the use of statins. We now have over twenty years of prescription use and many large well controlled trials with statin therapy for hypercholesterolemia. There is only one significant and well documented adverse effect with this group of drugs, rhabdomyolysis. Significant muscle damage is very rare when statin therapy is used in patients carefully screened for concomitant use of other drugs which may interfere with statin catabolism and excretion. Patients with severely impaired liver function are also at risk due to the importance of hepatic excretion of all statins. Chronic myalgias or other pain syndromes have not been confirmed by blinded placebo controlled trials. A significant and reproducible rise in liver enzymes (alanine and aspartate aminotransferases) is observed in 1 to 3% of patients but actual liver damage may not occur at all. Benign and transient proteinuria occurs without evidence of altered renal function. Creatinine clearance is usually increased by statins. Peripheral neuropathy may be a rare adverse effect and this needs further study. Statins are very effective at reducing the incidence of myocardial infarction, stroke and other manifestations of vascular disease. The adverse event rates are very uncommon and the benefit risk ratio is extremely high.

Statin Use and Breast Cancer Risk in the Nurses' Health Study.

PubMed

Borgquist, Signe; Tamimi, Rulla M; Chen, Wendy Y; Garber, Judy E; Eliassen, A Heather; Ahern, Thomas P

2016-01-01

Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82-1.1; current users: HRadj, 1.1; 95% CI, 0.92-1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. ©2016 American Association for Cancer Research.

Statin use and breast cancer risk in the Nurses’ Health Study

PubMed Central

Borgquist, Signe; Tamimi, Rulla M.; Chen, Wendy Y.; Garber, Judy E.; Eliassen, A. Heather; Ahern, Thomas P.

2016-01-01

Pre-clinical studies support an anti-cancer effect of statin drugs, yet epidemiological evidence remains inconsistent regarding their role in breast cancer primary prevention. Here we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses’ Health Study cohort. Post-menopausal Nurses’ Health Study participants without a cancer history were followed from 2000 until 2012 (n=79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence (former users: HRadj=0.96, 95% CI: 0.82, 1.1; current users: HRadj=1.1, 95% CI: 0.92, 1.3). Associations did not differ by estrogen receptor status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histological subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. PMID:26762806

Pre-hemorrhage statin use and the risk of vasospasm following aneurysmal subarachnoid hemorrhage

PubMed Central

Moskowitz, Shaye I.; Ahrens, Christine; Provencio, J Javier; Chow, Michael; Rasmussen, Peter A

2010-01-01

Background and Purpose Aneurysmal subarachnoid hemorrhage (SAH) is often followed by delayed ischemic deficits attributable to cerebral vasospasm. Recent studies suggest a positive impact of statin therapy on the incidence of vasospasm. This study was designed to assess whether a history of prior use of statin therapy was associated with a lower risk of vasospasm in patients with SAH. Methods We performed a comprehensive retrospective review of patients with aneurysmal SAH between 1997 and 2004. Clinical demographics and imaging data for all patients were reviewed and a logistic regression analysis was performed to identify the predictors of cerebral vasospasm, defined as a combination of clinical signs with radiographic confirmation. Results 308 patients were included. Mean age was higher in the group receiving statins (64 +/- 12 versus 54+/- 12 years). Hunt and Hess scores and treatment modality were not significantly different between the groups. Vasospasm was observed in 31% of patients not taking a statin (n=282) versus 23% taking a statin (n=26), without achieving statistical significance. Discontinuation of the statin did not affect risk of vasospasm. Conclusions Use of a statin prior to an aneurysmal SAH trended to reduce the incidence of subsequent vasospasm, without achieving statistical significance. PMID:18423529

Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors.

PubMed

Choi, Min-Koo; Shin, Ho Jung; Choi, Young-Lim; Deng, Jian-Wei; Shin, Jae-Gook; Song, Im-Sook

2011-01-01

The purpose of this study was to investigate the effect of genetic variations in organic anion-transporting polypeptide 1B1 (OATP1B1) and Na(+)/taurocholate co-transporting polypeptide (NTCP) on the uptake of various statins having different affinities for these transporters. The functional activities and simultaneous expression of NTCP and OATP1B1 were confirmed by the uptake of taurocholate and estrone-3-sulphate as representative substrates for NTCP and OATP1B1, respectively, and by an immunofluorescence analysis. The substrate specificities of NTCP and OATP1B1 for statins and the effects of genetic variations on the uptake of rosuvastatin, pitavastatin, and atorvastatin were measured. Based on the K(m) values and intrinsic clearances of the three statins, pitavastatin was taken up more efficiently than rosuvastatin and atorvastatin by OATP1B1. Consequently, the cellular accumulation of pitavastatin was modulated according to the genetic variation of OATP1B1 (OATP1B1*15), rather than NTCP*2. In contrast, NTCP*2 displayed greater transport of atorvastatin and rosuvastatin, compared with NTCP wild type. Thus, the measurements of decreased rosuvastatin and atorvastatin transport by OATP1B1*15 were confounded by the presence of NTCP and its genetic variant, NTCP*2. In conclusion, the functional consequences of genetic variants of NTCP and OATP1B1 may be different for various statins, depending on the substrate specificity of the OATP1B1 and NTCP transporters.

[Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology Position Statement on Dyslipidemia Management. Differences Between the European and American Guidelines].

PubMed

Lobos Bejarano, José María; Galve, Enrique; Royo-Bordonada, Miguel Ángel; Alegría Ezquerra, Eduardo; Armario, Pedro; Brotons Cuixart, Carlos; Camafort Babkowski, Miguel; Cordero Fort, Alberto; Maiques Galán, Antonio; Mantilla Morató, Teresa; Pérez Pérez, Antonio; Pedro-Botet, Juan; Villar Álvarez, Fernando; González-Juanatey, José Ramón

2015-01-01

The publication of the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of high blood cholesterol has had a strong impact due to the paradigm shift in its recommendations. The Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology reviewed this guideline and compared it with current European guidelines on cardiovascular prevention and dyslipidemia management. The most striking aspect of the American guideline is the elimination of the low-density lipoprotein cholesterol treat-to-target strategy and the adoption of a risk reduction strategy in 4 major statin benefit groups. In patients with established cardiovascular disease, both guidelines recommend a similar therapeutic strategy (high-dose potent statins). However, in primary prevention, the application of the American guidelines would substantially increase the number of persons, particularly older people, receiving statin therapy. The elimination of the cholesterol treat-to-target strategy, so strongly rooted in the scientific community, could have a negative impact on clinical practice, create a certain amount of confusion and uncertainty among professionals, and decrease follow-up and patient adherence. Thus, this article reaffirms the recommendations of the European guidelines. Although both guidelines have positive aspects, doubt remains regarding the concerns outlined above. In addition to using risk charts based on the native population, the messages of the European guideline are more appropriate to the Spanish setting and avoid the possible risk of overtreatment with statins in primary prevention. Copyright © 2014 SEHLELHA. Published by Elsevier Espana. All rights reserved.

