Insulin pump therapy: what is the evidence for using different types of boluses for coverage of prandial insulin requirements?

PubMed

Heinemann, Lutz

2009-11-01

Bolus infusion of insulin along with a meal is a standard procedure with continuous subcutaneous insulin infusion. Modern insulin pumps allow applying this bolus in four different ways: infusion of the total dose at once or splitting the dose into two boluses, infusion of a part of the bolus in the usual manner plus infusion of the other part over a prolonged period of time (with a higher infusion rate than the basal rate), or infusion of the total dose in the form of an elevated basal rate. Depending on the composition of the given meal and its glycemic index, this is an attempt to match the circulating insulin levels to the rate of glucose absorption from the gut in order to minimize postprandial glycemic excursions. However, in the framework of evidence-based medicine, the benefits of this approach should be proven in appropriately designed clinical studies. Performance of meal-related studies requires careful attention to many aspects in order to allow meaningful evaluation of a given intervention (i.e., type of bolus). Critical evaluation of the clinical experimental studies and the one clinical study published about the impact of different types of boluses on postprandial metabolic control revealed fundamental shortcomings in study design and performance in these studies. Insufficient establishment of comparable preprandial glycemia and insulinemia on the different study days within and between the patients studied is one key aspect. Therefore, the recommendation made in most of these studies (i.e., use of dual-wave bolus) has to be accepted with care, until we have better evidence.

Open-loop glucose control: Automatic IOB-based super-bolus feature for commercial insulin pumps.

PubMed

Rosales, Nicolás; De Battista, Hernán; Vehí, Josep; Garelli, Fabricio

2018-06-01

Although there has been significant progress towards closed-loop type 1 diabetes mellitus (T1DM) treatments, most diabetic patients still treat this metabolic disorder in an open-loop manner, based on insulin pump therapy (basal and bolus insulin infusion). This paper presents a method for automatic insulin bolus shaping based on insulin-on-board (IOB) as an alternative to conventional bolus dosing. The methodology presented allows the pump to generate the so-called super-bolus (SB) employing a two-compartment IOB dynamic model. The extra amount of insulin to boost the bolus and the basal cutoff time are computed using the duration of insulin action (DIA). In this way, the pump automatically re-establishes basal insulin when IOB reaches its basal level. Thus, detrimental transients caused by manual or a-priori computations are avoided. The potential of this method is illustrated via in-silico trials over a 30 patients cohort in single meal and single day scenarios. In the first ones, improvements were found (standard treatment vs. automatic SB) both in percentage time in euglycemia (75g meal: 81.9 ± 15.59 vs. 89.51 ± 11.95, ρ ≃ 0; 100g meal: 75.12 ± 18.23 vs. 85.46 ± 14.96, ρ ≃ 0) and time in hypoglecymia (75g meal: 5.92 ± 14.48 vs. 0.97 ± 4.15, ρ=0.008; 100g meal: 9.5 ± 17.02 vs. 1.85 ± 7.05, ρ=0.014). In a single day scenario, considering intra-patient variability, the time in hypoglycemia was reduced (9.57 ± 14.48 vs. 4.21 ± 6.18, ρ=0.028) and improved the time in euglycemia (79.46 ± 17.46 vs. 86.29 ± 11.73, ρ=0.007). The automatic IOB-based SB has the potential of a better performance in comparison with the standard treatment, particularly for high glycemic index meals with high carbohydrate content. Both glucose excursion and time spent in hypoglycemia were reduced. Copyright © 2018 Elsevier B.V. All rights reserved.

Intensification of insulin therapy in patients with type 2 diabetes mellitus: An algorithm for basal-bolus therapy

PubMed Central

2012-01-01

The incidence of diabetes mellitus is projected to continue to increase worldwide over the next 20 years leading to increased costs in the management of the disease and its associated co-morbidities. Insulin replacement is one of many treatment options that can help to bring about near normoglycemia in the patient with type 2 diabetes mellitus (T2DM). Glycemic control as close to normoglycemia as possible can help to reduce the risk of microvascular and macrovascular complications, yet less than one-half of patients with T2DM achieve glycemic targets as recommended by practice guidelines. The purpose of this review is to provide guidance to primary care physicians for the initiation and intensification of basal-bolus insulin therapy in patients with T2DM. Two treatment algorithms that can be both patient- and physician-driven are proposed: a stepwise approach and a multiple daily injections approach. Evidence shaping the two approaches will be discussed alongside management issues that surround the patient treated with insulin: hypoglycemia, weight gain, patient education, and quality of life. PMID:22822902

Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

PubMed Central

Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

2015-01-01

Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

Combining Basal–Bolus Insulin Infusion for Tight Postprandial Glucose Control: An in Silico Evaluation in Adults, Children, and Adolescents

PubMed Central

Revert, Ana; Rossetti, Paolo; Calm, Remei; Vehí, Josep; Bondia, Jorge

2010-01-01

Background Achieving good postprandial glycemic control, without triggering hypoglycemia events, is a challenge of treatment strategies for type 1 diabetes subjects. Continuous subcutaneous insulin infusion, the gold standard of therapy, is based on heuristic adjustments of both basal and prandial insulin. Some tools, such as bolus calculators, are available to aid patients in selecting a meal-related insulin dose. However, they are still based on empiric parameters such as the insulin-to-carbohydrate ratio and on the physicians’ and patients’ ability to fit bolus mode to meal composition. Method In this article, a nonheuristic method for assessment of prandial insulin administration is presented and evaluated. An algorithm based on set inversion via interval analysis is used to coordinate basal and bolus insulin infusions to deal with postprandial glucose excursions. The evaluation is carried out through an in silico study using the 30 virtual patients available in the educational version of the Food and Drug Administration-accepted University of Virginia simulator. Results obtained using the standard bolus strategy and different coordinated basal–bolus solutions provided by the algorithm are compared. Results Coordinated basal–bolus solutions improve postprandial glucose performance in most cases, mainly in terms of reducing hypoglycemia risk, but also increasing the percentage of time in normoglycemia. Moreover, glycemic variability is reduced considerably by using these innovative solutions. Conclusions The algorithm presented here is a robust nonheuristic alternative to deal with postprandial glycemic control. It is shown as a powerful tool that could be integrated in future smart insulin pumps. PMID:21129338

[New insulin types in type 1 diabetes mellitus].

PubMed

Mesa, Jordi

2015-07-20

Since its discovery almost a century ago, insulin remains the mainstay of treatment of patients with type 1 diabetes mellitus. Although progress in the synthesis of new formulations has been remarkable, the physiological profile of insulin is still different from that observed with preparations available nowadays. In the last decade, the introduction into clinical practice of insulin analogues has allowed significantly improvement in glycemic control and has facilitated the spread of basal/bolus patterns, the most physiological ones until now. Despite the benefits of basal analogues, glycemia often varies considerably when used as a single daily injection and this is why new molecules have been further investigated. Improvement has been achieved especially in terms of duration and rate of hypoglycemia, the main limiting factor of intensive therapy. This article reviews the available data concerning the new basal insulin analogues, degludec, pegylated lispro and glargine U300, and new formulations currently under development. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Management of type 2 diabetes with Fixed-Ratio combination insulin degludec/liraglutide (IDEGLIRA) versus Basal-Bolus therapy (INSULIN GLARGINE U100 PLUS INSULIN ASPART): A Short-Term Cost-Effectiveness analysis in the UK setting.

PubMed

Drummond, R S; Malkin, Sjp; Du Preez, M; Lee, X Y; Hunt, B

2018-05-24

Insulin degludec/liraglutide (IDegLira) is a once-daily, single-injection, fixed-ratio combination of insulin degludec, a basal insulin with a half-life of more than 24 hours, and GLP-1 receptor agonist liraglutide. The present analysis evaluated the cost-effectiveness of IDegLira versus basal-bolus therapy (BBT) with insulin glargine U100 plus up to four times daily insulin aspart for management of type 2 diabetes in the UK. A Microsoft Excel model was used to evaluate the cost-utility of IDegLira versus BBT over a 1-year time horizon. Clinical input data were taken from the treat-to-target DUAL VII trial, conducted in patients unable to achieve adequate glycaemic control (Hb A1c <7.0%) with basal insulin, with IDegLira associated with lower rates of hypoglycaemia and reduced body mass index (BMI) in comparison with BBT, with similar Hb A1c reductions. Costs (GBP) and event-related disutilities were taken from published sources. Extensive sensitivity analyses were performed. IDegLira was associated with an improvement of 0.05 quality-adjusted life years (QALYs) versus BBT, due to reductions in non-severe hypoglycaemic episodes and BMI with IDegLira. Costs were higher with IDegLira by GBP 303 per patient, leading to an incremental cost-effectiveness ratio (ICER) of GBP 5,924 per QALY gained for IDegLira versus BBT. ICERs remained below GBP 20,000 per QALY gained across a range of sensitivity analyses. IDegLira is a cost-effective alternative to BBT with insulin glargine U100 plus insulin aspart, providing equivalent glycaemic control with a simpler treatment regimen for patients with type 2 diabetes inadequately controlled on basal insulin in the UK. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Flexibility of rapid-acting insulin analogues in children and adolescents with diabetes mellitus.

PubMed

Danne, Thomas

2007-01-01

Every year, approximately 70,000 children aged<15 years develop type 1 diabetes mellitus (DM) worldwide. Achieving glycosylated hemoglobin control is a very important aim, but quality-of-life concerns for the child and the family should also have high priority in the management of pediatric DM. This review outlines some of the issues involved in treating type 1 DM in children and adolescents, as well as the use of rapid-acting insulin analogues in basal-bolus therapy and continuous subcutaneous insulin infusion pumps. This review article was based on a presentation at a satellite symposium entitled "Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues "that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa. Treating children and adolescents with DM is a challenge that should not be ignored. Furthermore, DM in children is quite different from that in adults. Numerous factors have to be taken into account when evaluating treatment for children with DM in comparison with treatment for adult DM: sleep patterns; unpredictable activities, especially eating behaviors; limited size of injection sites, making it difficult to rotate injections; higher insulin sensitivity; and frequent infectious diseases. In addition, achieving normal psychosocial development may be just as important as achieving strict metabolic control in this population. Rapid-acting insulin analogues can be used effectively in these individuals with type 1 DM. The pharmacokinetic profile of insulin aspart suggests that it is suitable for flexible mealtime administration in children and adolescents. Indeed, clinical studies in children and adolescents have shown the efficacy and tolerability of postprandial administration of insulin aspart, particularly in comparison with soluble human insulin. Postprandial administration of insulin aspart, compared with preprandial soluble human insulin, has also been studied in

Insulin analogues in type 1 diabetes mellitus: getting better all the time.

PubMed

Mathieu, Chantal; Gillard, Pieter; Benhalima, Katrien

2017-07-01

The treatment of type 1 diabetes mellitus consists of external replacement of the functions of β cells in an attempt to achieve blood levels of glucose as close to the normal range as possible. This approach means that glucose sensing needs to be replaced and levels of insulin need to mimic physiological insulin-action profiles, including basal coverage and changes around meals. Training and educating patients are crucial for the achievement of good glycaemic control, but having insulin preparations with action profiles that provide stable basal insulin coverage and appropriate mealtime insulin peaks helps people with type 1 diabetes mellitus to live active lives without sacrificing tight glycaemic control. Insulin analogues enable patients to achieve this goal, as some have fast action profiles, and some have very slow action profiles, which gives people with type 1 diabetes mellitus the tools to achieve dynamic insulin-action profiles that enable tight glycaemic control with a risk of hypoglycaemia that is lower than that with human short-acting and long-acting insulins. This Review discusses the established and novel insulin analogues that are used to treat patients with type 1 diabetes mellitus and provides insights into the future development of insulin analogues.

Institution of basal-bolus therapy at diagnosis for children with type 1 diabetes mellitus.

PubMed

Adhikari, Soumya; Adams-Huet, Beverley; Wang, Yu-Chi A; Marks, James F; White, Perrin C

2009-04-01

We studied whether the institution of basal-bolus therapy immediately after diagnosis improved glycemic control in the first year after diagnosis for children with newly diagnosed type 1 diabetes mellitus. We reviewed the charts of 459 children > or =6 years of age who were diagnosed as having type 1 diabetes between July 1, 2002, and June 30, 2006 (212 treated with basal-bolus therapy and 247 treated with a more-conventional neutral protamine Hagedorn regimen). We abstracted data obtained at diagnosis and at quarterly clinic visits and compared groups by using repeated-measures, mixed-linear model analysis. We also reviewed the records of 198 children with preexisting type 1 diabetes mellitus of >1-year duration who changed from the neutral protamine Hagedorn regimen to a basal-bolus regimen during the review period. Glargine-treated subjects with newly diagnosed diabetes had lower hemoglobin A1c levels at 3, 6, 9, and 12 months after diagnosis than did neutral protamine Hagedorn-treated subjects (average hemoglobin A1c levels of 7.05% with glargine and 7.63% with neutral protamine Hagedorn, estimated across months 3, 6, 9, and 12, according to repeated-measures models adjusted for age at diagnosis and baseline hemoglobin A1c levels; treatment difference: 0.58%). Children with long-standing diabetes had no clinically important changes in their hemoglobin A1c levels in the first year after changing regimens. The institution of basal-bolus therapy with insulin glargine at the time of diagnosis of type 1 diabetes was associated with improved glycemic control, in comparison with more-conventional neutral protamine Hagedorn regimens, during the first year after diagnosis.

Efficacy of a basal bolus insulin protocol to treat prednisolone-induced hyperglycaemia in hospitalised patients.

PubMed

Burt, M G; Drake, S M; Aguilar-Loza, N R; Esterman, A; Stranks, S N; Roberts, G W

2015-03-01

Few studies have specifically investigated treatment of prednisolone-induced hyperglycaemia. To determine if a basal bolus insulin (BBI) protocol for inpatient hyperglycaemia is effective in patients prescribed acute prednisolone for an inflammatory disease. In a cross-sectional study, 66 patients with type 2 diabetes admitted to a general medical ward and treated with BBI for up to 5 days were studied. Twenty-four patients were taking prednisolone ≥10 mg/day to treat an acute inflammatory disease. The remaining 42 patients were a control group. The primary outcome was mean daily blood glucose level. There were no significant differences in glycosylated haemoglobin (8.1 ± 1.0 vs 8.1 ± 1.6%, P = 0.88), age (77 ± 11 vs 75 ± 14 years, P = 0.57), male sex (63 vs 60%, P = 0.81) or body mass index (30.0 ± 5.3 vs 30.2 ± 11.5 kg/m(2) , P = 0.90) between patients taking prednisolone and controls. Mean daily glucose concentration was higher in patients taking prednisolone than in controls (12.2 ± 0.3 vs 10.0 ± 0.1 mmol/L, P < 0.001). Blood glucose level was higher in patients on prednisolone at 1700 h (14.6 ± 0.6 vs 10.3 ± 0.3 mmol/L, P < 0.001) and 2100 h (14.5 ± 0.6 vs 10.5 ± 0.3 mmol/L, P < 0.001), with no significant differences at 0700 h and 1200 h. These findings occurred despite patients taking prednisolone receiving a higher daily insulin dose than controls (0.67-0.70 vs 0.61-0.65 U/kg, P = 0.001) because of higher doses of ultra-rapid-acting insulin at 1200 h and 1700 h. Hospitalised patients taking prednisolone had substantial afternoon and evening hyperglycaemia despite receiving BBI via a protocol for inpatient hyperglycaemia. Specific insulin regimens for prednisolone-induced hyperglycaemia are needed that recommend more insulin during this time period. © 2015 Royal Australasian College of Physicians.

The cost-effectiveness and budget impact of stepwise addition of bolus insulin in the treatment of type 2 diabetes: evaluation of the FullSTEP trial.

PubMed

Saunders, Rhodri; Lian, Jean; Karolicki, Boris; Valentine, William

2014-12-01

Abstract Background and aims: Intensification of basal insulin-only therapy in type 2 diabetes is often achieved through addition of bolus insulin 3-times daily. The FullSTEP trial demonstrated that stepwise addition (SWA) of bolus insulin aspart was non-inferior to full basal-bolus (FBB) therapy and reduced the rate of hypoglycemia. Here the cost-effectiveness and budget impact of SWA is evaluated. Cost-effectiveness and budget impact models were developed to assess the cost and quality-of-life (QoL) implications of intensification using SWA compared with FBB in the US setting. At assessment, SWA patients added one bolus dose to their current regimen if the HbA1c target was not met. SWA patients reaching three bolus doses used FBB event rates. Outcomes were evaluated at trial end and projected annually up to 5 years. Models captured hypoglycemic events, the proportion meeting HbA1c target, and self-measured blood glucose. Event rates and QoL utilities were taken from trial data and published literature. Costs were evaluated from a healthcare-payer perspective, reported in 2013 USD, and discounted (like clinical outcomes) at 3.5% annually. This analysis applies to patients with HbA1c 7.0-9.0% and body mass index <40 kg/m(2). SWA was associated with improved QoL and reduced costs compared with FBB. Improvement in QoL and cost reduction were driven by lower rates of hypoglycemia. Sensitivity analyses showed that outcomes were most influenced by the cost of bolus insulin and QoL impact of symptomatic hypoglycemia. Budget impact analysis estimated that, by moving from FBB to SWA, a health plan with 77,000 patients with type 2 diabetes, of whom 7.8% annually intensified to basal-bolus therapy, would save USD 1304 per intensifying patient over the trial period. SWA of bolus insulin should be considered a beneficial and cost-saving alternative to FBB therapy for the intensification of treatment in type 2 diabetes.

Effectiveness and tolerability of treatment intensification to basal-bolus therapy in patients with type 2 diabetes on previous basal insulin-supported oral therapy with insulin glargine or supplementary insulin therapy with insulin glulisine: the PARTNER observational study.

PubMed

Pfohl, Martin; Siegmund, Thorsten; Pscherer, Stefan; Pegelow, Katrin; Seufert, Jochen

2015-01-01

Due to the progressive nature of type 2 diabetes mellitus (T2DM), antidiabetic treatment needs to be continuously intensified to avoid long-term complications. In T2DM patients on either basal insulin-supported oral therapy (BOT) or supplementary insulin therapy (SIT) presenting with HbA1c values above individual targets for 3-6 months, therapy should be intensified. This study investigated effectiveness and tolerability of an intensification of BOT or SIT to a basal-bolus therapy (BBT) regimen in T2DM patients in daily clinical practice. This noninterventional, 8-month, prospective, multicenter study evaluated parameters of glucose control, occurrence of adverse events (eg, hypoglycemia), and acceptance of devices in daily clinical practice routine after 12 and 24 weeks of intensifying insulin therapy to a BBT regimen starting from either preexisting BOT with insulin glargine (pre-BOT) or preexisting SIT with ≥3 daily injections of insulin glulisine (pre-SIT). A total of 1,530 patients were documented in 258 German medical practices. A total of 1,301 patients were included in the full analysis set (55% male, 45% female; age median 64 years; body mass index median 30.8 kg/m(2); pre-BOT: n=1,072; pre-SIT: n=229), and 1,515 patients were evaluated for safety. After 12 weeks, HbA1c decreased versus baseline (pre-BOT 8.67%; pre-SIT 8.46%) to 7.73% and 7.66%, respectively (Δ mean -0.94% and -0.80%; P<0.0001). At week 24, HbA1c was further reduced to 7.38% and 7.30%, respectively (Δ mean -1.29% and -1.15%; P<0.0001), with a mean reduction of fasting blood glucose values in both treatment groups by more than 46 mg/dL. An HbA1c goal of ≤6.5% was reached by 17.9% (pre-BOT) and 18.6% (pre-SIT), and an HbA1c ≤7.0% by 46.1% (pre-BOT) and 43.0% (pre-SIT) of patients. During 24 weeks, severe as well as serious hypoglycemic events were rare (pre-BOT: n=5; pre-SIT: n=2; pretreated with both insulins: n=1). Intensifying glargine-based BOT or glulisine-based SIT to a BBT

Bolus Guide: A Novel Insulin Bolus Dosing Decision Support Tool Based on Selection of Carbohydrate Ranges

PubMed Central

Shapira, Gali; Yodfat, Ofer; HaCohen, Arava; Feigin, Paul; Rubin, Richard

2010-01-01

Background Optimal continuous subcutaneous insulin infusion (CSII) therapy emphasizes the relationship between insulin dose and carbohydrate consumption. One widely used tool (bolus calculator) requires the user to enter discrete carbohydrate values; however, many patients might not estimate carbohydrates accurately. This study assessed carbohydrate estimation accuracy in type 1 diabetes CSII users and compared simulated blood glucose (BG) outcomes using the bolus calculator and the “bolus guide,” an alternative system based on ranges of carbohydrate load. Methods Patients (n = 60) estimated the carbohydrate load of a representative sample of meals of known carbohydrate value. The estimated error distribution [coefficient of variation (CV)] was the basis for a computer simulation (n = 1.6 million observations) of insulin recommendations for the bolus guide and bolus calculator, translated into outcome blood glucose (OBG) ranges (≤60, 61–200, >201 mg/dl). Patients (n = 30) completed questionnaires assessing satisfaction with the bolus guide. Results The CV of typical meals ranged from 27.9% to 44.5%. The percentage of simulated OBG for the calculator and the bolus guide in the <60 mg/dl range were 20.8% and 17.2%, respectively, and 13.8% and 15.8%, respectively, in the >200 mg/dl range. The mean and median scores of all bolus guide satisfaction items and ease of learning and use were 4.17 and 4.2, respectively (of 5.0). Conclusion The bolus guide recommendation based on carbohydrate range selection is substantially similar to the calculator based on carbohydrate point estimation and appears to be highly accepted by type 1 diabetes insulin pump users. PMID:20663453

A feasibility study of a 3-day basal-bolus insulin delivery device in individuals with type 2 diabetes.

PubMed

Mader, Julia K; Lilly, Leslie C; Aberer, Felix; Korsatko, Stefan; Strock, Ellie; Mazze, Roger S; Damsbo, Peter; Pieber, Thomas R

2014-05-01

This study tested the feasibility of transition from multiple daily injections (MDI) to a 3-day, basal-bolus insulin delivery device (PaQ) for type 2 diabetes (T2D). Twenty MDI-treated individuals with T2D with HbA(1c) ≤9% (75 mmol/mol) were enrolled in a single-center, single-arm pilot study, lasting three 2-week periods: baseline (MDI), transition to PaQ, and PaQ therapy. Feasibility of use, glycemic control, safety, and patient satisfaction were assessed. Nineteen participants transitioned to PaQ treatment and demonstrated competency in assembling, placing, and using the device. Self-monitored blood glucose and blinded continuous glucose-monitoring data showed glycemic control similar to MDI. Study participants reported high satisfaction and device acceptance. PaQ treatment is both feasible and acceptable in individuals with T2D. Transition from MDI is easy and safe. PaQ treatment might lead to better therapy adherence and improvements in glycemic control and clinical outcomes.

Effect of insulin analogues on frequency of non-severe hypoglycaemia in patients with type 1 diabetes prone to severe hypoglycaemia: The HypoAna trial.

PubMed

Agesen, R M; Kristensen, P L; Beck-Nielsen, H; Nørgaard, K; Perrild, H; Christiansen, J S; Jensen, T; Hougaard, P; Parving, H H; Thorsteinsson, B; Tarnow, L; Pedersen-Bjergaard, U

2016-09-01

Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night. This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal-bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996). Analogue-based treatment resulted in a 6% (2-10%; P=0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32-46%; P<0.0001) reduction of non-severe nocturnal hypoglycaemia, seen for both symptomatic (48% [36-57%]; P<0.0001) and asymptomatic (28% [14-39%]; P=0.0004) nocturnal hypoglycaemia episodes. No clinically significant differences in hypoglycaemia occurrence were observed between the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Therapeutics of diabetes mellitus: focus on insulin analogues and insulin pumps.

PubMed

Valla, Vasiliki

2010-01-01

Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insulin delivery systems and the artificial pancreas. Intensive insulin therapy with multiple daily injections (MDI) allows better imitation of the physiological rhythm of insulin secretion. Longer-acting, basal insulin analogues provide concomitant improvements in safety, efficacy and variability of glycaemic control, followed by low risks of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII) provides long-term glycaemic control especially in type 1 diabetic patients, while reducing hypoglycaemic episodes and glycaemic variability. Continuous subcutaneous glucose monitoring (CGM) systems provide information on postprandial glucose excursions and nocturnal hypo- and/or hyperglycemias. This information enhances treatment options, provides a useful tool for self-monitoring and allows safer achievement of treatment targets. In the absence of a cure-like pancreas or islets transplants, artificial "closed-loop" systems mimicking the pancreatic activity have been also developed. Individualized treatment plans for insulin initiation and administration mode are critical in achieving target glycaemic levels. Progress in these fields is expected to facilitate and improve the quality of life of diabetic patients.

Combination Therapy With Exenatide Plus Pioglitazone Versus Basal/Bolus Insulin in Patients With Poorly Controlled Type 2 Diabetes on Sulfonylurea Plus Metformin: The Qatar Study

PubMed Central

Abdul-Ghani, Muhammad; Migahid, Osama; Megahed, Ayman; Adams, John; Triplitt, Curtis; DeFronzo, Ralph A.; Zirie, Mahmoud; Jayyousi, Amin

2017-01-01

OBJECTIVE The Qatar Study was designed to examine the efficacy of combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with long-standing poorly controlled type 2 diabetes mellitus (T2DM) on metformin plus a sulfonylurea. RESEARCH DESIGN AND METHODS The study randomized 231 patients with poorly controlled (HbA1c >7.5%, 58 mmol/mol) T2DM on a sulfonylurea plus metformin to receive 1) pioglitazone plus weekly exenatide (combination therapy) or 2) basal plus prandial insulin (insulin therapy) to maintain HbA1c <7.0% (53 mmol/mol). RESULTS After a mean follow-up of 12 months, combination therapy caused a robust decrease in HbA1c from 10.0 ± 0.6% (86 ± 5.2 mmol/mol) at baseline to 6.1 ± 0.1% (43 ± 0.7 mmol/mol) compared with 7.1 ± 0.1% (54 ± 0.8 mmol/mol) in subjects receiving insulin therapy. Combination therapy was effective in lowering the HbA1c independent of sex, ethnicity, BMI, or baseline HbA1c. Subjects in the insulin therapy group experienced significantly greater weight gain and a threefold higher rate of hypoglycemia than patients in the combination therapy group. CONCLUSIONS Combination exenatide/pioglitazone therapy is a very effective and safe therapeutic option in patients with long-standing poorly controlled T2DM on metformin plus a sulfonylurea. PMID:28096223

Basal-Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study.

PubMed

Okajima, Fumitaka; Nakamura, Yuko; Yamaguchi, Yuji; Shuto, Yuki; Kato, Katsuhito; Sugihara, Hitoshi; Emoto, Naoya

2018-04-04

Although reduction in the incidence of nocturnal hypoglycemia, as estimated by symptom or self-monitored plasma glucose, was shown to be more pronounced with 300 units/mL insulin glargine (Gla-300) than with 100 units/mL insulin glargine (Gla-100) in type 2 diabetes patients, the exact frequency of nocturnal hypoglycemia estimated with continuous glucose monitoring (CGM) has not been reported. Forty patients with type 2 diabetes who were admitted for glycemic control with basal-bolus insulin therapy (BBT) were randomized into the Gla-100 and Gla-300 groups. Insulin doses were adjusted to maintain blood glucose levels within 100-120 mg/dL at each meal. Plasma glucose and C-peptide profiles were estimated serially after admission and before discharge. Daily CGM was also performed before discharge. In the Gla-100 and Gla-300 groups, the mean duration of hospitalization was 15 ± 2 and 15 ± 1 days, respectively, and the mean basal insulin dose before discharge was 13 ± 7 and 15 ± 10 units, respectively. The dose of meal-time insulin was not different between the two groups. Compared with the Gla-300 group, the Gla-100 group had significantly lower nocturnal profiles of plasma glucose and C-peptide, but significantly higher frequency of CGM-estimated nocturnal hypoglycemia (10.7% ± 18.4% versus 1.2% ± 3.6%, P = 0.033). In type 2 diabetic patients, reduction in the incidence of CGM-estimated nocturnal hypoglycemia by BBT under tightly controlled diet therapy was higher with Gla-300 than with Gla-100. UMIN clinical trials registry (UMIN000023360).

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

PubMed

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and

Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy.

PubMed

Goldenberg, Ronald M; Berard, Lori

2018-01-01

Diabetes mellitus is a serious and increasingly prevalent condition in Canada and around the world. Treatment strategies have become increasingly complex, with a widening array of pharmacological agents available for glycemic management in type 2 diabetes mellitus (T2DM). New therapies that act in concert with available basal insulins may represent alternatives to basal insulin intensification with prandial or pre-mixed insulin. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently shown promise as useful additions to basal insulin, with significant reductions in glycated hemoglobin and potentially beneficial effects on body weight. This review will focus on pivotal clinical trials to assess the potential benefits of adding prandial GLP-1 RAs to basal insulin in patients with T2DM. Clinical studies combining prandial GLP-1 RAs and basal insulin (published between 2011 and July 2017) were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials (Issue 6, June 2017), and clinicaltrials.gov. Most of the studies presented in this review show that the addition of a prandial GLP-1 RA to basal insulin results in equal or slightly superior efficacy compared to the addition of prandial insulin, together with weight loss and less hypoglycemia. The results of the studies suggest that a prandial GLP-1 RA as an add-on to basal insulin may be a safe and effective treatment intensification option (vs basal-plus or basal-bolus insulin).

Optimizing the combination insulin bolus split for a high-fat, high-protein meal in children and adolescents using insulin pump therapy.

PubMed

Lopez, P E; Smart, C E; McElduff, P; Foskett, D C; Price, D A; Paterson, M A; King, B R

2017-10-01

To determine the optimum combination bolus split to maintain postprandial glycaemia with a high-fat and high-protein meal in young people with Type 1 diabetes. A total of 19 young people (mean age 12.9 ± 6.7 years) participated in a randomized, repeated-measures trial comparing postprandial glycaemic control across six study conditions after a high-fat and high-protein meal. A standard bolus and five different combination boluses were delivered over 2 h in the following splits: 70/30 = 70% standard /30% extended bolus; 60/40=60% standard/40% extended bolus; 50/50=50% standard/50% extended bolus; 40/60=40% standard/60% extended bolus; and 30/70=30% standard/70% extended bolus. Insulin dose was determined using the participant's optimized insulin:carbohydrate ratio. Continuous glucose monitoring was used to assess glucose excursions for 6 h after the test meal. Standard bolus and combination boluses 70/30 and 60/40 controlled the glucose excursion up to 120 min. From 240 to 300 min after the meal, the glucose area under the curve was significantly lower for combination bolus 30/70 compared with standard bolus (P=0.004). High-fat and high-protein meals require a ≥60% insulin:carbohydrate ratio as a standard bolus to control the initial postprandial rise. Additional insulin at an insulin:carbohydrate ratio of up to 70% is needed in the extended bolus for a high fat and protein meal to prevent delayed hyperglycaemia. © 2017 Diabetes UK.

Taking a Closer Look--Continuous Glucose Monitoring in Non-Critically Ill Hospitalized Patients with Type 2 Diabetes Mellitus Under Basal-Bolus Insulin Therapy.

PubMed

Schaupp, Lukas; Donsa, Klaus; Neubauer, Katharina M; Mader, Julia K; Aberer, Felix; Höll, Bernhard; Spat, Stephan; Augustin, Thomas; Beck, Peter; Pieber, Thomas R; Plank, Johannes

2015-09-01

Inpatient glucose management is based on four daily capillary blood glucose (BG) measurements. The aim was to test the capability of continuous glucose monitoring (CGM) for assessing the clinical impact and safety of basal-bolus insulin therapy in non-critically ill hospitalized patients with type 2 diabetes mellitus (T2DM). Eighty-four patients with T2DM (age, 68±10 years; glycosylated hemoglobin, 72±28 mmol/mol; body mass index, 31±7 kg/m(2)) were treated with basal-bolus insulin. CGM was performed with the iPro(®)2 system (Medtronic MiniMed, Northridge, CA) and calibrated retrospectively. A remarkable consistency between CGM and BG measurements and therapy improvement was shown over the study period of 501 patient-days. The number of CGM and BG measurements (CGM/BG) in the range from 3.9-10 mmol/L increased from 67.7%/67.2% (on Day 1) to 77.5%/78.6% (on the last day) (P<0.04). The number of low glycemic episodes (3.3 to <3.9 mmol/L) during nighttime detected by CGM was 15-fold higher, and the number of episodes >13.9 mmol/L detected by CGM during night was 12.5-fold higher than the values from the BG measurements. Ninety-nine percent of data points were in the clinically accurate or acceptable Clarke Error Grid Zones A+B, and the relative numbers of correctly identified episodes of <3.9 and >13.9 mmol/L detected by CGM (sensitivity) were 47.3% and 81.5%, respectively. Our data exhibit a good agreement between overall CGM and BG measurements, but there were a high number of missed hypo- and hyperglycemic episodes with BG measurements, particularly during nighttime. Overall assessment of glycemic control using CGM is feasible, whereas the use of CGM for individualized therapy decisions needs further improvement.

Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type I diabetic subjects.

PubMed

Kang, S; Creagh, F M; Peters, J R; Brange, J; Vølund, A; Owens, D R

1991-07-01

To compare postprandial glucose excursions and plasma free insulin-analogue levels after subcutaneous injection of three novel human insulin analogues (AspB10; AspB9, GluB27; and AspB28) with those after injection of soluble human insulin (Actrapid HM U-100). Six male subjects with insulin-dependent diabetes, at least 1 wk apart and after an overnight fast and basal insulin infusion, received 72 nmol (approximately 12 U) s.c. of soluble human insulin 30 min before, or 72 nmol of each of the three analogues immediately before, a standard 500-kcal meal. Mean basal glucoses were similar on the 4 study days. Compared to human insulin (6.3 +/- 0.8 mM), mean +/- SE peak incremental glucose rises were similar after analogues AspB10 (5.4 +/- 0.8 mM) and AspB9, GluB27 (5.4 +/- 0.7 mM) and significantly lower after analogue AspB28 (3.6 +/- 1.2 mM, P less than 0.02). Relative to soluble human insulin (100% +/- SE21), incremental areas under the glucose curve between 0 and 240 min were 79% +/- 34 (AspB10, NS), 70% +/- 29 (AspB9, GluB27, NS), and 43% +/- 23 (AspB28, P less than 0.02). Basal plasma free insulin levels were similar on the 4 study days. Plasma free insulin-analogue levels rose rapidly to peak 30 min after injection at 308 +/- 44 pM (AspB10); 1231 +/- 190 pM (AspB9, GluB27) and 414 +/- 42 pM (AspB28) and were significantly higher than corresponding (i.e., 30 min postmeal) plasma free insulin levels of 157 +/- 15 pM (P less than 0.02 in each case). Plasma profiles of the insulin analogues were more physiological than that of human insulin after subcutaneous injection. All three analogues given immediately before the meal are at least as effective as soluble human insulin given 30 min earlier. These analogues are promising potential candidates for short-acting insulins of the future.

Safely Converting an Entire Academic Medical Center From Sliding Scale to Basal Bolus Insulin via Implementation of the eGlycemic Management System.

PubMed

Newsom, Rosalina; Patty, Christopher; Camarena, Emma; Sawyer, Regina; McFarland, Raymie; Gray, Thomas; Mabrey, Melanie

2018-01-01

Hyperglycemia is common in the inpatient setting and providers frequently rely on sliding scale insulin. This case study reviews the experience of one hospital moving from high utilization of sliding scale to basal bolus insulin therapy. This Retrospective Quality Improvement Study describes the journey of clinicians at a 580-bed hospital to convert from high usage of SSI to BBI. Hyperglycemic adult patients prescribed insulin, with/without a diagnosis of diabetes, were included. Data over the first year showed that patients treated with Glucommander (GM) spent more time in the target range of 70-180 mg/dL than patients treated with non-Glucommander (non-GM), with 2,434 fewer hypoglycemic events and 40,589 fewer hyperglycemic events. Prior to implementation of GM, SSI was close to 95%, BBI at 5%. Within the first month of use, 96% usage of BBI was achieved. Reduction of hypoglycemic events (% of BG < 70 mg/dL) by 21% with 2.16% non-GM compared to GM at 1.74% and severe Hypoglycemia (% of BG < 50 mg/dL) by 50% in the ICU 3% non-GM compared to GM at 1.5%. In addition, patients treated with GM had a shorter LOS than patients treated with non-GM by 3.18 days and used 47.4% less point of care tests per patient. Glycemic management improved with use of eGMS. The conversion from SSI to BBI enhanced overall patient safety, eliminated the time and effort otherwise required when manually titrating insulin and reduced overall cost of care for patients on insulin therapy.

Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment.

PubMed

Langkjaer, L; Brange, J; Grodsky, G M; Guy, R H

1998-01-23

The aim of this study was to investigate the influence of association state and net charge of human insulin analogues on the rate of iontophoretic transport across hairless mouse skin, and the effect of different skin pretreatments on said transport. No insulin flux was observed with anodal delivery probably because of degradation at the Ag/AgCl anode. The flux during cathodal iontophoresis through intact skin was insignificant for human hexameric insulin, and only low and variable fluxes were observed for monomeric insulins. Using stripped skin on the other hand, the fluxes of monomeric insulins with two extra negative charges were 50-100 times higher than that of hexameric human insulin. Introducing three additional charges led to a further 2-3-fold increase in flux. Wiping the skin gently with absolute alcohol prior to iontophoresis resulted in a 1000-fold increase in transdermal transport of insulin relative to that across untreated skin, i.e. to almost the same level as stripping the skin. The alcohol pretreatment reduced the electrical resistance of the skin, presumably by lipid extraction. In conclusion, monomeric insulin analogues with at least two extra negative charges can be iontophoretically delivered across hairless mouse skin, whereas insignificant flux is observed with human, hexameric insulin. Wiping the skin with absolute alcohol prior to iontophoresis gave substantially improved transdermal transport of monomeric insulins resulting in clinically relevant delivery rates for basal treatment.

Switching to multiple daily injection therapy with glulisine improves glycaemic control, vascular damage and treatment satisfaction in basal insulin glargine-injected diabetic patients.

PubMed

Yanagisawa, Katsuyuki; Ashihara, Junya; Obara, Shinji; Wada, Norio; Takeuchi, Masayoshi; Nishino, Yuri; Maeda, Sayaka; Ishibashi, Yuji; Yamagishi, Sho-ichi

2014-11-01

Basal and bolus insulin therapy is required for strict blood control in diabetic patients, which could lead to prevention of vascular complications in diabetes. However, the optimal combination regimen is not well established. Fifty-nine diabetic patients (49 type 1 and 10 type 2; 52.9 ± 13.3 years old) whose blood glucose levels were uncontrolled (HbA1c  > 6.2%) by combination treatment of basal insulin glargine with multiple daily pre-meal injections of bolus short-acting insulin [aspart (n = 19), lispro (n = 37) and regular human insulin (n = 3)] for at least 8 weeks were enrolled in this study. We examined whether glycaemic control and vascular injury were improved by replacement of short-acting insulin with glulisine. Patient satisfaction was assessed with Diabetes Treatment Satisfaction Questionnaire. Although bolus and basal insulin doses were almost unchanged before and after replacement therapy, switching to glulisine insulin for 24 weeks significantly decreased level of HbA1c , advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), monocyte chemoattractant protein-1 (MCP-1) and urinary albumin excretion. In multiple stepwise regression analysis, change in MCP-1 values from baseline (ΔMCP-1) was a sole determinant of log urinary albumin excretion. ΔAGEs and ΔsRAGE were independently correlated with each other. The relationship between ΔMCP-1 and ΔsRAGE was marginally significant (p = 0.05). Replacement of short-acting insulin by glulisine significantly increased Diabetes Treatment Satisfaction Questionnaire scores. Our present study suggests that combination therapy of glargine with multiple daily pre-meal injections of glulisine might show superior efficacy in controlling blood glucose, preventing vascular damage and improving treatment satisfaction in diabetic patients. Copyright © 2014 John Wiley & Sons, Ltd.

Therapeutically interchangeable? A study of real-world outcomes associated with switching basal insulin analogues among US patients with type 2 diabetes mellitus using electronic medical records data.

PubMed

Levin, P; Wei, W; Miao, R; Ye, F; Xie, L; Baser, O; Gill, J

2015-03-01

To evaluate real-world clinical outcomes for switching basal insulin analogues [insulin glargine (GLA) and insulin detemir (DET)] among US patients with type 2 diabetes mellitus (T2DM). Using the GE Centricity Electronic Medical Records database, this retrospective study examined two cohorts: cohort 1, comprising patients previously on GLA and then either switching to DET (DET-S) or continuing with GLA (GLA-C); and cohort 2, comprising patients previously on DET and then either switching to GLA (GLA-S) or continuing with DET (DET-C). Within each cohort, treatment groups were propensity-score-matched on baseline characteristics. At 1-year follow-up, insulin treatment patterns, glycated haemoglobin (HbA1c) levels, hypoglycaemic events, weight and body mass index (BMI) were evaluated. The analysis included 13 942 patients: cohort 1: n = 10 657 (DET-S, n = 1797 matched to GLA-C, n = 8860) and cohort 2: n = 3285 (GLA-S, n = 858 matched to DET-C, n = 2427). Baseline characteristics were similar between the treatment groups in each cohort. At 1-year follow-up, in cohort 1, patients in the DET-S subgroup were significantly less persistent with treatment, more likely to use a rapid-acting insulin analogue, had higher HbA1c values, lower HbA1c reductions and lower proportions of patients achieving HbA1c <7.0 or <8.0% compared with patients in the GLA-C subgroup, while hypoglycaemia rates and BMI/weight values and change from baseline were similar in the two subgroups. In cohort 2, overall, there were contrasting findings between patients in the GLA-S and those in the DET-C subgroup. This study showed contrasting results when patients with T2DM switched between basal insulin analogues, although these preliminary results may be subject to limitations in the analysis. Nevertheless, this study calls into question the therapeutic interchangeability of GLA and DET, and this merits further investigation. © 2014 The Authors. Diabetes, Obesity and

[Adherence of type 2 diabetes patients on insulin analogues application: missed dose, time imprecision and dose reduction. The results of GAPP2TM(Global Attitudes of Physicians and Patient) survey in the Czech Republic].