Absence of anti-HMG-CoA reductase autoantibodies in severe self-limited statin-related myopathy.

PubMed

Floyd, James S; Brody, Jennifer A; Tiniakou, Eleni; Psaty, Bruce M; Mammen, Andrew

2016-06-01

Patients with self-limited statin-related myopathy improve spontaneously when statins are stopped. In contrast, patients with statin-associated autoimmune myopathy have autoantibodies recognizing 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and usually require immunosuppressive therapy to control their disease. On initial presentation, it can sometimes be difficult to distinguish between these 2 diseases, as both present with muscle pain, weakness, and elevated serum creatine kinase (CK) levels. The goal of this study was to determine whether patients with severe self-limited statin-related myopathy also make anti-HMGCR autoantibodies. We screened 101 subjects with severe self-limited cerivastatin-related myopathy for anti-HMGCR autoantibodies. No patient with severe self-limited cerivastatin-related myopathy had anti-HMGCR autoantibodies. Anti-HMGCR autoantibody testing can be used to help differentiate whether a patient has self-limited myopathy due to cerivastatin or autoimmune statin-associated myopathy; these findings may apply to other statins as well. Muscle Nerve 54: 142-144, 2016. © 2016 Wiley Periodicals, Inc.

SKELETAL MUSCLE ULTRASTRUCTURE AND FUNCTION IN STATIN-TOLERANT INDIVIDUALS

PubMed Central

Rengo, Jason L.; Callahan, Damien M.; Savage, Patrick D.; Ades, Philip A.; Toth, Michael J.

2015-01-01

Skeletal Muscle Ultrastructure and Function in Statin-Tolerant Individuals: Introduction Statins have well-known benefits on cardiovascular mortality, though up to 15% of patients experience side effects. With guidelines from the American Heart Association, American College of Cardiology, and American Diabetics Association expected to double the number of statin users, the overall incidence of myalgia and myopathy will increase. Methods We evaluated skeletal muscle structure and contractile function at the molecular, cellular, and whole tissue levels in 12 statin tolerant and 12 control subjects. Results Myosin isoform expression, fiber type distributions, single fiber maximal Ca2+-activated tension, and whole muscle contractile force were similar between groups. No differences were observed in myosin-actin cross-bridge kinetics in myosin heavy chain (MHC) I or IIA fibers. Discussion We found no evidence for statin-induced changes in muscle morphology at the molecular, cellular, or whole tissue levels. Collectively, our data show that chronic statin therapy in healthy asymptomatic individuals does not promote deleterious myofilament structural or functional adaptations. PMID:26059690

High glucose-boosted inflammatory responses to lipopolysaccharide are suppressed by statin.

PubMed

Nareika, A; Maldonado, A; He, L; Game, B A; Slate, E H; Sanders, J J; London, S D; Lopes-Virella, M F; Huang, Y

2007-02-01

It has been established that periodontal diseases are more prevalent and of greater severity in diabetic patients than in nondiabetic patients. Recent studies have underscored the role of monocytes and macrophages in periodontal tissue inflammation and destruction in diabetic patients. Although it has been shown that monocytes isolated from diabetic patients produce more inflammatory cytokines and that gingival crevicular fluid collected from diabetic patients contains higher levels of inflammatory cytokines than that obtained from nondiabetic patients, the underlying mechanisms are not well understood. U937 histiocytes cultured in medium containing either normal (5 mM) or high (25 mM) glucose were treated with 100 ng/ml of lipopolysaccharide for 24h. After the treatment, cytokines in the medium and cytokine mRNA in the cells were quantified using enzyme-linked immunosorbet assay and real-time polymerase chain reaction, respectively. In this study, we demonstrated that the pre-exposure of U937 histiocytes to high glucose concentrations markedly increased the lipopolysaccharide-induced secretion of pro-inflammatory cytokines and chemokines and the cellular inducible nitric oxide level compared with pre-exposure to normal glucose. Our data also showed that the increased secretion of cytokines was a result of increased mRNA expression. Furthermore, the effects of statin and peroxisome proliferators-activated receptor agonists on high glucose-enhanced secretion of cytokines were determined. The results showed that simvastatin, but not fenofibrate or pioglitazone, inhibited high glucose-enhanced cytokine release. This study has shown that high glucose concentrations and lipopolysaccharide act synergistically to stimulate the secretion of inflammatory mediators, and that statin is capable of suppressing the high glucose-boosted proinflammatory response. This study therefore delineates a novel mechanism by which hyperglycemia enhances the inflammatory responses of macrophages and suggests that statin may be useful in the treatment of periodontal disease in diabetic patients.

Statin myalgia is not associated with reduced muscle strength, mass or protein turnover in older male volunteers, but is allied with a slowing of time to peak power output, insulin resistance and differential muscle mRNA expression

PubMed Central

Mallinson, Joanne E.; Marimuthu, Kanagaraj; Murton, Andrew; Selby, Anna; Smith, Kenneth; Constantin‐Teodosiu, Dumitru; Rennie, Michael J.

2015-01-01

Key points Statins cause muscle‐specific side effects, most commonly muscle aches/weakness (myalgia), particularly in older people. Furthermore, evidence has linked statin use to increased risk of type 2 diabetes. However, the mechanisms involved are unknown.This is the first study to measure muscle protein turnover rates and insulin sensitivity in statin myalgic volunteers and age‐matched, non‐statin users under controlled fasting and fed conditions using gold standard methods.We demonstrate in older people that chronic statin myalgia is not associated with deficits in muscle strength and lean mass or the dysregulation of muscle protein turnover compared to non‐statin users. Furthermore, there were no between‐group differences in blood or muscle inflammatory markers.Statin users did, however, show blunting of muscle power output at the onset of dynamic exercise, increased abdominal adiposity, whole body and leg insulin resistance, and clear differential expression of muscle genes linked to mitochondrial dysfunction and apoptosis, which warrant further investigation. Abstract Statins are associated with muscle myalgia and myopathy, which probably reduce habitual physical activity. This is particularly relevant to older people who are less active, sarcopaenic and at increased risk of statin myalgia. We hypothesised that statin myalgia would be allied to impaired strength and work capacity in older people, and determined whether differences aligned with divergences in lean mass, protein turnover, insulin sensitivity and the molecular regulation of these processes. Knee extensor strength and work output during 30 maximal isokinetic contractions were assessed in healthy male volunteers, nine with no statin use (control 70.4 ± 0.7 years) and nine with statin myalgia (71.5 ± 0.9 years). Whole body and leg glucose disposal, muscle myofibrillar protein synthesis (MPS) and leg protein breakdown (LPB) were measured during fasting (≈5 mU l−1 insulin) and fed (≈40 mU l−1 insulin + hyperaminoacidaemia) euglyceamic clamps. Muscle biopsies were taken before and after each clamp. Lean mass, MPS, LPB and strength were not different but work output during the initial three isokinetic contractions was 19% lower (P < 0.05) in statin myalgic subjects due to a delay in time to reach peak power output. Statin myalgic subjects had reduced whole body (P = 0.05) and leg (P < 0.01) glucose disposal, greater abdominal adiposity (P < 0.05) and differential expression of 33 muscle mRNAs (5% false discovery rate (FDR)), six of which, linked to mitochondrial dysfunction and apoptosis, increased at 1% FDR. Statin myalgia was associated with impaired muscle function, increased abdominal adiposity, whole body and leg insulin resistance, and evidence of mitochondrial dysfunction and apoptosis. PMID:25620655

Rosuvastatin Attenuates the Elevation in Blood Pressure Induced by Overexpression of Human C-Reactive Protein

PubMed Central

Li, Xuguang; Yang, Guangtian; Edin, Matthew L.; Zeldin, Darryl C.; Wang, Dao Wen

2014-01-01

Background Our previous studies demonstrated that C-reactive protein (CRP) acts as an inflammatory factor to induce endothelial dysfunction and hypertension in rats. The anti-inflammatory effects of statins suggest that they may attenuate CRP-induced endothelial dysfunction and hypertension in Sprague Dawley (SD) rats. Methods Male SD rats were injected with an adeno-associated virus (AAV) to induce overexpression of human CRP (AAV-hCRP) or GFP control (AAV-GFP). Two months after injection, rats were administered rosuvastatin by daily oral gavage (10 mg/kg) for two additional months. Blood pressure was monitored, serum hCRP concentrations were assessed by ELISA, and vascular levels of endothelial nitric oxide synthase (eNOS), PI3K/Akt, Rho kinase, angiotensin type 1 (AT1) receptor, MAPK, SOD-1, and NADPH oxidase was determined by immunoblotting. Results Rosuvastatin administration attenuated the increased blood pressure and loss of vascular eNOS expression in AAV-hCRP-treated rats. Rosuvastatin also activated PI3K/Akt, inhibited Rho kinase activity, and downregulated the AT1 receptor expression in aorta. Rosuvastatin reduced production of ROS through downregulation of NADPH oxidase subunit p22 phox and gp91 phox, and upregulation of SOD-1 expression. Conclusions Rosuvastatin attenuated the increase in blood pressure in AAV-hCRP-treated rats through endothelial protection and antioxidant effects. Our data reveals a novel mechanism through which statins may lower blood pressure and suggests the potential use of statins in the treatment of hypertension. PMID:21562509

An electronic health record based model predicts statin adherence, LDL cholesterol, and cardiovascular disease in the United States Military Health System

PubMed Central

Lucas, Joseph E.; Bazemore, Taylor C.; Alo, Celan; Monahan, Patrick B.

2017-01-01

HMG-CoA reductase inhibitors (or “statins”) are important and commonly used medications to lower cholesterol and prevent cardiovascular disease. Nearly half of patients stop taking statin medications one year after they are prescribed leading to higher cholesterol, increased cardiovascular risk, and costs due to excess hospitalizations. Identifying which patients are at highest risk for not adhering to long-term statin therapy is an important step towards individualizing interventions to improve adherence. Electronic health records (EHR) are an increasingly common source of data that are challenging to analyze but have potential for generating more accurate predictions of disease risk. The aim of this study was to build an EHR based model for statin adherence and link this model to biologic and clinical outcomes in patients receiving statin therapy. We gathered EHR data from the Military Health System which maintains administrative data for active duty, retirees, and dependents of the United States armed forces military that receive health care benefits. Data were gathered from patients prescribed their first statin prescription in 2005 and 2006. Baseline billing, laboratory, and pharmacy claims data were collected from the two years leading up to the first statin prescription and summarized using non-negative matrix factorization. Follow up statin prescription refill data was used to define the adherence outcome (> 80 percent days covered). The subsequent factors to emerge from this model were then used to build cross-validated, predictive models of 1) overall disease risk using coalescent regression and 2) statin adherence (using random forest regression). The predicted statin adherence for each patient was subsequently used to correlate with cholesterol lowering and hospitalizations for cardiovascular disease during the 5 year follow up period using Cox regression. The analytical dataset included 138 731 individuals and 1840 potential baseline predictors that were reduced to 30 independent EHR “factors”. A random forest predictive model taking patient, statin prescription, predicted disease risk, and the EHR factors as potential inputs produced a cross-validated c-statistic of 0.736 for classifying statin non-adherence. The addition of the first refill to the model increased the c-statistic to 0.81. The predicted statin adherence was independently associated with greater cholesterol lowering (correlation = 0.14, p < 1e-20) and lower hospitalization for myocardial infarction, coronary artery disease, and stroke (hazard ratio = 0.84, p = 1.87E-06). Electronic health records data can be used to build a predictive model of statin adherence that also correlates with statins’ cardiovascular benefits. PMID:29155848

High-density lipoprotein particles, coronary heart disease, and niacin

USDA-ARS?s Scientific Manuscript database

In clinical trials, the use of statins in patients with high risk for cardiovascular disease (CVD) has resulted in a 25% to 40% decrease in major clinical events. However, despite a marked reduction (up to 60%) in LDL-C, approximately 50% (or more) of patients continue to have CVD events. This high ...

Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011-2012.

PubMed

Wong, Nathan D; Young, Daphnee; Zhao, Yanglu; Nguyen, Huy; Caballes, Jared; Khan, Irfan; Sanchez, Robert J