PubMed

Prázný, Martin

2014-11-01

Irregular insulin dose is one of the main problems associated with insulin therapy in patients with type 2 diabetes; its extent is not known precisely. The aim of survey conducted in the Czech Republic in the international project GAPP2 - Global Attitudes of Patients and Physicians was to determine the incidence and the impact of irregular use of basal insulin analogues in patients with type 2 diabetes, to point out the reasons for these irregularities and to focus on how physicians discuss irregular application of insulin with patients. The project GAPP2 is an international cross-sectional study performed on-line via the Internet using a questionnaire filled by diabetic patients treated with insulin analogues and physicians who treat these patients. The survey was conducted in two steps in 17 countries; the first step included 6 countries and was completed in the beginning of 2012, the second step involved 11 other countries including the Czech Republic with termination in 2014. The survey was designed to obtain the views of patients and physicians on certain aspects of insulin treatment and persistent issues in this field in the real daily practice. Special focus was on the incidence and management of hypoglycaemia as well as on irregularities of insulin application. In the part dedicated to adherence to basal insulin application were observed three types of irregular insulin therapy: missed dose, time imprecision of dose (± 2 hours vs. the prescribed time) and dose reduction in all cases in the past 30 days before completing the questionnaire. In addition, it was investigated the attitude and relation of patients to these issues. The results have shown that irregular insulin dose in the Czech Republic is less frequent than in other countries involved in the GAPP2 research. Nevertheless, approximately one fifth of diabetic patients using insulin analogues in basal-bolus or only basal therapy regimen is related to this problem. The last irregular insulin

Multinational Consensus: Insulin Initiation with Insulin Degludec/Aspart (IDegAsp).

PubMed

Kalra, Sanjay; Atkin, Stephen; Cervera, Antonio; Das, Ashok Kumar; Demir, Ozgur; Demir, Tevfik; Fariduddin, Md; Vo, Khoa Tuan; Ku, Bon Jeong; Kumar, Ajay; Latif, Zafar A; Malek, Rachid; Matawaran, Bien J; Mehta, Roopa; Tran, Nam Quang; Panelo, Araceli; Ruder, Sundeep; Saldana, Joel Rodriquez; Shaikh, Khalid A; Shakya, Amit; Shrestha, Dina; Unnikrishnan, A G

2018-05-23

Insulin degludec/aspart (IDegAsp) is the first soluble insulin co-formulation, combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In type 2 diabetes patients with oral antidiabetes agent (OAD) inadequacy, insulin initiation with IDegAsp once daily provides superior long-term glycemic control compared to insulin glargine, with similar fasting plasma glucose (FPG) and insulin doses, and numerically lower rates of overall and nocturnal hypoglycemia. Furthermore, in patients with uncontrolled type 2 diabetes previously treated with insulins, IDegAsp twice daily effectively improves glycated hemoglobin and FPG, with fewer hypoglycemic episodes versus premix insulins and basal bolus therapy. In patients with type 1 diabetes mellitus, IDegAsp once daily with two doses of IAsp is a convenient, yet effective, regimen as compared to the conventional 4-5 injection-based basal bolus therapy. IDegAsp is an appropriate and reasonable option for initiation of insulin therapy in both type 1 and type 2 diabetes.

Cross-reactivity of insulin analogues with three insulin assays.

PubMed

Dayaldasani, A; Rodríguez Espinosa, M; Ocón Sánchez, P; Pérez Valero, V

2015-05-01

Immunometric assays have recently shown higher specificity in the detection of human insulin than radioimmunoassays with almost no cross-reaction with proinsulin or C peptide. The introduction of the new insulin analogues on the market, however, has raised the need to define their cross-reactivity in these assays. Several studies have been published in this regard with different results. The analogues studied were insulins lispro, aspart, glargine, detemir, and glulisine. Insulin concentrations were measured in Immulite(®) 2000 and Advia Centaur(®) XP (Siemens Healthcare Diagnostics), and Elecsys(®) Modular Analytics E170 (Roche). All samples were processed 15 times in the same analytical run following a random sequence. Those samples which showed statistically and clinically significant changes in insulin concentration were reprocessed using increasing concentrations of analogue, and this was done twice, using two different serum pools, one with a low concentration of insulin and one with a high concentration of insulin. In the Elecsys(®) E170 analyser, glargine showed statistical changes (comparison of mean concentrations with p < 0.05) and clinically significant changes in measured insulin (percentage difference 986.2% > reference change value: 59.8%), and the interference increased with increasing concentrations of analogue; the differences were not significant in the case of the other analogues. In the Advia Centaur(®) and Immulite(®) 2000 only the results for glulisine did not present significance (percentage difference 44.7% < reference change value 103.5%). Increasing concentrations of aspart, glargine, and lispro showed increased interference in Immulite(®) 2000. In the Elecsys(®) E170 assay, relevant cross-reactivity was only detected with insulin glargine, whereas in the other analysers all analogues except glulisine showed significant interference. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Determinants of intensive insulin therapeutic regimens in patients with type 1 diabetes: data from a nationwide multicenter survey in Brazil

PubMed Central

2014-01-01

Background To evaluate the determinants of intensive insulin regimens (ITs) in patients with type 1 diabetes (T1D). Methods This multicenter study was conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 3,591 patients (56.0% female, 57.1% Caucasian). Insulin regimens were classified as follows: group 1, conventional therapy (CT) (intermediate human insulin, one to two injections daily); group 2 (three or more insulin injections of intermediate plus regular human insulin); group 3 (three or more insulin injections of intermediate human insulin plus short-acting insulin analogues); group 4, basal-bolus (one or two insulin injections of long-acting plus short-acting insulin analogues or regular insulin); and group 5, basal-bolus with continuous subcutaneous insulin infusion (CSII). Groups 2 to 5 were considered IT groups. Results We obtained complete data from 2,961 patients. Combined intermediate plus regular human insulin was the most used therapeutic regimen. CSII was used by 37 (1.2%) patients and IT by 2,669 (90.2%) patients. More patients on IT performed self-monitoring of blood glucose and were treated at the tertiary care level compared to CT patients (p < 0.001). The majority of patients from all groups had HbA1c levels above the target. Overweight or obesity was not associated with insulin regimen. Logistic regression analysis showed that economic status, age, ethnicity, and level of care were associated with IT (p < 0.001). Conclusions Given the prevalence of intensive treatment for T1D in Brazil, more effective therapeutic strategies are needed for long term-health benefits. PMID:24920963

A bolus/basal multiple injection regimen in type I diabetes. A multicentre trial using a new 'fountain-pen' device for short-acting human insulin as well as long-acting human insulin.

PubMed

Distiller, L A; Robertson, L I; Moore, R; Bonnici, F

1987-06-20

A trial was undertaken to ascertain the effect and acceptability of a multiple insulin injection regimen (MII) in patients with insulin-dependent diabetes mellitus using short-acting monocomponent human soluble insulin (Actrapid HM; Novo) for pre-meal bolus injections with the NovoPen injection device (Novo) and long-acting human insulin (Ultratard HM; Novo) at bedtime. Fifty-four patients, all previously on twice-daily short/intermediate-acting human insulin (Monotard HM; Novo) and Actrapid HM, were randomly selected. There was a significant overall improvement in diabetic control over the 12 weeks of the trial, the glycosylated haemoglobin (Hb A1) dropping from a mean of 9.8 +/- 2.2% to 8.6 +/- 1.7% (P less than 0.05). MII, using the NovoPen, was found to be more convenient than conventional insulin administration by 92% of the subjects. It is concluded that the NovoPen is a useful and convenient means of administering pre-meal boluses in an MII regimen, with a very high rate of acceptance by patients of all ages.

The Interactive Effect of Diabetes Family Conflict and Depression on Insulin Bolusing Behaviors for Youth.

PubMed

Maliszewski, Genevieve; Patton, Susana R; Midyett, L Kurt; Clements, Mark A

2017-05-01

Adherence to type 1 diabetes management declines as children enter adolescence. For youth, psychosocial variables including mood and interpersonal relationships play a large role in diabetes maintenance. The current study assessed the unique and interactive roles diabetes family conflict and depression have on insulin bolusing behaviors for youth ages 10-16 years. Ninety-one youth-parent dyads completed a survey assessing family conflict and depression. Mean daily blood glucose levels, mealtime insulin bolus scores ( BOLUS), and glycated hemoglobin (HbA1c) were collected from the medical record as outcome variables. Parent-reported diabetes-related family conflict and youths' endorsed depression both significantly predicted insulin bolusing behavior, R 2 = .13, F(2, 88) = 6.66, P < .05. The interaction of diabetes family conflict and youth depression played a significant role in youths' bolusing behaviors, above and beyond that which was predicted by conflict and depression separately, R 2 = .18, F change (1, 87) = 4.63, P < .05. BOLUS was negatively related to youths' hemoglobin A1c, r = -.556, P < .001 and mean daily blood glucose levels, r = -.428, P < .001. Among depressed youth, mealtime insulin BOLUS scores declined with greater diabetes-related family conflict, while there was no change in BOLUS scores among depressed youth living in families reporting less conflict. Findings underscore the importance of screening for depression and family conflict in youth experiencing or at risk for poor adherence to mealtime insulin and higher HbA1c levels.

Importance of Insulin Immunoassays in the Diagnosis of Factitious Hypoglycemia

PubMed Central

Nalbantoğlu Elmas, Özlem; Demir, Korcan; Soylu, Nusret; Çelik, Nilüfer; Özkan, Behzat

2014-01-01

We report two cases emphasizing the importance of insulin assays for evaluation of hypoglycemia in diabetic patients. Case 1 was a 96/12-year-old female patient with type 1 diabetes mellitus and case 2 was a 1010/12-year-old male patient with DIDMOAD. Both patients were on a basal-bolus insulin regimen. Both were admitted because of persistent hypoglycemia. Analyses of serum samples obtained at the time of hypoglycemia initially showed low insulin and C-peptide levels. Recurrent episodes of unexplained hypoglycemia necessitated measurement of insulin levels by using different insulin assays, which revealed hyperinsulinemic hypoglycemia with low C-peptide levels, findings which confirmed a diagnosis of factitious hypoglycemia. Surreptitious administration of insulin should not be excluded in diabetic patients with hypoglycemia without taking into account the rate of cross-reactivity of insulin analogues with the insulin assay used. PMID:25541899

The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide

PubMed Central

Barnett, A H

2012-01-01

In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM—exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m2, and patients with a BMI <35 kg/m2 who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m2) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. PMID:22051096

Comparison of treatment with continuous subcutaneous insulin infusion versus multiple daily insulin injections with bolus calculator in patients with type 1 diabetes.

PubMed

Pérez-García, L; Goñi-Iriarte, M J; García-Mouriz, M

2015-01-01

A study of the glycemic control, quality of life, and fear and perception of hypoglycemia by comparing continuous subcutaneous insulin infusion (CSII) group with multiple daily inyections (MDI) with bolus calculator group. This is a retrospective cohort study with following up during the first 12 months that CSII group (n=30) begins the use of "bolus wizard" and the MDI-calculator (n=30) group begins the use of the bolus calculator (Accu-Chek(®) Aviva Expert). HbA1c (3, 6 and 12 months). Questionnaires used: EsDQOL (quality of life), FH-15 (fear of hypoglycemia), and Clarke (perception of hypoglycemia). T Student and nonparametric tests. The average reduction in HbA1c during the study was significantly higher in CSII group (-0.56±0.84%) compared with the MDI group (0.097±0.94%), P=.028. The average basal insulin dose was significantly higher in the MDI group (at baseline, 6 and 12 months). No significant differences were found between the 2 treatment groups after analyzing the EsDQOL, FH-15 and Clarke questionnaires. In the CSII group, perceived quality of life assessed by the EsDQOL questionnaire was found to be better at the end of the study than at the beginning of using the insulin pump. The average reduction in HbA1c was significantly higher in the CSII group. In the CSII group, perceived quality of life was better at the end of the study than at the beginning. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Effects of switching from prandial premixed insulin therapy to basal plus two times bolus insulin therapy on glycemic control and quality of life in patients with type 2 diabetes mellitus

PubMed Central

Ito, Hiroyuki; Abe, Mariko; Antoku, Shinichi; Omoto, Takashi; Shinozaki, Masahiro; Nishio, Shinya; Mifune, Mizuo; Togane, Michiko

2014-01-01

Background The effects of switching from prandial premixed insulin therapy (PPT) injected three times a day to basal plus two times bolus insulin therapy (B2B) on glycemic control and quality of life were investigated in patients with type 2 diabetes mellitus. Methods The clinical course was prospectively observed during the first 16 weeks after switching to B2B (insulin glargine plus insulin glulisine before breakfast and dinner) in 27 subjects previously treated with PPT using 50/50 premixed insulin. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was administered at the start and end of the study. Results The glycated hemoglobin (HbA1c) level (8.3%±1.8% to 8.2%±1.1%) and the DTSQ score did not change between the start and end of the study. An improvement in HbA1c level was found in nine (33%) subjects. The change in HbA1c showed a significant negative correlation with baseline HbA1c, and was significantly better in patients with a baseline HbA1c >8.0% than in those with an HbA1c ≤8.0% (−0.9±2.0 versus 0.3±0.6, respectively, P=0.02). The change in DTSQ score representing treatment satisfaction was significantly greater in patients whose HbA1c level was improved than in those in whom it was not (2.7±3.6 versus −0.8±3.5, P=0.04). Conclusion B2B was noninferior to PPT with regard to HbA1c levels in patients with type 2 diabetes mellitus. B2B should be considered particularly for subjects whose glycemic control is poor despite PPT. PMID:24790413

Effects of switching from prandial premixed insulin therapy to basal plus two times bolus insulin therapy on glycemic control and quality of life in patients with type 2 diabetes mellitus.

PubMed

Ito, Hiroyuki; Abe, Mariko; Antoku, Shinichi; Omoto, Takashi; Shinozaki, Masahiro; Nishio, Shinya; Mifune, Mizuo; Togane, Michiko

2014-01-01

The effects of switching from prandial premixed insulin therapy (PPT) injected three times a day to basal plus two times bolus insulin therapy (B2B) on glycemic control and quality of life were investigated in patients with type 2 diabetes mellitus. The clinical course was prospectively observed during the first 16 weeks after switching to B2B (insulin glargine plus insulin glulisine before breakfast and dinner) in 27 subjects previously treated with PPT using 50/50 premixed insulin. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was administered at the start and end of the study. The glycated hemoglobin (HbA1c) level (8.3% ± 1.8% to 8.2% ± 1.1%) and the DTSQ score did not change between the start and end of the study. An improvement in HbA1c level was found in nine (33%) subjects. The change in HbA1c showed a significant negative correlation with baseline HbA1c, and was significantly better in patients with a baseline HbA1c >8.0% than in those with an HbA1c ≤ 8.0% (-0.9 ± 2.0 versus 0.3 ± 0.6, respectively, P = 0.02). The change in DTSQ score representing treatment satisfaction was significantly greater in patients whose HbA1c level was improved than in those in whom it was not (2.7 ± 3.6 versus -0.8 ± 3.5, P = 0.04). B2B was noninferior to PPT with regard to HbA1c levels in patients with type 2 diabetes mellitus. B2B should be considered particularly for subjects whose glycemic control is poor despite PPT.

Knowledge Translation to Optimize Adult Inpatient Glycemic Management with Basal Bolus Insulin Therapy and Improve Patient Outcomes.

PubMed

Helmle, Karmon E; Chacko, Sunita; Chan, Trevor; Drake, Alison; Edwards, Alun L; Moore, Glenda E; Philp, Leta C; Popeski, Naomi; Roedler, Rhonda L; Rogers, Edwin J R; Zimmermann, Gabrielle L; McKeen, Julie

2017-12-27

To develop and evaluate a Basal Bolus Insulin Therapy (BBIT) Knowledge Translation toolkit to address barriers to adoption of established best practice with BBIT in the care of adult inpatients. This study was conducted in 2 phases and focused on the hospitalist provider group across 4 acute care facilities in Calgary. Phase 1 involved a qualitative evaluation of provider and site specific barriers and facilitators, which were mapped to validated interventions using behaviour change theory. This informed the co-development and optimization of the BBIT Knowledge Translation toolkit, with each tool targeting a specific barrier to improved diabetes care practice, including BBIT ordering. In Phase 2, the BBIT Knowledge Translation toolkit was implemented and evaluated, focusing on BBIT ordering frequency, as well as secondary outcomes of hyperglycemia (patient-days with BG >14.0 mmol/L), hypoglycemia (patient-days with BG <4.0 mmol/L), and acute length of stay. Implementation of the BBIT Knowledge Translation toolkit resulted in a significant 13% absolute increase in BBIT ordering. Hyperglycemic patient-days were significantly reduced, with no increase in hypoglycemia. There was a significant, absolute 14% reduction in length of stay. The implementation of an evidence-informed, multifaceted BBIT Knowledge Translation toolkit effectively reduced a deeply entrenched in-patient diabetes care gap. The resulting sustained practice change improved patient clinical and system resource utilization outcomes. This systemic approach to implementation will guide further scale and spread of glycemic optimization initiatives. Copyright © 2018 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

Basal-bolus insulin therapy reduces maternal triglycerides in gestational diabetes without modifying cholesteryl ester transfer protein activity.

PubMed

Olmos, Pablo R; Borzone, Gisella R

2017-09-01

Macrosomia in the offspring of overweight/obese mothers with glucose-controlled gestational diabetes mellitus (GDM) is due to excessive rise of maternal triglycerides (TG). We aimed to ascertain whether basal-bolus insulin therapy (BBIT), or other components of the treatment, could reduce TG in GDM. We studied the records of 131 singleton pregnancies with GDM, using stepwise multiple linear regression, Mann-Whitney, χ 2 , and Jonckheere-Terpstra tests. As maternal TG increased steadily during normal pregnancy, these were transformed as z-scores. The atherogenic index of plasma (AIP) was calculated as a measure of cholesteryl ester transfer protein activity. Multiple regression showed that only BBIT (but neither limitation of weight gain nor metformin) reduced maternal TG z-scores (P = 0.011). When the 131 pregnancies were split into two groups - without BBIT (n = 58; HbA1c = 5.3 ± 0.3%) and with BBIT (n = 73; HbA1c = 5.4 ± 0.6; P = 0.2005) - we observed that BBIT (n = 73) reduced maternal TG z-scores in a dose-related fashion (Jonckheere-Terpstra P = 0.03817). The atherogenic index of plasma remained within normal range in both groups. BBIT (but not weight gain control nor metformin) reduced maternal TG in mothers with glucose-controlled GDM. This beneficial effect of BBIT was not related to changes in the cholesteryl ester transfer protein activity. © 2017 Japan Society of Obstetrics and Gynecology.

Insulin analogues for type 1 diabetes in children and adolescents.

PubMed

Galli-Tsinopoulou, A; Stergidou, D

2012-12-01

Since insulin is the unique and life-long therapy in type 1 diabetes and classical insulin preparations have certain limitations due to their pharmacokinetic and pharmacodynamic properties, the new insulin analogues aim to eliminate these limitations. Five insulin analogues are commercially available and approved for individuals with type 1 diabetes: three rapid-acting (insulin lispro, insulin aspart and insulin glulisine) and two long-acting insulin analogues (insulin glargine and insulin detemir). According to several studies conducted in children with type 1 diabetes, insulin analogues, due to their structural alterations, offer flexibility, reduction of nocturnal hypoglycemic episodes and decrease in postprandial hyperglycemic events, resulting in improved quality of life for diabetic children and their families. However, diabetes control measured with glycosylated hemoglobin A1c has been reported to be similar to conventional insulin preparations. Evidence-based medical reports indicate that insulin analogues are safe and effective, and therefore approved for children even from the age of 2 years. Moreover, suspicions and reports on the association of insulin analogues with carcinogenesis have not been established, requiring further investigation. This review reports the properties and characteristics of insulin analogues, as well as the results of current studies concerning pediatric patients with type 1 diabetes. Copyright 2012 Prous Science, S.A.U. or its licensors. All rights reserved.

Titration of basal insulin or immediate addition of rapid acting insulin in patients not at target using basal insulin supported oral antidiabetic treatment - A prospective observational study in 2202 patients.

PubMed

Siegmund, Thorsten; Pfohl, Martin; Forst, Thomas; Pscherer, Stefan; Bramlage, Peter; Foersch, Johannes; Borck, Anja; Seufert, Jochen

Optimal treatment intensification strategies in patients with type-2 diabetes mellitus (T2DM) receiving basal insulin supported oral antidiabetic therapy (BOT) remain controversial. The objective of the present study was to compare outcomes of BOT-intensification by either the uptitration of long-acting insulin glargine or by the immediate addition of a rapid acting insulin analogue (RAIA). This was a prospective, observational, 24-week study in T2DM patients with BOT using insulin glargine and baseline glycated hemoglobin (HbA1c) between 7.0 and 8.5%. Patients were stratified by their physicians to one of the following treatment intensification strategies: Basal insulin titration to target with discretionary subsequent addition of RAIA at weeks 12 or 24 (GLAR), or immediate addition of RAIA at baseline (GLARplus). A total of 3266 patients were prescreened of whom 2202 fulfilled the selection criteria. Of these, 1684 patients were documented in the GLAR group and 518 in the GLARplus group. In the GLAR group, in 91 (5.5%) and 21 patients (1.3%) RAIA was added at weeks 12 and 24, respectively. The groups displayed similar baseline characteristics; except, mean diabetes duration was slightly shorter in the GLAR group (8.7 vs. 9.4 years). During the study, insulin glargine dose was increased from 18.7 to 26.4U (plus 7.7U) in GLAR and from 24.9 to 27.3U (plus 2.4U) in GLARplus patients. Mean RAIA dose was 9.6±4.7U at the final visit. After 24 weeks, HbA1c was reduced by 0.8 and 0.9% in the GLAR and GLARplus groups, respectively (both p<0.001). An HbA1c of ≤7.0% was achieved in 49.2% of GLAR and 48.5% of GLARplus patients. In both groups, we observed improvements in cardiovascular risk factors such as lipids and blood pressure. The rates of symptomatic (1.6 vs. 1.7%) and severe (0.18 vs. 0.19%) hypoglycemic episodes were low and comparable in both groups. These findings provide evidence that treatment intensification in patients with type 2 diabetes not at glycemic

New Basal Insulins: a Clinical Perspective of Their Use in the Treatment of Type 2 Diabetes and Novel Treatment Options Beyond Basal Insulin.

PubMed

Frias, Patrick F; Frias, Juan Pablo

2017-08-18

The purpose of this review was to review advances in basal insulin formulations and new treatment options for patients with type 2 diabetes not achieving glycemic targets despite optimized basal insulin therapy. Advances in basal insulin formulations have resulted in products with increasingly favorable pharmacokinetic and pharmacodynamic properties, including flatter, peakless action profiles, less inter- and intra-patient variability, and longer duration of activity. These properties have translated to significantly reduced risk of hypoglycemia (particularly during the night) compared with previous generation basal insulins. When optimized basal insulin therapy is not sufficient to obtain or maintain glycemic goals, various options exist to improve glycemic control, including intensification of insulin therapy with the addition of prandial insulin or changing to pre-mixed insulin and, more recently, the addition of a GLP-1 receptor agonist, either as a separate injection or as a component of one of the new fixed-ratio combinations of a basal insulin and GLP-1 RA. New safer and often more convenient basal insulins and fixed ratio combinations containing basal insulin (and GLP-1 receptor agonist) are available today for patients with type 2 diabetes not achieving glycemic goals. Head-to-head studies comparing the latest generation basal insulins are underway, and future studies assessing the fixed-ratio combinations will be important to better understand their differentiating features.

Treatment duration (persistence) of basal insulin supported oral therapy (BOT) in Type-2 diabetic patients: comparison of insulin glargine with NPH insulin.

PubMed

Quinzler, Renate; Ude, Miriam; Franzmann, Alexandra; Feldt, Sandra; Schüssel, Katrin; Leuner, Kristina; Müller, Walter E; Dippel, Franz-Werner; Schulz, Martin

2012-01-01

To compare the persistence (treatment duration) of basal insulin supported oral therapy (BOT) using insulin glargine (GLA) or NPH insulin (NPH) in Type-2 diabetic patients. This retrospective cohort study reports results from an analysis of claims data from prescriptions for ambulatory patients within the German Statutory Health Insurance scheme. The study is based on claims data from more than 80% of German community pharmacies. Treatment duration until switching to a basal bolus treatment regimen (intensified conventional insulin therapy: ICT) was determined in insulin-naïve patients who began treatment with BOT using GLA or NPH between 01/2003 and 12/2006. A total of 97,998 patients (61,070 GLA and 36,928 NPH) were included. Within the observation period, 23.5% of GLA patients and 28.0% of NPH patients switched from BOT to ICT. The upper quartile of probability of continuation of therapy (the 75th percentile) was reached after 769 days in GLA patients and after 517 days in NPH patients. Therefore, the risk of switching to ICT was significantly higher with NPH compared to GLA: hazard ratios were 1.34 (99% CI: 1.29-1.38; unadjusted) and 1.22 (99% CI: 1.18-1.27) after adjustment for predefined covariates. Various sensitivity analyses using modified inclusion criteria and endpoint definitions were applied and these confirmed the initial results. Type-2 diabetic patients under BOT with GLA stayed significantly longer on the initial therapy before switching to ICT than patients on BOT using NPH.

Pitfalls of Insulin Pump Clocks

PubMed Central

Reed, Amy J.

2014-01-01

The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients’ visits, and should remind their patients to always verify these settings. PMID:25355713

The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide.

PubMed

Barnett, A H

2012-04-01

In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM-exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m(2) , and patients with a BMI <35 kg/m(2) who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m(2) ) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. © 2011 Blackwell Publishing Ltd.

A Review of the “Bolus Guide,” A New Insulin Bolus Dosing Support Tool Based on Selection of Carbohydrate Ranges

PubMed Central

Pańkowska, Ewa

2010-01-01

In this issue of Journal of Diabetes Science and Technology, Shapira and colleagues present new concepts of carbohydrate load estimation in intensive insulin therapy. By using a mathematical model, they attempt to establish how accurately carbohydrate food content should be maintained in order to keep postprandial blood glucose levels in the recommended range. Their mathematical formula, the “bolus guide” (BG), is verified by simulating prandial insulin dosing and responding to proper blood glucose levels. Different variants such as insulin sensitivity factor, insulin-to-carbohydrate ratio, and target blood glucose were taken into this formula in establishing the calculated proper insulin dose. The new approach presented here estimates the carbohydrate content by rearranging the carbohydrate load instead of the simple point estimation that the current bolus calculators (BCs) use. Computerized estimations show that the BG directives, as compared to a BC, result in more glucose levels above 200 mg/dl and thus indicate less hypoglycemia readings. PMID:20663454

Clinical inertia with regard to intensifying therapy in people with type 2 diabetes treated with basal insulin.

PubMed

Khunti, K; Nikolajsen, A; Thorsted, B L; Andersen, M; Davies, M J; Paul, S K

2016-04-01

To investigate whether clinical inertia, the failure to intensify treatment regimens when required, exists in people with type 2 diabetes treated with basal insulin. This was a retrospective cohort study involving patients with type 2 diabetes in the UK Clinical Practice Research Datalink database between January 2004 and December 2011, with follow-up until December 2013. A total of 11 696 patients were included in the analysis. Among all patients, 36.5% had their treatment intensified during the study period; of these, the treatment of 50.0, 42.5 and 7.4% was intensified with bolus or premix insulin or glucagon-like peptide-1 receptor agonists, respectively. The median time from initiation of basal insulin to treatment intensification was 4.3 years [95% confidence interval (CI) 4.1, 4.6]. Among patients clinically eligible for treatment intensification [glycated haemoglobin (HbA1c) ≥7.5% (58 mmol/mol)], 30.9% had their treatment regimen intensified. The median time to intensification in this group was 3.7 years (95% CI 3.4, 4.0). Increasing age, duration of diabetes, oral antihyperglycaemic agent usage and Charlson comorbidity index score were associated with a significant delay in the time to intensification (p < 0.05). Among patients with HbA1c ≥7.5% (58 mmol/mol), 32.1% stopped basal insulin therapy. Strategies should be developed to increase the number of patients undergoing therapy intensification and to reduce the delay in intensifying therapy for suitable patients on basal insulin. Initiatives to support patients continuing on insulin are also required. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Better Glycemic Control and Weight Loss With the Novel Long-Acting Basal Insulin LY2605541 Compared With Insulin Glargine in Type 1 Diabetes

PubMed Central

Rosenstock, Julio; Bergenstal, Richard M.; Blevins, Thomas C.; Morrow, Linda A.; Prince, Melvin J.; Qu, Yongming; Sinha, Vikram P.; Howey, Daniel C.; Jacober, Scott J.

2013-01-01

OBJECTIVE To compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes. RESEARCH DESIGN AND METHODS In this randomized, Phase 2, open-label, 2 × 2 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL. RESULTS LY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = −9.9 mg/dL [90% CI −14.6 to −5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02). CONCLUSIONS In type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses. PMID:23193209

Absorption kinetics and action profiles of subcutaneously administered insulin analogues (AspB9GluB27, AspB10, AspB28) in healthy subjects.

PubMed

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

The subcutaneous absorption and resulting changes in plasma insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations after subcutaneous bolus injection of three soluble human insulin analogues (AspB9GluB27, monomeric; AspB28, mixture of monomers and dimers; and AspB10, dimeric) and soluble human insulin were evaluated. Fasting healthy male volunteers (n = 7) were studied on five occasions 1 wk apart randomly receiving 0.6 nmol.kg-1 s.c. 125I-labeled AspB10 or soluble human insulin (Novolin R, Novo, Copenhagen); 1st study and 0.6 nmol.kg-1 s.c. 125I-labeled AspB28, AspB9GluB27 or soluble human insulin (2nd study). Residual radioactivity at the injection site was measured over 8 h with frequent venous sampling for plasma immunoreactive insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations. The three analogues were absorbed 2-3 times faster than human insulin. The mean +/- SE time to 50% residual radioactivity was 94 +/- 6 min for AspB10 compared with 184 +/- 10 min for human insulin (P less than 0.001), 83 +/- 8 min for AspB28 (P less than 0.005), and 63 +/- 9 min for AspB9GluB27 (P less than 0.001) compared with 182 +/- 21 min for human insulin. delta Peak plasma insulin analogue levels were significantly higher after each analogue than after human insulin (P less than 0.005). With all three analogues, the mean hypoglycemic nadir occurred earlier at 61-65 min postinjection compared with 201-210 min for the reference human insulins (P less than 0.005). The magnitude of the hypoglycemic nadir was greater after AspB9GluB27 (P less than 0.05) and AspB28 (P less than 0.001) compared with human insulin. There was a significantly faster onset and offset of responses in C-peptide and intermediary metabolite levels after the analogues than after human insulin (P less than 0.05). The rapid absorption and biological actions of these analogues offer potential therapeutic advantages over the current short

Prevention of Insulin-Induced Hypoglycemia in Type 1 Diabetes with Predictive Low Glucose Management System.

PubMed

Abraham, Mary B; de Bock, Martin; Paramalingam, Nirubasini; O'Grady, Michael J; Ly, Trang T; George, Carly; Roy, Anirban; Spital, Glenn; Karula, Sophy; Heels, Kristine; Gebert, Rebecca; Fairchild, Jan M; King, Bruce R; Ambler, Geoffrey R; Cameron, Fergus; Davis, Elizabeth A; Jones, Timothy W

2016-07-01

Sensor-augmented pump therapy (SAPT) with algorithms to predict impending low blood glucose and suspend insulin delivery has the potential to reduce hypoglycemia exposure. The aim of this study was to determine whether predictive low glucose management (PLGM) system is effective in preventing insulin-induced hypoglycemia in controlled experiments. Two protocols were used to induce hypoglycemia in an in-clinic environment. (A) Insulin bolus: Insulin was administered as a manual bolus through the pump. (B) Increased basal insulin: Hypoglycemia was induced by increasing basal rates overnight to 180%. For both protocols, participants were randomized and studied on 2 separate days; a control day with SAPT alone and an intervention day with SAPT and PLGM activated. The predictive algorithm was programmed to suspend basal insulin infusion when sensor glucose was predicted to be <80 mg/dL in 30 min. The primary outcome was the requirement for hypoglycemia treatment (symptomatic hypoglycemia or plasma glucose <50 mg/dL) and was compared in both control and intervention arms. With insulin bolus, 24/28 participants required hypoglycemia treatment with SAPT alone compared to 5/28 participants when PLGM was activated (P ≤ 0.001). With increased basal rates, all the eight SAPT-alone participants required treatment for hypoglycemia compared to only one with SAPT and PLGM. There was no post pump-suspend hyperglycemia with insulin bolus (P = 0.4) or increased basal rates (P = 0.69) in participants with 2-h pump suspension on intervention days. SAPT with PLGM reduced the requirement for hypoglycemia treatment following insulin-induced hypoglycemia in an in-clinic setting.

Automated bolus advisor control and usability study (ABACUS): does use of an insulin bolus advisor improve glycaemic control in patients failing multiple daily insulin injection (MDI) therapy? [NCT01460446

PubMed Central

2012-01-01

Background People with T1DM and insulin-treated T2DM often do not follow and/or adjust their insulin regimens as needed. Key contributors to treatment non-adherence are fear of hypoglycaemia, difficulty and lack of self-efficacy associated with insulin dose determination. Because manual calculation of insulin boluses is both complex and time consuming, people may rely on empirical estimates, which can result in persistent hypoglycaemia and/or hyperglycaemia. Use of automated bolus advisors (BA) has been shown to help insulin pump users to more accurately meet prandial insulin dosage requirements, improve postprandial glycaemic excursions, and achieve optimal glycaemic control with an increased time within optimal range. Use of a BA containing an early algorithm based on sliding scales for insulin dosing has also been shown to improve HbA1c levels in people treated with multiple daily insulin injections (MDI). We designed a study to determine if use of an automated BA can improve clinical and psychosocial outcomes in people treated with MDI. Methods/design The Automated Bolus Advisor Control and Usability Study (ABACUS) is a 6-month, prospective, randomised, multi-centre, multi-national trial to determine if automated BA use improves glycaemic control as measured by a change in HbA1c in people using MDI with elevated HbA1c levels (#62;7.5%). A total of 226 T1DM and T2DM participants will be recruited. Anticipated attrition of 20% will yield a sample size of 90 participants, which will provide #62;80% power to detect a mean difference of 0.5%, with SD of 0.9%, using a one-sided 5% t-test, with 5% significance level. Other measures of glycaemic control, self-care behaviours and psychosocial issues will also be assessed. Discussion It is critical that healthcare providers utilise available technologies that both facilitate effective glucose management and address concerns about safety and lifestyle. Automated BAs may help people using MDI to manage their diabetes more

Does a patient-managed insulin intensification strategy with insulin glargine and insulin glulisine provide similar glycemic control as a physician-managed strategy? Results of the START (Self-Titration With Apidra to Reach Target) Study: a randomized noninferiority trial.

PubMed

Harris, Stewart B; Yale, Jean-François; Berard, Lori; Stewart, John; Abbaszadeh, Babak; Webster-Bogaert, Susan; Gerstein, Hertzel C

2014-01-01

OBJECTIVE Diabetes self-management is universally regarded as a foundation of diabetes care. We determined whether comparable glycemic control could be achieved by self-titration versus physician titration of a once-daily bolus insulin dose in patients with type 2 diabetes who are unable to achieve optimal glycemia control with a basal insulin. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes, an HbA1c level >7% (53 mmol/mol), and either nocturnal hypoglycemia episodes or an insufficient basal insulin glargine level (with or without oral agents) to achieve a fasting plasma glucose level ≤6 mmol/L (108 mg/dL) were studied. Participants all had bolus insulin glulisine added at breakfast and were allocated to either algorithm-guided patient self-titration or physician titration. The primary outcome was an HbA1c level ≤7% (53 mmol/mol) without severe hypoglycemia. RESULTS After a mean (SD) follow-up of 159.4 days (36.2 days), 28.4% of participants in the self-titration arm vs. 21.2% in the physician titration arm achieved an HbA1c level of ≤7% (53 mmol/mol) without severe hypoglycemia (between-group absolute difference 7.2%; 95% CI -3.2 to 17.7). The lower end of this 95% confidence interval was within the predetermined noninferiority boundary of -5% (P noninferiority = 0.011). CONCLUSIONS In stable patients with type 2 diabetes who are receiving doses of basal insulin glargine who require bolus insulin, a simple bolus insulin patient-managed titration algorithm is as effective as a physician-managed algorithm.

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

PubMed Central

Moore, Mary Courtney; Smith, Marta S.; Sinha, Vikram P.; Beals, John M.; Michael, M. Dodson; Jacober, Scott J.; Cherrington, Alan D.

2014-01-01

The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg−1 ⋅ h−1 [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg−1 ⋅ h−1]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg−1 ⋅ min−1 within 5 h in control, LY0.25, LY0.375, and LY0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg-1 ⋅ min−1 in all groups, was higher in control (1.17 ± 0.38) versus LY0.25 (0.39 ± 0.33), LY0.375 (−0.01 ± 0.13), and LY0.5 (−0.09 ± 0.07). Likewise, the change from baseline in glucose Rd-to-Ra ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY0.25, LY0.375, and LY0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy. PMID:24089512

Lowest Glucose Variability and Hypoglycemia Are Observed With the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study).

PubMed

Bajaj, Harpreet S; Venn, Karri; Ye, Chenglin; Patrick, Avril; Kalra, Shivani; Khandwala, Hasnain; Aslam, Nadeem; Twum-Barima, David; Aronson, Ronnie

2017-02-01

There is a dearth of published literature comparing glucose variability (GV) between different insulin regimens in type 2 diabetes. This cohort study compares GV using continuous glucose monitoring (CGM) in patients with well-controlled type 2 diabetes using four common insulin regimens: basal insulin + oral drugs (BO), basal insulin + glucagon-like peptide 1 receptor agonist (GLP-1 RA) (BGLP), premixed insulin (PM), and basal-bolus insulin (BB). Consecutive patients from three endocrinology clinics who met study criteria-type 2 diabetes, age 18 to 80 years, BMI ≤ 45 kg/m 2 , stable insulin regimen for a minimum of 6 months, and stable A1C value ≤7.5% (58 mmol/mol) before study enrollment-underwent 6-day masked CGM. Hypoglycemia was defined as a sensor glucose concentration <70 mg/dL on CGM. A total of 160 patients with comparable baseline characteristics formed four equal insulin regimen cohorts. The daily glucose SD (the primary outcome) was significantly lower in the BGLP cohort versus the BO, PM, and BB cohorts (P = 0.03, P = 0.01, and P < 0.01, respectively), and remained so after adjusting for age, BMI, type 2 diabetes duration, and A1C. Similarly, daily hypoglycemia outcomes on CGM were least for the BGLP cohort. The lowest GV and lowest hypoglycemia were observed in patients using the combination of basal insulin with a GLP-1 RA, supporting the complementary glycemic action of these agents in type 2 diabetes. These observed benefits in GV and hypoglycemia may contribute to the cardiovascular outcome reduction seen with GLP-1 RA therapy and should be investigated further. © 2017 by the American Diabetes Association.

Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison.

PubMed

Robbins, David C; Beisswenger, Paul J; Ceriello, Antonio; Goldberg, Ronald B; Moses, Robert G; Pagkalos, Emmanuil M; Milicevic, Zvonko; Jones, Cate A; Sarwat, Samiha; Tan, Meng H

2007-11-01

In people without diabetes, approximately 50% of daily insulin secretion is basal and the remainder is postprandial. Hence, it would be expected that insulin replacement therapy in a 50/50 ratio with each meal would mimic physiologic insulin secretion better than treatment with once-daily basal insulin in patients with diabetes mellitus. Using lispro mix (LM) 50/50 before meals may be a logical approach to achieving glycemic targets (glycosylated hemoglobin [HbA(lc)] and pre- and postprandial blood glucose [BG] concentrations) in these patients. The aim of this study was to test the hypothesis that treatment with a premixed insulin analogue containing 50/50 basal + prandial insulins administered before each meal would achieve lower overall and mealtime glycemic control than once-daily basal insulin analogue, both plus metformin (Met), in patients with type 2 diabetes mellitus. This 24-week, randomized, open-label, parallel-group trial was conducted at 38 sites across Australia, Greece, India, The Netherlands, Poland, Puerto Rico, and the United States. Male and female patients aged 35 to 75 years with type 2 diabetes mellitus and an HbA(1c) level of 6.5% to 11.0%, who were receiving metformin and/or a sulfonylurea with a stable dose of 0 to 2 daily insulin injections over the previous 3 months were eligible. Patients were randomly assigned to receive LM50/50 (50% insulin lispro protamine suspension [ILPS] and 50% lispro) TID plus metformin (to a maximally tolerated daily dosage of 500-1000 mg BID) (LM50/50 + Met) or insulin glargine QD at bedtime plus metformin (500-1000 mg BID) (G + Met) for 24 weeks. With LM50/50 + Met, the insulin dose was titrated to target a fasting BG (FBG) level of <6.7 mmol/L (<120 mg/dL) and a 2-hour post-prandial BG (PPBG) level of <8.0 mmol/L (<144 mg/dL); those who did not reach the FBG target would be switched from presupper LM50/50 to LM75/25 (75% ILPS, 25% lispro). A total of 315 patients were randomized and received treatment (158

Design of insulin analogues for meal-related therapy.