2016-01-01

The 2013 American College of Cardiology/American Heart Association Cholesterol Management Guideline identifies 4 statin-eligible groups: (1) known atherosclerotic cardiovascular disease (ASCVD) aged ≥21 years, (2) low-density lipoprotein cholesterol (LDL-C) ≥ 190 mg/dL (4.9 mmol/L) aged ≥21 years, (3) diabetes mellitus aged 40 to 75 years with LDL-C 70 to 189 mg/dL (1.8-4.9 mmol/L), or (4) ≥7.5% 10-year ASCVD risk aged 40 to 75 years with LDL-C 70 to 189 mg/dL (1.8-4.9 mmol/L). We examined the number of statin-eligible US adults, statin use, LDL-C goal attainment, and adherence to lifestyle management. We identified subjects from the US National Health and Nutrition Examination Survey 2011-2012 in the 4 statin-eligible groups, proportion on statin, proportion at recommended LDL-C levels using National Lipid Association goals (<70 mg/dL [1.8 mmol/L] for very high risk and <100 mg/dL [2.6 mmol/L] for others), and adherence to lifestyle measures. Of 5206 adults (representing 219 million), 1677 adults representing 62.6 million adults fit into 1 of the 4 statin-eligible groups. Statin use was 63.7% for the ASCVD, 61.4% for the LDL-C ≥ 190 mg/dL (4.9 mmol/L), 43.2% for the diabetes mellitus, and 27.2% for the 10-year risk ≥7.5% groups. Of those on statins with LDL-C measured, 79.7%, 98.0%, 42.3%, and 46.8% were not at LDL-C goal. Adherence to recommended <6% calories from saturated fat ranged from 3.3% to 6.4% and ≥40 minutes of physical activity ≥3 times a week from 54.7% to 65.1% across statin-eligible groups. Many US adults eligible to receive statins based on American College of Cardiology/American Heart Association guidelines are not taking statins, and LDL-C levels still remain suboptimal. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Retrospective examination of lipid-lowering treatment patterns in a real-world high-risk cohort in the UK in 2014: comparison with the National Institute for Health and Care Excellence (NICE) 2014 lipid modification guidelines.

PubMed

Steen, Dylan L; Khan, Irfan; Ansell, David; Sanchez, Robert J; Ray, Kausik K

2017-02-17

In 2014, guidelines from the National Institute for Health and Care Excellence (NICE) provided updated recommendations on lipid-modifying therapy (LMT). We assessed clinical practice contemporaneous to release of these guidelines in a UK general practice setting for secondary and high-risk primary-prevention populations, and extrapolated the findings to UK nation level. Patients from The Health Improvement Network database with the following criteria were included: lipid profile in 2014 (index date); ≥20 years of age; ≥2 years representation in database prior to index; ≥1 statin indication either for atherosclerotic cardiovascular disease (ASCVD) or the non-ASCVD conditions high-risk diabetes mellitus and/or chronic kidney disease. Overall, 183 565 patients met the inclusion criteria (n=91 479 for ASCVD, 92 086 for non-ASCVD). In those with ASCVD, 79% received statin treatment and 31% received high-intensity statin. In the non-ASCVD group, 62% were on a statin and 57% received medium-intensity or high-intensity statin. In the ASCVD and non-ASCVD cohorts, 6% and 15%, respectively, were already treated according to dosing recommendations as per updated NICE guidelines. Extrapolation to the 2014 UK population indicated that, of the 3.3 million individuals with ASCVD, 2.4 million would require statin uptitration and 680 000 would require statin initiation (31% de novo initiation, 60% reinitiation, 9% addition to non-statin LMT) to achieve full concordance with updated guidelines. Of the 3.5 million high-risk non-ASCVD individuals, 1.6 million would require statin uptitration and 1.4 million would require statin initiation (59% de novo initiation, 36% reinitiation, 5% addition to non-statin LMT). A large proportion of UK individuals with ASCVD and high-risk non-ASCVD received statin treatment (79% and 62%, respectively) during the year of NICE 2014 guidelines release. Up to 94% of patients with ASCVD and 85% of high-risk non-ASCVD individuals, representing ∼3 million individuals in each group, would require statin uptitration or initiation to achieve full concordance with updated guidelines. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study.

PubMed

Mansur, Ashham; Steinau, Maximilian; Popov, Aron Frederik; Ghadimi, Michael; Beissbarth, Tim; Bauer, Martin; Hinz, José

2015-06-01

Previous investigations have presumed a potential therapeutic effect of statin therapy in patients with acute respiratory distress syndrome (ARDS). Statins are expected to attenuate inflammation in the lungs of patients with ARDS due to their anti-inflammatory effects. Clinical investigations of the role of statin therapy have revealed contradictory results. This study aimed to investigate whether pretreatment and continuous therapy with statins in patients with sepsis-associated ARDS are associated with 28-day survival according to disease severity (mild, moderate, or severe). Patients with sepsis-associated ARDS from the surgical intensive care were enrolled in this prospective observational investigation. ARDS was classified into three groups (mild, moderate, and severe); 28-day mortality was recorded as the primary outcome variable and organ failure was recorded as secondary outcome variable. Sequential Organ Failure Assessment scores and the requirements for organ support were evaluated throughout the observational period to assess organ failure. 404 patients with sepsis-associated ARDS were enrolled in this investigation. The distribution of the ARDS subgroups was 13 %, 59 %, and 28 % for mild, moderate, and severe disease, respectively. Statin therapy improved 28-day survival exclusively in the patients with severe ARDS compared with patients without statin therapy (88.5 % and 62.5 %, respectively; P = 0.0193). To exclude the effects of several confounders, we performed multivariate Cox regression analysis, which showed that statin therapy remained a significant covariate for mortality (hazard ratio, 5.46; 95 % CI, 1.38-21.70; P = 0.0156). Moreover, after carrying a propensity score-matching in the severe ARDS cohort, Kaplan-Meier survival analysis confirmed the improved 28-day survival among patients with statin therapy (P = 0.0205). Patients with severe ARDS who received statin therapy had significantly more vasopressor-free days compared with those without statin therapy (13 ± 7 and 9 ± 7, respectively; P = 0.0034), and they also required less extracorporeal membrane oxygenation (ECMO) therapy and had more ECMO-free days (18 ± 9 and 15 ± 9, respectively; P = 0.0873). This investigation suggests a beneficial effect of continuous statin therapy in patients with severe sepsis-associated ARDS and a history of prior statin therapy. Further study is warranted to elucidate this potential effect.

How to take statins

MedlinePlus

... tablets are also available. They include a statin plus medicine to manage another condition, such as high ... 24514899 . Lee JW, Morris JK, Wald NJ. Grapefruit Juice and Statins. Am J Med . 2016;129(1): ...

Synergistic effect of ezetimibe addition on coronary atheroma regression in patients with prior statin therapy: Subanalysis of PRECISE-IVUS trial.