PubMed

Brange, J

1993-01-01

The human insulin in replacement therapy has a hexameric structure. Hexamerization of the insulin molecule facilitates biosynthesis and beta-cell storage of insulin, but is unnecessary for biologic activity and appears to contribute to delayed absorption of exogenous insulin from the subcutis. Insulin analogues with reduced self-association that are produced through recombinant DNA techniques have been shown to have in vivo activity comparable to that of human insulin and absorption kinetics characterized by higher and more constant rates of disappearance from the subcutaneous injection site. In preliminary studies in patients receiving insulin therapy, monomeric insulin analogues have been found to provide glycemic control in the postprandial period that is at least equivalent to that of human insulin. Findings in these studies suggest that the use of such analogues may provide meal-related insulin effects closer to those observed in the physiologic state by limiting excessive postprandial glucose excursions and decreasing the risk of late hypoglycemia. Banting and Best revolutionized diabetes therapy 70 years ago with the extraction of insulin from animal pancreas glands (J Lab Clin Med 7:464-472, 1922). Since that time, many refinements of the therapeutic properties of pharmaceutical preparations of the hormone have been introduced. Until recently, however, such advances have been limited to improvements in insulin purity, insulin species, and adjustment of the composition of the vehicle with respect to auxiliary substances and other additives. With the advent of recombinant DNA techniques, it has become possible to optimize the insulin molecule itself for purposes of replacement therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Commentary on “Performance of a Glucose Meter with a Built-In Automated Bolus Calculator versus Manual Bolus Calculation in Insulin-Using Subjects”

PubMed Central

Rossetti, Paolo; Vehí, Josep; Revert, Ana; Calm, Remei; Bondia, Jorge

2012-01-01

Since the early 2000s, there has been an exponentially increasing development of new diabetes-applied technology, such as continuous glucose monitoring, bolus calculators, and “smart” pumps, with the expectation of partially overcoming clinical inertia and low patient compliance. However, its long-term efficacy in glucose control has not been unequivocally proven. In this issue of Journal of Diabetes Science and Technology, Sussman and colleagues evaluated a tool for the calculation of the prandial insulin dose. A total of 205 insulin-treated patients were asked to compute a bolus dose in two simulated conditions either manually or with the bolus calculator built into the FreeStyle InsuLinx meter, revealing the high frequency of wrong calculations when performed manually. Although the clinical impact of this study is limited, it highlights the potential implications of low diabetes-related numeracy in poor glycemic control. Educational programs aiming to increase patients’ empowerment and caregivers’ knowledge are needed in order to get full benefit of the technology. PMID:22538145

Switching to insulin glargine 300 U/mL: is duration of prior basal insulin therapy important?

PubMed

Bonadonna, Riccardo C; Renard, Eric; Cheng, Alice; Fritsche, Andreas; Cali, Anna; Melas-Melt, Lydie; Umpierrez, Guillermo E

2018-04-09

To assess the impact of duration of prior basal insulin therapy on study outcomes in people with type 2 diabetes mellitus receiving insulin glargine 300 U/mL (Gla-300) or insulin glargine 100 U/mL (Gla-100) for 6 months. A post hoc patient-level meta-analysis of data from the EDITION 1 and 2 studies. Outcomes included: HbA 1c , percentage of participants with ≥1 confirmed or severe hypoglycaemic event at night (00:00-05:59 h) or any time (24 h), and body weight change. Data were analysed according to duration of prior basal insulin use: >0-≤2 years, >2-≤5 years, >5 years. This meta-analysis included 1618 participants. HbA 1c change from baseline to month 6 was comparable between Gla-300 and Gla-100 groups, regardless of duration of prior basal insulin therapy. The lower risk with Gla-300 versus Gla-100 of ≥1 confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemic event, at night or any time (24 h), was unaffected by duration of prior basal insulin therapy. Similarly, weight change was unaffected by duration of prior basal insulin therapy. Switching to Gla-300 from other basal insulin therapies provided comparable glycaemic control with lower risk of hypoglycaemia versus Gla-100, regardless of duration of prior basal insulin therapy. Copyright © 2018. Published by Elsevier B.V.

[Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy].

PubMed

Pesić, Milica; Zivić, Sasa; Radenković, Sasa; Velojić, Milena; Dimić, Dragan; Antić, Slobodan

2007-04-01

Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin) for basal insulin supply in patients with type 1 diabetes. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IT) were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15); 2. NPH insulin twice daily (n = 15); 3. insulin glargine once daily (n = 18). Meal time insulin aspart was continued in all groups. Fasting blood glucose (FBG) was lower in the glargine group (7.30+/-0.98 mmol/1) than in the twice daily NPH group (7.47+/-1.06 mmol/1), but without significant difference. FBG was significantly higher in the once daily NPH group (8.44+/-0.85 mmol/l; p < 0.05). HbAlc after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72+/-0.86% to 6.87+/-0.50%), as well as in the twice daily NPH group (from 7.80+/-0.83% to 7.01+/-0.63%). Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56+/-2.09) than in both NPH groups (9.0+/-1.65 in twice daily NPH group and 8.13+/-1.30 in other NPH group) (episodes/patients-month, p < 0.05). Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbAlc and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

A Comparison of Inpatient Cost Per Day in General Surgery Patients with Type 2 Diabetes Treated with Basal-Bolus versus Sliding Scale Insulin Regimens.

PubMed

Phillips, Victoria L; Byrd, Anwar L; Adeel, Saira; Peng, Limin; Smiley, Dawn D; Umpierrez, Guillermo E

2017-01-01

The identification of cost-effective glycaemic management strategies is critical to hospitals. Treatment with a basal-bolus insulin (BBI) regimen has been shown to result in better glycaemic control and fewer complications than sliding scale regular insulin (SSI) in general surgery patients with type 2 diabetes mellitus (T2DM), but the effect on costs is unknown. We conducted a post hoc analysis of the RABBIT Surgery trial to examine whether total inpatient costs per day for general surgery patients with T2DM treated with BBI ( n  = 103) differed from those for patients with T2DM treated with SSI ( n  = 99) regimens. Data were collected from patient clinical and hospital billing records. Charges were adjusted to reflect hospital costs. General linearized models were used to estimate the risk-adjusted effects of BBI versus SSI treatment on average total inpatient costs per day. Risk-adjusted average total inpatient costs per day were $US5404. Treatment with BBI compared with SSI reduced average total inpatient costs per day by $US751 (14%; 95% confidence interval [CI] 20-4). Being treated in a university medical centre, being African American or having a bowel procedure or higher-volume pharmacy use significantly reduced costs per day. In general surgery patients with T2DM, a BBI regimen significantly reduced average total hospital costs per day compared with an SSI regimen. BBI has been shown to improve outcomes in a randomized controlled trial. Those results, combined with our findings regarding savings, suggest that hospitals should consider adopting BBI regimens in patients with T2DM undergoing surgery.

Continuous subcutaneous insulin infusion: Special needs for children.

PubMed

Adolfsson, Peter; Ziegler, Ralph; Hanas, Ragnar

2017-06-01

Continuous subcutaneous insulin infusion (CSII) is a very common therapy for children with type 1 diabetes. Due to physiological differences they have other requirements for their insulin pump than adults. The main difference is the need for very low basal rates. Even though most available insulin pumps reach a high accuracy at usual basal rates, accuracy decreases for lower rates. In addition, the lowest delivered amount at 1 time is limiting the fine tuning of the basal rate as well as the option for temporary basal rates. Alarms in case of occlusions depend on accumulation of a certain amount of insulin in the catheter, and therefore the time until such an alarm is triggered is much longer with lower basal rates. Accordingly, the risk for hyperglycemia developing into diabetic ketoacidosis increases. The availability of bolus advisors facilitates the calculation of meal and correction boluses for children and their parents. However, there are some differences between the calculators, and the settings that the calculation is based on are very important. Better connectivity, for example with a system for continuous glucose monitoring, might help to further increase safety in the use of CSII in children. When selecting an insulin pump for a child, the features and characteristics of available pumps should be properly compared to ensure an effective and safe therapy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Health economic evaluations comparing insulin glargine with NPH insulin in patients with type 1 diabetes: a systematic review

PubMed Central

2011-01-01

Background Compared to conventional human basal insulin (neutral protamine Hagedorn; NPH) the long-acting analogue insulin glargine (GLA) is associated with a number of advantages regarding metabolic control, hypoglycaemic events and convenience. However, the unit costs of GLA exceed those of NPH. This study aims to systematically review the economic evidence comparing GLA with NPH in basal-bolus treatment (intensified conventional therapy; ICT) of type 1 diabetes in order to facilitate informed decision making in clinical practice and health policy. Methods A systematic literature search was performed for the period of January 1st 2000 to December 1st 2009 via Embase, Medline, the Cochrane Library, the databases GMS (German Medical Science) and DAHTA (Deutsche Agentur für Health Technology Assessment), and the abstract books of relevant international scientific congresses. Retrieved studies were reviewed based on predefined inclusion criteria, methodological and quality aspects. In order to allow comparison between studies, currencies were converted using purchasing power parities (PPP). Results A total of 7 health economic evaluations from 4 different countries fulfilled the predefined criteria: 6 modelling studies, all of them cost-utility analyses, and one claims data analysis with a cost-minimisation design. One cost-utility analysis showed dominance of GLA over NPH. The other 5 cost-utility analyses resulted in additional costs per quality adjusted life year (QALY) gained for GLA, ranging from € 3,859 to € 57,002 (incremental cost effectiveness ratio; ICER). The cost-minimisation analysis revealed lower annual diabetes-specific costs in favour of NPH from the perspective of the German Statutory Health Insurance (SHI). Conclusions The incremental cost-utility-ratios (ICER) show favourable values for GLA with considerable variation. If a willingness-to-pay threshold of £ 30,000 (National Institute of Clinical Excellence, UK) is adopted, GLA is cost

Lixisenatide plus basal insulin in patients with type 2 diabetes mellitus: a meta-analysis.

PubMed

Charbonnel, Bernard; Bertolini, Monica; Tinahones, Francisco J; Domingo, Manuel Puig; Davies, Melanie

2014-01-01

The efficacy of the once-daily prandial GLP-1 receptor agonist lixisenatide plus basal insulin in T2DM was assessed by pooling results of phase III trials. A meta-analysis was performed of results from three trials in the GetGoal clinical program concerning lixisenatide or placebo plus basal insulin with/without OADs. The primary endpoint was change in HbA1c from baseline to week 24. Secondary endpoints were change in PPG, FPG, insulin dose, and weight from baseline to week 24. Hypoglycemia rates and several composite endpoints were assessed. Lixisenatide plus basal insulin was significantly more effective than basal insulin alone at reducing HbA1c at 24 weeks. Composite and secondary endpoints were improved significantly with lixisenatide plus basal insulin, with the exception of FPG, which showed no significant difference between the groups. Lixisenatide plus basal insulin was associated with an increased incidence of hypoglycemia versus basal insulin alone. Lixisenatide plus basal insulin resulted in significant improvement in glycemic control versus basal insulin alone, particularly in terms of controlling PPG. Prandial lixisenatide in combination with basal insulin is a suitable option for treatment intensification in patients with T2DM insufficiently controlled with basal insulin, as these agents have complementary effects on PPG and FPG, respectively. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Insulin biosimilars: the impact on rapid-acting analogue-based therapy.

PubMed

Franzè, S; Cilurzo, F; Minghetti, P

2015-04-01

The impending expiration of patent protection for recombinant insulins provides the opportunity to introduce cost-saving copies, named biosimilars, onto the market. Although there is broad experience in the production and characterisation of insulins, the development of copies is still a challenge. In this paper, the main features of insulins and the EU regulatory framework for their biosimilar products are reviewed. The main focus is on rapid-acting insulin analogues (Humalog(®); Novolog(®)/NovoRapid(®); Apidra(®)). Since they differ by one or two amino acids in chain B, production of one biosimilar for all three drug products is not feasible. However, from post-marketing-collected clinical data, rapid-acting insulin analogues seem to have similar therapeutic efficacy. It is reasonable to suppose that, for prescription to treatment-naïve patients, the cheaper biosimilar would be the preferred choice of physicians, either spontaneously or induced by health insurance. Therefore, its introduction will affect the market share of all the other rapid-acting insulin analogues.

Challenges and unmet needs in basal insulin therapy: lessons from the Asian experience.

PubMed

Chan, Wing Bun; Chen, Jung Fu; Goh, Su-Yen; Vu, Thi Thanh Huyen; Isip-Tan, Iris Thiele; Mudjanarko, Sony Wibisono; Bajpai, Shailendra; Mabunay, Maria Aileen; Bunnag, Pongamorn

2017-01-01

Basal insulin therapy can improve glycemic control in people with type 2 diabetes. However, timely initiation, optimal titration, and proper adherence to prescribed basal insulin regimens are necessary to achieve optimal glycemic control. Even so, glycemic control may remain suboptimal in a significant proportion of patients. Unique circumstances in Asia (eg, limited resources, management of diabetes primarily in nonspecialist settings, and patient populations that are predominantly less educated) coupled with the limitations of current basal insulin options (eg, risk of hypoglycemia and dosing time inflexibility) amplify the challenge of optimal basal insulin therapy in Asia. Significant progress has been made with long-acting insulin analogs (insulin glargine 100 units/mL and insulin detemir), which provide longer coverage and less risk of hypoglycemia over intermediate-acting insulin (Neutral Protamine Hagedorn insulin). Furthermore, recent clinical evidence suggests that newer long-acting insulin analogs, new insulin glargine 300 units/mL and insulin degludec, may address some of the unmet needs of current basal insulin options in terms of risk of hypoglycemia and dosing time inflexibility. Nevertheless, more can be done to overcome barriers to basal insulin therapy in Asia, through educating both patients and physicians, developing better patient support models, and improving accessibility to long-acting insulin analogs. In this study, we highlight the unique challenges associated with basal insulin therapy in Asia and, where possible, propose strategies to address the unmet needs by drawing on clinical experiences and perspectives in Asia.

Challenges and unmet needs in basal insulin therapy: lessons from the Asian experience

PubMed Central

Chan, Wing Bun; Chen, Jung Fu; Goh, Su-Yen; Vu, Thi Thanh Huyen; Isip-Tan, Iris Thiele; Mudjanarko, Sony Wibisono; Bajpai, Shailendra; Mabunay, Maria Aileen; Bunnag, Pongamorn

2017-01-01

Basal insulin therapy can improve glycemic control in people with type 2 diabetes. However, timely initiation, optimal titration, and proper adherence to prescribed basal insulin regimens are necessary to achieve optimal glycemic control. Even so, glycemic control may remain suboptimal in a significant proportion of patients. Unique circumstances in Asia (eg, limited resources, management of diabetes primarily in nonspecialist settings, and patient populations that are predominantly less educated) coupled with the limitations of current basal insulin options (eg, risk of hypoglycemia and dosing time inflexibility) amplify the challenge of optimal basal insulin therapy in Asia. Significant progress has been made with long-acting insulin analogs (insulin glargine 100 units/mL and insulin detemir), which provide longer coverage and less risk of hypoglycemia over intermediate-acting insulin (Neutral Protamine Hagedorn insulin). Furthermore, recent clinical evidence suggests that newer long-acting insulin analogs, new insulin glargine 300 units/mL and insulin degludec, may address some of the unmet needs of current basal insulin options in terms of risk of hypoglycemia and dosing time inflexibility. Nevertheless, more can be done to overcome barriers to basal insulin therapy in Asia, through educating both patients and physicians, developing better patient support models, and improving accessibility to long-acting insulin analogs. In this study, we highlight the unique challenges associated with basal insulin therapy in Asia and, where possible, propose strategies to address the unmet needs by drawing on clinical experiences and perspectives in Asia. PMID:29276400

Evaluation of the incremental cost to the National Health Service of prescribing analogue insulin

PubMed Central

Holden, Sarah E; Poole, Chris D; Morgan, Christopher Ll

2011-01-01

Introduction Insulin analogues have become increasingly popular despite their greater cost compared with human insulin. The aim of this study was to calculate the incremental cost to the National Health Service (NHS) of prescribing analogue insulin preparations instead of their human insulin alternatives. Methods Open-source data from the four UK prescription pricing agencies from 2000 to 2009 were analysed. Cost was adjusted for inflation and reported in UK pounds at 2010 prices. Results Over the 10-year period, the NHS spent a total of £2732 million on insulin. The total annual cost increased from £156 million to £359 million, an increase of 130%. The annual cost of analogue insulin increased from £18.2 million (12% of total insulin cost) to £305 million (85% of total insulin cost), whereas the cost of human insulin decreased from £131 million (84% of total insulin cost) to £51 million (14% of total insulin cost). If it is assumed that all patients using insulin analogues could have received human insulin instead, the overall incremental cost of analogue insulin was £625 million. Conclusion Given the high marginal cost of analogue insulin, adherence to prescribing guidelines recommending the preferential use of human insulin would have resulted in considerable financial savings over the period. PMID:22021891

Comparable Efficacy and Safety of Insulin Glulisine and Insulin Lispro When Given as Part of a Basal–Bolus Insulin Regimen in a 26-Week Trial in Pediatric Patients with Type 1 Diabetes

PubMed Central

Arslanian, Silva; Blatniczky, László; Peterkova, Valentina; Souhami, Elisabeth; Danne, Thomas

2011-01-01

Abstract Background We compared the efficacy and safety of insulin glulisine with insulin lispro as part of a basal–bolus regimen in children and adolescents with type 1 diabetes. Methods Overall, 572 children and adolescents (4–17 years old) using insulin glargine or neutral protamine Hagedorn insulin as basal insulin were enrolled in a 26-week, multicenter, open, centrally randomized, parallel-group, noninferiority study. Subjects were randomized to receive glulisine (n = 277) or lispro (n = 295) 0–15 min premeal. Results Baseline-to-endpoint hemoglobin A1c changes were similar between the two insulins: adjusted mean change (glulisine vs. lispro), 0.10% versus 0.16%; between-treatment difference (glulisine–lispro), &minsu;0.06, 95% confidence interval (−0.24; 0.12); and prespecified noninferiority margin, 0.4%. Overall, for all age groups together, the percentage of patients achieving American Diabetes Association age-specific A1c targets at endpoint was significantly higher (P = 0.039) with glulisine (38.4%) versus lispro (32.0%). From Month 4 to endpoint, both “all” and “severe” symptomatic hypoglycemia rates were similar (3.10 vs. 2.91 and 0.06 vs. 0.07 events/patient-month, respectively). Frequency and type of adverse events, serious adverse events, or hypoglycemia reported as serious adverse events were similar between both groups. Conclusions Glulisine was as effective as lispro in baseline-to-endpoint A1c change, and both treatments were similarly well tolerated. PMID:21291333

Clinical use of the co-formulation of insulin degludec and insulin aspart.

PubMed

Kumar, A; Awata, T; Bain, S C; Ceriello, A; Fulcher, G R; Unnikrishnan, A G; Arechavaleta, R; Gonzalez-Gálvez, G; Hirose, T; Home, P D; Kaku, K; Litwak, L; Madsbad, S; Pinget, M; Mehta, R; Mithal, A; Tambascia, M; Tibaldi, J; Christiansen, J S

2016-08-01

To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins. © 2016 John Wiley & Sons Ltd.

Correlates of basal insulin persistence among insulin-naïve people with type 2 diabetes: results from a multinational survey.

PubMed

Peyrot, Mark; Perez-Nieves, Magaly; Ivanova, Jasmina; Cao, Dachuang; Schmerold, Luke; Kalirai, Samaneh; Hadjiyianni, Irene

2017-10-01

People with T2DM who initiate basal insulin therapy often stop therapy temporarily or permanently soon after initiation. This study analyzes the reasons for and correlates of stopping and restarting basal insulin therapy among people with T2DM. An online survey was completed by 942 insulin-naïve adults with self-reported T2DM from Brazil, France, Germany, Japan, Spain, UK, and US. Respondents had initiated basal insulin therapy within the 3-24 months before survey participation and met criteria for one of three persistence groups: continuers had no gaps of ≥7 days in basal insulin treatment; interrupters had at least one gap in insulin therapy of ≥7 days within the first 6 months after initiation and had since restarted basal insulin; and discontinuers stopped using basal insulin within the first 6 months after initiation and had not restarted. Physician recommendations and cost were strongly implicated in patients stopping and not resuming insulin therapy. Continuous persistence was lower for patients with more worries about insulin initiation, greater difficulties and weight gain while using insulin, and higher for those using pens and perceiving their diabetes as severe. Repeated interruption of insulin therapy was associated with hyperglycemia and treatment burden while using insulin. Resumption and perceived likelihood of resumption were associated with hyperglycemia upon insulin cessation. Perceived likelihood of resumption among discontinuers was associated with perceived benefits of insulin. Better understanding of the risk factors for patient cessation and resumption of basal insulin therapy may help healthcare providers improve persistence with therapy.

Cysteine analogues potentiate glucose-induced insulin release in vitro

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

Ammon, H.P.; Hehl, K.H.; Enz, G.

1986-12-01

In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhancemore » insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.« less

A Randomized Controlled Study of an Insulin Dosing Application That Uses Recognition and Meal Bolus Estimations

PubMed Central

Pańkowska, Ewa; Ładyżyński, Piotr; Foltyński, Piotr; Mazurczak, Karolina

2016-01-01

Background: Throughout the insulin pump therapy, decisions of prandial boluses programming are taken by patients individually a few times every day, and, moreover, this complex process requires numerical skills and knowledge in nutrition components estimation. The aim of the study was to determine the impact of the expert system, supporting the patient’s decision on meal bolus programming, on the time in range of diurnal glucose excursion in patients treated with continuous subcutaneous insulin infusion (CSII). Methods: The crossover, randomized study included 12 adults, aged 19 to 53, with type 1 diabetes mellitus, duration ranging from 7 to 30 years. Patients were educated in complex food counting, including carbohydrate units (CU) and fat-protein units (FPU). Subsequently, they were randomly allocated to the experimental group (A), which used the expert software named VoiceDiab, and the control group (B), using a manual method of meal-bolus estimation. Results: It was found that 66.7% of patients within the A group statistically reported a relevant increase in the percentage (%) of sensor glucose (SG) in range (TIR 70-180 mg/dl), compared to the B group. TIR (median) reached 53.9% in the experimental group (A) versus 44% within the control group (B), P < .05. The average difference in the number of hypoglycemia episodes was not statistically significant (–0.2%, SD 11.6%, P = .93). The daily insulin requirement in both groups was comparable—the average difference in total daily insulin dose between two groups was 0.26 (SD 7.06 IU, P = .9). Conclusion: The expert system in meal insulin dosing allows improvement in glucose control without increasing the rates of hypoglycemia or the insulin requirement. PMID:28264177

In vitro and in vivo potency of insulin analogues designed for clinical use.

PubMed

Vølund, A; Brange, J; Drejer, K; Jensen, I; Markussen, J; Ribel, U; Sørensen, A R; Schlichtkrull, J

1991-11-01

Analogues of human insulin designed to have improved absorption properties after subcutaneous injection have been prepared by recombinant DNA technology. Five rapidly absorbed analogues, being predominantly in mono- or di-meric states in the pharmaceutical preparation, and a hexameric analogue with very low solubility at neutral pH and slow absorption, were studied. Receptor binding assays with HEP-G2 cells showed overall agreement with mouse free adipocyte assays. Two analogues, B28Asp and A21Gly + B27Arg + B30Thr-NH2, had nearly the same molar in vitro potency as human insulin. Another two showed increased adipocyte potency and receptor binding, B10Asp 194% and 333% and A8His + B4His + B10Glu + B27His 575% and 511%, while B9Asp + B27Glu showed 29% and 18% and the B25Asp analogue only 0.12% and 0.05% potency. Bioassays in mice or rabbits of the analogues except B25Asp showed that they had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation in in vivo potency reflects the differences in receptor binding affinity. Relative to human insulin a low concentration is sufficient for a high affinity analogue to produce a given receptor complex formation and metabolic response. In conclusion, human insulin and analogues with markedly different in vitro potencies were equipotent in terms of hypoglycaemic effect. This is in agreement with the concept that elimination of insulin from blood and its subsequent degradation is mediated by insulin receptors.

A retrospective database analysis of insulin use patterns in insulin-naïve patients with type 2 diabetes initiating basal insulin or mixtures

PubMed Central

Bonafede, Machaon MK; Kalsekar, Anupama; Pawaskar, Manjiri; Ruiz, Kimberly M; Torres, Amelito M; Kelly, Karen R; Curkendall, Suellen M

2010-01-01

Objective: To describe insulin persistence among patients with type 2 diabetes initiating insulin therapy with basal insulin or insulin mixtures and determine factors associated with nonpersistence. Research design and methods: The Thomson Reuters MarketScan® databases were used to retrospectively analyze insulin-naïve patients with type 2 diabetes by initiating insulin therapy. Insulin use was described using a variety of measures. The persistence to insulin was described using both a gap-based measure and the number of claims measure. Results: Patients in the basal insulin cohort (N = 15,255) primarily used insulin analogs (88.1%) and vial and syringe (97%). Patients in the mixture cohort (N = 2,732) were more likely to initiate on human insulin mixtures (62.5%) and vial and syringe (68.1%). Average time between insulin refills was 80 and 71 days for basal and mixture initiators, respectively. Nearly, 75% of basal insulin initiators and 65% of insulin mixture initiators had a 90-day gap in insulin prescriptions. More than half of all the patients had at least one insulin prescription per quarter. Patients initiating with insulin analogs were more likely to be persistent compared with those initiating with human insulin across both cohorts and measures of persistence (P < 0.001). Conclusion: Persistence to insulin therapy is poorer than one would anticipate, but appears to be higher in users of insulin analogs and insulin mixtures. PMID:20622915

Effect of bromocriptine-QR therapy on glycemic control in subjects with type 2 diabetes mellitus whose dysglycemia is inadequately controlled on insulin.

PubMed

Chamarthi, Bindu; Cincotta, Anthony H

2017-05-01

The concurrent use of an insulin sensitizer in type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control on basal-bolus insulin may help improve glycemic control while limiting further insulin requirement. Bromocriptine-QR (B-QR), a quick release, sympatholytic, dopamine D2 receptor agonist therapy for T2DM, is a postprandial insulin sensitizer. This study evaluated the effect of B-QR on dysglycemia in T2DM subjects with suboptimal glycemic control on basal-bolus insulin plus metformin. The effect of once-daily morning administration of B-QR on dysglycemia was evaluated in 60 T2DM subjects derived from the Cycloset Safety Trial, with HbA1c >7% on basal-bolus insulin plus metformin at baseline, randomized to B-QR (N = 44) versus placebo (N = 16) and completed 12 weeks of study drug treatment. The analyses also included a subset of subjects on high-dose insulin (total daily insulin dose (TDID) ≥70 units; N = 36: 27 B-QR; 9 placebo). Subjects were well matched at baseline. After 12 weeks of B-QR treatment, mean % HbA1c decreased by -0.73% relative to baseline (p < 0.001) and by -1.13 relative to placebo (p < 0.001). In the high-dose insulin subset, B-QR therapy resulted in % HbA1c reductions of -0.95 and -1.49 relative to baseline (p < 0.001) and placebo (p = 0.001) respectively. Secondary analyses of treatment effect at 24 and 52 weeks demonstrated similar influences of B-QR on HbA1c. The fasting plasma glucose (FPG) and TDID changes within each treatment group were not significant. More subjects achieved HbA1c ≤7 at 12 weeks with B-QR relative to placebo (36.4% B-QR vs 0% placebo, Fisher's exact 2-sided p = 0.003 in the entire cohort and 37% vs 0%, 2-sided p = 0.039 in the high-dose insulin subset). B-QR therapy improves glycemic control in T2DM subjects whose glycemia is poorly controlled on metformin plus basal-bolus insulin, including individuals on high-dose basal-bolus insulin. This glycemic impact occurred without

Insulin detemir: a review of its use in the management of diabetes mellitus.

PubMed

Keating, Gillian M

2012-12-03

Insulin detemir (Levemir®) is a long-acting insulin analogue indicated for use as basal insulin therapy in patients with type 1 or 2 diabetes mellitus. The protracted action of insulin detemir is explained by increased self-association and reversible binding to albumin, which slows its systemic absorption from the injection site. In glucose-clamp studies, less within-patient variability in glucose-lowering effect was seen with insulin detemir than with neutral protamine Hagedorn (NPH) insulin or insulin glargine in patients with type 1 or 2 diabetes. The beneficial effect of insulin detemir on glycaemic control was shown in numerous randomized, open-label, multicentre trials, including when used as basal-bolus therapy in patients with type 1 or 2 diabetes and as basal therapy in addition to oral antidiabetic drugs in insulin-naive patients with type 2 diabetes. In terms of glycosylated haemoglobin (HbA(1c)).[primary endpoint in most trials], insulin detemir was generally at least as effective as NPH insulin, insulin glargine or insulin lispro protamine suspension in patients with type 1 or 2 diabetes, and at least as effective as biphasic insulin aspart in patients with type 2 diabetes. Less within-patient variability in blood glucose was also generally seen with insulin detemir than with NPH insulin in patients with type 1 or 2 diabetes. Significantly less weight gain was generally seen with insulin detemir than with NPH insulin in patients with type 1 diabetes or with insulin detemir than with NPH insulin, insulin glargine, insulin lispro protamine suspension or biphasic insulin aspart (in one study) in patients with type 2 diabetes (i.e. insulin detemir generally had a weight-sparing effect). The addition of insulin detemir to liraglutide plus metformin improved glycaemic control in insulin-naive patients with type 2 diabetes and inadequate glycaemic control, although a significantly greater reduction in bodyweight was seen in patients receiving liraglutide

Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus.

PubMed

Fullerton, Birgit; Siebenhofer, Andrea; Jeitler, Klaus; Horvath, Karl; Semlitsch, Thomas; Berghold, Andrea; Plank, Johannes; Pieber, Thomas R; Gerlach, Ferdinand M

2016-06-30

Short-acting insulin analogue use for people with diabetes is still controversial, as reflected in many scientific debates. To assess the effects of short-acting insulin analogues versus regular human insulin in adults with type 1 diabetes. We carried out the electronic searches through Ovid simultaneously searching the following databases: Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to 14 April 2015), EMBASE (1988 to 2015, week 15), the Cochrane Central Register of Controlled Trials (CENTRAL; March 2015), ClinicalTrials.gov and the European (EU) Clinical Trials register (both March 2015). We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues with regular human insulins in the treatment of adults with type 1 diabetes who were not pregnant. Two review authors independently extracted data and assessed trials for risk of bias, and resolved differences by consensus. We graded overall study quality using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. We used random-effects models for the main analyses and presented the results as odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes. We identified nine trials that fulfilled the inclusion criteria including 2693 participants. The duration of interventions ranged from 24 to 52 weeks with a mean of about 37 weeks. The participants showed some diversity, mainly with regard to diabetes duration and inclusion/exclusion criteria. The majority of the trials were carried out in the 1990s and participants were recruited from Europe, North America, Africa and Asia. None of the trials was carried out in a blinded manner so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the trials. Furthermore, several trials showed inconsistencies in

Continuous Glucose Monitoring During Basal-Bolus Therapy Using Insulin Glargine 300 U mL(-1) and Glargine 100 U mL (-1) in Japanese People with Type 1 Diabetes Mellitus: A Crossover Pilot Study.

PubMed

Jinnouchi, Hideaki; Koyama, Masayoshi; Amano, Atsushi; Takahashi, Yoshinori; Yoshida, Akira; Hieshima, Kunio; Sugiyama, Seigo; Kurinami, Noboru; Jinnouchi, Tomio; Becker, Reinhard

2015-06-01

New insulin glargine 300 U mL(-1) (Gla-300) is a basal insulin that shows more stable and prolonged pharmacokinetic and pharmacodynamic profiles than insulin glargine 100 U mL(-1) (Gla-100). This study used continuous glucose monitoring (CGM) to compare 24-h glucose profiles in a Japanese population using Gla-300 versus Gla-100. This was an exploratory 8.4-week, single-center, 2-sequence, 2-period, open-label crossover study. Japanese adults with type 1 diabetes mellitus (T1DM) treated with basal-bolus insulin, with glycated hemoglobin (HbA1c) 6.5-10.0% and median fasting self-monitored plasma glucose concentration ≤13 mmol L(-1), were randomized to Gla-300 followed by Gla-100 (subgroup 1) or vice versa (subgroup 2), with no washout period. CGM was performed on the last 3 days of the screening period and each treatment period. Primary endpoint was comparison of 24-h glucose variability (area under the curve [AUC]mean_24 h) on the second day of each CGM measurement with Gla-300 versus Gla-100. Baseline and end of treatment period values for HbA1c, fasting plasma glucose (FPG) and daily basal/mealtime insulin doses were recorded. Hypoglycemia and adverse events (AEs) were recorded. Twenty participants were randomized (10 to subgroup 1 and 10 to subgroup 2). Participants showed comparable glucose variability over 24 h (AUCmean_24 h during treatment with Gla-300 or Gla-100 (treatment ratio 0.96; 90% confidence interval 0.79, 1.16). HbA1c and FPG were generally stable across both treatment periods. There was a trend towards fewer participants experiencing ≥1 hypoglycemia event at any time (24 h) and at night (00:00-05:59 h) with Gla-300 versus Gla-100. Treatment-emergent AEs, reported by 9/20 (45%) and 4/20 (20%) participants during Gla-300 and Gla-100 treatment, respectively, were unrelated to study medication. In this cohort of Japanese people with T1DM, no between-treatment difference was observed in glucose variability with Gla-300 versus Gla-100, as

Carbohydrate-to-insulin ratio is estimated from 300-400 divided by total daily insulin dose in type 1 diabetes patients who use the insulin pump.

PubMed

Kuroda, Akio; Yasuda, Tetsuyuki; Takahara, Mitsuyoshi; Sakamoto, Fumie; Kasami, Ryuichi; Miyashita, Kazuyuki; Yoshida, Sumiko; Kondo, Eri; Aihara, Ken-ichi; Endo, Itsuro; Matsuoka, Taka-aki; Kaneto, Hideaki; Matsumoto, Toshio; Shimomura, Iichiro; Matsuhisa, Munehide

2012-11-01

To optimize insulin dose using insulin pump, basal and bolus insulin doses are widely calculated from total daily insulin dose (TDD). It is recommended that total daily basal insulin dose (TBD) is 50% of TDD and that the carbohydrate-to-insulin ratio (CIR) equals 500 divided by TDD. We recently reported that basal insulin requirement is approximately 30% of TDD. We therefore investigated CIR after adjustment of the proper basal insulin rate. Forty-five Japanese patients with type 1 diabetes were investigated during several weeks of hospitalization. The patients were served standard diabetes meals (25-30 kcal/kg of ideal body weight). Each meal omission was done to confirm basal insulin rate. Target blood glucose level was set at 100 and 150 mg/dL before and 2 h after each meal, respectively. After the basal insulin rate was fixed and target blood glucose levels were achieved, TBD, CIR, TDD, and their products were determined. Mean (±SD) blood glucose levels before and 2 h after meals were 121±47 and 150±61 mg/dL, respectively. TDD was 31.5±9.0 U, and TBD was 27.0±6.5% of TDD. CIR×TDD of breakfast was significantly lower than those of lunch and supper (288±73 vs. 408±92 and 387±83, respectively; P<0.01). CIR has diurnal variance and is estimated from the formula CIR=300/TDD at breakfast or CIR=400/TDD at lunch and supper in type 1 diabetes patients. These results indicate that the insulin dose has been underestimated by using previously established calculations.

Insulin appearance of subcutaneously infused insulin: influence of the basal rate pulse interval of the infusion pump.

PubMed

Birch, K; Hildebrandt, P; Jensen, B M; Kühl, C; Brange, J

1985-05-01

To compare the metabolic control and the pharmacokinetics of infused insulin using an insulin pump (Auto-Syringe AS 6C) which provides the basal rate in pulses every 2-10 min with a pump (Medix Syringe Driver 209) providing the basal rate in pulses every 15-60 min, 6 C-peptide negative diabetic patients received, in random order, identical, but individual, insulin treatment during one 4-day period using the Auto-Syringe pump and another 4-day period using the Medix pump. On the fourth day of each period, blood glucose and plasma-free insulin were estimated every 30 min for 7 hr and every 5 min for the next hour. Plasma-free insulin was significantly higher on 3 time points out of the 26 possible when using the Medix pump, but this was not reflected in the blood glucose concentrations which were similar in the 2 periods. The results indicate that, from a metabolic and pharmacokinetic point of view, insulin pumps working with larger intervals between the basal rate pulses are just as good as the more technically advanced and hence often more expensive pumps which provide the basal rate in more and smaller pulses.

The automatic regulation of the basal dose on the insulin pump for the treatment of patients that have diabetes type 1

PubMed Central

Mehanović, Sifet; Mujić, Midhat

2010-01-01

Diabetes mellitus type 1 is a chronic metabolic disorder, and its main characteristic is Hyperglycemia. It usually occurs in the early years because of the absolute or relative absence of the active insulin that is caused by the autoimmune disease of the β cells of the pancreas. Despite the numerous researches and efforts of the scientists, the therapy for Diabetes type 1 is based on the substitution of insulin. Even though the principles of the therapy have not changed so much, still some important changes have occurred in the production and usage of insulin. Lately, the insulin pumps are more frequent in the therapy for Diabetes type 1. The functioning of the pump is based on the continuing delivery of insulin in a small dose (“the basal dose”), that keeps the level of glycemia in the blood constant. The increase of glycemia during the meal is reduced with the additional dose of insulin (“the bolus dose”). The use of the insulin pumps and the continuing glucose sensors has provided an easier and more efficient monitoring of the diabetes, a better metabolic control and a better life quality for the patient and his/her family. This work presents the way of automatic regulation of the basal dose of insulin through the synthesis of the functions of the insulin pump and the continuing glucose sensor. The aim is to give a contribution to the development of the controlling algorithm on the insulin pump for the automatic regulation of the glucose concentration in the blood. This could be a step further which is closer to the delivery of the dose of insulin that is really needed for the basic needs of the organism, and a significant contribution is given to the development of the artificial pancreas. PMID:20507288

The automatic regulation of the basal dose on the insulin pump for the treatment of patients that have Diabetes type 1.

PubMed

Mehanović, Sifet; Mujić, Midhat

2010-05-01

Diabetes mellitus type 1 is a chronic metabolic disorder, and its main characteristic is Hyperglycemia. It usually occurs in the early years because of the absolute or relative absence of the active insulin that is caused by the autoimmune disease of the beta cells of the pancreas. Despite the numerous researches and efforts of the scientists, the therapy for Diabetes type 1 is based on the substitution of insulin. Even though the principles of the therapy have not changed so much, still some important changes have occurred in the production and usage of insulin. Lately, the insulin pumps are more frequent in the therapy for Diabetes type 1. The functioning of the pump is based on the continuing delivery of insulin in a small dose ("the basal dose"), that keeps the level of glycemia in the blood constant. The increase of glycemia during the meal is reduced with the additional dose of insulin ("the bolus dose"). The use of the insulin pumps and the continuing glucose sensors has provided an easier and more efficient monitoring of the diabetes, a better metabolic control and a better life quality for the patient and his/her family. This work presents the way of automatic regulation of the basal dose of insulin through the synthesis of the functions of the insulin pump and the continuing glucose sensor. The aim is to give a contribution to the development of the controlling algorithm on the insulin pump for the automatic regulation of the glucose concentration in the blood. This could be a step further which is closer to the delivery of the dose of insulin that is really needed for the basic needs of the organism, and a significant contribution is given to the development of the artificial pancreas.

Use of an Automated Bolus Calculator Reduces Fear of Hypoglycemia and Improves Confidence in Dosage Accuracy in Patients with Type 1 Diabetes Mellitus Treated with Multiple Daily Insulin Injections

PubMed Central

Barnard, Katharine; Parkin, Christopher; Young, Amanda; Ashraf, Mansoor

2012-01-01

Background Many patients do not intensify their insulin regimens. It is believed that lack of adherence may be largely due to fear of hypoglycemia. We hypothesized that utilization of an automated bolus calculator (bolus advisor) might reduce fear of hypoglycemia and encourage patients to achieve improved glycemic control. Method We surveyed 1,412 type 1 diabetes mellitus (T1DM) patients treated with multiple daily insulin injection therapy at 270 hospitals in the United Kingdom and Republic of Ireland to assess their attitudes and behaviors regarding insulin therapy after use of a bolus advisor (Accu-Chek® Aviva Expert blood glucose meter and bolus advisor system, Roche Diagnostics). The device automatically calculates bolus dosages based on current blood glucose values, anticipated meal intake, and other parameters. Results Five hundred eighty-eight T1DM patients responded to the survey. Respondents were predominantly female, age <1 to 70 years, with diabetes duration of <1 to >15 years. Respondents had 4–12 weeks prior experience using the bolus advisor. 76.7% of respondents indicated current bolus advisor use to calculate insulin boluses for meals/snacks always or quite often. 52.0% of respondents indicated that fear of hypoglycemia was reduced (39.0%) or significantly reduced (13.0%). 78.8% indicated that confidence in the insulin dose calculation improved (50.8%) or significantly improved (28.0%). 89.3% indicated that the bolus advisor made bolus calculation easy or very easy compared with manual calculation. Conclusions Most patients felt that using the bolus advisor was easier than manual bolus calculation, improved their confidence in the accuracy of their bolus dosage, and reduced their fear of hypoglycemia. Randomized trials are needed to confirm these perceptions and determine whether bolus advisor use improves clinical outcomes. PMID:22401332

An additional bolus of rapid-acting insulin to normalise postprandial cardiovascular risk factors following a high-carbohydrate high-fat meal in patients with type 1 diabetes: A randomised controlled trial.

PubMed

Campbell, Matthew D; Walker, Mark; Ajjan, Ramzi A; Birch, Karen M; Gonzalez, Javier T; West, Daniel J

2017-07-01

To evaluate an additional rapid-acting insulin bolus on postprandial lipaemia, inflammation and pro-coagulation following high-carbohydrate high-fat feeding in people with type 1 diabetes. A total of 10 males with type 1 diabetes [HbA 1c 52.5 ± 5.9 mmol/mol (7.0% ± 0.5%)] underwent three conditions: (1) a low-fat (LF) meal with normal bolus insulin, (2), a high-fat (HF) meal with normal bolus insulin and (3) a high-fat meal with normal bolus insulin with an additional 30% insulin bolus administered 3-h post-meal (HFA). Meals had identical carbohydrate and protein content and bolus insulin dose determined by carbohydrate-counting. Blood was sampled periodically for 6-h post-meal and analysed for triglyceride, non-esterified-fatty acids, apolipoprotein B48, glucagon, tumour necrosis factor alpha, fibrinogen, human tissue factor activity and plasminogen activator inhibitor-1. Continuous glucose monitoring captured interstitial glucose responses. Triglyceride concentrations following LF remained similar to baseline, whereas triglyceride levels following HF were significantly greater throughout the 6-h observation period. The additional insulin bolus (HFA) normalised triglyceride similarly to low fat 3-6 h following the meal. HF was associated with late postprandial elevations in tumour necrosis factor alpha, whereas LF and HFA was not. Fibrinogen, plasminogen activator inhibitor-1 and tissue factor pathway levels were similar between conditions. Additional bolus insulin 3 h following a high-carbohydrate high-fat meal prevents late rises in postprandial triglycerides and tumour necrosis factor alpha, thus improving cardiovascular risk profile.

Comparison of medication adherence in diabetes mellitus patients on human versus analogue insulins.

PubMed

Machado-Alba, Jorge Enrique; Medina-Morales, Diego Alejandro; Echeverri-Cataño, Luis Felipe

2017-02-01

Objetive: This study evaluated the results of treatment adherence scales in two cohorts of patients with diabetes mellitus treated either with human or analogue insulins. A cohort study was conducted in diabetes mellitus patients older than 18 that were being treated with human or analogue insulins. Two instruments were applied to each patient [medication possession ratio, Morisky-Green test] to evaluate treatment adherence. A total of 238 patients, were included. The majority (69.4%) of the subjects had human insulin and 30.6% had insulin analogue prescriptions. Out of the total, 163 (68.5%) cases were classified as adherent to therapy, according to the type of insulin, as follows: 69.9% for conventional and 65.3% for analogues; without differences between the groups (CI95%:0.450-1.458). The adherence to treatment was more probable in patients with elementary-secondary education (OR:2.341; CI95%:1.199-4.568) and less probable for those in the age range of 31-45 years (OR:0.427; CI95%:0.187-0.971). The results of this study show that there are no significant statistical differences in adherence when comparing human with analogue insulin therapy. Strategies to improve treatment adherence are particularly important since they improve the clinical results.

Systematic Review of the Cost Effectiveness of Insulin Analogues in Type 1 and Type 2 Diabetes Mellitus.

PubMed

Shafie, Asrul Akmal; Ng, Chin Hui; Tan, Yui Ping; Chaiyakunapruk, Nathorn

2017-02-01

Insulin analogues have a pharmacokinetic advantage over human insulin and are increasingly used to treat diabetes mellitus. A summary of their cost effectiveness versus other available treatments was required. Our objective was to systematically review the published cost-effectiveness studies of insulin analogues for the treatment of patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). We searched major databases and health technology assessment agency reports for economic evaluation studies published up until 30 September 2015. Two reviewers performed data extraction and assessed the quality of the data using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines. Seven of the included studies assessed short-acting insulin analogues, 12 assessed biphasic insulin analogues, 30 assessed long-acting insulin analogues and one assessed a combination of short- and long-acting insulin analogues. Only 17 studies involved patients with T1DM, all were modelling studies and 12 were conducted in Canada. The incremental cost-effectiveness ratios (ICERs) for short-acting insulin analogues ranged from dominant to $US435,913 per quality-adjusted life-year (QALY) gained, the ICERs for biphasic insulin analogues ranged from dominant to $US57,636 per QALY gained and the ICERs for long-acting insulin analogues ranged from dominant to $US599,863 per QALY gained. A total of 15 studies met all the CHEERS guidelines reporting quality criteria. Only 26 % of the studies assessed heterogeneity in their analyses. Current evidence indicates that insulin analogues are cost effective for T1DM; however, evidence for their use in T2DM is not convincing. Additional evidence regarding compliance and efficacy is required to support the broader use of long-acting and biphasic insulin analogues in T2DM. The value of insulin analogues depends strongly on reductions in hypoglycaemia event rates and its efficacy in lowering glycated haemoglobin

Siphon effects on continuous subcutaneous insulin infusion pump delivery performance.

PubMed

Zisser, Howard C; Bevier, Wendy; Dassau, Eyal; Jovanovic, Lois

2010-01-01

The objective was to quantify hydrostatic effects on continuous subcutaneous insulin infusion (CSII) pumps during basal and bolus insulin delivery. We tested CSII pumps from Medtronic Diabetes (MiniMed 512 and 515), Smiths Medical (Deltec Cozmo 1700), and Insulet (OmniPod) using insulin aspart (Novolog, Novo Nordisk). Pumps were filled and primed per manufacturer's instructions. The fluid level change was measured using an inline graduated glass pipette (100 microl) when the pipette was moved in relation to the pump (80 cm Cosmo and 110 cm Medtronics) and when level. Pumps were compared during 1 and 5 U boluses and basal insulin delivery of 1.0 and 1.5 U/h. Pronounced differences were seen during basal delivery in pumps using 80-100 cm tubing. For the 1 U/h rate, differences ranged from 74.5% of the expected delivery when the pumps were below the pipettes and pumping upward to 123.3% when the pumps were above the pipettes and pumping downward. For the 1.5 U/h rate, differences ranged from 86.7% to 117.0% when the pumps were below or above the pipettes, respectively. Compared to pumps with tubing, OmniPod performed with significantly less variation in insulin delivery. Changing position of a conventional CSII pump in relation to its tubing results in significant changes in insulin delivery. The siphon effect in the tubing may affect the accuracy of insulin delivery, especially during low basal rates. This effect has been reported when syringe pumps were moved in relation to infusion sites but has not been reported with CSII pumps. 2010 Diabetes Technology Society.

Pitfalls of insulin pump clocks: technical glitches that may potentially affect medical care in patients with diabetes.

PubMed

Aldasouqi, Saleh A; Reed, Amy J

2014-11-01

The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients' visits, and should remind their patients to always verify these settings. © 2014 Diabetes Technology Society.

Consensus on Insulin Dose and Titration Algorithms in Ambulatory Care of Type 2 Diabetes in India.

PubMed

Kovil, Rajiv; Chawla, Manoj; Rajput, Rajesh; Singh, A K; Sinha, Binayak; Ghosal, Samit; Ballani, Piya; Gupta, Sunil; Tanna, Snehal; Bandukwala, S M; Shah, Tejas; Negalur, Vijay; Bhoraskar, Anil; Aravind, S R; Zargar, Abdul H; Kesavadev, Jothydev; Das, Ashok Kumar

2017-02-01

Insulin is the oldest of the currently available treatment options in Type 2 diabetes mellitus (T2DM) and is considered as the most effective glucose lowering agent. Despite this, decision on starting insulin therapy is often delayed in India as well as worldwide due to various barriers at both patient and physician levels. Appropriate insulin dosing and titration is also critical to the successful achievement of tight glycaemic control. To provide simple and easily implementable guidelines to primary care physicians on appropriate insulin dosing and titration of various insulin regimens for both initiation and intensification. Each insulin regimen (once daily [OD] basal, OD, twice daily and thrice daily premixed, basal-plus and basal-bolus) was presented and evaluated for dosing and titration based on established guidelines, data from approved pack inserts, and published scientific literature. These evaluations were then factored into the national context based on the expert committee representatives patient-physician experience in their clinical practice and common therapeutic practices followed in India. Recommendations for dosing and titration of basal, basal-plus, premixed and basal-bolus insulins were developed. The key recommendations are that insulin doses can be adjusted once or twice weekly; adjustment can be based on lowest/mean of three recent self-monitoring of plasma glucose pre-meal/fasting plasma glucose (FPG) values. The titration should be based on FPG or pre-meal value of 80-130 mg/dL and the dose should be reduced by 10-20% for patients reporting hypoglycaemia(<70mg/dL). The consensus based recommendations mentioned in this paper will be a useful reference tool for health care practitioners, to initiate, optimise and intensify insulin therapy and to successfully achieve optimal glucose control.

Management of type-1 and type-2 diabetes by insulin injections in diabetology clinics - a scientific research review.

PubMed

Aziz, Kamran M A

2012-05-01

Better control of the diabetic metabolic state will prevent the diabetes complications. However in current clinical practice, it is sometimes difficult to achieve this goal. Additionally, physicians find themselves in an equivocal position to initiate insulin therapy, its selection, combining with Oral agents and further management. The current article was written to focus on diabetes pathogenesis at molecular level, its classification and management by insulin injections. Knowledge of basic biochemistry, pharmacology with kinetics of Insulin is essential for diabetes management. Nonetheless, it should be a priority to search for evidence based clinical methodologies for selecting the patients for initiating, modifying or combining the insulin therapy. Type-1 diabetic patients are best controlled on basal bolus insulin regimens. However in type-2 diabetes, metformin with lifestyle modifications should be the first line therapy, thereafter combined with oral hypoglycemic agents or shifting to insulin gradually if diabetes remains uncontrolled. Metformin is recommended to be prescribed with insulin as compared to oral hypoglycemic agents which should be discontinued while starting insulin. Monitoring the insulin therapy on regular visits to diabetologist and diabetes multidisciplinary team remains the integral part of diabetes management. The review also outlines relevant and recent insulin analogue patents for the management of Diabetes.

Implementation of subcutaneous insulin protocol for non-critically ill hospitalized patients in andalusian tertiary care hospitals.

PubMed

Martínez-Brocca, María Asunción; Morales, Cristóbal; Rodríguez-Ortega, Pilar; González-Aguilera, Beatriz; Montes, Cristina; Colomo, Natalia; Piédrola, Gonzalo; Méndez-Muros, Mariola; Serrano, Isabel; Ruiz de Adana, Maria Soledad; Moreno, Alberto; Fernández, Ignacio; Aguilar, Manuel; Acosta, Domingo; Palomares, Rafael

2015-02-01

In 2009, the Andalusian Society of Endocrinology and Nutrition designed a protocol for subcutaneous insulin treatment in hospitalized non-critically ill patients (HIP). To analyze implementation of HIP at tertiary care hospitals from the Andalusian Public Health System. A descriptive, multicenter study conducted in 8 tertiary care hospitals on a random sample of non-critically ill patients with diabetes/hyperglycemia (n=306) hospitalized for ≥48 hours in 5 non-surgical (SM) and 2 surgical (SQ) departments. Type 1 and other specific types of diabetes, pregnancy and nutritional support were exclusion criteria. 288 patients were included for analysis (62.5% males; 70.3±10.3 years; 71.5% SM, 28.5% SQ). A scheduled subcutaneous insulin regimen based on basal-bolus-correction protocol was started in 55.9% (95%CI: 50.5-61.2%) of patients, 63.1% SM vs. 37.8% SQ (P<.05). Alternatives to insulin regimen based on basal-bolus-correction included sliding scale insulin (43.7%), diet (31.3%), oral antidiabetic drugs (17.2%), premixed insulin (1.6%), and others (6.2%). For patients previously on oral antidiabetic drugs, in-hospital insulin dose was 0.32±0.1 IU/kg/day. In patients previously on insulin, in-hospital insulin dose was increased by 17% [-13-53], and in those on insulin plus oral antidiabetic drugs, in-hospital insulin dose was increased by 26.4% [-6-100]. Supplemental insulin doses used for<40 IU/day and 40-80 IU/day were 72.2% and 56.7% respectively. HbA1c was measured in 23.6% of patients (95CI%: 18.8-28.8); 27.7% SM vs. 13.3% SQ (P<.05). Strategies are needed to improve implementation of the inpatient subcutaneous insulin protocol, particularly in surgical departments. Sliding scale insulin is still the most common alternative to insulin regimen based on basal-bolus-correction scheduled insulin. Metabolic control assessment during hospitalization should be encouraged. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Treatment persistence in the use of basal insulins in Poland and Germany
.

PubMed

Rathmann, Wolfgang; Czech, Marcin; Franek, Edward; Kostev, Karel

2017-02-01

To compare short-term basal insulin therapy persistence and its predictors in Poland and Germany. Persistence was defined as proportions of patients remaining on the initial basal insulin (analogs: Poland: n = 6,889, Germany: n = 454,067; neutral protamine Hagedorn (NPH) insulins: Poland: n = 50,761, Germany: n = 226,064) over 2 years based on nationwide prescription databases (LRx; IMS Health) in Poland and Germany from 2013 to 2015. Persistence was evaluated by Kaplan-Meier curves (log-rank tests). Risk of discontinuation of initial basal insulin was investigated using Cox regression models adjusting for age, sex, comedication with other glucose-lowering agents and baseline or comedication with antihypertensives, lipid-lowering drugs, antidepressants, and antiepileptics. In Poland, 2-year persistence was 83.0% in analog insulin and 73.3% in NPH users (p < 0.001). In Germany, persistence was also higher in patients with analog insulins (92.6% vs. 79.0%; p < 0.001). Analog insulin users were less likely to discontinue basal insulin compared with NPH users (adjusted hazard ratio (95%CI): Poland: 0.73 (0.67 - 0.79); Germany: 0.27 (0.27 - 0.28)). Higher age (> 75 vs. ≤ 60 years: Poland: 1.24 (1.16 - 1.33), Germany: 1.09 (1.07 - 1.11)) and GLP-1 receptor agonist use (Poland: 2.76 (1.38 - 5.53), Germany: 1.21 (1.16 - 1.26)) were related to higher risk of discontinuation. Male sex, metformin, sulfonylurea, thiazolidinedione, and short-acting insulin prescriptions as well as antihypertensive, anti-epileptic, and lipid-lowering drug use were associated with lower risk of discontinuation in both countries (all p < 0.05). This real-world study shows that both in Poland and Germany treatment persistence of newly-prescribed basal insulin is influenced by type of insulin (analog vs. NPH) and by glucose-lowering and other comedications.
.

Insulin therapy in children and adolescents with type 1 diabetes.

PubMed

Malik, Faisal S; Taplin, Craig E

2014-04-01

Treatment of type 1 diabetes mellitus (T1DM) requires lifelong administration of exogenous insulin. The primary goal of treatment of T1DM in children and adolescents is to maintain near-normoglycemia through intensive insulin therapy, avoid acute complications, and prevent long-term microvascular and macrovascular complications, while facilitating as close to a normal life as possible. Effective insulin therapy must, therefore, be provided on the basis of the needs, preferences, and resources of the individual and the family for optimal management of T1DM. To achieve target glycemic control, the best therapeutic option for patients with T1DM is basal-bolus therapy either with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Many formulations of insulin are available to help simulate endogenous insulin secretion as closely as possible in an effort to eliminate the symptoms and complications of hyperglycemia, while minimizing the risk of hypoglycemia secondary to therapy. When using MDI, basal insulin requirements are given as an injection of long- or intermediate-acting insulin analogs, while meal-related glucose excursions are controlled with bolus injections of rapid-acting insulin analogs. Alternatively, CSII can be used, which provides a 24-h preselected but adjustable basal rate of rapid-acting insulin, along with patient-activated mealtime bolus doses, eliminating the need for periodic injections. Both MDI treatment and CSII therapy must be supported by comprehensive education that is appropriate for the individual needs of the patient and family before and after initiation. Current therapies still do not match the endogenous insulin profile of pancreatic β-cells, and all still pose risks of suboptimal control, hypoglycemia, and ketosis in children and adolescents. The safety and success of a prescribed insulin regimen is, therefore, dependent on self-monitoring of blood glucose and/or a continuous glucose monitoring system

Basal plasma insulin and homeostasis model assessment (HOMA) are indicators of insulin sensitivity in cats.

PubMed

Appleton, D J; Rand, J S; Sunvold, G D

2005-06-01

The objective of this study was to compare simpler indices of insulin sensitivity with the minimal model-derived insulin sensitivity index to identify a simple and reliable alternative method for assessing insulin sensitivity in cats. In addition, we aimed to determine whether this simpler measure or measures showed consistency of association across differing body weights and glucose tolerance levels. Data from glucose tolerance and insulin sensitivity tests performed in 32 cats with varying body weights (underweight to obese), including seven cats with impaired glucose tolerance, were used to assess the relationship between Bergman's minimal model-derived insulin sensitivity index (S(I)), and various simpler measures of insulin sensitivity. The most useful overall predictors of insulin sensitivity were basal plasma insulin concentrations and the homeostasis model assessment (HOMA), which is the product of basal glucose and insulin concentrations divided by 22.5. It is concluded that measurement of plasma insulin concentrations in cats with food withheld for 24 h, in conjunction with HOMA, could be used in clinical research projects and by practicing veterinarians to screen for reduced insulin sensitivity in cats. Such cats may be at increased risk of developing impaired glucose tolerance and type 2 diabetes mellitus. Early detection of these cats would enable preventative intervention programs such as weight reduction, increased physical activity and dietary modifications to be instigated.

Trends in the use and cost of human and analogue insulins in a Colombian population, 2011-2015.

PubMed

Torres, D R; Portilla, A; Machado-Duque, M E; Machado-Alba, J E

2017-12-01

Diabetes mellitus is a common disease among the general population and imposes considerable costs on health care systems. Insulin is used to treat type 1 diabetes mellitus and as an adjuvant to oral agents in advanced stages of type 2 diabetes mellitus. The objective was to describe the trends in use and cost of human and analogue insulins for Colombian patients. Descriptive retrospective analysis of prescriptions of human and analogue insulins on a monthly basis for the period from July 1, 2011 to February 2, 2015. Information was collected for the database population of two insurance companies. Frequencies and proportions were calculated; estimated economic impact was expressed as net cost and cost per thousand inhabitants per day. During the observation period, there was continuous growth in use of insulin, mainly in analogue forms (34.0% growth). At the start of the study, 10.4% of subjects were using an analogue insulin; this figure was 62.6% at the end of the study. In 2012, the average cost per 1000 inhabitants/day was US$1.7 for analogue and US$0.8 for human insulins. At the end of the observation period these costs had risen to US$9.2 for analogue (441.1% increase) and fallen to US$0.5 for human insulin (58.3% decrease). There has been an increase in the unit cost and frequency of use of insulin analogues for anti-diabetic therapy in Colombian patients. Moreover, there is controversy over whether insulin analogues are a more cost-effective treatment than human insulins for the general diabetic population. Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Evaluation of the long-term cost-effectiveness of IDegLira versus liraglutide added to basal insulin for patients with type 2 diabetes failing to achieve glycemic control on basal insulin in the USA.

PubMed

Hunt, B; Mocarski, M; Valentine, W J; Langer, J

2017-07-01

IDegLira, a fixed ratio combination of insulin degludec and glucagon-like peptide-1 receptor agonist liraglutide, utilizes the complementary mechanisms of action of these two agents to improve glycemic control with low risk of hypoglycemia and avoidance of weight gain. The aim of the present analysis was to assess the long-term cost-effectiveness of IDegLira vs liraglutide added to basal insulin, for patients with type 2 diabetes not achieving glycemic control on basal insulin in the US setting. Projections of lifetime costs and clinical outcomes were made using the IMS CORE Diabetes Model. Treatment effect data for patients receiving IDegLira and liraglutide added to basal insulin were modeled based on the outcomes of a published indirect comparison, as no head-to-head clinical trial data is currently available. Costs were accounted in 2015 US dollars ($) from a healthcare payer perspective. IDegLira was associated with small improvements in quality-adjusted life expectancy compared with liraglutide added to basal insulin (8.94 vs 8.91 discounted quality-adjusted life years [QALYs]). The key driver of improved clinical outcomes was the greater reduction in glycated hemoglobin associated with IDegLira. IDegLira was associated with mean costs savings of $17,687 over patient lifetimes vs liraglutide added to basal insulin, resulting from lower treatment costs and cost savings as a result of complications avoided. The present long-term modeling analysis found that IDegLira was dominant vs liraglutide added to basal insulin for patients with type 2 diabetes failing to achieve glycemic control on basal insulin in the US, improving clinical outcomes and reducing direct costs.

Current european regulatory perspectives on insulin analogues.

PubMed

Enzmann, Harald G; Weise, Martina

2011-07-07

Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions.

Automatic Adaptation of Basal Insulin Using Sensor-Augmented Pump Therapy.

PubMed

Herrero, Pau; Bondia, Jorge; Giménez, Marga; Oliver, Nick; Georgiou, Pantelis

2018-03-01

People with insulin-dependent diabetes rely on an intensified insulin regimen. Despite several guidelines, they are usually impractical and fall short in achieving optimal glycemic outcomes. In this work, a novel technique for automatic adaptation of the basal insulin profile of people with diabetes on sensor-augmented pump therapy is presented. The presented technique is based on a run-to-run control law that overcomes some of the limitations of previously proposed methods. To prove its validity, an in silico validation was performed. Finally, the artificial intelligence technique of case-based reasoning is proposed as a potential solution to deal with variability in basal insulin requirements. Over a period of 4 months, the proposed run-to-run control law successfully adapts the basal insulin profile of a virtual population (10 adults, 10 adolescents, and 10 children). In particular, average percentage time in target [70, 180] mg/dl was significantly improved over the evaluated period (first week versus last week): 70.9 ± 11.8 versus 91.1 ± 4.4 (adults), 46.5 ± 11.9 versus 80.1 ± 10.9 (adolescents), 49.4 ± 12.9 versus 73.7 ± 4.1 (children). Average percentage time in hypoglycemia (<70 mg/dl) was also significantly reduced: 9.7 ± 6.6 versus 0.9 ± 1.2 (adults), 10.5 ± 8.3 versus 0.83 ± 1.0 (adolescents), 10.9 ± 6.1 versus 3.2 ± 3.5 (children). When compared against an existing technique over the whole evaluated period, the presented approach achieved superior results on percentage of time in hypoglycemia: 3.9 ± 2.6 versus 2.6 ± 2.2 (adults), 2.9 ± 1.9 versus 2.0 ± 1.5 (adolescents), 4.6 ± 2.8 versus 3.5 ± 2.0 (children), without increasing the percentage time in hyperglycemia. The present study shows the potential of a novel technique to effectively adjust the basal insulin profile of a type 1 diabetes population on sensor-augmented insulin pump therapy.

Cost-Effectiveness of IDegLira Versus Insulin Intensification Regimens for the Treatment of Adults with Type 2 Diabetes in the Czech Republic.

PubMed

Kvapil, Milan; Prázný, Martin; Holik, Pavel; Rychna, Karel; Hunt, Barnaby

2017-12-01

The aim of this study was to evaluate the long-term cost-effectiveness of the insulin degludec/liraglutide combination (IDegLira) versus basal insulin intensification strategies for patients with type 2 diabetes mellitus (T2DM) not optimally controlled on basal insulin in the Czech Republic. Cost-effectiveness was evaluated using the QuintilesIMS Health CORE Diabetes model, an interactive internet-based model that simulates clinical outcomes and costs for cohorts of patients with diabetes. The analysis was conducted from the perspective of the Czech Republic public payer. Sensitivity analyses were conducted to explore the sensitivity of the model to plausible variations in key parameters. The use of IDegLira was associated with an improvement in the quality-adjusted life expectancy of 0.31 quality-adjusted life-years (QALYs), at an additional cost of Czech Koruna (CZK) 107,829 over a patient's lifetime compared with basal-bolus therapy, generating an incremental cost-effectiveness ratio (ICER) of CZK 345,052 per QALY gained. In a scenario analysis, IDegLira was associated with an ICER of CZK 693,763 per QALY gained compared to basal insulin + glucagon-like peptide-1 receptor agonist (GLP-1 RA). The ICERs are below the generally accepted willingness-to-pay threshold (CZK 1,100,000/QALY gained at the time of this analysis). Results from this evaluation suggest that IDegLira is a cost-effective treatment option compared with basal-bolus therapy and basal insulin + GLP-1 RA for patients with T2DM in the Czech Republic whose diabetes is not optimally controlled with basal insulin. Novo Nordisk.

Concepts and clinical use of ultra-long basal insulin.

PubMed

Eliaschewitz, Freddy Goldberg; Barreto, Tânia

2016-01-01

Diabetes mellitus (DM) is a public health issue, affecting around 382 million people worldwide. In order to achieve glycemic goals, insulin therapy is the frontline therapy for type 1 DM patients; for patients with type 2 DM, use of insulin therapy is an option as initial or add-on therapy for those not achieving glycemic control. Despite insulin therapy developments seen in the last decades, several barriers remain for insulin initiation and optimal maintenance in clinical practice. Fear of hypoglycemia, weight gain, pain associated with blood testing and injection-related pain are the most cited reasons for not starting insulin therapy. However, new generation of basal insulin formulations, with longer length of action, have shown the capability of providing adequate glycemic control with lower risk of hypoglycemia.

Economic Impact of Treatment Duration and Persistence with Basal Insulin in Previously Insulin-Naive Users.

PubMed

Kalirai, Samaneh; Duan, Ran; Liu, Dongju; Reed, Beverly L

2017-03-01

Although insulin is a well-established therapy that is associated with improved clinical outcomes, adherence and persistence with insulin regimens are poor in patients with type 2 diabetes mellitus (T2DM). Diabetes-related health care costs and the impact of insulin persistence patterns on these health care costs have been previously studied; however, these aspects of insulin therapy have limited data beyond the first year of use and have not been characterized among patients previously naive to basal insulin. To (a) describe and compare medical- and pharmacy-related costs, health care resource utilization, and comorbidities and complications during the initial year and second (experienced) year of basal insulin therapy, and (b) describe and compare the impact of continuous versus interrupted basal insulin use during each year. This was a retrospective observational database analysis using claims from multiple U.S. commercial health plans (Truven Health MarketScan) in previously insulin-naive patients with T2DM who were initiated on basal insulin. Data collected included all-cause and diabetes-related medical and pharmacy costs, health care resource utilization (i.e., number and type of outpatient visits, hospitalization, emergency department [ED] visits), medication use, and preselected comorbidities and complications. This cost analysis described and compared health care costs and resource use between the initial and experienced years and further compared health care costs and resource use between continuers and interrupters within each of those years. A total of 23,645 patients were included in the analysis; 12,224 were classified as continuers and 11,421 were classified as interrupters. Among all patients, mean increases from the initial year to the experienced year were observed for all-cause medical costs ($12,690-$13,408; P = 0.048), all-cause pharmacy costs ($6,253-$6,559; P < 0.001), and all-cause health care costs ($18,943-$19,967; P = 0.006), after

Predictors of early discontinuation of basal insulin therapy in type 2 diabetes in primary care.

PubMed

Kostev, K; Dippel, F W; Rathmann, W

2016-04-01

To identify patient-related characteristics and other impact factors predicting early discontinuation of basal insulin therapy in type 2 diabetes in primary care. A total of 4837 patients who started basal insulin therapy (glargine: n=3175; NPH: n=1662) in 1072 general and internal medicine practices throughout Germany were retrospectively analyzed (Disease Analyser Database: 01/2008-03/2014). Early discontinuation was defined as switching back to oral antidiabetic drugs (OAD) therapy within 90 days after first basal insulin prescription (index date, ID). Patient records were assessed 365 days prior and post ID. Logistic regression models were used to adjust for age, sex, diabetes duration, diabetologist care, disease management program participation, HbA1c, and comorbidity. Within 3 months after ID, 202 (6.8%) of glargine patients switched back to OAD (NPH: 130 (8.5%); p<0.05). In multivariable logistic regression, predictors of early basal insulin discontinuation were ≥1 documented hypoglycemia before ID (adjusted Odds ratio; 95% CI: 2.20; 1.27-3.82), diagnosed depression (1.31; 1.01-1.70) and referrals to specialists within 90 days after ID (2.06; 1.61-2.63). Diabetologist care (0.57; 0.36-0.89) and glargine treatment (vs. NPH: 0.78; 0.61-0.98) were related to a lower odds of having early insulin discontinuation. Less than 10% of type 2 diabetes patients switched back to oral antidiabetic drugs within 90 days after start of basal insulin therapy. In particular, patients with baseline depression and frequent or severe hypoglycemia have a higher likelihood for early discontinuation of basal insulin, whereas use of insulin glargine and diabetologist care are related to an increased chance of continuous insulin treatment. Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

In Silico Assessment of Literature Insulin Bolus Calculation Methods Accounting for Glucose Rate of Change.

PubMed

Cappon, Giacomo; Marturano, Francesca; Vettoretti, Martina; Facchinetti, Andrea; Sparacino, Giovanni

2018-05-01

The standard formula (SF) used in bolus calculators (BCs) determines meal insulin bolus using "static" measurement of blood glucose concentration (BG) obtained by self-monitoring of blood glucose (SMBG) fingerprick device. Some methods have been proposed to improve efficacy of SF using "dynamic" information provided by continuous glucose monitoring (CGM), and, in particular, glucose rate of change (ROC). This article compares, in silico and in an ideal framework limiting the exposition to possibly confounding factors (such as CGM noise), the performance of three popular techniques devised for such a scope, that is, the methods of Buckingham et al (BU), Scheiner (SC), and Pettus and Edelman (PE). Using the UVa/Padova Type 1 diabetes simulator we generated data of 100 virtual subjects in noise-free, single-meal scenarios having different preprandial BG and ROC values. Meal insulin bolus was computed using SF, BU, SC, and PE. Performance was assessed with the blood glucose risk index (BGRI) on the 9 hours after meal. On average, BU, SC, and PE improve BGRI compared to SF. When BG is rapidly decreasing, PE obtains the best performance. In the other ROC scenarios, none of the considered methods prevails in all the preprandial BG conditions tested. Our study showed that, at least in the considered ideal framework, none of the methods to correct SF according to ROC is globally better than the others. Critical analysis of the results also suggests that further investigations are needed to develop more effective formulas to account for ROC information in BCs.

Frequency of blood glucose testing among insulin-treated diabetes mellitus patients in the United Kingdom.

PubMed

Lee, Won Chan; Smith, Elise; Chubb, Barrie; Wolden, Michael Lyng

2014-03-01

Through a retrospective database analysis, this study seeks to provide an understanding of the utilization of SMBG by insulin therapy and diabetes type and to estimate healthcare costs of blood glucose monitoring in the UK diabetes population. Data were obtained from the IMS LifeLink Electronic Medical Record-Europe (EMR-EU) Database, a longitudinal database containing anonymized patient records from physician-practice data systems of office-based physicians in the UK. Depending on the insulin types used for type 1 and type 2 diabetes, patients were sub-categorized into one of four insulin regimen groups (basal, bolus, pre-mixed, or basal-bolus). Frequency of blood glucose testing was assessed descriptively throughout the 12-month post-index period, and generalized linear models were used to evaluate the effect of baseline characteristics, including insulin type, on the likelihood of blood glucose test utilization. Healthcare resource utilization and costs for all-cause services were assessed by insulin type. This study identified 8322 type 1 and type 2 diabetes patients with two insulin pharmacy records between January 1, 2009 and December 31, 2010. After applying study inclusion and exclusion criteria, a total of 2676 (32.2%) insulin-treated diabetes mellitus patients in the UK were identified, with the number of pharmacy blood glucose test strips averaging 771.1 (median 600). The glucose testing frequency was lowest among basal-only insulin patients and pre-mixed insulin patients (mean=576.2 [median=450] and mean=599.5 [median=500], respectively; non-significantly different) compared to other insulin types. Although the data did not capture the glucose frequency comprehensively, it varied significantly by insulin types, and was higher than what is recommended in the guidelines for patients with type 2 diabetes.

Regional differences in insulin therapy regimens in five European countries
.

PubMed

Rathmann, Wolfgang; Czech, Marcin; Franek, Edward; Kostev, Karel

2017-05-01

The purpose of this study was to investigate differences of insulin therapy regimens in five European countries. Proportions of basal bolus therapy (intensified insulin therapy (ICT), basal insulin supported oral therapy (BOT), conventional therapy (CT), and short-acting prandial insulin (SIT) among insulin-treated diabetes patients in Germany (n = 64,055), the UK (n = 6,740), and France (n = 4,779) were estimated using representative general medicine practice databases (Disease Analyzer: 2014). Insulin regimens in Hungary (n = 40,769) and Poland (n = 68,136) were analyzed based on nationwide prescription databases (LRx: 2014). ICT was the most frequent insulin regimen (46 - 81%) in all countries except France (BOT > ICT). SIT showed the lowest use, ranging from 2.5% in the UK to 11.2% in Germany. BOT was more frequently used than CT in Germany and Hungary, which was just the opposite in the UK and Poland. The share of insulin analogs among all prescriptions was higher in Germany, the UK, and France (short-acting insulins: 59 - 98%; basal insulins: 70 - 93%) than in Hungary and Poland (short-acting insulins: 41 - 57%; basal insulins: 23 - 46%) (all p < 0.001). Despite national and international guidelines, insulin regimens differ substantially between European countries. Our results most likely reflect differences in regulations and reimbursement systems, national diabetes care systems as well as patient characteristics and expectations.
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Once-daily prandial lixisenatide versus once-daily rapid-acting insulin in patients with type 2 diabetes mellitus insufficiently controlled with basal insulin: analysis of data from five randomized, controlled trials.

PubMed

Raccah, Denis; Lin, Jay; Wang, Edward; Germé, Maeva; Perfetti, Riccardo; Bonadonna, Riccardo C; de Pablos-Velasco, Pedro; Roussel, Ronan; Rosenstock, Julio

2014-01-01

To compare the efficacy and safety of lixisenatide (LIXI), a once-daily prandial glucagon-like peptide-1 (GLP-1) receptor agonist, as add-on to basal insulin (Basal+LIXI) versus once-daily rapid-acting insulin (Basal+RAI) in patients with type 2 diabetes mellitus (T2DM). Data were extracted from five randomized controlled trials assessing the efficacy and safety of basal insulin+insulin glulisine (n=3) or basal insulin+LIXI (n=2). Patients in the Basal+LIXI cohort were matched to patients in the Basal+RAI cohort using propensity score matching. In the matched population, Basal+LIXI was twice as likely to reach composite outcomes of glycated haemoglobin (HbA1c) <7% and no symptomatic hypoglycaemia compared with the Basal+RAI group (odds ratio [OR]: 1.90; 95% confidence interval [CI]: 1.01, 3.55; P=0.0455), as well as HbA1c <7% and no severe hypoglycaemia (OR: 1.97; 95 CI: 1.06, 3.66; P=0.0311). Furthermore, Basal+LIXI was more than twice as likely to reach HbA1c <7%, no weight gain and no symptomatic hypoglycaemia (OR: 2.58; 95% CI: 1.23, 5.40; P=0.0119). Both basal+LIXI and Basal+RAI improved glycaemic control in patients with T2DM with inadequate glycaemic control on basal insulin. Basal+LIXI offers an effective therapeutic option to advance basal insulin therapy, improving glucose control without weight gain and with less risk of hypoglycaemia than prandial insulin. © 2013.

Insulin analogs with improved pharmacokinetic profiles.

PubMed

Brange; Vølund

1999-02-01

The aim of insulin replacement therapy is to normalize blood glucose in order to reduce the complications of diabetes. The pharmacokinetics of the traditional insulin preparations, however, do not match the profiles of physiological insulin secretion. The introduction of the rDNA technology 20 years ago opened new ways to create insulin analogs with altered properties. Fast-acting analogs are based on the idea that an insulin with less tendency to self-association than human insulin would be more readily absorbed into the systemic circulation. Protracted-acting analogs have been created to mimic the slow, steady rate of insulin secretion in the fasting state. The present paper provides a historical review of the efforts to change the physicochemical and pharmacological properties of insulin in order to improve insulin therapy. The available clinical studies of the new insulins are surveyed and show, together with modeling results, that new strategies for optimal basal-bolus treatment are required for utilization of the new fast-acting analogs.

Cost-effectiveness of liraglutide versus lixisenatide as add-on therapies to basal insulin in type 2 diabetes

PubMed Central

2018-01-01

Background We assessed the cost-effectiveness of the glucagon-like peptide 1 receptor agonists liraglutide 1.8 mg and lixisenatide 20 μg (both added to basal insulin) in patients with type 2 diabetes (T2D) in Sweden. Methods The Swedish Institute for Health Economics cohort model for T2D was used to compare liraglutide and lixisenatide (both added to basal insulin), with a societal perspective and with comparative treatment effects derived by indirect treatment comparison (ITC). Drug prices were 2016 values, and all other costs 2015 values. The cost-effectiveness of IDegLira (fixed-ratio combination of insulin degludec and liraglutide) versus lixisenatide plus basal insulin was also assessed, under different sets of assumptions. Results From the ITC, decreases in HbA1c were –1.32% and –0.43% with liraglutide and lixisenatide, respectively; decreases in BMI were –1.29 and –0.65 kg/m2, respectively. An estimated 2348 cases of retinopathy, 265 of neuropathy and 991 of nephropathy would be avoided with liraglutide compared with lixisenatide in a cohort of 10,000 patients aged over 40 years. In the base-case analysis, total direct costs were higher with liraglutide than lixisenatide, but costs associated with complications were lower. The cost/quality-adjusted life-year (QALY) for liraglutide added to basal insulin was SEK30,802. Base-case findings were robust in sensitivity analyses, except when glycated haemoglobin (HbA1c) differences for liraglutide added to basal insulin were abolished, suggesting these benefits were driving the cost/QALY. With liraglutide 1.2 mg instead of liraglutide 1.8 mg (adjusted for efficacy and cost), liraglutide added to basal insulin was dominant over lixisenatide 20μg.IDegLira was dominant versus lixisenatide plus basal insulin when a defined daily dose was used in the model. Conclusions The costs/QALY for liraglutide, 1.8 or 1.2 mg, added to basal insulin, and for IDegLira (all compared with lixisenatide 20 μg added to basal

Cost-effectiveness of liraglutide versus lixisenatide as add-on therapies to basal insulin in type 2 diabetes.

PubMed

Ericsson, Åsa; Glah, Divina; Lorenzi, Maria; Jansen, Jeroen P; Fridhammar, Adam

2018-01-01

We assessed the cost-effectiveness of the glucagon-like peptide 1 receptor agonists liraglutide 1.8 mg and lixisenatide 20 μg (both added to basal insulin) in patients with type 2 diabetes (T2D) in Sweden. The Swedish Institute for Health Economics cohort model for T2D was used to compare liraglutide and lixisenatide (both added to basal insulin), with a societal perspective and with comparative treatment effects derived by indirect treatment comparison (ITC). Drug prices were 2016 values, and all other costs 2015 values. The cost-effectiveness of IDegLira (fixed-ratio combination of insulin degludec and liraglutide) versus lixisenatide plus basal insulin was also assessed, under different sets of assumptions. From the ITC, decreases in HbA1c were -1.32% and -0.43% with liraglutide and lixisenatide, respectively; decreases in BMI were -1.29 and -0.65 kg/m2, respectively. An estimated 2348 cases of retinopathy, 265 of neuropathy and 991 of nephropathy would be avoided with liraglutide compared with lixisenatide in a cohort of 10,000 patients aged over 40 years. In the base-case analysis, total direct costs were higher with liraglutide than lixisenatide, but costs associated with complications were lower. The cost/quality-adjusted life-year (QALY) for liraglutide added to basal insulin was SEK30,802. Base-case findings were robust in sensitivity analyses, except when glycated haemoglobin (HbA1c) differences for liraglutide added to basal insulin were abolished, suggesting these benefits were driving the cost/QALY. With liraglutide 1.2 mg instead of liraglutide 1.8 mg (adjusted for efficacy and cost), liraglutide added to basal insulin was dominant over lixisenatide 20μg.IDegLira was dominant versus lixisenatide plus basal insulin when a defined daily dose was used in the model. The costs/QALY for liraglutide, 1.8 or 1.2 mg, added to basal insulin, and for IDegLira (all compared with lixisenatide 20 μg added to basal insulin) were below the threshold considered low

Prevention of Hypoglycemia during Exercise in Children with Type 1 Diabetes by Suspending Basal Insulin

PubMed Central

2006-01-01

Background Strategies for preventing hypoglycemia during exercise in children with T1D have not been well studied. DirecNet conducted a study to determine whether stopping basal insulin could reduce the frequency of hypoglycemia occurring during exercise. Methods Using a randomized, crossover design, 49 children 8–17y with T1D on insulin pump therapy were studied during structured exercise sessions on two days. On one day basal insulin was stopped during exercise and on the other day it was continued. Each exercise session, performed from approximately 4–5 p.m., consisted of four 15-minute treadmill cycles at a target heart rate of 140 beats/minute (interspersed with three 5-minute rest breaks over 75 minutes) followed by a 45 minute observation period. Frequently sampled glucose concentrations (measured in the DirecNet Central Laboratory) were measured prior to, during, and following the exercise. Results Hypoglycemia (≤70 mg/dL) during exercise occurred less frequently when the basal insulin was discontinued than when it was continued (16% vs. 43%; P=0.003). Hyperglycemia (increase from baseline of ≥20% to ≥200 mg/dL) 45 minutes after the completion of exercise was more frequent without basal insulin (27% vs. 4%; P=0.002). There were no cases of abnormal blood ketone levels. Conclusion Discontinuing basal insulin during exercise is an effective strategy for reducing hypoglycemia in children with T1D, but the risk of hyperglycemia is increased. PMID:17003293

Gap junctions and other mechanisms of cell-cell communication regulate basal insulin secretion in the pancreatic islet.