PubMed

Tsujita, Kenichi; Yamanaga, Kenshi; Komura, Naohiro; Sakamoto, Kenji; Sugiyama, Seigo; Sumida, Hitoshi; Shimomura, Hideki; Yamashita, Takuro; Oka, Hideki; Nakao, Koichi; Nakamura, Sunao; Ishihara, Masaharu; Matsui, Kunihiko; Sakaino, Naritsugu; Nakamura, Natsuki; Yamamoto, Nobuyasu; Koide, Shunichi; Matsumura, Toshiyuki; Fujimoto, Kazuteru; Tsunoda, Ryusuke; Morikami, Yasuhiro; Matsuyama, Koushi; Oshima, Shuichi; Kaikita, Koichi; Hokimoto, Seiji; Ogawa, Hisao

2016-09-01

The IMPROVE-IT trial showed that the clinical benefit of statin/ezetimibe combination appeared to be pronounced in patients with prior statin therapy. We hypothesized that the antiatherosclerotic effect of atorvastatin/ezetimibe combination was pronounced in patients with statin pretreatment. In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound-guided percutaneous coronary intervention were randomized to atorvastatin/ezetimibe combination or atorvastatin alone. The dosage of atorvastatin was uptitrated with a treatment goal of lowering low-density lipoprotein cholesterol to below 70 mg/dl in both groups. Serial volumetric intravascular ultrasound was performed at baseline and 9-12 month follow-up to quantify the coronary plaque response in 202 patients. We compared the intravascular ultrasound endpoints in all subjects, stratified by the presence or absence of statin pretreatment. The baseline low-density lipoprotein cholesterol level (100.7 ± 23.1 mg/dl vs. 116.4 ± 25.9 mg/dl, p < 0.001) and lathosterol (55 (38 to 87)) µg/100 mg total cholesterol vs. 97 (57 to 149) µg/100 mg total cholesterol, p < 0.001) was significantly lower, and campesterol/lathosterol ratio (3.9 (2.4 to 7.4) vs. 2.6 (1.5 to 4.1), p < 0.001) was significantly increased in patients with statin pretreatment. Contrary to the patients without statin pretreatment (-1.3 (-3.1 to -0.1)% vs. -0.9 (-2.3 to 0.9)%, p = 0.12), the atorvastatin/ezetimibe combination showed a significantly stronger reduction in delta percent atheroma volume, compared with atorvastatin alone, in patients with statin pretreatment (-1.8 (-3.6 to -0.3)% vs. -0.1 (-1.6 to 0.8)%, p = 0.002). Compensatory increase in cholesterol absorption observed in statin-treated patients might attenuate the inhibitory effects of statins on coronary plaque progression. A low-dose statin/ezetimibe combination might be a promising option in statin-hyporesponder. © The European Society of Cardiology 2016.

Statin-Associated Muscle-Related Adverse Effects: A Case Series of 354 Patients

PubMed Central

Cham, Stephanie; Evans, Marcella A.; Denenberg, Julie O.; Golomb, Beatrice A.

2016-01-01

Study Objective To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs). Design Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative. Setting University-affiliated health care system. Subjects Three hundred fifty-four patients (age range 34–86 yrs) who self-reported muscle-related problems associated with statin therapy. Measurements and Main Results Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy. Conclusion This study complements available information on the properties and natural history of statin-associated MAEs, affirming dose dependence and strong QOL impact. The data indicating a dose-dependent relationship between MAE risk and recurrence suggest lower potency statins or discontinuation may bear consideration for ameliorating symptoms. PMID:20500044

Statin-associated muscle-related adverse effects: a case series of 354 patients.

PubMed

Cham, Stephanie; Evans, Marcella A; Denenberg, Julie O; Golomb, Beatrice A

2010-06-01

To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs). Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative. University-affiliated health care system. Three hundred fifty-four patients (age range 34-86 yrs) who self-reported muscle-related problems associated with statin therapy. Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy. This study complements available information on the properties and natural history of statin-associated MAEs, affirming dose dependence and strong QOL impact. The data indicating a dose-dependent relationship between MAE risk and recurrence suggest lower potency statins or discontinuation may bear consideration for ameliorating symptoms.

Vitamin D status modifies the association between statin use and musculoskeletal pain: a population based study.

PubMed

Morioka, Travis Y; Lee, Alice J; Bertisch, Suzanne; Buettner, Catherine

2015-01-01

Past studies examining the effect of vitamin D on statin myalgia have been variable; however, these studies were done in limited samples not representative of the general population. We aimed to evaluate whether vitamin D status modifies the association between statin use and musculoskeletal pain in a sample representative of the general population. We conducted a cross-sectional study using the National Health and Nutrition Examination Survey 2001-2004. Musculoskeletal symptoms and statin use were self-reported. Vitamin D status was assessed using serum 25 hydroxyvitamin D (25[OH]D), categorized as <15 ng/mL or ≥15 ng/mL. To evaluate if vitamin D status modifies the association between statin use and prevalent musculoskeletal pain, we performed multivariable-adjusted logistic regression models stratified by 25(OH)D status. Among 5907 participants ≥40 years old, mean serum 25(OH)D was 23.6 ng/mL (95% CI, 22.9-24.3). In stratified multivariable-adjusted logistic regression models, individuals with 25(OH)D <15 ng/mL, using a statin had a significantly higher odds of musculoskeletal pain compared to those not using a statin (adjusted odds ratio [aOR], 1.90; 95% CI, 1.18-3.05). Among those with 25(OH)D ≥15 ng/mL, we found no significant association between statin use and musculoskeletal pain (aOR, 0.91; 95% CI, 0.71-1.16). Among adults ≥ 40 years old with 25(OH)D <15 ng/mL, statin users had nearly 2 times greater odds of reporting musculoskeletal pain compared to non-statin users. Our findings support the hypothesis that vitamin D deficiency modifies the risk of musculoskeletal symptoms experienced with statin use. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Efficacy and tolerability of adding coenzyme A 400 U/d capsule to stable statin therapy for the treatment of patients with mixed dyslipidemia: an 8-week, multicenter, double-Blind, randomized, placebo-controlled study

PubMed Central

2014-01-01

Background Patients with mixed hyperlipidemia usually are in need of combination therapy to achieve low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) target values for reduction of cardiovascular risk. This study investigated the efficacy and safety of adding a new hypolipidemic agent, coenzyme A (CoA) to stable statin therapy in patients with mixed hyperlipidemia. Methods In this multi-center, 8-week, double-blind study, adults who had received ≥8 weeks of stable statin therapy and had hypertriglyceridemia (TG level at 2.3-6.5 mmol/L) were randomized to receive CoA 400 U/d or placebo plus stable dosage of statin. Efficacy was assessed by the changes in the levels and patterns of lipoproteins. Tolerability was assessed by the incidence and severity of adverse events (AEs). Results A total of 304 patients with mixed hyperlipidemia were randomized to receive CoA 400 U/d plus statin or placebo plus statin (n = 152, each group). After treatment for 8 weeks, the mean percent change in TG was significantly greater with CoA plus statin compared with placebo plus statin (-25.9% vs -4.9%, respectively; p = 0.0003). CoA plus statin was associated with significant reductions in TC (-9.1% vs -3.1%; p = 0.0033), LDL-C (-9.9% vs 0.1%; p = 0.003), and non- high-density lipoprotein cholesterol (-13.5% vs -5.7%; p = 0.0039). There was no significant difference in the frequency of AEs between groups. No serious AEs were considered treatment related. Conclusions In these adult patients with persistent hypertriglyceridemia, CoA plus statin therapy improved TG and other lipoprotein parameters to a greater extent than statin alone and has no obviously adverse effect. Trial registration Current Controlled Trials ClinicalTrials.gov ID NCT01928342. PMID:24382338

Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study.