PubMed

Benninger, R K P; Head, W Steven; Zhang, Min; Satin, Leslie S; Piston, David W

2011-11-15

Cell-cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca(2+)](i)) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca(2+)](i) ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell-cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36(-/-)), and these results were compared to those obtained using fully isolated β-cells. K(ATP) loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36(-/-) islets, elevations in [Ca(2+)](i) persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36(-/-) islets was minimally altered. [Ca(2+)](i) was further elevated under basal conditions, but insulin release still suppressed in K(ATP) loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell-cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca(2+)](i) signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion.

Anticipatory guidance in type 2 diabetes to improve disease management; next steps after basal insulin.

PubMed

Johnson, Eric L; Frias, Juan P; Trujillo, Jennifer M

2018-05-01

The alarming rise in the number of people living with type 2 diabetes (T2D) presents primary care physicians with increasing challenges associated with long-term chronic disease care. Studies have shown that the majority of patients are not achieving or maintaining glycemic goals, putting them at risk of a wide range of diabetes-related complications. Disease- and self-management programs have been shown to help patients improve their glycemic control, and are likely to be of particular benefit for patients with diabetes dealing with these issues. Anticipatory guidance is an individualized, proactive approach to patient education and counseling by a health-care professional to support patients in better coping with problems before they arise. It has been shown to improve disease outcomes in a variety of chronic conditions, including diabetes. While important at all stages, anticipatory guidance may be of particular importance during changes in treatment regimens, and especially during transition to, and escalation of, insulin-based regimens. The aim of this article is to provide advice to physicians on anticipatory guidance for basal-insulin dosing, focusing on appropriate basal-insulin-dose increase and prevention of potentially deleterious basal-insulin doses, so called overbasalization. It also provides an overview of new treatment options for patients with T2D who are not well controlled on basal-insulin therapy, fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists, and advice on the type of anticipatory guidance needed to ensure safe and appropriate switching to these therapies.

Use of the DISST Model to Estimate the HOMA and Matsuda Indexes Using Only a Basal Insulin Assay

PubMed Central

Docherty, Paul D.; Chase, J. Geoffrey

2014-01-01

Background: It is hypothesized that early detection of reduced insulin sensitivity (SI) could prompt intervention that may reduce the considerable financial strain type 2 diabetes mellitus (T2DM) places on global health care. Reduction of the cost of already inexpensive SI metrics such as the Matsuda and HOMA indexes would enable more widespread, economically feasible use of these metrics for screening. The goal of this research was to determine a means of reducing the number of insulin samples and therefore the cost required to provide an accurate Matsuda Index value. Method: The Dynamic Insulin Sensitivity and Secretion Test (DISST) model was used with the glucose and basal insulin measurements from an Oral Glucose Tolerance Test (OGTT) to predict patient insulin responses. The insulin response to the OGTT was determined via population based regression analysis that incorporated the 60-minute glucose and basal insulin values. Results: The proposed method derived accurate and precise Matsuda Indices as compared to the fully sampled Matsuda (R = .95) using only the basal assay insulin-level data and 4 glucose measurements. Using a model employing the basal insulin also allows for determination of the 1-day HOMA value. Conclusion: The DISST model was successfully modified to allow for the accurate prediction an individual’s insulin response to the OGTT. In turn, this enabled highly accurate and precise estimation of a Matsuda Index using only the glucose and basal insulin assays. As insulin assays account for the majority of the cost of the Matsuda Index, this model offers a significant reduction in assay cost. PMID:24876431

A review of the new GLP-1 receptor agonist/basal insulin fixed-ratio combination products.

PubMed

Nuffer, Wesley; Guesnier, Ashley; Trujillo, Jennifer M

2018-03-01

There have been several new treatment approaches established for the management of hyperglycemia in type 2 diabetes (T2D), with treatment guidelines listing both glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and basal insulin therapies as considerations for patients who have failed to control their blood glucose with oral antidiabetic agents. New studies have highlighted the importance of initiating combination therapy earlier in the T2D disease process to avoid clinical inertia and prevent the long-term complications arising from uncontrolled diabetes. Until recently, both GLP-1 RAs and basal insulin therapies were only available as single agents, but there are now two combination pen devices that deliver both a GLP-1 RA and basal insulin simultaneously. This article reviews the current clinical evidence evaluating the use of these combination GLP-1 RA/basal insulin preparations to treat T2D, presents both potential benefits as well as possible downsides with the use of these agents, and discusses the current place in therapy these products represent in the management of T2D.

Once-weekly exenatide as adjunct treatment of type 1 diabetes mellitus in patients receiving continuous subcutaneous insulin infusion therapy.

PubMed

Traina, Andrea N; Lull, Melinda E; Hui, Adrian C; Zahorian, Toni M; Lyons-Patterson, Jane

2014-08-01

The use of once-weekly exenatide in type 2 diabetes mellitus is well supported, but little is known about its effectiveness in type 1 diabetes. The objective of this study was to determine the clinical efficacy of once-weekly exenatide on glycemic control in patients with type 1 diabetes when added to basal-bolus insulin therapy. For this retrospective study, patients with type 1 diabetes, aged 18 years and older, receiving continuous subcutaneous insulin infusion, using a continuous glucose monitoring device or regularly measuring blood glucose levels and receiving 2 mg of exenatide once weekly for at least 3 months were included. Demographic information, glycated hemoglobin (A1C), body weight, body mass index, systolic and diastolic blood pressures, total daily insulin dose, basal and bolus insulin doses, 28-day continuous subcutaneous insulin infusion glucose average and incidence of hypoglycemia were collected at baseline and 3 months after beginning therapy with once-weekly exenatide. An electronic medical record search identified 11 patients with type 1 diabetes who met the inclusion criteria. Comparing baseline and 3 months after initiation of once-weekly exenatide revealed reductions of 0.6% in A1C (p=0.013), 3.7% in body weight (p=0.008), 1.7 kg/m(2) in body mass index (p=0.003), 13% in total daily insulin dose (p=0.011) and 9.3 units in bolus insulin dose (p=0.015). This study revealed that the addition of once-weekly exenatide to insulin therapy for type 1 diabetes patients leads to significant improvements in A1C, body weight, body mass index and insulin doses. Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Subthalamic nucleus stimulation does not influence basal glucose metabolism or insulin sensitivity in patients with Parkinson's disease.

PubMed

Lammers, Nicolette M; Sondermeijer, Brigitte M; Twickler, Th B Marcel; de Bie, Rob M; Ackermans, Mariëtte T; Fliers, Eric; Schuurman, P Richard; La Fleur, Susanne E; Serlie, Mireille J

2014-01-01

Animal studies have shown that central dopamine signaling influences glucose metabolism. As a first step to show this association in an experimental setting in humans, we studied whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), which modulates the basal ganglia circuitry, alters basal endogenous glucose production (EGP) or insulin sensitivity in patients with Parkinson's disease (PD). We studied 8 patients with PD treated with DBS STN, in the basal state and during a hyperinsulinemic euglycemic clamp using a stable glucose isotope, in the stimulated and non-stimulated condition. We measured EGP, hepatic insulin sensitivity, peripheral insulin sensitivity (Rd), resting energy expenditure (REE), glucoregulatory hormones, and Parkinson symptoms, using the Unified Parkinson's Disease Rating Scale (UPDRS). Basal plasma glucose and EGP did not differ between the stimulated and non-stimulated condition. Hepatic insulin sensitivity was similar in both conditions and there were no significant differences in Rd and plasma glucoregulatory hormones between DBS on and DBS off. UPDRS was significantly higher in the non-stimulated condition. DBS of the STN in patients with PD does not influence basal EGP or insulin sensitivity. These results suggest that acute modulation of the motor basal ganglia circuitry does not affect glucose metabolism in humans.

Budget impact of treating commercially insured type 1 and type 2 diabetes patients in the United States with insulin degludec compared to insulin glargine.

PubMed

Weatherall, James; Bloudek, Lisa; Buchs, Sarah

2017-02-01

To quantify the annual budget impact if all US commercially insured type 1 diabetes mellitus patients on basal-bolus therapy (T1DM BBT ), type 2 diabetes mellitus patients on basal-oral therapy (T2DM BOT ), and type 2 diabetes mellitus patients on basal-bolus therapy (T2DM BBT ) switched from insulin glargine (IGlar) to insulin degludec (IDeg). A short-term (1 year) budget impact model was developed to evaluate the costs of IDeg vs. IGlar in three treatment groups (T1DM BBT , insulin-naïve T2DM BOT , and T2DM BBT ) through a simulation for a potential US health plan population of 35 million. The analysis captured direct medical costs associated with insulin treatment (insulin, needles, and self-monitored glucose testing) and costs related to managing hypoglycemic episodes. There were a total of 59,780 T1DM BBT patients, 383,145 T2DM BOT patients, and 171,325 T2DM BBT patients expected to be using long-acting insulin. A sensitivity analysis on the entire US population was also conducted. Among T1DM BBT patients, IDeg was associated with an annual cost savings of -$357.13 per patient per year (PPPY), driven primarily by reduced insulin utilization. IDeg was also found to be cost saving among T2DM BOT patients (-$1206.61 PPPY), driven primarily by reductions in the cost of treating severe hypoglycemic episodes. Among T2DM BBT patients, IDeg was associated with an additional cost to the plan of $1420.04 PPPY; however, this result was driven by a higher insulin dose for IDeg compared to IGlar. Overall, IDeg demonstrated cost savings of $240 million per year, which accounted for total cost savings of 3.5% vs. IGlar. The results of this analysis suggest that the reduced insulin utilization and fewer hypoglycemic episodes associated with IDeg may translate into reduced costs for payers. The model is limited by simplification of a complex disease state and assumptions surrounding disease state, treatment patterns, and costs. Therefore, results may not accurately reflect

Leptin-induced basal Akt phosphorylation and its implication in exercise-mediated improvement of insulin sensitivity.

PubMed

Zheng, Xianjie; Niu, Sen

2018-01-29

Physical exercise is an efficient therapeutical tool in the management of insulin resistance (IR) and related metabolic diseases. Leptin, the well-known obesity hormone and the absence of which leads to IR, showed controversial effects on IR as research continues. Thus, in this study, a detailed investigation of the effect of leptin on exercise-mediated improvement of insulin sensitivity and its underlying mechanism was carried out. Using a rat model of chronic or acute swimming exercise training, we found that serum leptin increased 1 h after either acute exercise or the last session of chronic exercise, when impaired insulin action was observed in previous reports. However, chronic exercise reducd basal serum leptin levels and promoted insulin sensitivity compared with sedentary controls or rats subjected to one bout of aerobic exercise. Our animal results indicated the potential linkage between leptin and insulin sensitivity, which is further investigated in the skeletal muscle L6 cells. Leptin treatment in L6 cells promoted the basal levels of insulin signaling as well as glucose uptake, while blocking JAK2 signaling with either pharmacological intervention (JAK2 inhibitor AG490) or genetic manipulation (siRNA knockdown) decreased the basal levels of insulin signaling. Furthermore, leptin treatment inhibited insulin-stimulated insulin signaling and glucose uptake, while blocking JAK2 signaling restored leptin-attenuated insulin sensitivity. Taken together, our results demonstrated that reduced serum leptin, at least in part, contributes to exercise-mediated improvement of insulin sensitivity, indicating JAK2 as a potent therapeutical target of insulin resistance. Copyright © 2018 Elsevier Inc. All rights reserved.

The role of basal insulin and GLP-1 receptor agonist combination products in the management of type 2 diabetes

PubMed Central

Inman, Taylor R.; Plyushko, Erika; Austin, Nicholas P.; Johnson, Jeremy L.

2018-01-01

The prevalence of type 2 diabetes necessitates the development of new treatment options to individualize therapy. Basal insulin has been a standard treatment option for years, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have grown in use over the past decade due to glucose-lowering efficacy and weight loss potential. There are two new combination injectable products that have recently been approved combining basal insulins with GLP-1 RAs in single pen-injector devices. United States guidelines recently emphasize the option to use combination injectable therapy with GLP-1 RAs and basal insulin once the basal insulin has been optimally titrated as a second- or third-line agent in addition to metformin without reaching the goal A1c. Insulin glargine/lixisenatide 100/33 (IGlarLixi) can be dosed between 15 and 60 units once daily from a single pen-injector device. Insulin degludec/liraglutide 100/3.6 (IDegLira) can be dosed between 10 and 50 units once daily, also from a single pen-injector device. Maximum doses, while measured in units, correspond to limits defined by each individual GLP-1 RA. The dual use of basal insulin plus GLP-1 RA is non-inferior compared with basal insulin plus a single injection of prandial insulin at the largest meal and compared with twice daily-dosed premixed insulins; and this combination is associated with weight loss and less hypoglycemia. These new combination products could help providers effectively and efficiently follow clinical practice guidelines while enhancing patient adherence with injectable medications. PMID:29796245

The role of basal insulin and GLP-1 receptor agonist combination products in the management of type 2 diabetes.

PubMed

Inman, Taylor R; Plyushko, Erika; Austin, Nicholas P; Johnson, Jeremy L

2018-05-01

The prevalence of type 2 diabetes necessitates the development of new treatment options to individualize therapy. Basal insulin has been a standard treatment option for years, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have grown in use over the past decade due to glucose-lowering efficacy and weight loss potential. There are two new combination injectable products that have recently been approved combining basal insulins with GLP-1 RAs in single pen-injector devices. United States guidelines recently emphasize the option to use combination injectable therapy with GLP-1 RAs and basal insulin once the basal insulin has been optimally titrated as a second- or third-line agent in addition to metformin without reaching the goal A1c. Insulin glargine/lixisenatide 100/33 (IGlarLixi) can be dosed between 15 and 60 units once daily from a single pen-injector device. Insulin degludec/liraglutide 100/3.6 (IDegLira) can be dosed between 10 and 50 units once daily, also from a single pen-injector device. Maximum doses, while measured in units, correspond to limits defined by each individual GLP-1 RA. The dual use of basal insulin plus GLP-1 RA is non-inferior compared with basal insulin plus a single injection of prandial insulin at the largest meal and compared with twice daily-dosed premixed insulins; and this combination is associated with weight loss and less hypoglycemia. These new combination products could help providers effectively and efficiently follow clinical practice guidelines while enhancing patient adherence with injectable medications.

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Mumbai cohort of the A1chieve study.

PubMed

Talwalkar, P G; Gupta, Vishal; Kovil, Rajiv

2013-11-01

The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Mumbai, India. A total of 2112 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1561), insulin detemir (n = 313), insulin aspart (n = 144), basal insulin plus insulin aspart (n = 53) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 8.7%) and insulin user (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naïve: -1.4%, insulin users: -1.8%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Evaluation of Intradermal and Subcutaneous Infusion Set Performance Under 24-Hour Basal and Bolus Conditions

PubMed Central

McVey, Elaine; Keith, Steven; Herr, Joshua K.; Sutter, Diane; Pettis, Ronald J.

2015-01-01

Background: This study sought to assess the function and delivery reliability of intradermal (ID) infusion sets used with commercial insulin pumps. Method: Healthy subjects (n = 43) were randomized to either ID or subcutaneous (SC) arms, and received basal/bolus placebo delivery for 24 hours. Subjects received 4 of 8 infusion set combinations (ID: microneedle design A or B, with 2 pump brands [Animas or MiniMed]; SC: Teflon Quickset or steel Rapid-D, Animas pump only, with or without overtaping) and were evaluated for pump occlusion alarms, fluid leakage, pain, and tissue tolerability. A novel algorithm was developed to determine flow consistency based on fluid pressure, and the duration and occurrence rate for periods of unalarmed but interrupted flow (“silent occlusions’”) were compared. Results: ID delivery was successfully maintained over the 24-hour infusion period. The number of silent occlusions was lower for ID microneedle cannula design B than A (P < .01) and lower for Rapid-D SC device compared to Quick-set (P = .03). There was no significant difference in the number of occlusion alarms between the ID and SC devices with the Animas pump. However, the pumps tested with ID devices had significantly different alarm rates (MiniMed 29.5%, Animas 0%, P < .001). Leakage and tissue tolerability were comparable across devices. Conclusion: The ID infusion set reliably delivered diluent for an extended 24-hour period in healthy subjects and was well tolerated. Silent occlusion flow interruptions could be detected in both ID and SC infusion sets using a proprietary algorithm. This algorithm is a promising method for quantitatively evaluating infusion set flow performance. PMID:26319228

Systematic review and meta-analysis of short-acting insulin analogues in patients with diabetes mellitus.

PubMed

Plank, Johannes; Siebenhofer, Andrea; Berghold, Andrea; Jeitler, Klaus; Horvath, Karl; Mrak, Peter; Pieber, Thomas R

2005-06-27

This article compares the effect of treatment with short-acting insulin (SAI) analogues vs regular insulin on glycemic control, hypoglycemic episodes, quality of life, and diabetes-specific complications. Electronic searches (Cochrane Library, MEDLINE, and EMBASE) and additional searching (pharmaceutical companies, experts, approval agencies, abstracts of diabetology meetings) were performed. Two reviewers independently screened randomized controlled trials to determine inclusion. Forty-two randomized controlled trials that assessed the effect of SAI analogues vs regular insulin in 7933 patients with type 1 diabetes mellitus, type 2 diabetes mellitus, and gestational diabetes mellitus were identified. The weighted mean difference between hemoglobin A(1c) values obtained using SAI analogues and regular insulin was -0.12% (95% confidence interval [CI], -0.17% to -0.07%) for adult patients with type 1 diabetes mellitus and -0.02% (95% CI, -0.10% to 0.07%) for patients with type 2 diabetes mellitus. The standardized mean difference for overall hypoglycemia (episodes per patient per month) was -0.05 (95% CI, -0.22 to 0.11) and -0.04 (95% CI, -0.12 to 0.04) comparing SAI analogues with regular insulin in adult patients with type 1 and type 2 diabetes mellitus, respectively. No differences between treatments were observed in children with type 1 diabetes, pregnant women with type 1 diabetes mellitus, and women with gestational diabetes. Concerning quality of life, improvement was observed only in open-label studies in patients with type 1 diabetes mellitus. No differences were seen in a double-blinded study of patients with type 1 or in the studies of patients with type 2 diabetes mellitus. Our analysis suggests only a minor benefit to hemoglobin A(1c) values in adult patients with type 1 diabetes mellitus but no benefit in the remaining population with type 2 or gestational diabetes from SAI analogue treatment.

Evaluation of the quality of life of patients with diabetes mellitus treated with conventional or analogue insulins.

PubMed

Machado-Alba, Jorge Enrique; Medina-Morales, Diego Alejandro; Echeverri-Cataño, Luis Felipe

2016-06-01

The results of two scales that measure quality of life of patients with diabetes mellitus treated with conventional or analogue insulin were evaluated and compared. Descriptive, observational, cross-sectional study, conducted in the cities of Pereira and Manizales, Colombia, in a care facility between 1 August 2013 and 30 March 2014. A total of 238 patients diagnosed with diabetes mellitus type 1 or type 2 who had been undergoing treatment with conventional or analogue insulin for at least 6months. Comparison of the results of the Diabetes 39 (specific) and European Quality of Life-5 Dimensions (EQ-5D) (generic) tools it was performed. Comparisons between the results of the two instruments were performed. Tests for parametric and non-parametric distribution (Pearson's correlation coefficient, Mann-Whitney U test, Student's t-test and Wilcoxon test) were used. The mean age was 57.7±16.6years. Conventional insulin was prescribed to 69.6% of patients, and analogue insulin was prescribed to 30.4% of patients. Diabetes-39 (D-39) showed 24.7% of subjects with a high quality of life. No statistically significant differences were found when comparing patients prescribed conventional or analogue insulin (p=0.35; 95% confidence interval [CI]: 0.375-1.419). In the EQ-5D survey, 45.7% claimed to have a high quality of life, without statistically significant differences between groups (p=0.56; 95%CI: 0.676-2.047). No differences between patients receiving conventional insulin versus analogue insulin were detected in terms of quality of life. The group aged over 60years requires special attention to improve their quality of life, and programs should focus on those individuals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Internalization and localization of basal insulin peglispro in cells.

PubMed

Moyers, Julie S; Volk, Catherine B; Cao, Julia X C; Zhang, Chen; Ding, Liyun; Kiselyov, Vladislav V; Michael, M Dodson

2017-10-15

Basal insulin peglispro (BIL) is a novel, PEGylated insulin lispro that has a large hydrodynamic size compared with insulin lispro. It has a prolonged duration of action, which is related to a delay in insulin absorption and a reduction in clearance. Given the different physical properties of BIL compared with native insulin and insulin lispro, it is important to assess the cellular internalization characteristics of the molecule. Using immunofluorescent confocal imaging, we compared the cellular internalization and localization patterns of BIL, biosynthetic human insulin, and insulin lispro. We assessed the effects of BIL on internalization of the insulin receptor (IR) and studied cellular clearance of BIL. Co-localization studies using antibodies to either insulin or PEG, and the early endosomal marker EEA1 showed that the overall internalization and subcellular localization pattern of BIL was similar to that of human insulin and insulin lispro; all were rapidly internalized and co-localized with EEA1. During ligand washout for 4 h, concomitant loss of insulin, PEG methoxy group, and PEG backbone immunostaining was observed for BIL, similar to the loss of insulin immunostaining observed for insulin lispro and human insulin. Co-localization studies using an antibody to the lysosomal marker LAMP1 did not reveal evidence of lysosomal localization for insulin lispro, human insulin, BIL, or PEG using either insulin or PEG immunostaining reagents. BIL and human insulin both induced rapid phosphorylation and internalization of human IR. Our findings show that treatment of cells with BIL stimulates internalization and localization of IR to early endosomes. Both the insulin and PEG moieties of BIL undergo a dynamic cellular process of rapid internalization and transport to early endosomes followed by loss of cellular immunostaining in a manner similar to that of insulin lispro and human insulin. The rate of clearance for the insulin lispro portion of BIL was slower than

Validation of Algorithms for Basal Insulin Rate Reductions in Type 1 Diabetic Patients Practising Physical Activity

ClinicalTrials.gov

2013-04-19

Type 1 Diabetes With a Subcutaneous Insulin Pump; Adjustment of the Recommended Basal Insulin Flow Rate in the Event of Physical Activity; Adjustment of the Recommended Prandial Insulin in the Event of Physical Activity

Effect of long acting somatostatin-analogue, SMS 201 995, on gut hormone secretion in normal subjects.

PubMed

Kraenzlin, M E; Wood, S M; Neufeld, M; Adrian, T E; Bloom, S R

1985-06-15

SMS 201 995 is a new long acting analogue of somatostatin. We have investigated its effect on basal and meal stimulated secretion of gut hormones and have shown that after a single s.c. injection of 50 micrograms it lowers significantly the basal plasma levels of pancreatic polypeptide, secretin, motilin, pancreatic glucagon and insulin, it also effectively suppresses the postprandial release of pancreatic polypeptide, gastrin, secretin, gastric inhibitory peptide, pancreatic glucagon and insulin. Except for the usual brief discomfort of an injection, no symptoms or untoward effects were observed.

Glycaemic control and prevalence of hypoglycaemic events in children and adolescents with type 1 diabetes mellitus treated with insulin analogues.

PubMed

Plavšić, Ljiljana; Mitrović, Katarina; Todorović, Sladjana; Vuković, Rade; Milenković, Tatjana; Zdravković, Dragan

2014-09-01

An ideal insulin regimen for children and adolescents with type 1 diabetes mellitus (T1DM) should be physiological, flexibile and predictable, protecting against hypoglycaemia. The aim of this study was to evaluate the influence of insulin analogues on glycaemic control and the occurance of hypoglycaemic episodes in children and adolescents with T1DM. The study group consisted of 151 children and adolescents (90 boys, 61 girls) treated with human insulins for at least 12 months before introducing insulin analogues. All the patients were divided into two groups: the group I consisted of 72 (47.7%) patients treated with three injections of regular human insulin before meals and long-acting analogue (RHI/LA), and the group II of 79 (52.30%) patients treated with a combination of rapid-acting and long-acting analogue (RA/LA). The levels of glycated hemoglobin (HbA1c) and the number of hypoglycaemic episodes were assessed at the beginning of therapy with insulin analogues, and after 6 and 12 months. The mean HbA1c was significantly lower in the group I (RHI/LA) after 6 months (9.15% vs 8.20%, p < 0.001) and after 12 months (9.15% vs 8.13%, p < 0.001) as well as in the group II (RA/LA) after 6 months (9.40% vs 8.240%, p < 0.001) and after 12 months of insulin analogues treatment (9.40% vs 8.38%, p < 0.001). The frequency of severe hypoglycaemia was significantly lower in both groups after 6 months (in the group I from 61.1% to 4.2% and in the group II from 54.4% to 1.3%, p < 0.001), and after 12 months (in the group I from 61.1% to 1.4% and in the group II from 54.4% to 1.3%, p < 0.001). Significantly better HbA1c values and lower risk of severe hypoglycaemia were established in children and adolescents with T1DM treated with insulin analogues.

Insulin lispro low mixture twice daily versus basal insulin glargine once daily and prandial insulin lispro once daily in patients with type 2 diabetes requiring insulin intensification: a randomized phase IV trial.

PubMed

Tinahones, F J; Gross, J L; Onaca, A; Cleall, S; Rodríguez, A

2014-10-01

To compare the efficacy and safety of two insulin intensification strategies in patients with type 2 diabetes inadequately controlled on basal insulin glargine with metformin and/or pioglitazone. A multinational, randomized, open-label trial that compared insulin lispro low mixture (LM25; n = 236) twice daily with a basal-prandial regimen of insulin glargine once daily and insulin lispro once daily (IGL; n = 240) over 24 weeks in patients with HbA1c 7.5-10.5% and fasting plasma glucose ≤ 6.7 mmol/l. The primary objective was to assess non-inferiority [per-protocol (PP) population], and then superiority [intention-to-treat (ITT) population], of LM25 versus IGL according to change in HbA1c after 24 weeks (non-inferiority margin 0.4%, two-sided significance level 0.05). Estimated change [least squares (LS) mean (95% CI)] in HbA1c after 24 weeks: -1.30 (-1.44, -1.16)% with LM25 and -1.08 (-1.22, -0.94)% with IGL. Non-inferiority was shown [LS mean (95% CI) HbA1c treatment difference -0.21 (-0.38, -0.04) (PP population)]; gated superiority assessment showed a statistically significant advantage for LM25 (p = 0.010; ITT population). Mean blood glucose, glycaemic variability, overall tolerability and hypoglycaemic episodes per patient-year did not show significant differences between treatments during the study. In patients with type 2 diabetes inadequately controlled on once-daily basal insulin glargine and metformin and/or pioglitazone, intensification with LM25 was superior to a basal-prandial approach in terms of reduction in HbA1c after 24 weeks and did not increase hypoglycaemia episodes. © 2014 The Authors. Diabetes, Obesity and Metabolism published by JohnWiley & Sons Ltd.

Insulin glargine 300 units/mL: A new basal insulin product for diabetes mellitus.

PubMed

Clements, Jennifer N; Bello, Larkin

2016-03-15

The pharmacokinetics, efficacy, and safety of U-300 insulin glargine for the management of diabetes are reviewed. U-300 (300 units/mL) insulin glargine is a long-acting basal insulin with low within-day variability, high day-to-day reproducibility, longer duration, and constant pharmacokinetic profile compared with U-100 (100 units/mL) insulin glargine. U-300 was evaluated in six randomized, active-comparator, open-label, Phase III clinical studies (EDITION trials) among patients with type 1 or 2 diabetes. The primary endpoint for all EDITION studies was the reduction in glycosylated hemoglobin from baseline to six months. Safety endpoints included confirmed or nocturnal hypoglycemia between week 9 and month 6 and the change in weight from baseline. For hypoglycemic episodes, U-300 insulin glargine was superior to U-100 insulin glargine when comparing the risk of hypoglycemia. U-300 insulin glargine is supplied in a prefilled device (for safety purposes) and packaged in boxes of three or five pens. It is still early to determine the role of U-300 insulin glargine in diabetes management. When compared with U-100 insulin glargine, U-300 insulin glargine appeared to be associated with a lower risk of hypoglycemia and nocturnal hypoglycemia, most likely due to its pharmacokinetics. The wholesale average cost of U-300 insulin glargine is $335.48 per box of three pens. The efficacy outcomes of U-300 insulin glargine were similar to those of U-100 insulin glargine, but the constant pharmacokinetic profile and longer duration of action of U-300 insulin glargine may help certain patients with type 1 or type 2 diabetes achieve better glycemic control. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Northern Tunisia cohort of the A1chieve study

PubMed Central

Blouza, Samira; Jamoussi, Henda

2013-01-01

Background: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Northern Tunisia. Results: A total of 443 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 137), insulin detemir (n = 243), insulin aspart (n = 11), basal insulin plus insulin aspart (n = 39) and other insulin combinations (n = 13). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 10.2%) and insulin user (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naïve: −2.1%, insulin users: −0.9%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID:24404473

Does Reducing Basal Insulin During Ramadan Fasting by Children and Adolescents with Type 1 Diabetes Decrease the Risk of Symptomatic Hypoglycemia?

PubMed

Deeb, Asma; Al Qahtani, Nabras; Attia, Salima; Al Suwaidi, Hana; Nagelkerke, Nico

2016-09-01

Ramadan fasting by patients with type 1 diabetes might predispose them to hypoglycemia. There are no data on the optimal way of adjusting basal insulin during fasting. We aim at studying whether reducing basal insulin during Ramadan reduces the frequency of symptomatic hypoglycemia. We enrolled children and adolescents with type 1 diabetes who intended to fast during Ramadan. Logbooks were given to subjects to mark days fasted, symptomatic hypoglycemia, and dose of basal insulin on all days of Ramadan. Logbooks were examined. Glucometers and insulin pumps were downloaded. Seventy-five patients were enrolled. The age was 10.2-18.9 (14.5) years. Sixty-eight patients had results analyzed. Forty-one patients were on pumps, and 27 patients were on multiple daily injections (MDI). Mean HbA1c was 7.9 (1.2) and 8.4 (1.3) for the pump and the MDI, respectively (P = 0.007). Thirty-nine patients had hypoglycemia leading to breaking fast. The mean number of episodes of breaking fast was 3 (1-8). Thirty-five of the 68 patients had reduced basal insulin. The difference in the frequency of hypoglycemia in those who reduced/did not reduce insulin was not statistically significant (P > 0.10). Fifteen patients on MDI and 24 patients on pumps had at least one episode of breaking fast. Six and 18 of the patients on MDI and pumps, respectively, reduced basal insulin (P > 0.10). This is the first study examining the impact of reduction of basal insulin on hypoglycemia in adolescents. Reducing basal insulin during Ramadan fasting does not decrease the risk of symptomatic hypoglycemia. Use of the insulin pump does not appear to be different from MDI in the frequency of occurrence of hypoglycemia.

Effectiveness of insulin glargine in type 2 diabetes mellitus patients failing glycaemic control with premixed insulin: Adriatic countries data meta-analysis.

PubMed

Cigrovski Berkovic, Maja; Petrovski, Goran; Grulovic, Natasa

2016-10-01

Type 2 diabetes mellitus (T2DM) is a progressive disease, often requiring exogenous insulin therapy and treatment intensification. Despite new therapies, most patients do not reach the recommended HbA1c targets, among them a significant proportion of patients on premixed insulins. The aim was to summarize published data in Adriatic countries on effectiveness of insulin glargine based therapy in type 2 diabetic patients suboptimally controlled on premix insulin. A meta-analysis was carried out in major medical databases up to April 2014, focusing on Adriatic region. We searched observational studies with duration of at least 6 months, evaluating effectiveness and safety of insulin glargine (IGlar), in combination with OAD or bolus insulin in patients with T2 failing premixed insulin therapy. Outcomes included values of HbA1c, fasting blood glucose and two hours post-prandial glucose concentration as well as changes in body mass index after at least 6 months of study duration. Three prospective, observational, multicentric trials (698 patients in total) were included. The basal bolus regimen with glargine significantly reduced HbA1c (Mean Difference, MD=2.27, CI [1.76, 2.78]), fasting glucose (MD=5.15, CI [4.86, 5.44]) and 2-hours postprandial glucose concentration (MD=6.94, CI [6.53, 7.34]). No significant changes were found in BMI after switching from premixes to IGlar based treatment. Insulin glargine based therapy following premix failure is efficacious and safe option of type 2 diabetes treatment intensification.

A Review of the Clinical Efficacy and Safety of Insulin Degludec and Glargine 300 U/mL in the Treatment of Diabetes Mellitus.

PubMed

Woo, Vincent C

2017-08-01

The treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) using insulin is not ideal at this time. Despite advances made with basal insulin analogues, many individuals achieve less than optimal glycemic control or are at risk for hypoglycemia. Currently available basal insulin analogues do not deliver steady, peakless, continuous insulin for >24 hours and are associated with adverse events, including hypoglycemia. The objective of this paper was to review the clinical efficacy and safety of upcoming long-acting insulin analogues such as insulin degludec and insulin glargine 300 U/mL (Gla-300). A comprehensive literature search of PubMed and Google Scholar was conducted from 1966 to 2015. The search included randomized controlled trials that specifically assessed the efficacy and safety of insulin degludec and Gla-300 in patients with T1DM and T2DM. The efficacy of insulin degludec and Gla-300 in achieving glycemic control has been reported in clinical trials in adults with T1DM and T2DM. Not only did a large number of patients succeed in meeting glycosylated hemoglobin targets, but they also experienced reductions in hypoglycemic events. These 2 therapies are associated with a reduced risk of nocturnal hypoglycemia and are generally well tolerated. The long-acting insulin analogues insulin degludec and Gla-300 are promising therapies in the treatment of T1DM and T2DM. Their improved insulin delivery for >24 hours offers glycemic control with a good safety profile. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Do Perceptions of Insulin Pump Usability Impact Attitudes Toward Insulin Pump Therapy? A Pilot Study of Individuals With Type 1 and Insulin-Treated Type 2 Diabetes

PubMed Central

Gilgen, Emily

2014-01-01

Background: We assessed the impact of perceived insulin pump usability on attitudes toward insulin pump therapy in diabetic individuals currently treated with multiple daily insulin injections (MDI). Method: This comparative, single-arm study recruited 28 adults with type 1 (n = 16) and insulin-treated type 2 diabetes (n = 12) to evaluate 2 current insulin pumps: Medtronic Revel 723 (Pump 1), Asante Snap Insulin Pump (Pump 2). Participants were randomized 1:1 to 1 of 2 assessment sequences: Pump 1 followed by Pump 2; and Pump 2 followed by Pump 1. Structured observational protocols were utilized to assess participants’ ability and time required to learn/perform common tasks associated with pump setup/use. Participants used a modified version of the System Usability Scale (SUS) and investigator-developed questionnaires to rate pump usability and task difficulty; pre-post questionnaires assessed changes in attitudes toward insulin pump therapy. Results: All participants completed the study. SUS scores showed Pump 2 to be more usable than Pump 1 on all usability attributes. Participants rated Pump 2 more positively than Pump 1, overall mean SUS scores of 5.7 versus 4.1 respectively, F(1, 52) = 32.7, P < .001, and SUS scores were higher if participants used the Pump 2 last, 5.3 versus 4.4 for Pump 1 last, F(1, 52) = 10.8, P < .01. Pump 2 was preferred for all tasks: manual bolus (86%), bolus calculation (71%), managing basal rates (93%), interpreting alarms (96%), transferring settings (100%), changing insulin and infusion sets (93%), all P < .05. Conclusions: Perceptions of pump usability can directly impact acceptance and use of features that may benefit those who wear them. Simpler pump devices that decrease perceptions of complexity may encourage broader use of this technology. PMID:25269659

Comparison of the impact of human vs analogue insulins on glycosylated haemoglobin in a population with diabetes mellitus.

PubMed

Machado-Alba, Jorge Enrique; Medina-Morales, Diego Alejandro

2016-12-01

To compare the effect on metabolic control of treatment with conventional and analogue insulins for patients with diabetes mellitus. Retrospective cohort study held in cities of Colombia (Pereira and Manizales). People insured by the paid healthcare system, who were diagnosed with diabetes mellitus type 1 and 2, and treated with conventional and analogue insulin for at least 6 months prior to the start of the study were sampled and followed up for 18 months. Data were collected from clinical records for each patient. Treatment groups were compared according to the type of insulin received. A total of 313 patients were included; overall, 56.9% were women and the mean age was 57.3 years. No statistically significant difference was found in glycosylated haemoglobin reduction at 3, 6 and 18 months when comparing patients receiving glargine vs NPH insulin (P=.403) and NPH plus zinc crystalline insulin vs glargine plus glulisine (P=.514). The percentage of patients with metabolic control increased from 27.8% to 34.2% during follow-up with all types of insulin. Insulin analogues were not superior to human insulin for glycaemic control. A significant proportion of patients did not attain the treatment goals; therefore, it is necessary to implement measures to improve the monitoring and control of diabetes mellitus. © 2016 John Wiley & Sons Ltd.

Unknown Safety and Efficacy of Smartphone Bolus Calculator Apps Puts Patients at Risk for Severe Adverse Outcomes.

PubMed

Hirsch, Irl B; Parkin, Christopher G

2016-07-01

Manual calculation of bolus insulin dosages can be challenging for individuals treated with multiple daily insulin injections (MDI) therapy. Automated bolus calculator capability has recently been made available via enhanced blood glucose meters and smartphone apps. Use of this technology has been shown to improve glycemic control and reduce glycemic variability without changing hypoglycemia; however, the clinical utility of app-based bolus calculators has not been demonstrated. Moreover, recent evidence challenges the safety and efficacy of these smartphone apps. Although the ability to automatically calculate bolus insulin dosages addresses a critical need of MDI-treated individuals, this technology raises concerns about efficacy of treatment and the protection of patient safety. This article discusses key issues and considerations associated with automated bolus calculator use. © 2016 Diabetes Technology Society.

Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26.

PubMed

Papaioannou, Anastasios; Kuyucak, Serdar; Kuncic, Zdenka

2017-09-01

Due to the increasing prevalence of diabetes, finding therapeutic analogues for insulin has become an urgent issue. While many experimental studies have been performed towards this end, they have limited scope to examine all aspects of the effect of a mutation. Computational studies can help to overcome these limitations, however, relatively few studies that focus on insulin analogues have been performed to date. Here, we present a comprehensive computational study of insulin analogues-three mutant insulins that have been identified with hyperinsulinemia and three mutations on the critical B26 residue that exhibit similar binding affinity to the insulin receptor-using molecular dynamics simulations with the aim of predicting how mutations of insulin affect its activity, dynamics, energetics and conformations. The time evolution of the conformers is studied in long simulations. The probability density function and potential of mean force calculations are performed on each insulin analogue to unravel the effect of mutations on the dynamics and energetics of insulin activation. Our conformational study can decrypt the key features and molecular mechanisms that are responsible for an enhanced or reduced activity of an insulin analogue. We find two key results: 1) hyperinsulinemia may be due to the drastically reduced activity (and binding affinity) of the mutant insulins. 2) Y26 B S and Y26 B E are promising therapeutic candidates for insulin as they are more active than WT-insulin. The analysis in this work can be readily applied to any set of mutations on insulin to guide development of more effective therapeutic analogues.

Fields of application of continuous subcutaneous insulin infusion in the treatment of diabetes and implications in the use of rapid-acting insulin analogues.

PubMed

Pitocco, D; Rizzi, A; Scavone, G; Tanese, L; Zaccardi, F; Manto, A; Ghirlanda, G

2013-09-01

In western countries, diabetes mellitus, because of macrovascular and microvascular complications related to it, is still an important cause of death. Patients with type 1 diabetes mellitus (T1DM) have a six-time higher risk of mortality than healthy patients. Since the Diabetes Control and Complications Trial (DCCT) established how an intensive therapy is necessary to prevent diabetes mellitus complications, many studies have been conducted to understand which method is able to reach an optimal metabolic control. In the past 30 years continuous subcutaneous insulin infusion established/introduced as a validate alternative to multiple daily injections. Several trials demonstrated that, when compared to MDI, CSII brings to a better metabolic control, in terms of a reduction of glycated hemoglobin and blood glucose variability, hypoglycemic episodes and improvement in quality of life. Because of their pharmacokinetic and pharmacodynamic characteristics, rapid-action insulin analogues are imposed as best insulin to be used in CSII. The rapid onset and the fast reached peak make them better mimic the way how pancreas secretes insulin. CSII by pump is not free from issues. Catheter occlusions, blockages, clogs can arrest insulin administration. The consequent higher levels of glycemic values, can easily bring to the onset of ketoacidosis, with an high risk for patients' life. Aspart is a rapid analogue obtained by aminoacidic substitution. It is as effective as lispro and glulisine in gaining a good metabolic control and even better in reducing glucose variability. Some studies tried to compare rapid analogues in terms of stability. Obtained data are controversial. An in vivo study evidenced higher stability or glulisine, while studies in vitro highlighted a higher safety of aspart. Nowadays it is not possible to assess which analogues is safer. When the infusion set is changed every 48 hours equivalent rates of occlusions have been observed.