PubMed

Gordon, Jacob A; Buonerba, Carlo; Pond, Gregory; Crona, Daniel; Gillessen, Silke; Lucarelli, Giuseppe; Rossetti, Sabrina; Dorff, Tanya; Artale, Salvatore; Locke, Jennifer A; Bosso, Davide; Milowsky, Matthew Ivan; Witek, Mira Sofie; Battaglia, Michele; Pignata, Sandro; Cherhroudi, Cyrus; Cox, Michael E; De Placido, Pietro; Ribera, Dario; Omlin, Aurelius; Buonocore, Gaetano; Chi, Kim; Kollmannsberger, Christian; Khalaf, Daniel; Facchini, Gaetano; Sonpavde, Guru; De Placido, Sabino; Eigl, Bernhard J; Di Lorenzo, Giuseppe

2018-04-13

Statins may potentiate the effects of anti-hormonal agents for metastatic castration-resistant prostate cancer (mCRPC) through further disruption of essential steroidogenic processes. We investigated the effects of statin use on clinical outcomes in patients with mCRPC receiving abiraterone or enzalutamide. This was a retrospective multicenter study including patients that received abiraterone or enzalutamide for mCRPC. The effect of concurrent statin use on outcomes was evaluated. The associations of statins with early (≤12 weeks) prostate-specific antigen (PSA) declines (> 30%), cancer-specific survival and overall survival (OS) were evaluated after controlling for known prognostic factors. Five hundred and ninety-eight patients treated with second-line abiraterone or enzalutamide after docetaxel for mCRPC were included. A total of 199 men (33.3%) received statins during abiraterone/enzalutamide treatment. Median OS was 20.8 months (95% CI = 18.3-23.2) for patients who received statins, versus 12.9 months (95% CI = 11.4-14.6) for patients who did not receive statins ( P < 0.001). After adjusting for age, alkaline phosphatase, PSA, neutrophil-to-lymphocytes ratio, Charlson comorbidity score, Gleason score, visceral disease, hemoglobin, opiate use and abiraterone versus enzalutamide treatment, the use of statin therapy was associated with a 53% reduction in the overall risk of death (hazard ratio [HR] = 0.47; 95% CI = 0.35-0.63; P < 0.001). Statin use was also associated with a 63% increased odds of a > 30% PSA decline within the first 12 weeks of treatment (OR = 1.63; 95% CI = 1.03-2.60; P = 0.039). In this retrospective cohort, statin use was significantly associated with both prolonged OS and cancer-specific survival and increased early > 30% PSA declines. Prospective validation is warranted.

Primary prevention with statins and incident diabetes in hypertensive patients at high cardiovascular risk.

PubMed

Izzo, R; de Simone, G; Trimarco, V; Giudice, R; De Marco, M; Di Renzo, G; De Luca, N; Trimarco, B

2013-11-01

The ESC/ESH guidelines for arterial hypertension recommend using statins for patients with high cardiovascular (CV) risk for both secondary and primary prevention. A recent meta-analysis, combining previous studies on statins, concluded that they are associated with a 9% increased risk of incident type 2 diabetes mellitus (DM). There is no information on whether statins increase incidence of DM in primary prevention. We evaluated risk of incident DM in relation to statin prescription in 4750 hypertensive, non-diabetic outpatients (age 58.57 ± 9.0 yrs, 42.3% women), from the CampaniaSalute Network, without chronic kidney disease more than grade 3, free of prevalent CV disease and with at least 12 months of follow-up. DM was defined according to ADA criteria. At the end of follow-up period (55.78 ± 42.5 months), 676 patients (14%) were on statins. These patients were older (62.54 ± 7.3 vs 57.91 ± 9.1 yrs; p < 0.0001), more often female (49% vs 41.2%; p = 0.0001), with higher initial total cholesterol (217.93 ± 44.3 vs 205.29 ± 36.6 mg/dl), non-HDL cholesterol (167.16 ± 44.5 vs 155.18 ± 36.7 mg/dl) and triglycerides (150.69 ± 85.2 vs 130.98 ± 72.0 mg/dl; all p < 0.0001) than patients no taking statins, without other differences in clinical and laboratory characteristics. At the end of follow-up, prevalence of DM was 18.1% among patients on statins and 7.2% among those without lipid-lowering therapy (p < 0.0001). However, incident DM was 10.2% in patients on statins and 8.7% in those free of statin therapy (NS). In real-life outpatient environment, statin prescription for primary prevention is not associated with increased risk of incident DM. Copyright © 2012 Elsevier B.V. All rights reserved.

Statins attenuate but do not eliminate the reverse epidemiology of total serum cholesterol in patients with non-ischemic chronic heart failure.

PubMed

Fröhlich, Hanna; Raman, Nandita; Täger, Tobias; Schellberg, Dieter; Goode, Kevin M; Kazmi, Syed; Grundtvig, Morten; Hole, Torstein; Cleland, John G F; Katus, Hugo A; Agewall, Stefan; Clark, Andrew L; Atar, Dan; Frankenstein, Lutz

2017-07-01

In patients with chronic heart failure (CHF) increasing levels of total serum cholesterol are associated with improved survival - while statin usage is not. The impact of statin treatment on the "reverse epidemiology" of cholesterol is unclear. 2992 consecutive patients with non-ischemic CHF due to left ventricular systolic dysfunction from the Norwegian CHF Registry and the CHF Registries of the Universities of Hull, UK, and Heidelberg, Germany, were studied. 1736 patients were individually double-matched on both cholesterol levels and the individual propensity scores for statin treatment. All-cause mortality was analyzed as a function of baseline cholesterol and statin use in both the general and the matched sample. 1209 patients (40.4%) received a statin. During a follow-up of 13,740 patient-years, 360 statin users (29.8%) and 573 (32.1%) statin non-users died. When grouped according to total cholesterol levels as low (≤3.6mmol/L), moderate (3.7-4.9mmol/L), high (4.8-6.2mmol/L), and very high (>6.2mmol/L), we found improved survival with very high as compared with low cholesterol levels. This association was present in statin users and non-users in both the general and matched sample (p<0.05 for each group comparison). The negative association of total cholesterol and mortality persisted when cholesterol was treated as a continuous variable (HR 0.83, 95%CI 0.77-0.90, p<0.001 for matched patients), but it was less pronounced in statin users than in non-users (F-test p<0.001). Statins attenuate but do not eliminate the reverse epidemiological association between increasing total serum cholesterol and improved survival in patients with non-ischemic CHF. Copyright © 2017 Elsevier B.V. All rights reserved.