Optimizing Insulin Glargine Plus One Injection of Insulin Glulisine in Type 2 Diabetes in the ELEONOR Study

PubMed Central

Nicolucci, Antonio; Del Prato, Stefano; Vespasiani, Giacomo

2011-01-01

OBJECTIVE To determine the functional health status and treatment satisfaction in patients with type 2 diabetes from the Evaluation of Lantus Effect ON Optimization of use of single dose Rapid insulin (ELEONOR) study that investigated whether a telecare program helps optimization of basal insulin glargine with one bolus injection of insulin glulisine. RESEARCH DESIGN AND METHODS Functional health status and treatment satisfaction were investigated using the 36-Item Short-Form (SF-36) Health Survey, the World Health Organization Well-Being Questionnaire (WBQ), and the Diabetes Treatment Satisfaction Questionnaire. RESULTS Of 291 randomized patients, 238 completed the study (telecare: 114; self-monitoring blood glucose: 124). Significant improvements were detected in most SF-36 domains, in WBQ depression and anxiety scores, and in treatment satisfaction, without differences between study groups. CONCLUSIONS An insulin regimen that substantially improves metabolic control, while minimizing the risk of hypoglycemia, can positively affect physical and psychologic well-being and treatment satisfaction irrespective of the educational support system used. PMID:21953799

Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.

PubMed

Vora, J; Bain, S C; Damci, T; Dzida, G; Hollander, P; Meneghini, L F; Ross, S A

2013-02-01

Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Absorption of subcutaneously infused insulin: influence of the basal rate pulse interval.

PubMed

Hildebrandt, P; Birch, K; Jensen, B M; Kühl, C; Brange, J

1985-01-01

Eight insulin-dependent diabetic patients were given two constant infusions (each 1 IU/h) of 125I-labeled insulin into the abdominal subcutaneous tissue for about 12 h. Insulin was infused in pulses into one side of the abdomen in 6-min intervals (by means of an Auto-Syringe pump) and in the other side of the abdomen, insulin was infused in 1-h intervals (by means of a Medix pump). The size of the subcutaneous depots was continuously measured by counting the radioactivity at the infusion sites. After starting the infusions, the two depots were built up to steady-state levels at the same time and of the same size (approximately 3 IU) and with similar absorption rates. Thus, during basal rate insulin infusion, identical insulin absorption kinetics was achieved, irrespective of a 10-fold difference in the pulse rate.

Degludec, a new ultra-long-acting basal insulin for the treatment of diabetes mellitus type 1 and 2: advances in clinical research.

PubMed

Muñoz Torres, Manuel

2014-03-01

Degludec is the most recent molecule of the ultra-long-acting basal insulin analogues approved for human use. It forms soluble multihexamers which after subcutaneous injection are converted into monomers, and are thus slowly and continuously absorbed into the bloodstream. This absorption mechanism confers degludec an ultra-long and stable action profile, with no concentration peaks. This paper discusses the most recent studies in patients with type 1 and 2 diabetes mellitus, which showed degludec to be non inferior in decreasing HbA1c, ensuring optimum glycemic control similar to that achieved with insulin glargine or detemir. Degludec also had an improved safety profile, as it was associated to a significantly lower rate of nocturnal hypoglycemia in both types of diabetes and to a potentially lower overall hypoglycemia rate in type 2 DM. Degludec also opens the possibility to use more flexible regimens. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

Insulin glargine 300 U/mL for basal insulin therapy in type 1 and type 2 diabetes mellitus.

PubMed

Lau, Ip Tim; Lee, Ka Fai; So, Wing Yee; Tan, Kathryn; Yeung, Vincent Tok Fai

2017-01-01

To review published clinical studies on the efficacy and safety of new insulin glargine 300 units/mL (Gla-300), a new long-acting insulin analog, for the treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM). Data sources comprised primary research articles on Gla-300, including pharmacodynamic, pharmacokinetic, and clinical studies. In pharmacodynamic and pharmacokinetic studies, Gla-300 showed a flatter time-action profile and longer duration of action than Gla-100. Noninferiority of Gla-300 versus Gla-100 for lowering of glycated hemoglobin was demonstrated in Phase III clinical studies covering a range of T1DM and T2DM patient populations. Over 6-12 months of follow-up, Gla-300 consistently showed comparable glycemic efficacy with less hypoglycemia vs Gla-100, even during the first 8 weeks of treatment. Although titrated insulin doses were 11%-17% higher with Gla-300 vs Gla-100, changes in body weight were similar or favored Gla-300. Clinical studies provide evidence that the pharmacodynamic and pharmacokinetic properties of Gla-300 may translate into clinical benefits in both T1DM and T2DM. Gla-300 may provide a new option for people initiating basal insulin, those requiring higher basal insulin doses, those with T1DM, and those who may be at increased risk for hypoglycemia, such as people with chronic kidney disease, the elderly, and those with cardiovascular comorbidities.

Insulin glargine 300 U/mL for basal insulin therapy in type 1 and type 2 diabetes mellitus

PubMed Central

Lau, Ip Tim; Lee, Ka Fai; So, Wing Yee; Tan, Kathryn; Yeung, Vincent Tok Fai

2017-01-01

Objective To review published clinical studies on the efficacy and safety of new insulin glargine 300 units/mL (Gla-300), a new long-acting insulin analog, for the treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM) Materials and methods Data sources comprised primary research articles on Gla-300, including pharmacodynamic, pharmacokinetic, and clinical studies. Results In pharmacodynamic and pharmacokinetic studies, Gla-300 showed a flatter time–action profile and longer duration of action than Gla-100. Noninferiority of Gla-300 versus Gla-100 for lowering of glycated hemoglobin was demonstrated in Phase III clinical studies covering a range of T1DM and T2DM patient populations. Over 6–12 months of follow-up, Gla-300 consistently showed comparable glycemic efficacy with less hypoglycemia vs Gla-100, even during the first 8 weeks of treatment. Although titrated insulin doses were 11%–17% higher with Gla-300 vs Gla-100, changes in body weight were similar or favored Gla-300. Conclusion Clinical studies provide evidence that the pharmacodynamic and pharmacokinetic properties of Gla-300 may translate into clinical benefits in both T1DM and T2DM. Gla-300 may provide a new option for people initiating basal insulin, those requiring higher basal insulin doses, those with T1DM, and those who may be at increased risk for hypoglycemia, such as people with chronic kidney disease, the elderly, and those with cardiovascular comorbidities. PMID:28721081

Analysis of insulin pump settings in children and adolescents with type 1 diabetes mellitus.

PubMed

Lau, Yu Ning; Korula, Sophy; Chan, Albert K; Heels, Kristine; Krass, Ines; Ambler, Geoffrey

2016-08-01

To characterize current insulin pump settings used in young patients with type 1 diabetes mellitus (T1DM) and to assess their relationship to glycemic control. This retrospective study included patients aged <18 yr old with T1DM >1 yr using a Medtronic pump device. Pump data including number of blood glucose (BG) tests per day, basal and bolus insulin parameters, carbohydrate ratio (CR), and insulin sensitivity factors (ISFs) were averaged over 14 d for statistical analyses. Anthropometric data and recent glycosylated hemoglobin A1c (HbA1c) were recorded. A total of 292 patients (144 males and 148 females) were included in the study. Participants had a median age (interquartile range, IQR) of 12.9 yr (10.0-15.1 yr) and pump duration of 2.8 yr (1.5-4.2 yr). No significant differences in median HbA1c (IQR) were observed in preschool [n = 14; HbA1c 7.8% (7.3-8.3%)], prepubertal [n = 105; HbA1c 8.1% (7.7-8.9%)], and adolescent subjects [n = 173; HbA1c 8.4% (7.7-9.0%)]. Adolescents took significantly fewer boluses and BG tests per day compared with younger children (p < 0.05). Age-specific diurnal variation in basal insulin delivery was noted. Additionally, stronger carbohydrate cover and weaker corrections were used in real-life compared with theoretical 500 and 100 rules, respectively. Lower HbA1c was associated with higher number of daily boluses, greater number of BG tests per day, lower average CR/500 rule ratio, and higher average ISF/100 rule ratio adjusted for age (R(2) = 0.22; p < 0.01). Insulin pump therapy requires continuous adjustments and glycemic targets are achieved by a minority. We believe this is the first study in pediatric cohort looking at association between CR and ISF with glycemic control. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Glucose supply and insulin demand dynamics of antidiabetic agents.

PubMed

Monte, Scott V; Schentag, Jerome J; Adelman, Martin H; Paladino, Joseph A

2010-03-01

For microvascular outcomes, there is compelling historical and contemporary evidence for intensive blood glucose reduction in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). There is also strong evidence to support macrovascular benefit with intensive blood glucose reduction in T1DM. Similar evidence remains elusive for T2DM. Because cardiovascular outcome trials utilizing conventional algorithms to attain intensive blood glucose reduction have not demonstrated superiority to less aggressive blood glucose reduction (Action to Control Cardiovascular Risk in Diabetes; Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; and Veterans Affairs Diabetes Trial), it should be considered that the means by which the blood glucose is reduced may be as important as the actual blood glucose. By identifying quantitative differences between antidiabetic agents on carbohydrate exposure (CE), hepatic glucose uptake (HGU), hepatic gluconeogenesis (GNG), insulin resistance (IR), peripheral glucose uptake (PGU), and peripheral insulin exposure (PIE), we created a pharmacokinetic/pharmacodynamic model to characterize the effect of the agents on the glucose supply and insulin demand dynamic. Glucose supply was defined as the cumulative percentage decrease in CE, increase in HGU, decrease in GNG, and decrease in IR, while insulin demand was defined as the cumulative percentage increase in PIE and PGU. With the glucose supply and insulin demand effects of each antidiabetic agent summated, the glucose supply (numerator) was divided by the insulin demand (denominator) to create a value representative of the glucose supply and insulin demand dynamic (SD ratio). Alpha-glucosidase inhibitors (1.25), metformin (2.20), and thiazolidinediones (TZDs; 1.25-1.32) demonstrate a greater effect on glucose supply (SD ratio >1), while secretagogues (0.69-0.81), basal insulins (0.77-0.79), and bolus insulins (0

Insulin use and persistence in patients with type 2 diabetes adding mealtime insulin to a basal regimen: a retrospective database analysis

PubMed Central

2011-01-01

Background The objective of this study was to characterize insulin use and examine factors associated with persistence to mealtime insulin among patients with type 2 diabetes (T2D) on stable basal insulin therapy initiating mealtime insulin therapy. Methods Insulin use among patients with T2D initiating mealtime insulin was investigated using Thomson Reuters MarketScan® research databases from July 2001 through September 2006. The first mealtime insulin claim preceded by 6 months with 2 claims for basal insulin was used as the index event. A total of 21 months of continuous health plan enrollment was required. Patients were required to have a second mealtime insulin claim during the 12-month follow-up period. Persistence measure 1 defined non-persistence as the presence of a 90-day gap in mealtime insulin claims, effective the date of the last claim prior to the gap. Persistence measure 2 required 1 claim per quarter to be persistent. Risk factors for non-persistence were assessed using logistic regression. Results Patients initiating mealtime insulin (n = 4752; 51% male, mean age = 60.3 years) primarily used vial/syringe (87%) and insulin analogs (60%). Patients filled a median of 2, 3, and 4 mealtime insulin claims at 3, 6, and 12 months, respectively, with a median time of 76 days between refills. According to measure 1, persistence to mealtime insulin was 40.7%, 30.2%, and 19.1% at 3, 6, and 12 months, respectively. Results for measure 2 were considerably higher: 74.3%, 55.3%, and 42.2% of patients were persistent at 3, 6, and 12 months, respectively. Initiating mealtime insulin with human insulin was a risk factor for non-persistence by both measures (OR < 0.80, p < 0.01). Additional predictors of non-persistence at 12 months included elderly age, increased insulin copayment, mental health comorbidity, and polypharmacy (p < 0.05 for all). Conclusions Mealtime insulin use and persistence were both considerably lower than expected, and were significantly lower

Novel hepato-preferential basal insulin peglispro (BIL) does not differentially affect insulin sensitivity compared with insulin glargine in patients with type 1 and type 2 diabetes.

PubMed

Porksen, Niels; Linnebjerg, Helle; Garhyan, Parag; Lam, Eric C Q; Knadler, Mary P; Jacober, Scott J; Hoevelmann, Ulrike; Plum-Moerschel, Leona; Watkins, Elaine; Gastaldelli, Amalia; Heise, Tim

2017-04-01

Basal insulin peglispro (BIL) is a novel PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and reduced peripheral effects, which results in a hepato-preferential action. In Phase 3 trials, patients with T1DM treated with BIL had lower prandial insulin requirements, yet improved prandial glucose control, relative to insulin glargine (GL). We hypothesized that this may be because of an enhanced sensitivity to prandial insulin with BIL resulting from lower chronic peripheral insulin action. Two open-label, randomized, 2-period crossover clinical studies were conducted in 28 patients with T1DM and 24 patients with T2DM. In each study period, patients received once-daily, individualized, stable, subcutaneous doses of BIL or GL for 5 weeks before a euglycaemic 2-step hyperinsulinemic clamp procedure (with [6,6- 2 H 2 ]-glucose in 12 of the patients with T1DM). M-values were derived from the clamp procedure for all patients, with rate of glucose appearance (Ra) and disappearance (Rd) and insulin sensitivity index (SI) determined from the clamps with [6,6- 2 H 2 ]-glucose. There were no statistically significant differences between BIL and GL in key measures of hepatic (% Ra suppression during the low-dose insulin infusion; 78.7% with BIL, 81.8% with GL) or peripheral (M-value and M/I during the high-dose insulin infusion, Rd and SI) insulin sensitivity in patients with T1DM or T2DM. The need to reduce prandial insulin observed with BIL during phase 3 trials cannot be explained by the differential effects of BIL and GL on sensitivity to prandial insulin in either T1DM or T2DM. © 2016 John Wiley & Sons Ltd.

Hypoglycemia in patients with type 2 diabetes newly initiated on basal insulin in the US in a community setting: impact on treatment discontinuation and hospitalization.

PubMed

Dalal, Mehul R; Kazemi, Mahmood R; Ye, Fen

2017-02-01

To evaluate the impact of 6 month hypoglycemia on treatment discontinuation and hospitalization of patients initiating basal insulin for type 2 diabetes (T2D) in real-world practice. This was a retrospective cohort study of patient-level data using electronic medical records (EMRs) in the Predictive Health Intelligence diabetes dataset. Data from adult patients with T2D initiating basal insulin glargine, insulin detemir, or Neutral Protamine Hagedorn insulin between January 2008 and March 2014 was analyzed. The date of first basal insulin prescription in an outpatient setting was the index date. A 12 month baseline prior to the index date was established; follow-up was 6-24 months from the index date. Patients were assigned to cohorts by experience of hypoglycemia (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code or blood glucose test) in the first 6 months following the index date; with hypoglycemia and without hypoglycemia cohorts were compared for basal insulin treatment discontinuation and hospitalization. Overall, 49,062 patients were included; 5159 (10.5%) experienced hypoglycemia in the 6 months following basal insulin initiation. In the first 12 months, 68.1% of patients in the with hypoglycemia cohort discontinued basal insulin versus 53.9% in the without hypoglycemia cohort (p < .0001); more patients in the with hypoglycemia cohort had at least one hospitalization in the first year of follow-up (50.1% vs. 14.6%; p < .0001). Patients with hypoglycemia soon after initiating basal insulin are at greater risk of discontinuation of their basal insulin therapy and hospitalization versus those who did not have hypoglycemic events within the first 6 months of basal insulin initiation. A limitation of this study is that it was a retrospective analysis of EMR data and the study may not be representative of all US patients with T2D on basal insulin and it cannot be assumed that every hypoglycemic event was

Clinical experience with insulin detemir type 2 diabetes mellitus, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rabat-Sale-Zemmour-Zaer Region cohort of the A1chieve study.

PubMed

Chraibi, Abdelmjid; Belmejdoub, Ghizlane

2013-11-01

The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66 726) in routine clinical care across four continents. Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rabat-Sale-Zemmour-Zaer region, Morocco. A total of 424 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 177), insulin detemir (n = 150), insulin aspart (n = 11), basal insulin plus insulin aspart (n = 45) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 10.1%) and insulin user (mean HbA1c: 9.4%) groups. After 24 weeks of treatment, all the study groups showed improvement in HbA1c (insulin naïve: -2.5%, insulin users: -1.8%). Major hypoglycaemia was observed in the insulin user group after 24 weeks (0.1 events/patient-year). SADRs were reported in 0.5% of insulin users. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Basal insulin persistence, associated factors, and outcomes after treatment initiation among people with type 2 diabetes mellitus in the US.

PubMed

Perez-Nieves, Magaly; Kabul, Samaneh; Desai, Urvi; Ivanova, Jasmina I; Kirson, Noam Y; Cummings, Alice Kate; Birnbaum, Howard G; Duan, Ran; Cao, Dachuang; Hadjiyianni, Irene

2016-01-01

To assess basal insulin persistence, associated factors, and economic outcomes for insulin-naïve people with type 2 diabetes mellitus (T2DM) in the US. People aged ≥18 years diagnosed with T2DM initiating basal insulin between April 2006 and March 2012 (index date), no prior insulin use, and continuous insurance coverage for 6 months before (baseline) and 24 months after index date (follow-up period) were selected using de-identified administrative claims data in the US. Based on whether there were ≥30 day gaps in basal insulin use in the first year post-index, patients were classified as continuers (no gap), interrupters (≥1 prescription after gap), and discontinuers (no prescription after gap). Factors associated with persistence - assessed using multinomial logistic regression model; annual healthcare resource use and costs during follow-up period - compared separately between continuers and interrupters, and continuers and discontinuers. Of the 19,110 people included in the sample (mean age: 59 years, ∼60% male), 20% continued to use basal insulin, 62% had ≥1 interruption, and 18% discontinued therapy in the year after initiation. Older age, multiple antihyperglycemic drug use, and injectable antihyperglycemic use during baseline were associated with significantly higher likelihoods of continuing basal insulin. Relative to interrupters and discontinuers, continuers had fewer emergency department visits, shorter hospital stays, and lower medical costs (continuers: $10,890, interrupters: $13,674, discontinuers: $13,021), but higher pharmacy costs (continuers: $7449, interrupters: $5239, discontinuers: $4857) in the first year post-index (p < 0.05 for all comparisons). Total healthcare costs were similar across the three cohorts. Findings for the second year post-index were similar. The majority of people in this study interrupted or discontinued basal insulin treatment in the year after initiation; and incurred higher medical resource use and

Insulin Glargine 300 U/mL: A Review in Diabetes Mellitus.

PubMed

Blair, Hannah A; Keating, Gillian M

2016-03-01

Insulin glargine 300 U/mL (Toujeo(®)) is a long-acting basal insulin analogue approved for the treatment of diabetes mellitus. Insulin glargine 300 U/mL has a more stable and prolonged pharmacokinetic/pharmacodynamic profile than insulin glargine 100 U/mL (Lantus(®)), with a duration of glucose-lowering activity exceeding 24 h. In several 6-month phase III trials, insulin glargine 300 U/mL achieved comparable glycaemic control to that seen with insulin glargine 100 U/mL in patients with type 1 or type 2 diabetes, albeit with consistently higher daily basal insulin requirements. These improvements in glycaemic control were maintained during longer-term (12 months) treatment. Insulin glargine 300 U/mL was generally associated with a lower risk of nocturnal hypoglycaemia than insulin glargine 100 U/mL in insulin-experienced patients with type 2 diabetes, while the risk of nocturnal hypoglycaemia did not significantly differ between treatment groups in insulin-naïve patients with type 2 diabetes or in patients with type 1 diabetes. To conclude, once-daily subcutaneous insulin glargine 300 U/mL is an effective and generally well tolerated basal insulin therapy option for patients with type 1 or type 2 diabetes.

COMPARISON OF THREE ALGORITHMS FOR BASAL INSULIN IN TRANSITIONING STABLE POST-CARDIOTHORACIC SURGERY PATIENTS FROM INTRAVENOUS TO SUBCUTANEOUS INSULIN

PubMed Central

Dungan, Kathleen; Hall, Christine; Schuster, Dara; Osei, Kwame

2011-01-01

Objective The objective was to determine the efficacy of an algorithim containing aspart dosed according to carbohydrate intake and one of 3 initial doses of detemir in stable cardiac surgery patients requiring intravenous (IV) insulin. Methods Patients were extubated, off pressors and otherwise stable, requiring at least 1 unit/hr of IV insulin at least 48 hours following surgery. Subjects were randomized to once daily detemir at 50, 65, or 80% of IV basal insulin requirements and received aspart according to carbohydrate intake. The dose of detemir was adjusted daily over 72 hours. Results The number of patients with an initial morning glucose 80–130 mg/dl was 36, 63, and 56% of patients at the 50, 65, and 80% doses (p=0.12) (n=82). However, the mean overall glucose at 24 and 72 hours was similar between groups, and 86, 93, and 92% achieved a mean glucose 80–180 mg/dl at 72 hours (p=0.60). Hypoglycemia (<65 mg/dl) only occurred in the 65% (21%) and 80% (12%) groups over the first 72 hours (p=0.02 in the 50% compared to the 65 and 80% groups combined) with one event <40 mg/dl in the 80% group. There was no loss of glycemic control by the end of the once daily dosing interval. Conclusions Glycemic targets can be achieved without hypoglycemia by 72 hours in most cardiac surgery patients requiring IV insulin with a regimen containing an initial detemir dose of 50% of basal IV insulin requirements and prandial and supplemental insulin. PMID:21550950

Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis.

PubMed

Dawoud, Dalia; O'Mahony, Rachel; Wonderling, David; Cobb, Jill; Higgins, Bernard; Amiel, Stephanie A

2018-02-01

To assess the relative efficacy and safety of basal insulin regimens in adults with type 1 diabetes mellitus (T1DM). A systematic review and Bayesian network meta-analysis (NMA) of randomized controlled trials comparing two or more basal insulin regimens were conducted. The following basal insulin regimens were included: Neutral Protamine Hagedorn (iNPH) (once [od], twice [bid], and four times daily [qid]), insulin detemir (iDet) (od and bid), insulin glargine 100 IU (iGlarg) (od), and insulin degludec (iDegl) (od). We searched the following databases: MEDLINE via OVID, Embase via OVID, and the Cochrane Library (Wiley). Study quality was appraised using Cochrane risk-of-bias checklist for randomized controlled trials. Two outcomes (change in hemoglobin A 1c [HbA 1c ] and rate of severe/major hypoglycemia [SH]) were analyzed. Network inconsistency was assessed using Bucher and chi-square tests. Thirty studies met the eligibility criteria. Twenty-five were included in the HbA 1c network and 16 in the SH network. All studies were of moderate quality. No network inconsistency was evident in the HbA 1c network. Of the seven regimens of interest, iDet (bid) had the highest probability of being best (mean change in HbA 1c -0.48; 95% credible interval -0.69 to -0.29). In contrast, the SH network demonstrated both considerable uncertainty and significant network inconsistency (χ 2 test, P = 0.003). Of the specified frequency regimens, iDet (bid) had the highest probability of being the best basal insulin regimen in terms of reduction in HbA 1c . Ranking of the regimens in terms of the SH rate was highly uncertain and no clear conclusion could be made. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

EADSG Guidelines: Insulin Therapy in Diabetes.

PubMed

Silver, Bahendeka; Ramaiya, Kaushik; Andrew, Swai Babu; Fredrick, Otieno; Bajaj, Sarita; Kalra, Sanjay; Charlotte, Bavuma M; Claudine, Karigire; Makhoba, Anthony

2018-04-01

drugs (OADs) (B). If the desired glucose targets are not met, rapid-acting or short-acting (bolus or prandial) insulin can be added at mealtime to control the expected postprandial raise in glucose. An insulin regimen should be adopted and individualized but should, to the extent possible, closely resemble a natural physiologic state and avoid, to the extent possible, wide fluctuating glucose levels (C). Blood glucose monitoring is an integral part of effective insulin therapy and should not be omitted in the patient's care plan. Fasting plasma glucose (FPG) values should be used to titrate basal insulin, whereas both FPG and postprandial glucose (PPG) values should be used to titrate mealtime insulin (B). Metformin combined with insulin is associated with decreased weight gain, lower insulin dose, and less hypoglycemia when compared with insulin alone (C). Oral medications should not be abruptly discontinued when starting insulin therapy because of the risk of rebound hyperglycemia (D). Analogue insulin is as effective as human insulin but is associated with less postprandial hyperglycemia and delayed hypoglycemia (B). The shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular (IM) injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them (A). Many patients in East Africa reuse syringes for various reasons, including financial. This is not recommended by the manufacturer and there is an association between needle reuse and lipohypertrophy. However, patients who reuse needles should not be subjected to alarming claims of excessive morbidity from this practice (A). Health care

A novel pen-based Bluetooth-enabled insulin delivery system with insulin dose tracking and advice.

PubMed

Bailey, Timothy S; Stone, Jenine Y

2017-05-01

Diabetes is growing in prevalence internationally. As more individuals require insulin as part of their treatment, technology evolves to optimize delivery, improve adherence, and reduce dosing errors. Insulin pens outperform vial and syringe in simplicity, dosing accuracy, and user preference. Bolus advisors improve dosing confidence and treatment adherence. The InPen System offers a novel approach to treatment via a wireless pen that syncs to a mobile application featuring a bolus advisor, enabling convenient insulin dose tracking and more accurate bolus advice among other features. Areas covered: Existing technology for insulin delivery and bolus advice are reviewed. The mechanics and functionality of the InPen device are delineated. Findings from formative testing and usability studies of the InPen system are reported. Future directions for the InPen system in the treatment of diabetes are discussed. Expert opinion: Diabetes management is complex and largely data-driven. The InPen System offers a promising new opportunity to avail insulin pen-users of features known to improve treatment efficacy, which have otherwise primarily been available to those using pumps. Given that the majority of insulin users do not use insulin pumps, the InPen System is poised to improve glucose control in a significant portion of the diabetes population.

Effect of naloxone on plasma insulin, insulin-like growth factor I, and its binding protein 1 in patients with polycystic ovarian disease.

PubMed

Laatikainen, T; Anttila, L; Suikkari, A M; Ruutiainen, K; Erkkola, R; Seppälä, M

1990-09-01

Insulin and insulin-like growth factors (IGFs) stimulate ovarian steroidogenesis, and hyperinsulinemia is often accompanied by hyperandrogenemia in women with polycystic ovarian disease (PCOD). Because opioid peptides are involved in the regulation of insulin secretion, we studied the effect of naloxone-induced opiate receptor blockade on the circulating levels of insulin, IGF-I, and IGF binding protein 1 (IGFBP-1) in 13 nonobese and 7 obese PCOD patients and in 6 healthy subjects. In obese PCOD patients, the mean basal insulin concentration was significantly higher and the IGFBP-1 concentration lower than in nonobese PCOD patients. Plasma IGF-I levels were elevated both in obese and nonobese PCOD patients. After an intravenous bolus of 10 mg naloxone, no significant changes were found in the circulating insulin or IGF-I levels, whereas IGFBP-1 levels decreased in nonobese PCOD patients and remained low in obese PCOD patients. No significant decrease was found in healthy subjects. These results suggest that, in addition to insulin, endogenous opioids are involved in the regulation of serum IGFBP-1 level.

Common Standards of Basal Insulin Titration in T2DM

PubMed Central

Arnolds, Sabine; Heise, Tim; Flacke, Frank; Sieber, Jochen

2013-01-01

Type 2 diabetes mellitus has become a worldwide major health problem, and the number of people affected is steadily increasing. Thus, not all patients suffering from the disease can be treated by specialized diabetes centers or outpatient clinics, but by primary care physicians. The latter, however, might have time constraints and have to deal with many kinds of diseases or with multimorbid patients, so their focus is not so much on lowering high blood glucose values. Thus, the physicians, as well as the patients themselves, are often reluctant to initiate and adjust insulin therapy, although basal insulin therapy is considered the appropriate strategy after oral antidiabetic drug failure, according to the latest international guidelines. A substantial number of clinical studies have shown that insulin initiation and optimization can be managed successfully by using titration algorithms—even in cases where patients themselves are the drivers of insulin titration. Nevertheless, tools and strategies are needed to facilitate this process in the daily life of both primary health care professionals and patients with diabetes. PMID:23759411

Omitting late-night eating may cause hypoglycemia in "well controlled" basal insulin-treated type 2 diabetes.

PubMed

King, Allen B; Clark, Dawn

2015-03-01

To assess hypoglycemia caused by eating the last meal of the day earlier or its omission in "well controlled" type 2 diabetes mellitus patients treated with once-nightly basal insulin. Previously basal insulin-titrated subjects (n = 20) (fasting plasma glucose, FPG, <110 mg/dL and no self-reported hypoglycemia) underwent continuous glucose monitoring (CGM) during 3 consecutive eating conditions of 3 days each; (1) usual eating, (2) the last meal restricted to 18:00, and (3) 1 sequential meal omitted/day thereby creating a fasting day after transposing the 4-hour period after a meal with that when the meal was omitted. One 24-hour (00:00 to 00:00) period within each eating condition was selected for comparison. The mean duration in all hypoglycemic ranges doubled (P = .0584 or greater) when the last meal was omitted or eaten at 18:09 ± 0:39 instead of 19:43 ± 1:01, the usual time for the subjects' undisturbed eating. The mean duration of hypoglycemia was greatest between 00:00 to 06:00 compared to the 3 other 6-hour periods of the day. Increased hypoglycemia occurs when the subject's last meal is eaten earlier or omitted and may not be recognized because it occurs predominately during sleep. When titrating basal insulin from the morning FPG, considerations should be given to the effect of the last meal of the day and possible hypoglycemia between 00:00 and 06:00 to avoid excessive basal insulin treatment.

Glycemic control and maternal and fetal outcomes in pregnant women with type 1 diabetes according to the type of basal insulin.

PubMed

Chico, A; Herranz, L; Corcoy, R; Ramírez, O; Goya, M M; Bellart, J; González-Romero, S; Codina, M; Sánchez, P; Cortázar, A; Acosta, D; Picón, M J; Rubio, J A; Megía, A; Sancho, M A; Balsells, M; Solá, E; González, N L; López-López, J

2016-11-01

To examine the potential role of the type of basal insulin on glycemic control and maternal and foetal outcomes in pregnant women with type 1 diabetes (T1DM). Retrospective cohort study of pregnancies attended at 18 Spanish tertiary hospitals. T1DM, singleton pregnancies, delivery between 2002-2010, and use of the same basal and prandial insulin from before pregnancy until delivery. A total of 1534 pregnancies were included. The basal insulin most commonly used was Neutral Protamine Hagedorn (NPH) (51.7%), followed by glargine (23.2%) and continuous subcutaneous insulin infusion (CSII) (21.1%). CSII users had longer diabetes duration. Multiple logistic regression analysis showed that CSII was independently associated with lower doses of insulin, higher glycated haemoglobin (HbA 1c ) in all trimesters, and higher rates of miscarriage, preterm birth and neonatal hypoglycemia. Glargine was related to a higher risk of preterm birth and a small-for-gestational age infant (SGA). The odds ratios (OR) of the associations between insulin type and clinical outcomes (from 0.642 to 4.894) have a relevant magnitude. In this observational study of pregnant women with T1DM, the type of basal insulin was independently associated with metabolic variables and foetal outcomes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Rosuvastatin Treatment Affects Both Basal and Glucose-Induced Insulin Secretion in INS-1 832/13 Cells

PubMed Central

Salunkhe, Vishal A.; Elvstam, Olof; Eliasson, Lena; Wendt, Anna

2016-01-01

Rosuvastatin is a member of the statin family. Like the other statins it is prescribed to lower cholesterol levels and thereby reduce the risk of cardiovascular events. Rosuvastatin lowers the cholesterol levels by inhibiting the key enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) in the cholesterol producing mevalonate pathway. It has been recognized that apart from their beneficial lipid lowering effects, statins also exhibit diabetogenic properties. The molecular mechanisms behind these remain unresolved. To investigate the effects of rosuvastatin on insulin secretion, we treated INS-1 832/13 cells with varying doses (20 nM to 20 μM) of rosuvastatin for 48 h. At concentrations of 2 μM and above basal insulin secretion was significantly increased. Using diazoxide we could determine that rosuvastatin did not increase basal insulin secretion by corrupting the KATP channels. Glucose-induced insulin secretion on the other hand seemed to be affected differently at different rosuvastatin concentrations. Rosuvastatin treatment (20 μM) for 24–48 h inhibited voltage-gated Ca2+ channels, which lead to reduced depolarization-induced exocytosis of insulin-containing granules. At lower concentrations of rosuvastatin (≤ 2 μM) the stimulus-secretion coupling pathway was intact downstream of the KATP channels as assessed by the patch clamp technique. However, a reduction in glucose-induced insulin secretion could be observed with rosuvastatin concentrations as low as 200 nM. The inhibitory effects of rosuvastatin on glucose-induced insulin secretion could be reversed with mevalonate, but not squalene, indicating that rosuvastatin affects insulin secretion through its effects on the mevalonate pathway, but not through the reduction of cholesterol biosynthesis. Taken together, these data suggest that rosuvastatin has the potential to increase basal insulin secretion and reduce glucose-induced insulin secretion. The latter is possibly an unavoidable

Primary care physician perspectives on basal insulin initiation and maintenance in patients with type 2 diabetes mellitus.

PubMed

Kalirai, Samaneh; Stephenson, Judith; Perez-Nieves, Magaly; Grabner, Michael; Hadjiyianni, Irene; Geremakis, Caroline; Pollom, Roy Daniel; Reed, Beverly; Fisher, Lawrence

2018-04-01

To describe primary care physicians' (PCPs) perceptions of patient reactions and concerns about insulin initiation and identify opportunities for increased support. Cross-sectional, online survey of PCPs prescribing basal insulin to adults with type 2 diabetes mellitus (T2DM). PCPs were identified from administrative claims of a large commercial health plan and descriptive results of PCP responses were reported. PCPs (N=100) treated an average of 17 patients receiving insulin during a typical week. More than 85% of insulin initiation recommendations originated with PCPs. Most offered glucose monitoring instructions (96%) and advice on diet, exercise, and diabetes management (96%); 35% provided insulin titration algorithms; 93% reported that patients often or always took their insulin daily within 3 months of initiation; 31% of PCPs reported monthly office contacts with patients for the first 3 months; 16% reported no outreach efforts; fewer than 20% connected patients with support groups. When starting basal insulin, PCPs reported patients feeling personal failure regarding their diabetes treatment (33% often/always) and lacking confidence in their ability to manage insulin therapy (38% often/always). Study results identify additional opportunities for assisting patients in making the transition to insulin, including more frequent direct outreach to monitor insulin usage. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Initiation of Basal Insulin Analog Treatment for Type 2 Diabetes and Reasons Behind Patients' Treatment Persistence Behavior: Real-World Data from Germany.

PubMed

Moennig, Elisabeth; Perez-Nieves, Magaly; Hadjiyianni, Irene; Cao, Dachuang; Ivanova, Jasmina; Klask, Ralf

2018-05-01

Poor treatment persistence can affect the real-world effectiveness of insulin therapy. A cross-sectional online survey in 942 patients with type 2 diabetes from 7 different countries evaluated patient experience when initiating basal insulin and the reasons behind insulin persistence patterns. Here, we report the quantitative results for the subset of patients from Germany. Adults with type 2 diabetes who had initiated basal insulin during the last 3-24 months, identified from market-research panels, participated in the survey. Patients were asked if they had ≥7-day gaps in basal insulin treatment, and were then classified as "continuers" (no gap since starting insulin), "interrupters" (≥1 gap within the first 6 months after starting insulin and subsequently restarted insulin), or "discontinuers" (stopped insulin within the first 6 months after starting and had not restarted at the time of the survey). For each country, 50 participants were planned per persistence category. Enrollment ended if the target quota was reached or enrollment plateaued. Data were analyzed overall and separately for each persistence cohort. The 131 participants from Germany included 55 (42.0%) continuers, 50 (38.2%) interrupters and 26 (19.9%) discontinuers. The most common motivations to initiate basal insulin therapy were encouragement by physician or other healthcare provider (HCP; 54.2%) and expectation to improve glycemic control (42.0%). More than 95% of participants received training before and during insulin initiation (considered as helpful by 81.7%); most (67.2%) preferred in-person training. Continuers more frequently felt that insulin would help to manage diabetes and that their own views were considered when initiating insulin, they reported less concerns and challenges before and during insulin initiation than interrupters or discontinuers. The most common motivations to continue basal insulin were improved glycemic control (72.7%), improved physical well-being (49

Insulin signaling in various equine tissues under basal conditions and acute stimulation by intravenously injected insulin.

PubMed

Warnken, Tobias; Brehm, Ralph; Feige, Karsten; Huber, Korinna

2017-10-01

The aim of the study was to analyze key proteins of the equine insulin signaling cascade and their extent of phosphorylation in biopsies from muscle tissue (MT), liver tissue (LT), and nuchal AT, subcutaneous AT, and retroperitoneal adipose tissues. This was investigated under unstimulated (B1) and intravenously insulin stimulated (B2) conditions, which were achieved by injection of insulin (0.1 IU/kg bodyweight) and glucose (150 mg/kg bodyweight). Twelve warmblood horses aged 15 ± 6.8 yr (yr), weighing 559 ± 79 kg, and with a mean body condition score of 4.7 ± 1.5 were included in the study. Key proteins of the insulin signaling cascade were semiquantitatively determined using Western blotting. Furthermore, modulation of the cascade was assessed. The basal expression of the proteins was only slightly influenced during the experimental period. Insulin induced a high extent of phosphorylation of insulin receptor in LT (P < 0.01) but not in MT. Protein kinase B and mechanistic target of rapamycin expressed a higher extent of phosphorylation in all tissues in B2 biopsies. Adenosine monophosphate protein kinase, as a component related to insulin signaling, expressed enhanced phosphorylation in MT (P < 0.05) and adipose tissues (nuchal AT P < 0.05; SCAT P < 0.01; retroperitoneal adipose tissue P < 0.05), but not in LT at B2. Tissue-specific variations in the acute response of insulin signaling to intravenously injected insulin were observed. In conclusion, insulin sensitivity in healthy horses is based on a complex concerted action of different tissues by their variations in the molecular response to insulin. Copyright © 2017 Elsevier Inc. All rights reserved.

Muscle-Specific Deletion of Rictor Impairs Insulin-Stimulated Glucose Transport and Enhances Basal Glycogen Synthase Activity▿

PubMed Central

Kumar, Anil; Harris, Thurl E.; Keller, Susanna R.; Choi, Kin M.; Magnuson, Mark A.; Lawrence, John C.

2008-01-01

Rictor is an essential component of mTOR (mammalian target of rapamycin) complex 2 (mTORC2), a kinase complex that phosphorylates Akt at Ser473 upon activation of phosphatidylinositol 3-kinase (PI-3 kinase). Since little is known about the role of either rictor or mTORC2 in PI-3 kinase-mediated physiological processes in adult animals, we generated muscle-specific rictor knockout mice. Muscle from male rictor knockout mice exhibited decreased insulin-stimulated glucose uptake, and the mice showed glucose intolerance. In muscle lacking rictor, the phosphorylation of Akt at Ser473 was reduced dramatically in response to insulin. Furthermore, insulin-stimulated phosphorylation of the Akt substrate AS160 at Thr642 was reduced in rictor knockout muscle, indicating a defect in insulin signaling to stimulate glucose transport. However, the phosphorylation of Akt at Thr308 was normal and sufficient to mediate the phosphorylation of glycogen synthase kinase 3 (GSK-3). Basal glycogen synthase activity in muscle lacking rictor was increased to that of insulin-stimulated controls. Consistent with this, we observed a decrease in basal levels of phosphorylated glycogen synthase at a GSK-3/protein phosphatase 1 (PP1)-regulated site in rictor knockout muscle. This change in glycogen synthase phosphorylation was associated with an increase in the catalytic activity of glycogen-associated PP1 but not increased GSK-3 inactivation. Thus, rictor in muscle tissue contributes to glucose homeostasis by positively regulating insulin-stimulated glucose uptake and negatively regulating basal glycogen synthase activity. PMID:17967879

Dietary fat acutely increases glucose concentrations and insulin requirements in patients with type 1 diabetes: implications for carbohydrate-based bolus dose calculation and intensive diabetes management.

PubMed

Wolpert, Howard A; Atakov-Castillo, Astrid; Smith, Stephanie A; Steil, Garry M

2013-04-01

Current guidelines for intensive treatment of type 1 diabetes base the mealtime insulin bolus calculation exclusively on carbohydrate counting. There is strong evidence that free fatty acids impair insulin sensitivity. We hypothesized that patients with type 1 diabetes would require more insulin coverage for higher-fat meals than lower-fat meals with identical carbohydrate content. We used a crossover design comparing two 18-h periods of closed-loop glucose control after high-fat (HF) dinner compared with low-fat (LF) dinner. Each dinner had identical carbohydrate and protein content, but different fat content (60 vs. 10 g). Seven patients with type 1 diabetes (age, 55 ± 12 years; A1C 7.2 ± 0.8%) successfully completed the protocol. HF dinner required more insulin than LF dinner (12.6 ± 1.9 units vs. 9.0 ± 1.3 units; P = 0.01) and, despite the additional insulin, caused more hyperglycemia (area under the curve >120 mg/dL = 16,967 ± 2,778 vs. 8,350 ± 1,907 mg/dL⋅min; P < 0001). Carbohydrate-to-insulin ratio for HF dinner was significantly lower (9 ± 2 vs. 13 ± 3 g/unit; P = 0.01). There were marked interindividual differences in the effect of dietary fat on insulin requirements (percent increase significantly correlated with daily insulin requirement; R(2) = 0.64; P = 0.03). This evidence that dietary fat increases glucose levels and insulin requirements highlights the limitations of the current carbohydrate-based approach to bolus dose calculation. These findings point to the need for alternative insulin dosing algorithms for higher-fat meals and suggest that dietary fat intake is an important nutritional consideration for glycemic control in individuals with type 1 diabetes.

Real-world clinical responses in patients with type 2 diabetes mellitus adding exenatide BID (EBID) or mealtime insulin to basal insulin: a retrospective study using electronic medical record data.

PubMed

Lang, Kathleen; Nguyen, Hiep; Huang, Huan; Bauer, Elise; Levin, Philip

2018-06-01

Exenatide twice daily (EBID) and mealtime insulin are effective add-on therapies to basal insulin for type 2 diabetes patients in clinical trials. This study used electronic medical record (EMR) data to evaluate analogous real-world clinical responses. Adult patients initiating EBID or mealtime insulin as add-on to basal insulin during January 2008-March 2013 were identified in a US EMR database. EBID patients were propensity score matched 1:1 to mealtime insulin patients. Cohorts were followed for 12 months before (baseline) and 6 months after the index. A1C, hypoglycemic events, change in weight, and other clinical measures were evaluated by A1C attainment level (<6.5, < 7, < 7.5, <8, <9%) and baseline A1C. In total, 1249 EBID patients were matched to 1249 mealtime insulin patients. During follow-up, the percentage reaching A1C levels was similar for EBID vs mealtime insulin cohorts for all attainment levels (<7%: 27.8% vs 24.2%; < 9%: 79.7% vs 79.2%; p = NS). The percentage reaching A1C < 7% was similar for both cohorts with different baseline A1C. EBID patients had less hypoglycemia at all attainment levels (3.1% vs 11.1% [<6.5%]; 2.5% vs 4.7% [<9%]; all p < .03) and more weight loss (-9.0 vs -3.2 lb [<6.5%]; -3.4 vs +0.8 lb [<9%]; all p < .01). EBID added to basal insulin was as effective in a real-world setting as mealtime insulin added to basal insulin in reducing A1C, with less weight gain and less hypoglycemia for a wide range of A1C attainment levels and baseline values.

Automated mandatory bolus versus basal infusion for maintenance of epidural analgesia in labour.

PubMed

Sng, Ban Leong; Zeng, Yanzhi; de Souza, Nurun Nisa A; Leong, Wan Ling; Oh, Ting Ting; Siddiqui, Fahad Javaid; Assam, Pryseley N; Han, Nian-Lin R; Chan, Edwin Sy; Sia, Alex T

2018-05-17

Childbirth may cause the most severe pain some women experience in their lifetime. Epidural analgesia is an effective form of pain relief during labour and is considered to be the reference standard. Traditionally epidural analgesia has been delivered as a continuous infusion via a catheter in the epidural space, with or without the ability for the patient to supplement the analgesia received by activating a programmable pump to deliver additional top-up doses, known as patient-controlled epidural analgesia (PCEA). There has been interest in delivering maintenance analgesic medication via bolus dosing (automated mandatory bolus - AMB) instead of the traditional continuous basal infusion (BI); recent randomized controlled trials (RCTs) have shown that the AMB technique leads to improved analgesia and maternal satisfaction. To assess the effects of automated mandatory bolus versus basal infusion for maintaining epidural analgesia in labour. We searched CENTRAL, MEDLINE, Embase, the World Health Organization International Clinial Trials Registry Platform (WHO-ICTRP) and ClinicalTrials.gov on 16 January 2018. We screened the reference lists of all eligible trials and reviews. We also contacted authors of included studies in this field in order to identify unpublished research and trials still underway, and we screened the reference lists of the included articles for potentially relevant articles. We included all RCTs that compared the use of bolus dosing AMB with continuous BI for providing pain relief during epidural analgesia for labour in women. We used the standard methodological procedures expected by Cochrane. Our primary outcomes were: risk of breakthrough pain with the need for anaesthetic intervention; risk of caesarean delivery; risk of instrumental delivery. Secondary outcomes included: duration of labour; local anaesthetic consumption. We used GRADE to assess the certainty of evidence for each outcome. We included 12 studies with a total of 1121 women. Ten

Continuous Transversus Abdominis Plane Nerve Blocks: Does Varying Local Anesthetic Delivery Method-Automatic Repeated Bolus Versus Continuous Basal Infusion-Influence the Extent of Sensation to Cold?: A Randomized, Triple-Masked, Crossover Study in Volunteers.

PubMed

Khatibi, Bahareh; Said, Engy T; Sztain, Jacklynn F; Monahan, Amanda M; Gabriel, Rodney A; Furnish, Timothy J; Tran, Johnathan T; Donohue, Michael C; Ilfeld, Brian M

2017-04-01

It remains unknown whether continuous or scheduled intermittent bolus local anesthetic administration is preferable for transversus abdominis plane (TAP) catheters. We therefore tested the hypothesis that when using TAP catheters, providing local anesthetic in repeated bolus doses increases the cephalad-caudad cutaneous effects compared with a basal-only infusion. Bilateral TAP catheters (posterior approach) were inserted in 24 healthy volunteers followed by ropivacaine 2 mg/mL administration for a total of 6 hours. The right side was randomly assigned to either a basal infusion (8 mL/h) or bolus doses (24 mL administered every 3 hours for a total of 2 bolus doses) in a double-masked manner. The left side received the alternate treatment. The primary end point was the extent of sensory deficit as measured by cool roller along the axillary line at hour 6 (6 hours after the local anesthetic administration was initiated). Secondary end points included the extent of sensory deficit as measured by cool roller and Von Frey filaments along the axillary line and along a transverse line at the level of the anterior superior iliac spine at hours 0 to 6. Although there were statistically significant differences between treatments within the earlier part of the administration period, by hour 6 the difference in extent of sensory deficit to cold failed to reach statistical significance along the axillary line (mean = 0.9 cm; SD = 6.8; 95% confidence interval -2.0 to 3.8; P = .515) and transverse line (mean = 2.5 cm; SD = 10.1; 95% confidence interval -1.8 to 6.8; P = .244). Although the difference between treatments was statistically significant at various early time points for the horizontal, vertical, and estimated area measurements of both cold and mechanical pressure sensory deficits, no comparison remained statistically significant by hour 6. No evidence was found in this study involving healthy volunteers to support the hypothesis that changing the local anesthetic

Clinical experience with insulin detemir type 2 diabetes mellitus, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rabat-Sale-Zemmour-Zaer Region cohort of the A1chieve study

PubMed Central

Chraibi, Abdelmjid; Belmejdoub, Ghizlane

2013-01-01

Background: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66 726) in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rabat-Sale-Zemmour-Zaer region, Morocco. Results: A total of 424 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 177), insulin detemir (n = 150), insulin aspart (n = 11), basal insulin plus insulin aspart (n = 45) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 10.1%) and insulin user (mean HbA1c: 9.4%) groups. After 24 weeks of treatment, all the study groups showed improvement in HbA1c (insulin naïve: −2.5%, insulin users: −1.8%). Major hypoglycaemia was observed in the insulin user group after 24 weeks (0.1 events/patient-year). SADRs were reported in 0.5% of insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID:24404470

The role of insulin glulisine to improve glycemic control in children with diabetes mellitus.

PubMed

Lih, Anna; Hibbert, Emily; Wong, Tang; Girgis, Christian M; Garg, Nidhi; Carter, John N

2010-11-26

Glulisine (Apidra(®)) is a rapid-acting human insulin analog approved for use in children with diabetes mellitus ≥4 years of age. Management of children with type 1 diabetes has seen a shift in favor of mimicking normal physiological insulin responses with multiple daily injections or continuous subcutaneous insulin infusions (CSII). Few studies have compared the rapid-acting insulin analogs in this population but limited data indicate that glulisine is as effective as lispro when used in a basal-bolus regimen. This review appraises the current available studies and reviews on insulin glulisine in children. An extensive keyword search of 'insulin glulisine', 'insulin analogs', and 'Apidra' in the pediatric population was performed. These studies have suggested that glulisine is safe, well tolerated, and is an effective option in the diabetes armamentarium. Further studies are needed to determine its safety for use in CSII pumps in the pediatric population.

Variability of Basal Rate Profiles in Insulin Pump Therapy and Association with Complications in Type 1 Diabetes Mellitus.

PubMed

Laimer, Markus; Melmer, Andreas; Mader, Julia K; Schütz-Fuhrmann, Ingrid; Engels, Heide-Rose; Götz, Gabriele; Pfeifer, Martin; Hermann, Julia M; Stettler, Christoph; Holl, Reinhard W

2016-01-01

Traditionally, basal rate profiles in continuous subcutaneous insulin infusion therapy are individually adapted to cover expected insulin requirements. However, whether this approach is indeed superior to a more constant BR profile has not been assessed so far. This study analysed the associations between variability of BR profiles and acute and chronic complications in adult type 1 diabetes mellitus. BR profiles of 3118 female and 2427 male patients from the "Diabetes-Patienten-Verlaufsdokumentation" registry from Germany and Austria were analysed. Acute and chronic complications were recorded 6 months prior and after the most recently documented basal rate. The "variability index" was calculated as variation of basal rate intervals in percent and describes the excursions of the basal rate intervals from the median basal rate. The variability Index correlated positively with severe hypoglycemia (r = .06; p<0.001), hypoglycemic coma (r = .05; p = 0.002), and microalbuminuria (r = 0.05; p = 0.006). In addition, a higher variability index was associated with higher frequency of diabetic ketoacidosis (r = .04; p = 0.029) in male adult patients. Logistic regression analysis adjusted for age, gender, duration of disease and total basal insulin confirmed significant correlations of the variability index with severe hypoglycemia (β = 0.013; p<0.001) and diabetic ketoacidosis (β = 0.012; p = 0.017). Basal rate profiles with higher variability are associated with an increased frequency of acute complications in adults with type 1 diabetes.

Adherence to Insulin Pump Behaviors in Young Children With Type 1 Diabetes Mellitus.

PubMed

Patton, Susana R; Driscoll, Kimberly A; Clements, Mark A

2017-01-01

Parents of young children are responsible for daily type 1 diabetes (T1DM) cares including insulin bolusing. For optimal insulin pump management, parents should enter a blood glucose result (SMBG) and a carbohydrate estimate (if food will be consumed) into the bolus advisor in their child's pump to assist in delivering the recommended insulin bolus. Previously, pump adherence behaviors were described in adolescents; we describe these behaviors in a sample of young children. Pump data covering between 14-30 consecutive days were obtained for 116 children. Assessed adherence to essential pump adherence behaviors (eg, SMBG, carbohydrate entry, and insulin use) and adherence to 3 Wizard/Bolus Advisor steps: SMBG-carbohydrate entry-insulin bolus delivered. Parents completed SMBG ≥4 times on 99% of days, bolused insulin ≥3 times on 95% of days, and entered carbohydrates ≥3 times on 93% of days, but they corrected for hyperglycemia (≥250 mg/dl or 13.9 mmol/l) only 63% of the time. Parents completed Wizard/Bolus Advisor steps (SMBG, carbohydrate entry, insulin bolus) within 30 minutes for 43% of boluses. Inverse correlations were found between children's mean daily glucose and the percentage of days with ≥4 SMBG and ≥3 carbohydrate entries as well as the percentage of boluses where all Wizard/Bolus Advisor steps were completed. Parents of young children adhered to individual pump behaviors, but showed some variability in their adherence to Wizard/Bolus Advisor steps. Parents showed low adherence to recommendations to correct for hyperglycemia. Like adolescents, targeting pump behaviors in young children may have the potential to optimize glycemic control.

Performance of an Electronic Diary System for Intensive Insulin Management in Global Diabetes Clinical Trials

PubMed Central

Zhang, Shuyu; Mou, Jiani; Hackett, Andy P.; Raymond, Stephen A.; Chang, Annette M.

2015-01-01

Abstract Background: This report describes the performance of a wireless electronic diary (e-diary) system for data collection and enhanced patient–investigator interactions during intensive insulin management in diabetes clinical trials. Materials and Methods: We implemented a customized electronic communication system featuring an e-diary and a Web portal in three global, randomized, controlled Phase 3 clinical trials testing basal insulin peglispro compared with insulin glargine, both combined with prandial insulin lispro, in patients with type 1 or type 2 diabetes mellitus (T1DM and T2DM, respectively). We collected data during 28 weeks of study e-diary use for the report. Results: Patients (n=2,938) in 31 countries used e-diaries to transmit 2,439,087 blood glucose (BG) values, 96% of which were associated by the patient with a protocol time point during the 72-h response window. Of 208,192 hypoglycemia events captured, 96% had a BG value, and 95% had treatments and outcomes entered by patients within the 72-h window. Patients recorded administration of 1,964,477 insulin doses; 93% of basal insulin doses were adherent with the investigator prescription. Investigators adjusted 13 basal and 92 bolus insulin prescriptions per patient-year using the e-diary system. After 26 weeks of treatment and e-diary use in the combined study arms, hemoglobin A1c values decreased by 0.6% or 1.6% and fasting BG decreased by 7.8 or 28 mg/dL in patients with T1DM or T2DM, respectively. Conclusions: The e-diary system enabled comprehensive data collection and facilitated communication between investigators and patients for intensive insulin management in three global clinical trials testing basal insulins. PMID:25826466

The GesTIO protocol experience: safety of a standardized order set for subcutaneous insulin regimen in elderly hospitalized patients.

PubMed

Franchin, Alessandro; Maran, Alberto; Bruttomesso, Daniela; Corradin, Maria L; Rossi, Francesco; Zanatta, Federica; Barbato, Gian-Maria; Sicolo, Nicola; Manzato, Enzo

2017-12-01

In non-critical hospitalized patients with diabetes mellitus, guidelines suggest subcutaneous insulin therapy with basal-bolus regimen, even in old and vulnerable inpatients. To evaluate safety, efficacy, and benefit on clinical management of the GesTIO protocol, a set of subcutaneous insulin administration rules, in old and vulnerable non-ICU inpatients. Retrospective, observational study. Patients admitted to Geriatric Clinic of Padua were studied. 88 patients matched the inclusion criteria: type 2 diabetes or hospital-related hyperglycemia, ≥65 years, regular measurements of capillary glycemia, and basal-bolus subcutaneous insulin regimen managed by "GesTIO protocol" for five consecutive days. ratio of patients with blood glucose (BG) <3.9 mmol/l; number of BG per patient in target range (5-11.1 mmol/l); daily mean BG; and calls to physicians for adjusting insulin therapy. Mean age was 82 ± 7 years. 9.1% patients experienced mild hypoglycaemia, and no severe hypoglycaemia was reported. The median number of BG per patients in target range increased from 2.0 ± 2 to 3.0 ± 2 (p < 0.001). The daily mean BG decreased from 11.06 ± 3.03 to 9.64 ± 2.58 mmol/l (-12.8%, p < 0.005). The mean number of calls to physicians per patient decreased from 0.83 to 0.45 (p < 0.05). Treatment with GesTIO protocol allows a safe and effective treatment even in very old and vulnerable inpatients with a faster management insulin therapy.

Improving the Computational Effort of Set-Inversion-Based Prandial Insulin Delivery for Its Integration in Insulin Pumps

PubMed Central

León-Vargas, Fabian; Calm, Remei; Bondia, Jorge; Vehí, Josep

2012-01-01

Objective Set-inversion-based prandial insulin delivery is a new model-based bolus advisor for postprandial glucose control in type 1 diabetes mellitus (T1DM). It automatically coordinates the values of basal–bolus insulin to be infused during the postprandial period so as to achieve some predefined control objectives. However, the method requires an excessive computation time to compute the solution set of feasible insulin profiles, which impedes its integration into an insulin pump. In this work, a new algorithm is presented, which reduces computation time significantly and enables the integration of this new bolus advisor into current processing features of smart insulin pumps. Methods A new strategy was implemented that focused on finding the combined basal–bolus solution of interest rather than an extensive search of the feasible set of solutions. Analysis of interval simulations, inclusion of physiological assumptions, and search domain contractions were used. Data from six real patients with T1DM were used to compare the performance between the optimized and the conventional computations. Results In all cases, the optimized version yielded the basal–bolus combination recommended by the conventional method and in only 0.032% of the computation time. Simulations show that the mean number of iterations for the optimized computation requires approximately 3.59 s at 20 MHz processing power, in line with current features of smart pumps. Conclusions A computationally efficient method for basal–bolus coordination in postprandial glucose control has been presented and tested. The results indicate that an embedded algorithm within smart insulin pumps is now feasible. Nonetheless, we acknowledge that a clinical trial will be needed in order to justify this claim. PMID:23294789

Simulation-Based Evaluation of Dose-Titration Algorithms for Rapid-Acting Insulin in Subjects with Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antihyperglycemic Medications.

PubMed

Ma, Xiaosu; Chien, Jenny Y; Johnson, Jennal; Malone, James; Sinha, Vikram

2017-08-01

The purpose of this prospective, model-based simulation approach was to evaluate the impact of various rapid-acting mealtime insulin dose-titration algorithms on glycemic control (hemoglobin A1c [HbA1c]). Seven stepwise, glucose-driven insulin dose-titration algorithms were evaluated with a model-based simulation approach by using insulin lispro. Pre-meal blood glucose readings were used to adjust insulin lispro doses. Two control dosing algorithms were included for comparison: no insulin lispro (basal insulin+metformin only) or insulin lispro with fixed doses without titration. Of the seven dosing algorithms assessed, daily adjustment of insulin lispro dose, when glucose targets were met at pre-breakfast, pre-lunch, and pre-dinner, sequentially, demonstrated greater HbA1c reduction at 24 weeks, compared with the other dosing algorithms. Hypoglycemic rates were comparable among the dosing algorithms except for higher rates with the insulin lispro fixed-dose scenario (no titration), as expected. The inferior HbA1c response for the "basal plus metformin only" arm supports the additional glycemic benefit with prandial insulin lispro. Our model-based simulations support a simplified dosing algorithm that does not include carbohydrate counting, but that includes glucose targets for daily dose adjustment to maintain glycemic control with a low risk of hypoglycemia.

Glycaemic control and hypoglycaemia in people with type 2 diabetes switching from twice-daily basal insulin to once-daily insulin glargine 300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup analysis).

PubMed

Roussel, Ronan; d'Emden, Michael C; Fisher, Miles; Ampudia-Blasco, F Javier; Stella, Peter; Bizet, Florence; Cali, Anna M G; Wysham, Carol H

2018-02-01

In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla-300) and glargine 100 U/mL (Gla-100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice-daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice-daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla-300 or Gla-100 (least squares mean difference -0.01%; 95% confidence interval [CI] -0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI -0.25 to 0.57, in EDITION 2). Participants previously receiving twice-daily insulin in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 vs Gla-100 at night (00:00-05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla-300 provided similar glycaemic control with less hypoglycaemia compared with Gla-100 in people with T2DM switching from twice-daily to once-daily basal insulin. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Glycaemic control and hypoglycaemia in people with type 2 diabetes switching from twice‐daily basal insulin to once‐daily insulin glargine 300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup analysis)

PubMed Central

d'Emden, Michael C.; Fisher, Miles; Ampudia‐Blasco, F. Javier; Stella, Peter; Bizet, Florence; Cali, Anna M. G.; Wysham, Carol H.

2017-01-01

In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla‐300) and glargine 100 U/mL (Gla‐100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice‐daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice‐daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla‐300 or Gla‐100 (least squares mean difference −0.01%; 95% confidence interval [CI] −0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI −0.25 to 0.57, in EDITION 2). Participants previously receiving twice‐daily insulin in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla‐300 vs Gla‐100 at night (00:00–05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla‐300 provided similar glycaemic control with less hypoglycaemia compared with Gla‐100 in people with T2DM switching from twice‐daily to once‐daily basal insulin. PMID:28736942

The effects of exenatide twice daily compared to insulin lispro added to basal insulin in Latin American patients with type 2 diabetes: A retrospective analysis of the 4B trial.

PubMed

de Lapertosa, Silvia Beatriz Gorban; Frechtel, Gustavo; Hardy, Elise; Sauque-Reyna, Leobardo

2016-12-01

Socioeconomic changes in Latin American countries have led to an increased prevalence of type 2 diabetes (T2D). We examined the effects of exenatide twice daily (BID) or insulin lispro, each added to insulin glargine, in Latin American patients with T2D. This was a subgroup analysis of patients from Argentina and Mexico in the 4B study (N=114). Patients with glycated hemoglobin (HbA1c) of 7.0-10.0% (53-86mmol/mol) after 12weeks of intensive basal insulin optimization were randomized to exenatide BID or thrice-daily insulin lispro added to insulin glargine and metformin. After 30weeks, addition of exenatide BID or insulin lispro resulted in significant (P<0.0001) reductions in HbA1c (exenatide BID: -0.9% [-10mmol/mol]; insulin lispro: -1.2% [-13mmol/mol]). Weight was stable in the exenatide BID group (-0.1kg) and increased significantly (+3.4kg; P<0.0001) with insulin lispro. Major and minor hypoglycemia occurred less frequently (40 vs. 253 events) with exenatide BID compared with insulin lispro. Gastrointestinal adverse events of nausea, diarrhea, and vomiting occurred more frequently with exenatide BID than with insulin lispro. Both exenatide BID and prandial insulin lispro, each added to basal insulin glargine, were effective at reducing HbA1c in Latin American patients. Treatment with exenatide BID resulted in stable weight but more gastrointestinal adverse events. Treatment with insulin lispro resulted in weight gain and an increased risk of hypoglycemia. These findings support the addition of exenatide BID to insulin glargine as an option for Latin American patients unable to achieve glycemic control on basal insulin alone. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Treatment Intensification in Type 2 Diabetes: A Real-World Study of 2-OAD Regimens, GLP-1 RAs, or Basal Insulin.

PubMed

Blonde, Lawrence; Raccah, Denis; Lew, Elisheva; Meyers, Juliana; Nikonova, Elena; Ajmera, Mayank; Davis, Keith L; Bertolini, Monica; Guerci, Bruno

2018-06-01

Treatment guidelines recommend a stepwise approach to glycemia management in patients with type 2 diabetes (T2D), but this may result in uncontrolled glycated hemoglobin A1c (HbA1c) between steps. This retrospective analysis compared clinical and economic outcomes among patients with uncontrolled T2D initiating two oral antidiabetes drugs (OADs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), or basal insulin in a real-world setting. Adults with T2D on OAD monotherapy were identified in the MarketScan claims database (2007-2014). Those initiating two OADs (simultaneously or sequentially), GLP-1 RAs, or basal insulin were selected (date of initiation was termed the 'index date'); patients were required to have HbA1c > 7.0% in the 6 months pre-index date. HbA1c was compared from 6 months pre- to 1-year post-index. Annual all-cause healthcare utilization and costs were reported over the 1-year follow-up period. Data for 6054 patients were analyzed (2-OAD, n = 4442; GLP-1 RA, n = 361; basal insulin, n = 1251). Baseline HbA1c was high in all cohorts, but highest in the basal-insulin cohort. Treatment initiation resulted in reductions in HbA1c in all cohorts, which was generally maintained throughout the follow-up period. Average HbA1c reductions from the 6 months pre- to 1 year post-index date were -1.2% for GLP-1 RA, -1.6% for OADs, and -1.8% for basal insulin. HbA1c < 7.0% at 1 year occurred in 32.6%, 47.5%, and 41.1% of patients, respectively. Annual healthcare costs (mean [SD]) were lowest for OAD (US$10,074 [$22,276]) followed by GLP-1 RA (US$14,052 [$23,829]) and basal insulin (US$18,813 [$37,332]). Despite robust HbA1c lowering following treatment initiation, many patients did not achieve HbA1c < 7.0%. Basal insulin, generally prescribed for patients with high baseline HbA1c, was associated with a large reduction in HbA1c and with higher costs. Therapy intensification at an appropriate time could lead to clinical and economic

Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes

PubMed Central

Gallagher, Emily J.; Zelenko, Zara; Tobin-Hess, Aviva; Werner, Ulrich; Tennagels, Norbert; LeRoith, Derek

2016-01-01

Aims/hypothesis Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present. In this study, we aimed to determine whether a non-metabolisable form of insulin glargine induced murine breast cancer growth. Methods A mouse model of type 2 diabetes (MKR) was used for these studies. MKR mice were injected with two murine mammary cancer cell lines: Mvt-1 cells (derived from MMTV-c-Myc/Vegf tumours) and Met1 cells (derived from MMTV-polyoma virus middle T antigen tumours). Mice were treated with 25 U/kg per day of the long-acting insulin analogues, insulin glargine, insulin detemir, insulin degludec or non-metabolisable glargine, or vehicle. Results No difference in tumour growth was seen in terms of tumour size after insulin glargine, detemir, degludec or vehicle injections. Non-metabolisable glargine did not increase tumour growth compared with insulin glargine or vehicle. Insulin glargine and non-metabolisable glargine led to insulin receptor phosphorylation in vivo rather than IGF-1 receptor phosphorylation. Conclusions/interpretation These results demonstrate that in a mouse model of type 2 diabetes, at high concentrations, basal insulin analogues and a non-metabolisable glargine analogue do not promote the progression of breast tumours. PMID:27241182

Optimal insulin pump dosing and postprandial glycemia following a pizza meal using the continuous glucose monitoring system.

PubMed

Jones, Susan M; Quarry, Jill L; Caldwell-McMillan, Molly; Mauger, David T; Gabbay, Robert A

2005-04-01

We attempted to identify an optimal insulin pump meal bolus by comparing postprandial sensor glucose values following three methods of insulin pump meal bolusing for a consistent pizza meal. Twenty-four patients with type 1 diabetes participated in a study to compare postprandial glucose values following three meal bolus regimens for a consistent evening pizza meal. Each participant utilized the following insulin lispro regimens on consecutive evenings, and glucose values were tracked by the Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA): (a) single-wave bolus (100% of insulin given immediately); (b) 4-h dual-wave bolus (50% of insulin given immediately and 50% given over a 4-h period); and (c) 8-h dual-wave bolus (50% of insulin given immediately and 50% given over a 8-h period). Total insulin bolus amount was kept constant for each pizza meal. Divergence in blood glucose among the regimens was greatest at 8-12 h. The 8-h dual-wave bolus provided the best glycemic control and lowest mean glucose values (singlewave bolus, 133 mg/dL; 4-h dual-wave bolus, 145 mg/dL; 8-h dual-wave bolus, 104 mg/dL), leading to a difference in mean glucose of 29 mg/dL for the single-wave bolus versus the 8-h dual-wave bolus and 42 mg/dL for the 4-h dual-wave bolus versus the 8-h dual-wave bolus. The lower mean glucose in the 8-h dual-wave bolus was not associated with any increased incidence of hypoglycemia. Use of a dual-wave bolus extended over an 8-h period following a pizza meal provided significantly less postprandial hyperglycemia in the late postprandial period (8-12 h) with no increased risk of hypoglycemia.

Fixed ratio combinations of glucagon like peptide 1 receptor agonists with basal insulin: a systematic review and meta-analysis.

PubMed

Liakopoulou, Paraskevi; Liakos, Aris; Vasilakou, Despoina; Athanasiadou, Eleni; Bekiari, Eleni; Kazakos, Kyriakos; Tsapas, Apostolos

2017-06-01

Basal insulin controls primarily fasting plasma glucose but causes hypoglycaemia and weight gain, whilst glucagon like peptide 1 receptor agonists induce weight loss without increasing risk for hypoglycaemia. We conducted a systematic review and meta-analysis of randomised controlled trials to investigate the efficacy and safety of fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists. We searched Medline, Embase, and the Cochrane Library as well as conference abstracts up to December 2016. We assessed change in haemoglobin A 1c , body weight, and incidence of hypoglycaemia and gastrointestinal adverse events. We included eight studies with 5732 participants in the systematic review. Switch from basal insulin to fixed ratio combinations with a glucagon like peptide 1 receptor agonist was associated with 0.72% reduction in haemoglobin A 1c [95% confidence interval -1.03 to -0.41; I 2  = 93%] and 2.35 kg reduction in body weight (95% confidence interval -3.52 to -1.19; I 2  = 93%), reducing also risk for hypoglycaemia [odds ratio 0.70; 95% confidence interval 0.57 to 0.86; I 2  = 85%] but increasing incidence of nausea (odds ratio 6.89; 95% confidence interval 3.73-12.74; I 2  = 79%). Similarly, switching patients from treatment with a glucagon like peptide 1 receptor agonist to a fixed ratio combination with basal insulin was associated with 0.94% reduction in haemoglobin A 1c (95% confidence interval -1.11 to -0.77) and an increase in body weight by 2.89 kg (95% confidence interval 2.17-3.61). Fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists improve glycaemic control whilst balancing out risk for hypoglycaemia and gastrointestinal side effects.

Achieve control: a pragmatic clinical trial of insulin glargine 300 U/mL versus other basal insulins in insulin-naïve patients with type 2 diabetes.

PubMed

Oster, Gerry; Sullivan, Sean D; Dalal, Mehul R; Kazemi, Mahmood R; Rojeski, Maria; Wysham, Carol H; Sung, Jennifer; Johnstone, Bryan; Cali, Anna M G; Wei, L J; Traylor, Louise; Anhalt, Henry; Hull, Michelle; Van Vleet, John; Meneghini, Luigi F

2016-11-01

This study aims to compare the effectiveness of insulin glargine 300 U/mL (Gla-300) with its accompanying patient support program with that of other basal insulin and available patient support programs in patients with type 2 diabetes (T2D) in a real-world setting in terms of achieving HEDIS (Healthcare Effectiveness Data and Information Set) individualized glycemic targets without documented symptomatic hypoglycemia. Achieve Control is a US-based, multicenter, randomized, open-label, active-controlled, parallel group pragmatic Phase IV trial in insulin-naïve patients with T2D uncontrolled on ≥2 oral antidiabetes drugs (OAD) and/or glucagon-like peptide-1 receptor antagonists (GLP-1 RA). Inclusion criteria include a diagnosis of T2D, age ≥18 years, and glycated hemoglobin (HbA1c) between 8.0% and 11.0%. Patients will be assigned to either the Gla-300 or other basal insulin group. The primary end point is the proportion of patients achieving HEDIS HbA1c targets (<8.0% [64 mmol/mol] in patients with comorbidities or aged ≥65 years; <7.0% [58 mmol/mol] in all other patients) without occurrence of symptomatic hypoglycemia (blood glucose ≤70 mg/dL) from baseline to 6 months. Secondary end points include rates of documented symptomatic nocturnal hypoglycemia and severe hypoglycemia; change from baseline in HbA1c, fasting glucose, and body weight; treatment persistence; patient-reported outcomes; and healthcare resource utilization. Planned enrollment is 3270 patients across approximately 400 clinical sites. Pragmatic clinical trials offer the potential to assess comparative effectiveness in broadly based patient populations receiving care (with or without a corresponding educational support program) in real-world clinical settings. The results of Achieve Control should elucidate the benefits of management of T2D with Gla-300 versus other basal insulins in terms of patient outcomes, experiences, and perceptions, and its impact on healthcare resource

Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

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

Žáková, Lenka; Kletvíková, Emília; Lepšík, Martin

[AsnB26]- and [GlyB26]-insulin mutants attain a B26-turn like fold without assistance of chemical modifications. Their structures match the insulin receptor interface and expand the spectrum of insulin conformations. The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that inmore » all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.« less

Treatment intensification using long-acting insulin -predictors of future basal insulin supported oral therapy in the DIVE registry.

PubMed

Danne, Thomas; Bluhmki, Tobias; Seufert, Jochen; Kaltheuner, Matthias; Rathmann, Wolfgang; Beyersmann, Jan; Bramlage, Peter

2015-10-07

In patients with type-2 diabetes receiving oral antidiabetic drugs (OADs), the addition of insulin is frequently required to achieve sufficient control over blood glucose levels. It is, however, difficult to predict if, when and in which patients insulin therapy will be needed. We aimed to identify patient related variables associated with the addition of basal insulin to oral therapy resulting in a basal supported oral therapy (BOT). DIVE (DIabetes Versorgungs-Evaluation) is a prospective, observational, multi-centre diabetes registry established in Germany in 2011. For the present explorative analysis, 31,008 patients with type-2 diabetes prescribed at least one OAD were included. Patients who had previously received insulin and those over 90 years old were excluded. The event of interest was defined as the initiation of BOT during the observational period. Cause-specific Cox proportional hazards models based on a competing risk framework were applied for risk quantification. Multivariable adjusted hazard ratios demonstrated that longer diabetes duration, higher BMI, poorer glycaemic control, documentation of any micro- or macrovascular comorbidity, the presence of concomitant non-antidiabetic pharmacotherapies, and greater numbers of prescribed OADs increased the likelihood of BOT initiation. On the other hand BOT initiation was less likely in patients with older age and female gender. Analysing the likelihood of OAD termination without initiation of BOT provided supportive evidence for the variables predictive of BOT initiation. Analysis of the DIVE registry has resulted in the identification of a number of factors that may be predictive for the initiation of BOT for type-2 diabetes patients initially prescribed one or more OADs. Poor glycaemic control, the presence of vascular comorbidities and concomitant medications, and a greater number of OADs were all detected to increase the risk of a switch to BOT. Female gender and younger age showed protective

Basal insulin initiation use and experience among people with type 2 diabetes mellitus with different patterns of persistence: results from a multi-national survey.

PubMed

Perez-Nieves, Magaly; Ivanova, Jasmina I; Hadjiyianni, Irene; Zhao, Chen; Cao, Dachuang; Schmerold, Luke; Kalirai, Samaneh; King, Sarah; DeLozier, Amy M; Birnbaum, Howard G; Peyrot, Mark

2017-10-01

People with type 2 diabetes mellitus (T2DM) often interrupt basal insulin treatment soon after initiation. This study aimed to describe the experiences during and after basal insulin initiation among people with T2DM with different persistence patterns. Adults with T2DM from France, Germany, Spain, UK, US, Brazil, and Japan were identified from consumer panels for an online survey. Respondents who initiated basal insulin 3-24 months prior to survey date were categorized as continuers (no gaps of ≥7 days in insulin treatment); interrupters (first gap ≥7 days within 6 months of initiation and restarted insulin); and discontinuers (stopped insulin for ≥7 days within 6 months of initiation without restarting). Among 942 participants, continuers were older than interrupters and discontinuers (46, 37, and 38 years, respectively, p < .01). Continuers reported having fewer concerns before and after insulin initiation than interrupters and discontinuers, while interrupters had the most concerns. Continuers also reported fewer challenges during the first week of insulin use. Continuers were more likely to respond that insulin use had a positive impact on specific aspects of life than interrupters and discontinuers, for example on glycemic control (73.0%, 63.0%, and 61.8%, respectively; p < .01 vs. continuers). Among people with T2DM with different persistence patterns after basal insulin initiation there were significant differences in patient characteristics and experience during and after insulin initiation. Interrupters and discontinuers more frequently reported having concerns and challenges during the initiation process, negative impacts after initiation, and less improvement in glycemic control than continuers.

Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature

PubMed Central

Balena, R; Hensley, I E; Miller, S; Barnett, A H

2013-01-01

Treatment algorithms for type 2 diabetes call for intensification of therapy over time as the disease progresses and glycaemic control worsens. If diet, exercise and oral antihyperglycaemic medications (OAMs) fail to maintain glycaemic control then basal insulin is added and ultimately prandial insulin may be required. However, such an intensification strategy carries risk of increased hypoglycaemia and weight gain, both of which are associated with worse long-term outcomes. An alternative strategy is to intensify therapy by the addition of a short-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) rather than prandial insulin. Short-acting GLP-1 RAs such as exenatide twice daily are particularly effective at reducing postprandial glucose while basal insulin has a greater effect on fasting glucose, providing a physiological rationale for this complementary approach. This review analyzes the latest randomized controlled clinical trials of insulin/GLP-1 RA combination therapy and examines results from ‘real-world’ use of the combinations as reported through observational and clinical practice studies. The most common finding across all types of studies was that combination therapy improved glycaemic control without weight gain or an increased risk of hypoglycaemia. Many studies reported weight loss and a reduction in insulin use when a GLP-1 RA was added to existing insulin therapy. Overall, the relative degree of benefit to glycaemic control and weight was influenced by the insulin titration employed in conjunction with the GLP-1 RA. The greatest glycaemic benefits were observed in studies with structured titration of insulin to glycaemic targets while the greatest weight benefits were observed in studies with a protocol-specified focus on insulin sparing. The adverse event profile of GLP-1 RAs in the reviewed trials was similar to that reported with GLP-1 RAs as monotherapy or in combination with OAMs with gastrointestinal events being the most commonly

Basal insulin treatment intensification in patients with type 2 diabetes mellitus: A comprehensive systematic review of current options.

PubMed

Raccah, D

2017-04-01

As type 2 diabetes mellitus progresses, most patients require treatment with basal insulin in combination with another agent to achieve recommended glycaemic targets. The purpose of this systematic review was to examine the evidence supporting the use of the available add-on treatments [rapid-acting insulin (RAI), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors] to basal insulin. MEDLINE, EMBASE and EBSCOhost were searched for English-language articles, and all those captured were original articles (case studies and narrative reviews were omitted). Data on study design, population demographics, interventions and outcomes were tabulated. The extracted outcome data included changes in glycated haemoglobin (HbA 1c ), fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), as well as body weight and safety data. A total of 88 publications were deemed relevant. All treatments reduced HbA 1c and FPG. The most pronounced reductions in PPG, an unmet need in patients not controlled by basal insulin, were seen following administration of RAIs and short-acting GLP-1 RAs, although data for this outcome are generally lacking. Body weight benefits were observed with GLP-1 RAs and SGLT-2 inhibitors. However, as only articles in English were included, the result was a possible publication bias, while the diversity of study designs and drug combinations limited comparisons between studies. The evidence supports effectiveness of the available add-on treatments to basal insulin. However, other factors, such as potential body-weight increases, convenience/compliance and adverse events, particularly hypoglycaemia, should be considered on a patient-by-patient basis to optimalize treatment outcomes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Safety and efficacy of insulin glargine 300 u/mL compared with other basal insulin therapies in patients with type 2 diabetes mellitus: a network meta-analysis.

PubMed

Freemantle, Nick; Chou, Engels; Frois, Christian; Zhuo, Daisy; Lehmacher, Walter; Vlajnic, Aleksandra; Wang, Hongwei; Chung, Hsing-Wen; Zhang, Quanwu; Wu, Eric; Gerrits, Charles

2016-02-15

To compare the efficacy and safety of a concentrated formulation of insulin glargine (Gla-300) with other basal insulin therapies in patients with type 2 diabetes mellitus (T2DM). This was a network meta-analysis (NMA) of randomised clinical trials of basal insulin therapy in T2DM identified via a systematic literature review of Cochrane library databases, MEDLINE and MEDLINE In-Process, EMBASE and PsycINFO. Changes in HbA1c (%) and body weight, and rates of nocturnal and documented symptomatic hypoglycaemia were assessed. 41 studies were included; 25 studies comprised the main analysis population: patients on basal insulin-supported oral therapy (BOT). Change in glycated haemoglobin (HbA1c) was comparable between Gla-300 and detemir (difference: -0.08; 95% credible interval (CrI): -0.40 to 0.24), neutral protamine Hagedorn (NPH; 0.01; -0.28 to 0.32), degludec (-0.12; -0.42 to 0.20) and premixed insulin (0.26; -0.04 to 0.58). Change in body weight was comparable between Gla-300 and detemir (0.69; -0.31 to 1.71), NPH (-0.76; -1.75 to 0.21) and degludec (-0.63; -1.63 to 0.35), but significantly lower compared with premixed insulin (-1.83; -2.85 to -0.75). Gla-300 was associated with a significantly lower nocturnal hypoglycaemia rate versus NPH (risk ratio: 0.18; 95% CrI: 0.05 to 0.55) and premixed insulin (0.36; 0.14 to 0.94); no significant differences were noted in Gla-300 versus detemir (0.52; 0.19 to 1.36) and degludec (0.66; 0.28 to 1.50). Differences in documented symptomatic hypoglycaemia rates of Gla-300 versus detemir (0.63; 0.19 to 2.00), NPH (0.66; 0.27 to 1.49) and degludec (0.55; 0.23 to 1.34) were not significant. Extensive sensitivity analyses supported the robustness of these findings. NMA comparisons are useful in the absence of direct randomised controlled data. This NMA suggests that Gla-300 is also associated with a significantly lower risk of nocturnal hypoglycaemia compared with NPH and premixed insulin, with glycaemic control comparable to

Insulin during pregnancy, labour and delivery.

PubMed

de Valk, Harold W; Visser, Gerard H A

2011-02-01

Optimal glycaemic control is of the utmost importance to achieve the best possible outcome of a pregnancy complicated by diabetes. This holds for pregnancies in women with preconceptional type 1 or type 2 diabetes as well as for pregnancies complicated by gestational diabetes. Glycaemic control is conventionally expressed in the HbA1c value but the HbA1c value does not completely capture the complexity of glycaemic control. The daily glucose profile measured by the patients themselves through measurements performed in capillary blood obtained by finger stick provides valuable information needed to adjust insulin therapy. Hypoglycaemia is the major threat to the pregnant woman or the woman with tight glycaemic control in the run-up to pregnancy. Repetitive hypoglycaemia can lead to hypoglycaemia unawareness, which is reversible with prevention of hypoglycaemia. A delicate balance should be struck between preventing hyperglycaemia and hypoglycaemia. Insulin requirements are not uniform across the day: it is low during the night with a more or less pronounced rise at dawn, followed by a gradual decrease during the remainder of the day. A basal amount of insulin is needed to regulate the endogenous glucose production, short-acting insulin shots are needed to handle exogenous glucose loads. Insulin therapy means two choices: the type of insulin used and the method of insulin administration. Regarding the type of insulin, the choice is between human and analogue insulins. The analogue short-acting insulin aspart has been shown to be safe during pregnancy in a randomised trial and has received registration for this indication; the short-acting analogue insulin lispro has been shown to be safe in observational studies. No such information is available on the long-acting insulin analogues detemir and glargine and both are prescribed off-label with human long-acting insulin as obvious alternatives. Randomised trials have not been able to show superiority of continuous

Insulin detemir improves glycemic control and reduces hypoglycemia in children with type 1 diabetes: findings from the Turkish cohort of the PREDICTIVE observational study.