Statin-Associated Autoimmune Myopathy: A Systematic Review of 100 Cases.

PubMed

Nazir, Salik; Lohani, Saroj; Tachamo, Niranjan; Poudel, Dilliram; Donato, Anthony

2017-04-01

Statins are a group of drugs that reduce the levels of triglycerides and cholesterol in blood by inhibiting HMG-CoA reductase, an enzyme involved in rate limiting step in cholesterol synthesis. About 2-20% patients on statins develop toxic myopathies, which usually resolve on discontinuation of statin. More recently, an immune-mediated necrotizing myopathy has been found to be associated with statin use which in most cases requires treatment with immunosuppressants. To perform a systematic review on published case reports and case series of statin-associated autoimmune myopathy. A comprehensive search of PUBMED, EMBASE, Cochrane library and ClinicalTrials.gov databases was performed for relevant articles from inception until March 19, 2016 to identify cases of statin-associated necrotizing myopathy and characterize their symptoms, evaluation and response to treatment. A total of 16 articles describing 100 patients with statin-associated autoimmune myopathy were identified. The mean age of presentation was 64.72 years, and 54.44% were males. The main presenting clinical feature was proximal muscle weakness, which was symmetric in 83.33% of patients. The mean creatine kinase (CK) was 6853 IU/l. Anti-HMG-CoA reductase antibody was positive in all cases tested (n = 57/57, 100%). In patients with no anti-HMG-CoA antibody results, diagnosis was established by findings of necrotizing myopathy on biopsy. Among the 83 cases where muscle biopsy information was available, 81.48% had necrosis, while 18.51% had combination of necrosis and inflammation. Most (83.82%) patients received two or more immunosuppressants to induce remission. Ninety-one percent had resolution of symptoms after treatment. Statin-associated necrotizing myopathy is a symmetric proximal muscle weakness associated with extreme elevations of CK. It is common in males and can occur after months of statin use. It is associated with necrosis on muscle biopsy and the presence of anti-HMG-CoA reductase antibodies. It usually requires discontinuation and immune suppression for resolution. Rechallenge with statin is unsuccessful in most cases.

ATP-dependent transport of statins by human and rat MRP2/Mrp2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellis, Lucy C.J., E-mail: Luc_ellis@yahoo.co.uk; Hawksworth, Gabrielle M.; Weaver, Richard J.

2013-06-01

Multidrug resistance associated protein-2, MRP2 (human), Mrp2 (rat) are an efflux transporter, responsible for the transport of numerous endogenous and xenobiotic compounds including taurocholate, methotrexate and carboxydichlorofluorescein (CDF). The present study aims to characterise transport of statins by human and rat MRP2/Mrp2 using membrane and vesicle preparations. All statins tested (simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, lovastatin and rosuvastatin) stimulated vanadate-sensitive ATPase activity in membranes expressing human or rat MRP2/Mrp2, suggesting that all statins are substrates of human and rat MRP2/Mrp2. The substrate affinity (Km) of all statins for MRP2/Mrp2 was comparable and no correlation between lipophilicity (logD{sub 7.0}) and Kmmore » was seen. All statins also inhibited uptake of the fluorescent Mrp2 substrate, CDF (1 μM) into vesicles expressing human or rat MRP2/Mrp2 with similar IC{sub 50} values. Fitting of the inhibitory data to the hill slope equation, gave hill coefficients (h) of greater than one, suggesting that transport involved more than one binding site for inhibitors of MPR2 and Mrp2. We conclude that statins were transported by both human and rat MRP2/Mrp2 with similar affinity. Statins were also shown to compete with other substrates for transport by MRP2/Mrp2 and that this transport involved more than one binding site on the Mrp2/MRP2 protein. - Highlights: • We characterised MRP2 (human)/Mrp2 (rat)-mediated transport of statins. • We show statins were transported by human and rat MRP2/Mrp2. • Statins competed with a known substrate for transport by MRP2/Mrp2. • Competition involved more than one binding site on the MRP2/Mrp2 protein.« less

Effectiveness of statins for secondary prevention in elderly patients after acute myocardial infarction: an evaluation of class effect

PubMed Central

Zhou, Zheng; Rahme, Elham; Abrahamowicz, Michal; Tu, Jack V.; Eisenberg, Mark J.; Humphries, Karin; Austin, Peter C.; Pilote, Louise

2005-01-01

Background Clinical trials have shown the benefits of statins after acute myocardial infarction (AMI). However, it is unclear whether different statins exert a similar effect in reducing the incidence of recurrent AMI and death when used in clinical practice. Methods We conducted a retrospective cohort study (1997–2002) to compare 5 statins using data from medical administrative databases in 3 provinces (Quebec, Ontario and British Columbia). We included patients aged 65 years and over who were discharged alive after their first AMI-related hospital stay and who began statin treatment within 90 days after discharge. The primary end point was the combined outcome of recurrent AMI or death from any cause. The secondary end point was death from any cause. Adjusted hazard ratios (HRs) for each statin compared with atorvastatin as the reference drug were estimated using Cox proportional hazards regression analysis. Results A total of 18 637 patients were prescribed atorvastatin (n = 6420), pravastatin (n = 4480), simvastatin (n = 5518), lovastatin (n = 1736) or fluvastatin (n = 483). Users of different statins showed similar baseline characteristics and patterns of statin use. The adjusted HRs (and 95% confidence intervals) for the combined outcome of AMI or death showed that each statin had similar effects when compared with atorvastatin: pravastatin 1.00 (0.90–1.11), simvastatin 1.01 (0.91– 1.12), lovastatin 1.09 (0.95–1.24) and fluvastatin 1.01 (0.80– 1.27). The results did not change when death alone was the end point, nor did they change after adjustment for initial daily dose or after censoring of patients who switched or stopped the initial statin treatment. Interpretation Our results suggest that, under current usage, statins are equally effective for secocondary prevention in elderly patients after AMI. PMID:15851712

Metabolic syndrome is associated with muscle symptoms among statin users.

PubMed

Brinton, Eliot A; Maki, Kevin C; Jacobson, Terry A; Sponseller, Craig A; Cohen, Jerome D

2016-01-01

Muscle symptoms have been associated with statin use, but the relationship of statin-associated muscle symptoms with metabolic syndrome (MS) has not been reported previously. To evaluate the relationships between MS and its individual components with statin-associated muscle symptoms. Data were analyzed from the Understanding Statin Use in America and Gaps in Education (USAGE) study. Modified criteria to define the MS were used based on self-reported survey data. Among USAGE subjects, the MS was present in 1364 of 3992 men (34.2%) and in 1716 women of 6149 women (27.9%). Subjects with the MS were 19% more likely (P = .0002) to report new or worsening muscle symptoms while on a statin. Three MS criteria-increased BMI, elevated triglycerides (TG), and low high-density lipoprotein cholesterol (HDL-C)-were associated with increased odds of muscle symptoms, by 18%, 32%, and 28%, respectively (all P < .001). The presence of MS also predicted increased odds of having discontinued a statin due to muscle symptoms (13% higher, P = .043). Among criteria for the MS, elevated TG (38% higher odds, P < .0001) and low HDL-C (37% higher odds, P = .0003) were positively associated with statin discontinuation, whereas hypertension (13% lower odds, P = .019) and diabetes mellitus (12% lower odds, P = .036) were inversely associated. USAGE participants with MS were more likely to report experiencing muscle symptoms while taking a statin and to have discontinued a statin due to muscle symptoms. This appears to be attributable mainly to associations of muscle symptoms with elevated TG and low HDL-C levels. Additional research is warranted to confirm and further investigate these associations. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review

PubMed Central

De Vera, Mary A; Bhole, Vidula; Burns, Lindsay C; Lacaille, Diane

2014-01-01

Aims While suboptimal adherence to statin medication has been quantified in real-world patient settings, a better understanding of its impact is needed, particularly with respect to distinct problems of medication taking. Our aim was to synthesize current evidence on the impacts of statin adherence, discontinuation and persistence on cardiovascular disease and mortality outcomes. Methods We conducted a systematic review of peer-reviewed studies using a mapped search of Medline, Embase and International Pharmaceutical Abstracts databases. Observational studies that met the following criteria were included: defined patient population; statin adherence exposure; defined study outcome [i.e. cardiovascular disease (CVD), mortality]; and reporting of statin-specific results. Results Overall, 28 studies were included, with 19 studies evaluating outcomes associated with statin adherence, six with statin discontinuation and three with statin persistence. Among adherence studies, the proportion of days covered was the most widely used measure, with the majority of studies reporting increased risk of CVD (statistically significant risk estimates ranging from 1.22 to 5.26) and mortality (statistically significant risk estimates ranging from 1.25 to 2.54) among non-adherent individuals. There was greater methodological variability in discontinuation and persistence studies. However, findings of increased CVD (statistically significant risk estimates ranging from 1.22 to 1.67) and mortality (statistically significant risk estimates ranging from 1.79 to 5.00) among nonpersistent individuals were also consistently reported. Conclusions Observational studies consistently report an increased risk of adverse outcomes associated with poor statin adherence. These findings have important implications for patients and physicians and emphasize the importance of monitoring and encouraging adherence to statin therapy. PMID:25364801

Improved Biochemical Outcomes With Statin Use in Patients With High-Risk Localized Prostate Cancer Treated With Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kollmeier, Marisa A.; Katz, Matthew S.; Mak, Kimberley

Purpose: To investigate the association between 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and biochemical and survival outcomes after high-dose radiotherapy (RT) for prostate cancer. Methods and Materials: A total of 1711 men with clinical stage T1-T3 prostate cancer were treated with conformal RT to a median dose of 81 Gy during 1995-2007. Preradiotherapy medication data were available for 1681 patients. Three hundred eighty-two patients (23%) were taking a statin medication at diagnosis and throughout RT. Nine hundred forty-seven patients received a short-course of neoadjuvant and concurrent androgen-deprivation therapy (ADT) with RT. The median follow-up was 5.9 years. Results: The 5-more » and 8-year PSA relapse-free survival (PRFS) rates for statin patients were 89% and 80%, compared with 83% and 74% for those not taking statins (p = 0.002). In a multivariate analysis, statin use (hazard ratio [HR]0.69, p = 0.03), National Comprehensive Cancer Network (NCCN) low-risk group, and ADT use were associated with improved PRFS. Only high-risk patients in the statin group demonstrated improvement in PRFS (HR 0.52, p = 0.02). Across all groups, statin use was not associated with improved distant metastasis-free survival (DMFS) (p = 0.51). On multivariate analysis, lower NCCN risk group (p = 0.01) and ADT use (p = 0.005) predicted improved DMFS. Conclusions: Statin use during high-dose RT for clinically localized prostate cancer was associated with a significant improvement in PRFS in high-risk patients. These data suggest that statins have anticancer activity and possibly provide radiosensitization when used in conjunction with RT in the treatment of prostate cancer.« less

Impact of Incident Diabetes on Atherosclerotic Cardiovascular Disease According to Statin Use History among Postmenopausal Women

PubMed Central

Ma, Yunsheng; Persuitte, Gioia M.; Andrews, Christopher; Hovey, Kathleen M.; LaMonte, Michael J.; Culver, Annie L.; Manson, JoAnn E.; Phillips, Lawrence S.; Liu, Simin; Eaton, Charles; Martin, Lisa W.; Howard, Barbara V.; Balasubramanian, Raji; Bird, Chloe E.; Ockene, Ira S.; Sturgeon, Susan R.; Ockene, Judith K.; Tinker, Lesley; Nassir, Rami; Rossouw, Jacques

2016-01-01

Objective To compare impact of incident diabetes on atherosclerotic cardiovascular disease (ASCVD) risk among postmenopausal women according to statin use. Research Design and Methods Prospective data from 120,499 postmenopausal women without prevalent diabetes or cardiovascular disease at baseline from the Women’s Health Initiative (WHI) were used. Incident diabetes was self-reported annually and defined as treatment with pills or injectable medication for diabetes. Current statin use was determined at enrollment and years 1, 3, 6, 9 and 13.5 in the three clinical trial arms, and at baseline, year 3, and 13.5 for the observational study. The primary outcome was incident ASCVD events, self-reported annually and adjudicated by blinded local and central physicians. Incident diabetes and statin use status were fitted as time-varying covariates in Cox regression models to assess ASCVD risk during an average follow-up of 13.6 years. Results For those not on statins at the time of diabetes diagnosis, there was a 42% increased risk of ASCVD [hazard ratio (HR)=1.42, 95% CI, 1.28–1.58] among women with incident diabetes vs. those without diabetes. Among women on statins, there was a 39% increased risk of ASCVD (HR=1.39, 95% CI, 1.12–1.74) in women with incident diabetes vs. those without diabetes. The increased ASCVD risk due to diabetes was similar between women before or after initiating statins (p=0.89). Conclusions Whether diabetes was diagnosed before or after statin use did not alter the increased risk of ASCVD associated with diabetes. Mitigating the increased incidence of diabetes in statin users could increase the ASCVD benefit-to-risk ratio of statins. PMID:27188186