PubMed

Kurtoglu, Selim; Atabek, Mehmet Emre; Dizdarer, Ceyhun; Pirgon, Ozgur; Isguven, Pinar; Emek, Sevil

2009-09-01

Insulin detemir is a basal insulin analog designed to produce a superior pharmacokinetic profile to basal formulations of human insulin. It has shown consistently improved tolerability in comparison to neutral protamine Hagedorn (NPH) insulin in adult cohorts, but there are relatively few publications involving pediatric cohorts. The efficacy and safety of insulin detemir in children with type 1 diabetes was assessed using data from the Turkish cohort of PREDICTIVE (a large, multinational, observational) study. The children investigated were using basal-bolus therapy involving NPH insulin or insulin glargine at baseline but were switched to insulin detemir as part of routine clinical care by their physicians. Twelve weeks of treatment with insulin detemir significantly reduced mean hemoglobin A1c (9.7-8.9%, p < 0.001) and mean fasting glucose [185-162 mg/dL (10.3-9 mmol/L), p < 0.01]. Fasting glucose variability was also lower after treatment with insulin detemir than previously (on either NPH or glargine, p < 0.05). The frequencies of total, major and nocturnal hypoglycemic events were significantly reduced with insulin detemir relative to baseline, with an estimated mean of 6.89 fewer events/patient/yr overall (p < 0.001) and 2.6 fewer nocturnal events/patient/yr (p < 0.01). Weight and insulin dose remained relatively unchanged. Twelve weeks of treatment with insulin detemir improved glycemic control and reduced hypoglycemia in children with type 1 diabetes. This improved tolerability might allow further dose titration and therefore additional improvements in glucose control.

Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial.

PubMed

Bretzel, Reinhard G; Nuber, Ulrike; Landgraf, Wolfgang; Owens, David R; Bradley, Clare; Linn, Thomas

2008-03-29

-28] events per patient per year; p<0.0001). Respective mean weight gains were 3.01 (SD 4.33) kg and 3.54 (4.48) kg. The improvement of treatment satisfaction was greater for insulin glargine than for insulin lispro (mean difference 3.13; 95% CI 2.04-4.22). A therapeutic regimen involving the addition of either basal or prandial insulin analogue is equally effective in lowering haemoglobin A(1c). We conclude that insulin glargine provides a simple and effective option that is more satisfactory to patients than is lispro for early initiation of insulin therapy, since it was associated with a lower risk of hypoglycaemia, fewer injections, less blood glucose self monitoring, and greater patient satisfaction than was insulin lispro. Sanofi-Aventis.

A Toolbox to Improve Algorithms for Insulin-Dosing Decision Support

PubMed Central

Donsa, K.; Plank, J.; Schaupp, L.; Mader, J. K.; Truskaller, T.; Tschapeller, B.; Höll, B.; Spat, S.; Pieber, T. R.

2014-01-01

Summary Background Standardized insulin order sets for subcutaneous basal-bolus insulin therapy are recommended by clinical guidelines for the inpatient management of diabetes. The algorithm based GlucoTab system electronically assists health care personnel by supporting clinical workflow and providing insulin-dose suggestions. Objective To develop a toolbox for improving clinical decision-support algorithms. Methods The toolbox has three main components. 1) Data preparation: Data from several heterogeneous sources is extracted, cleaned and stored in a uniform data format. 2) Simulation: The effects of algorithm modifications are estimated by simulating treatment workflows based on real data from clinical trials. 3) Analysis: Algorithm performance is measured, analyzed and simulated by using data from three clinical trials with a total of 166 patients. Results Use of the toolbox led to algorithm improvements as well as the detection of potential individualized subgroup-specific algorithms. Conclusion These results are a first step towards individualized algorithm modifications for specific patient subgroups. PMID:25024768

Contrasting weight changes with LY2605541, a novel long-acting insulin, and insulin glargine despite similar improved glycaemic control in T1DM and T2DM.

PubMed

Jacober, S J; Rosenstock, J; Bergenstal, R M; Prince, M J; Qu, Y; Beals, J M

2014-04-01

The basal insulin analogue LY2605541, a PEGylated insulin lispro with prolonged duration of action, was previously shown to be associated with modest weight loss in Phase 2, randomized, open-label trials in type 2 (N=288) and type 1 (N=137) diabetes mellitus (T2DM and T1DM), compared with modest weight gain with insulin glargine. Exploratory analyses were conducted to further characterize these findings. Pearson correlations between change in body weight and other variables were calculated. Continuous variables were analysed using a mixed linear model with repeated measurements. Proportions of subjects with weight loss were analysed using Fisher's exact test for T2DM and Nagelkerke's method for T1DM. Weight loss was more common in LY2605541-treated patients than in patients treated with insulin glargine (T2DM: 56.9 vs. 40.2%, p=0.011; T1DM: 66.1 vs. 40.3%, p<0.001). More LY2605541-treated patients experienced ≥5% weight loss compared to patients treated with glargine (T2DM: 4.8 vs. 0%, p=0.033; T1DM: 11.9 vs. 0.8%, p<0.001). In both the T1DM and T2DM studies, weight change did not correlate with baseline body mass index (BMI), or change in HDL-cholesterol in either treatment group. No consistent correlations were found across both studies between weight change and any of the variables assessed; however, weight change was significantly correlated with hypoglycaemia rate in glargine-treated T2DM patients. In two Phase 2 trials, improved glycaemic control with long-acting basal insulin analogue LY2605541 is associated with weight loss in previously insulin-treated patients. This weight change is independent of baseline BMI or hypoglycaemia.

What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus.

PubMed

Chan, Wing B; Luk, Andrea; Chow, Wing S; Yeung, Vincent T F

2017-06-01

There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short-acting, prandial, and long-acting GLP-1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short-acting prandial GLP-1RA lixisenatide, with a focus on treatment of Asian patients with T2DM. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Hypoglycemia After Initiation of Basal Insulin in Patients with Type 2 Diabetes in the United States: Implications for Treatment Discontinuation and Healthcare Costs and Utilization.

PubMed

Dalal, Mehul R; Kazemi, Mahmood; Ye, Fen; Xie, Lin

2017-09-01

Hypoglycemia and fear of hypoglycemia may contribute to basal insulin discontinuation, poor glycemic control, and increased healthcare burden in patients with type 2 diabetes (T2D). This study aimed to determine the impact of hypoglycemia soon after basal insulin initiation on treatment discontinuation and economic outcomes in patients with T2D. Hypoglycemic events within 6 months of basal insulin initiation were identified using retrospective cohort data from patients with T2D, at least 18 years of age, initiated on basal insulin therapy in the Clinformatics™ Data Mart for Multiplan claims database from January 1, 2008, through August 31, 2012. Data were adjusted for baseline characteristics. Discontinuation was established for patients with 12-month follow-up data, while discontinuation risk was assessed in the extended analysis (6- to 24-month follow-up) by Cox regression analysis. Healthcare use and costs were determined. Of 55,608 patients, 4.5% experienced hypoglycemia within 6 months of basal insulin initiation. Patients with hypoglycemia were more likely to discontinue basal insulin within 12 months of initiation (79.0% vs. 74.2%; P < 0.001). Data, adjusted for baseline characteristics such as age, any baseline hypoglycemia, and use of oral antidiabetes drugs, showed that patients with hypoglycemia had a greater risk of discontinuation (hazard ratio 1.16; 95% confidence interval 1.03, 1.32; P = 0.0164), were more likely to have a hospitalization (41.0% vs. 24.3%; P < 0.001) or an ED visit (55.8% vs. 35.1%; P < 0.001), and had higher diabetes-related ($13,662 vs. $7506; P < 0.001) and all-cause ($30,719 vs. $19,079; P < 0.001) healthcare costs. US patients with T2D who experienced hypoglycemia within 6 months of basal insulin initiation were more likely to discontinue treatment, accompanied by a greater healthcare burden. Sanofi US, Inc.

Basal insulin and cardiovascular and other outcomes in dysglycemia.

PubMed

Gerstein, Hertzel C; Bosch, Jackie; Dagenais, Gilles R; Díaz, Rafael; Jung, Hyejung; Maggioni, Aldo P; Pogue, Janice; Probstfield, Jeffrey; Ramachandran, Ambady; Riddle, Matthew C; Rydén, Lars E; Yusuf, Salim

2012-07-26

The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested. We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups. The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97). When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine

Safety and efficacy of saxagliptin for glycemic control in non-critically ill hospitalized patients.

PubMed

Garg, Rajesh; Schuman, Brooke; Hurwitz, Shelley; Metzger, Cheyenne; Bhandari, Shreya

2017-01-01

To evaluate whether saxagliptin is non-inferior to basal-bolus insulin therapy for glycemic control in patients with controlled type 2 diabetes mellitus (T2DM) admitted to hospital with non-critical illnesses. This was an open-label, randomized controlled clinical trial. Patients received either saxagliptin or basal-bolus insulin, both with correctional insulin doses. The main study outcome was the mean daily blood glucose (BG) after the first day of randomization. Of 66 patients completing the study, 33 (age 69±10 years, 40% men) were randomized to saxagliptin and 33 (age 67±10 years, 52% men) to basal-bolus insulin therapy. The mean daily BG was 149.8±22.0 mg/dL in the saxagliptin group and 146.9±30.5 mg/dL in the insulin group (p=0.59). With an observed group difference of 2.9 mg/dL and an a priori margin of 20 mg/dL, inferiority of saxagliptin was rejected in favor of non-inferiority (p=0.007). There was no significant difference in the percentage of high or low BG values. The insulin group received a higher number of insulin injections (2.3±1.7/day vs 1.2±1.9/day; p<0.001) as well as a higher daily insulin dose (13.3±12.9 units/day vs 2.4±3.3 units/day; p<0.001) than did the saxagliptin group. Continuous BG monitoring showed that glycemic variability was lower in the saxagliptin group as compared to the insulin group. Patient satisfaction scores were similar in the two groups. We conclude that saxagliptin use is non-inferior to basal-bolus insulin in non-critically ill hospitalized patients with T2DM controlled on 0-2 oral agents without insulin. Saxagliptin use may decrease glycemic variability in these patients. NCT02182895.

Glucagon-like peptide-1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis.

PubMed

Singh, Sonal; Wright, Eugene E; Kwan, Anita Y M; Thompson, Juliette C; Syed, Iqra A; Korol, Ellen E; Waser, Nathalie A; Yu, Maria B; Juneja, Rattan

2017-02-01

Since 2005, several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been approved to treat people with type 2 diabetes. These agents are considered for use at the same point in the treatment paradigm as basal insulins. A comprehensive comparison of these drug classes, therefore, can help inform treatment decisions. This systematic review and meta-analysis assessed the clinical efficacy and safety of GLP-1 RAs compared with basal insulins. MEDLINE, EMBASE, CENTRAL and PubMed databases were searched. Randomized clinical trials (RCTs) of ≥16 weeks' duration comparing GLP-1 RAs vs basal insulins in adults with type 2 diabetes inadequately controlled with oral antihyperglycemic drugs were included. Data on the change from baseline to 26 weeks (±10 weeks) of treatment in hemoglobin A1c (HbA1c) and weight, as well as the proportion of patients experiencing hypoglycaemia, were extracted. Fixed-effect pairwise meta-analyses were conducted where data were available from ≥2 studies. Fifteen RCTs were identified and 11 were meta-analysed. The once-weekly GLP-1 RAs, exenatide long acting release (LAR) and dulaglutide, led to greater, statistically significant mean HbA1c reductions vs basal insulins (exenatide: -0.31% [95% confidence interval -0.42, -0.19], dulaglutide: -0.39% [-0.49, -0.29]) whilst once-daily liraglutide and twice-daily exenatide did not (liraglutide: 0.06% [-0.06, 0.18], exenatide: 0.01% [-0.11, 0.13]). Mean weight reduction was seen with all GLP-1 RAs while mean weight gain was seen with basal insulins. Interpretation of the analysis of hypoglycaemia was limited by inconsistent definitions and reporting. Because of the limited number of available studies sensitivity analyses to explore heterogeneity could not be conducted. Although weight reduction is seen with all GLP-1 RA's, only the once-weekly agents, exenatide LAR and dulaglutide, demonstrate significant HbA1c reductions when compared to basal insulins. © 2016 The Authors. Diabetes

Twenty-four-hour simultaneous subcutaneous basal-bolus administration of insulin and amylin in adolescents with type 1 diabetes decreases postprandial hyperglycemia

USDA-ARS?s Scientific Manuscript database

The purpose of this study was to examine the effect of continuous subcutaneous (sc) replacement of amylin and insulin for a 24-h period on glucose homeostasis in adolescents with type 1 diabetes. Thirteen adolescents with type 1 diabetes on insulin pump therapy participated in a randomized, controll...

Relationship between treatment persistence and A1C trends among patients with type 2 diabetes newly initiating basal insulin

PubMed Central

Xie, Lin; Pan, Chunshen; Wang, Yuexi; Vaidya, Neel; Ye, Fen; Preblick, Ronald; Meneghini, Luigi

2018-01-01

This study examines the relationship between glycated haemoglobin (A1C) levels and treatment persistence with, or time to discontinuation of, basal insulin in patients with type 2 diabetes (T2D) newly initiating insulin. Claims data were extracted from the Optum Clinformatics database from January 2010 to June 2015. Adult patients with T2D initiating insulin glargine 100 U/mL (Gla‐100) or insulin detemir (DET) with ≥1 A1C measurement during 12‐month baseline and 18‐month follow‐up periods were included. Patients with a refill gap of >90 days were considered non‐persistent; otherwise, patients were considered persistent with insulin. The main outcome was A1C, measured closest to the end of each quarter during the follow‐up period. A total of 3993 of 109 934 patients met the inclusion criteria (43.0% persistent; 57.0% non‐persistent). Persistent patients were older (54.7 vs 52.7 years; P < .001), were more likely to be male (59.4% vs 54.4%; P = .002), and had significantly lower mean unadjusted A1C values at 18 months (8.26% vs 8.60%; P < .001) and quarterly. Only 43.0% of adults initiating basal insulin persisted with treatment for 18 months, with earlier discontinuation associated with higher A1C. PMID:29278460

Improved glycaemic control and treatment satisfaction with a simple wearable 3-day insulin delivery device among people with Type 2 diabetes.

PubMed

Mader, J K; Lilly, L C L; Aberer, F; Poettler, T; Johns, D; Trautmann, M; Warner, J; Pieber, T R

2018-06-11

To evaluate the PAQ ® (CeQur SA, Horw, Switzerland), a wearable 3-day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes. Adults with Type 2 diabetes with HbA 1c concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single-arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA 1c , seven-point self-monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects. A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m 2 , Type 2 diabetes duration 17 ± 8 years, HbA 1c 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selected. After 12 weeks of PAQ wear, significant improvements from baseline were seen [HbA 1c -16 ± 9 mmol/mol (95% CI -20, -12) or -1.5 ± 0.9% (95% CI -1.8, -1.1) P<0.0001], and at all seven self-monitored blood glucose readings time points (P ≤0.03). Total daily insulin dose increased by 12.1 ± 19.5 U (95% CI 3.9, 20.4; P=0.0058), the number of meal time boluses increased by 0.9 ± 1.5/day (95% CI 0.3, 1.5; P=0.0081) and body weight remained stable. Six participants had mild to moderate catheter site reactions and one mild skin irritation occurred. No participant experienced severe hypoglycaemia. Adults with Type 2 diabetes were safely transitioned from insulin injections to the PAQ and had significantly improved glycaemic control and treatment satisfaction with insulin therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Enhancing automatic closed-loop glucose control in type 1 diabetes with an adaptive meal bolus calculator - in silico evaluation under intra-day variability.

PubMed

Herrero, Pau; Bondia, Jorge; Adewuyi, Oloruntoba; Pesl, Peter; El-Sharkawy, Mohamed; Reddy, Monika; Toumazou, Chris; Oliver, Nick; Georgiou, Pantelis

2017-07-01

Current prototypes of closed-loop systems for glucose control in type 1 diabetes mellitus, also referred to as artificial pancreas systems, require a pre-meal insulin bolus to compensate for delays in subcutaneous insulin absorption in order to avoid initial post-prandial hyperglycemia. Computing such a meal bolus is a challenging task due to the high intra-subject variability of insulin requirements. Most closed-loop systems compute this pre-meal insulin dose by a standard bolus calculation, as is commonly found in insulin pumps. However, the performance of these calculators is limited due to a lack of adaptiveness in front of dynamic changes in insulin requirements. Despite some initial attempts to include adaptation within these calculators, challenges remain. In this paper we present a new technique to automatically adapt the meal-priming bolus within an artificial pancreas. The technique consists of using a novel adaptive bolus calculator based on Case-Based Reasoning and Run-To-Run control, within a closed-loop controller. Coordination between the adaptive bolus calculator and the controller was required to achieve the desired performance. For testing purposes, the clinically validated Imperial College Artificial Pancreas controller was employed. The proposed system was evaluated against itself but without bolus adaptation. The UVa-Padova T1DM v3.2 system was used to carry out a three-month in silico study on 11 adult and 11 adolescent virtual subjects taking into account inter-and intra-subject variability of insulin requirements and uncertainty on carbohydrate intake. Overall, the closed-loop controller enhanced by an adaptive bolus calculator improves glycemic control when compared to its non-adaptive counterpart. In particular, the following statistically significant improvements were found (non-adaptive vs. adaptive). Adults: mean glucose 142.2 ± 9.4vs. 131.8 ± 4.2mg/dl; percentage time in target [70, 180]mg/dl, 82.0 ± 7.0vs. 89.5 ± 4

Linagliptin improves glycemic control after 1 year as add-on therapy to basal insulin in Asian patients with type 2 diabetes mellitus.

PubMed

Sheu, Wayne H-H; Park, Sung Woo; Gong, Yan; Pinnetti, Sabine; Bhattacharya, Sudipta; Patel, Sanjay; Seck, Thomas; Woerle, Hans-Juergen

2015-03-01

To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents. This was a post hoc analysis of Asian patients from a global ≥52 week study in which patients on basal insulin were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo (NCT00954447). Basal insulin dose remained stable for 24 weeks, after which adjustments could be made according to the investigator's discretion to improve glycemic control. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) from baseline to 24 weeks. Data were available for 154 Asian patients (80 linagliptin, 74 placebo). Baseline HbA1c (standard deviation [SD]) was 8.6 (0.9)% (70 [10] mmol/mol). The placebo-corrected mean change (standard error [SE]) in HbA1c from baseline was -0.9 (0.1)% (-10 [1] mmol/mol) (95% confidence interval [CI]: -1.2, -0.7; p<0.0001) at Week 24 and -0.9 (0.1)% (-10 [1] mmol/mol) (95% CI: -1.1, -0.6; p<0.0001) at Week 52. The frequency of adverse events (linagliptin 81.3%, placebo 91.9%) and hypoglycemia (Week 24: linagliptin 25.0%, placebo 25.7%; treatment end: linagliptin 28.8%, placebo 35.1%) was similar between groups. By Week 52, changes (SE) in mean body weight were similar in both groups (linagliptin -0.67 [0.26] kg, placebo -0.38 [0.25] kg). This study was limited by the post hoc nature of the analysis and the small number of patients in the subgroup. However, the results suggest that linagliptin significantly improves glycemic control in Asian patients with T2DM inadequately controlled by basal insulin, without increasing the risk for hypoglycemia or weight gain. ClinicalTrials identifier: NCT00954447.

Insulin prices, availability and affordability: a cross-sectional survey of pharmacies in Hubei Province, China.

PubMed

Liu, Chenxi; Zhang, Xinping; Liu, Chaojie; Ewen, Margaret; Zhang, Zinan; Liu, Guoqin

2017-08-24

Poor access to affordable insulin results in serious and needless complications and premature deaths for those with diabetes who need this essential medicine. To help address this issue, we assessed insulin availability, prices, affordability and price components in Hubei Province as China has the heaviest burden of diabetes globally. In 2016, insulin availability and price data was collected in the capital and five other cities. A total of 30 public sector outlets (hospitals and primary care institutions) and 30 private pharmacies were sampled, using an adaptation of the World Health Organization/Health Action International methodology, Data was collected for all human and analogue insulins in stock, then analyzed by type (prandial, basal or pre-mixed) and duration of action. Prices were expressed as Median Price Ratios (MPRs) to Australian PBS prices. Price components were tracked for five insulin products in two cities.. Affordability was assessed as the number of days' wages of the lowest paid unskilled government worker needed to purchase 10 ml 100 IU/ml (approximately 30 days' supply). Mean availability was highest in public hospitals for prandial (70%), basal (80%) and pre-mixed insulin (90%). In primary care institutions and private pharmacies mean availability ranged from 10% to 33%. Median prices of all insulin types were higher that Australian PBS prices in all three sectors for human and analogue insulins (ranging from1.36-2.59 times). Patients have to pay 4 to 16 days' wages to purchase a month's treatment depending on the insulin type and sector. The largest component of the patient price was the manufacturers' selling price (60%). Taxes in the form of import duties and VAT are applied in some sectors. The availability of insulin in primary care institutions and private retail pharmacies was very low in Hubei. Only public hospitals had good insulin availability. Insulin prices were high in all sectors making this life-saving medicine unaffordable

Controlled delivery of basal insulin from phase-sensitive polymeric systems after subcutaneous administration: in vitro release, stability, biocompatibility, in vivo absorption, and bioactivity of insulin.

PubMed

Al-Tahami, Khaled; Oak, Mayura; Singh, Jagdish

2011-06-01

The purpose of this study was to investigate the phase-sensitive delivery systems (D,L-polylactide in triacetin) for controlled delivery of insulin at basal level. The effect of varying concentration of zinc, polymer, and insulin on the in vitro release of insulin was evaluated. Stability of released insulin was investigated by differential scanning calorimetry, circular dichroism, and matrix-assisted laser desorption/ionization time of flight mass spectrometry. In Vivo insulin absorption and bioactivity were studied in diabetic rats. In vitro and In Vivo biocompatibility of delivery systems were evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and skin histology, respectively. Extended release profiles of insulin for 2, 4, and 8 weeks from delivery systems containing 20%, 30%, and 40% (w/v) polymer concentration was observed. A ratio of 1:5 insulin hexamer to zinc was shown to be optimum. Physical and chemical stability of released insulin was greatly conserved. In Vivo studies demonstrated controlled release of insulin with reduction in blood glucose for approximately 1 month. In vitro and In Vivo studies demonstrated that the delivery system was biocompatible and controlled the delivery of insulin for longer durations after single subcutaneous injection. Copyright © 2010 Wiley-Liss, Inc.

Glucose-stimulated insulin response in pregnant sheep following acute suppression of plasma non-esterified fatty acid concentrations

PubMed Central

Regnault, Timothy RH; Oddy, Hutton V; Nancarrow, Colin; Sriskandarajah, Nadarajah; Scaramuzzi, Rex J

2004-01-01

Background Elevated non-esterified fatty acids (NEFA) concentrations in non-pregnant animals have been reported to decrease pancreatic responsiveness. As ovine gestation advances, maternal insulin concentrations fall and NEFA concentrations increase. Experiments were designed to examine if the pregnancy-associated rise in NEFA concentration is associated with a reduced pancreatic sensitivity to glucose in vivo. We investigated the possible relationship of NEFA concentrations in regulating maternal insulin concentrations during ovine pregnancy at three physiological states, non-pregnant, non-lactating (NPNL), 105 and 135 days gestational age (dGA, term 147+/- 3 days). Methods The plasma concentrations of insulin, growth hormone (GH) and ovine placental lactogen (oPL) were determined by double antibody radioimmunoassay. Insulin responsiveness to glucose was measured using bolus injection and hyperglycaemic clamp techniques in 15 non-pregnant, non-lactating ewes and in nine pregnant ewes at 105 dGA and near term at 135 dGA. Plasma samples were also collected for hormone determination. In addition to bolus injection glucose and insulin Area Under Curve calculations, the Mean Plasma Glucose Increment, Glucose Infusion Rate and Mean Plasma Insulin Increment and Area Under Curve were determined for the hyperglycaemic clamp procedures. Statistical analysis of data was conducted with Students t-tests, repeated measures ANOVA and 2-way ANOVA. Results Maternal growth hormone, placental lactogen and NEFA concentrations increased, while basal glucose and insulin concentrations declined with advancing gestation. At 135 dGA following bolus glucose injections, peak insulin concentrations and insulin area under curve (AUC) profiles were significantly reduced in pregnant ewes compared with NPNL control ewes (p < 0.001 and P < 0.001, respectively). In hyperglycaemic clamp studies, while maintaining glucose levels not different from NPNL ewes, pregnant ewes displayed significantly

Continuous subcutaneous insulin infusion allows tolerance induction and diabetes treatment in a type 1 diabetic child with insulin allergy.

PubMed

Hasselmann, C; Pecquet, C; Bismuth, E; Raverdy, C; Sola-Gazagnes, A; Lobut, J-B; Carel, J-C; Tubiana-Rufi, N

2013-04-01

Insulin allergy is a rare but serious and challenging condition in patients with type 1 diabetes (T1D). This is a case report of an 8-year-old boy with T1D and an allergy to insulin. Three months after being diagnosed with T1D, the patient developed progressive skin reactions to insulin, characterized by small 1.5-cm pruritic wheals at injection sites that persisted for several days. Seven months after diagnosis, he experienced two episodes of generalized urticaria with systemic symptoms that were seen within a few seconds of insulin injection. Examination revealed lipoatrophy of the thighs. Intradermal skin tests were positive for protamine, glargine and lispro. The patient was started on a continuous subcutaneous insulin infusion (CSII) tolerance induction protocol, consisting of a very low basal rate that was progressively increased, with the first bolus given under medical supervision, and was well tolerated for 4 months. After this period of time, the skin wheals reappeared, localized to the infusion sites, but without urticaria or any other generalized reactions. Intradermal skin tests were repeated and were again positive. Serum insulin-specific IgE measured 30 months after the first allergic reactions were positive. After 3 years, pump therapy is ongoing and blood glucose control has remained relatively good (HbA1c 7.6%). In T1D children with insulin allergy, CSII can successfully be used to both induce insulin tolerance and allow diabetes insulin therapy, although insulin desensitization cannot always be fully achieved. The induction protocol was easily manageable partly due to the "honeymoon" period that the patient was still in, but it should nonetheless be used even when the patient has higher insulin requirements. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Comparison of insulin intensification strategies with insulin lispro low mixture twice daily versus basal insulin glargine and prandial insulin lispro once daily in East Asian and Caucasian patients with type 2 diabetes mellitus.

PubMed

Jeong, In-Kyung; Chung, Choon Hee; Zhou, Zhiguang; Han, Jeong Hee; Duan, Ran; Edralin, Diana M; Rodriguez, Angel

2017-04-01

This analysis evaluated efficacy and safety of insulin lispro low mixture (LM25) twice daily (breakfast and dinner) versus basal insulin glargine (bedtime) plus prandial insulin lispro (IGL) once daily before the largest meal in East Asian (EA) and Caucasian patients with type 2 diabetes mellitus who failed to reach glycemic targets on basal insulin glargine with metformin and/or pioglitazone. Included patients had an HbA1c ≥7.5% and ≤10.5% and fasting plasma glucose ≤6.7 mmol/L. Primary outcome was HbA1c change at 24 weeks. Baseline mean HbA1c was numerically similar between groups in EA (n = 79) and Caucasian (n = 278) patients. Mean (± SD) HbA1c decreased significantly from baseline to 24 weeks for LM25 and IGL in both subpopulations (EA: -1.32 ± 0.96% and -0.89 ± 0.96%; Caucasian: -1.24 ± 0.98% and -1.04 ± 0.97; all P < 0.0001). The respective proportions reaching HbA1c ≤7.0% at Week 24 in the LM25 and IGL groups were 33.3% and 22.9% (EA) and 37.2% and 34.1% (Caucasian). Mean (± SD) rates of hypoglycemia per 30 days in the LM25 and IGL groups were 0.74 ± 1.16 and 1.22 ± 1.36 (EA) and 1.38 ± 2.04 and 1.65 ± 2.43 (Caucasian). Mean (± SD) weight gain changes in the LM25 and IGL groups were 0.62 ± 2.78 and 0.51 ± 2.63 kg (EA) and 1.77 ± 2.91 and 0.67 ± 3.09 kg (Caucasian). Both strategies improved glycemic control in a small group of EA and Caucasian patients not adequately controlled on insulin glargine plus metformin and/or pioglitazone. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Real-world evidence concerning clinical and economic outcomes of switching to insulin glargine 300 units/mL vs other basal insulins in patients with type 2 diabetes using basal insulin.

PubMed

Zhou, Fang Liz; Ye, Fen; Berhanu, Paulos; Gupta, Vineet E; Gupta, Rishab A; Sung, Jennifer; Westerbacka, Jukka; Bailey, Timothy S; Blonde, Lawrence

2018-05-01

This retrospective cohort study compared real-world clinical and healthcare-resource utilization (HCRU) data in patients with type 2 diabetes using basal insulin (BI) who switched to insulin glargine 300 units/mL (Gla-300) or another BI. Data from the Predictive Health Intelligence Environment database 12 months before (baseline) and 6 months after (follow-up) the switch date (index date, March 1, 2015 to May 31, 2016) included glycated haemoglobin A1c (HbA1c), hypoglycaemia, HCRU and associated costs. Baseline characteristics were balanced using propensity score matching. Change in HbA1c from baseline was similar in both matched cohorts (n = 1819 in each). Hypoglycaemia incidence and adjusted event rate were significantly lower with Gla-300. Patients switching to Gla-300 had a significantly lower incidence of HCRU related to hypoglycaemia. All-cause and diabetes-related hospitalization and emergency-department HCRU were also favourable for Gla-300. Lower HCRU translated to lower costs in patients using Gla-300. In this real-world study, switching to Gla-300 reduced the risk of hypoglycaemia in patients with type 2 diabetes when compared with those switching to another BI, resulting in less HCRU and potential savings of associated costs. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Clinical Benefits Over Time Associated with Use of V-Go Wearable Insulin Delivery Device in Adult Patients with Diabetes: A Retrospective Analysis.

PubMed

Sutton, David; Higdon, Charissa D; Nikkel, Carla; Hilsinger, Karrie A

2018-05-10

Advances in insulin delivery have improved outcomes in patients with diabetes. This study evaluated the impact of V-Go ® Wearable Insulin Delivery device on glycated hemoglobin (A1C) and insulin total daily dose (TDD) in patients with diabetes not achieving glycemic targets. Electronic medical record data was obtained for adult patients with A1C > 7% treated at a multicenter endocrine practice who initiated V-Go between August 2012 and August 2015. Data were collected at baseline and for up to four follow-up visits, and were analyzed overall, stratified by insulin use at baseline, and for patients prescribed a basal-bolus insulin regimen delivered by multiple daily injections (MDI) at baseline. Economic evaluations were conducted in patients previously prescribed MDI regimens. Patients (N = 103) were evaluated after a mean of 2, 6, 10, and 14 months of V-Go use. Baseline glycemic control was poor (A1C > 9%) in 59% of patients. Significant, sustained reductions in A1C compared with baseline were observed at every visit (p < 0.0001), with mean ± SE decrease of 1.67 ± 0.24% after 14 months. For patients prescribed insulin at baseline (n = 80), TDD was significantly reduced at all visits (p < 0.0001), with mean ± SE reduction of 17 ± 4.5 units/day at 14 months. Patients previously prescribed MDI therapy (n = 58) benefited from 1.53 ± 0.31% (p < 0.001) A1C reduction and TDD decrease of 30 ± 5 units/day after 14 months. Direct pharmacy wholesale acquisition costs for diabetes therapeutics were reduced by $25.00/patient/month. Use of V-Go was associated with improved glycemic control and decreased TDD. For patients previously prescribed basal-bolus MDI therapy, switching to insulin therapy with V-Go resulted in pharmacy cost savings based on wholesale acquisition costs. V-Go offers an efficacious method of insulin delivery that improves outcomes in patients and can reduce costs. Valeritas, Inc.

Perceptions of diabetes control among people with type 2 diabetes treated with basal insulin in Sweden, Switzerland, and the United Kingdom.

PubMed

Brod, Meryl; Pfeiffer, Kathryn M; Barnett, Anthony H; Berntorp, Kerstin; Vilsbøll, Tina; Weissenberger, Benno

2016-07-11

To investigate perceptions of control among people with uncontrolled and well controlled type 2 diabetes (T2D) treated with basal insulin, as well as differences in perceptions and diabetes management practices between the two groups. Web surveys of 1012 people with uncontrolled T2D (HbA 1c >8.0% or 64 mmol/mol) on basal insulin in Sweden, Switzerland, and the UK and 295 people with well controlled T2D (HbA 1c <7.5% or 58 mmol/mol) on basal insulin in the UK were conducted. People with uncontrolled T2D perceived a wide range of factors as very/extremely important for deciding whether they are well controlled, including diet (80.7%), HbA 1c value (78.9%), times per day insulin taken (78.8%), insulin units taken per day (77.6%), and energy levels (74.5%). Fifty-one percent of uncontrolled respondents considered the past week or more recently when thinking about control. Perceived major obstacles to control included stress (75.4%), other health issues (70.8%), medicine side effects (69.9%), food cravings (69.8%), doctor not understanding individual situation (67.6%), and life crises (66.9%). Many uncontrolled respondents reported that diabetes was very/extremely interfering with their lives, including energy level (71.0%), performance at work (70.0%), general health (69.9%), and doing what one wants (69.3%). Analyses showed significant differences between well controlled and uncontrolled UK respondents. Compared to the uncontrolled, people with well controlled T2D were significantly more likely to consider the last 24 hours/current time when thinking about control (50% vs. 21%, p < 0.001) and reported greater healthcare contact related to diabetes and more frequent glucose measurement. Study limits include potential selection bias of web surveys and possible recall bias in patient-reported data. The results illuminate how people with T2D treated with basal insulin perceive control and show important differences between the well controlled and uncontrolled

Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue

NASA Astrophysics Data System (ADS)

Lee, Hyun Chul; Kim, Su-Jin; Kim, Kyung-Sup; Shin, Hang-Cheol; Yoon, Ji-Won

2000-11-01

A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic β cells by autoimmune responses specific to β cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.

Skipping meals or carbohydrate-free meals in order to determine Basal insulin requirements in subjects with type 1 diabetes mellitus?

PubMed

Uthoff, H; Lehmann, R; Sprenger, M; Wiesli, P

2010-05-01

Basal insulin dose requirements in patients with type 1 diabetes may be derived from the course of glucose concentrations in the fasting state; i. e. by skipping meals. The present study examined whether fasting tests could be replaced by carbohydrate-free meals. 16 adult patients with type 1 diabetes (10 male) on intensive insulin therapy participated in this prospective intervention study. Mean age (+/-SD) was 44+/-12 years, BMI 24+/-3 kg/m (2), mean HbA1c was 7.5+/-0.6% and duration of diabetes 15+/-12 years. All participants skipped dinner and plasma glucose concentrations were hourly monitored from 7 p.m. to 11 p.m. This blood glucose profile was compared with three test meals given at 7 p.m. at day 2-4, consumed either in the hospital (meal 1) or at home (meal 2 and 3). No insulin injection (except to basal insulin) was allowed. Test meals consisted of 2.5 g carbohydrate, 32.4 g protein, 52.0 g fat (according to 612 kcal). During 16 fasting tests plasma glucose concentration remained stable between 7.2+/-2.4 mmol/l at 7 p.m. and 6.8+/-2.8 mmol/l at 11 p.m. (p=0.461). Following the intake of near carbohydrate-free meals (48 tests), plasma glucose concentrations rose within 4 h from 6.7+/-2.0 at 7 p.m. to 9.8+/-3.4 mmol/l at 11 p.m. (p<0.0001). The increase in plasma glucose concentrations was similar in all three different meals tested. Plasma glucose concentrations significantly increase in patients with type 1 diabetes following the intake of carbohydrate-free meals. Carbohydrate-free meal-tests cannot replace skipping meal tests to determine the basal insulin requirement in patients with type 1 diabetes.

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme.

PubMed

Affholter, J A; Cascieri, M A; Bayne, M L; Brange, J; Casaretto, M; Roth, R A

1990-08-21

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, we have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor I (25 nM and approximately 16,000 nM, respectively), the first set of analogues studied were hybrid molecules of insulin and IGF I. IGF I mutants [insB1-17,17-70]IGF I, [Tyr55,Gln56]IGF I, and [Phe23,Phe24,Tyr25]IGF I have been synthesized and share the property of having insulin-like amino acids at positions corresponding to primary sites of cleavage of insulin by IDE. Whereas the first two exhibit affinities for IDE similar to that of wild type IGF I, the [Phe23,Phe24,Tyr25]IGF I analogue has a 32-fold greater affinity for the immobilized enzyme. Replacement of Phe-23 by Ser eliminates this increase. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants [B25-Asp]insulin and [B25-His]insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycemic control and adherence to basal insulin therapy in Taiwanese patients with type 2 diabetes mellitus.

PubMed

Chien, Ming-Nan; Chen, Yen-Ling; Hung, Yi-Jen; Wang, Shu-Yi; Lu, Wen-Tsung; Chen, Chih-Hung; Lin, Ching-Ling; Huang, Tze-Pao; Tsai, Ming-Han; Tseng, Wei-Kung; Wu, Ta-Jen; Ho, Cheng; Lin, Wen-Yu; Chen, Bill; Chuang, Lee-Ming

2016-11-01

The aim of the present study was to assess the glycemic control, adherence and treatment satisfaction in a real-world setting with basal insulin therapy in type 2 diabetes patients in Taiwan. This was a multicenter, prospective, observational registry. A total of 836 patients with type 2 diabetes taking oral antidiabetic drugs with glycated hemoglobin (HbA1c) >7% entered the study. Basal insulin was given for 24 weeks. All treatment choices and medical instructions were at the physician's discretion to reflect real-life practice. After 24-week treatment, 11.7% of patients reached set HbA1c goals without severe hypoglycemia (primary effectiveness end-point). HbA1c and fasting blood glucose were significantly decreased from (mean ± SD) 10.1 ± 1.9% to 8.7 ± 1.7% (-1.4 ± 2.1%, P < 0.0001) and from 230.6 ± 68.8 mg/dL to 159.1 ± 55.6 mg/dL (-67.4 ± 72.3 mg/dL, P < 0.0001), respectively. Patients received insulin therapy at a frequency of nearly one shot per day on average, whereas self-monitoring of blood glucose was carried out approximately four times a week. Hypoglycemia was reported by 11.4% of patients, and only 0.7% of patients experienced severe hypoglycemia. Slight changes in weight (0.7 ± 2.4 kg) and a low incidence of adverse drug reactions (0.4%) were also noted. The score of 7-point treatment satisfaction rated by patients was significantly improved by 1.9 ± 1.7 (P < 0.0001). Basal insulin therapy was associated with a decrease in HbA1c and fasting blood glucose, and an improved treatment satisfaction. Most patients complied with physicians' instructions. The treatment was generally well tolerated by patients with type 2 diabetes, but findings pointed out the need to reinforce the early and appropriate uptitration to achieve treatment targets. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements.

PubMed

Pearson, Scott M; Trujillo, Jennifer M

2018-04-01

We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 ( n = 95) or insulin degludec ( n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1-12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19-60 interquartile range (IQR)] units at baseline to 34.5 (19-70 IQR) units after follow up ( p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different ( p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 ( p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different.

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements

PubMed Central

Trujillo, Jennifer M.

2018-01-01

Background: We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. Methods: This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 (n = 95) or insulin degludec (n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1–12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Results: Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19–60 interquartile range (IQR)] units at baseline to 34.5 (19–70 IQR) units after follow up (p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different (p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 (p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Conclusions: Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different. PMID:29619208

Factors associated with reaching or not reaching target HbA1c after initiation of basal or premixed insulin in patients with type 2 diabetes.

PubMed

Scheen, A J; Schmitt, H; Jiang, H H; Ivanyi, T

2017-02-01

To evaluate factors associated with reaching or not reaching target glycated haemoglobin (HbA 1c ) levels by analysing the respective contributions of fasting hyperglycaemia (FHG), also referred to as basal hyperglycaemia, vs postprandial hyperglycaemia (PHG) before and after initiation of a basal or premixed insulin regimen in patients with type 2 diabetes. This post-hoc analysis of insulin-naïve patients in the DURABLE study randomised to receive either insulin glargine or insulin lispro mix 25 evaluated the percentages of patients achieving a target HbA 1c of <7.0% (<53mmol/mol) per baseline HbA 1c quartiles, and the effect of each insulin regimen on the relative contributions of PHG and FHG to overall hyperglycaemia. Patients had comparable demographic characteristics and similar HbA 1c and FHG values at baseline in each HbA 1c quartile regardless of whether they reached the target HbA 1c . The higher the HbA 1c quartile, the greater was the decrease in HbA 1c , but also the smaller the percentage of patients achieving the target HbA 1c . HbA 1c and FHG decreased more in patients reaching the target, resulting in significantly lower values at endpoint in all baseline HbA 1c quartiles with either insulin treatment. Patients not achieving the target HbA 1c had slightly higher insulin doses, but lower total hypoglycaemia rates. Smaller decreases in FHG were associated with not reaching the target HbA 1c , suggesting a need to increase basal or premixed insulin doses to achieve targeted fasting plasma glucose and improve patient response before introducing more intensive prandial insulin regimens. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Novel Simple Insulin Delivery Device Reduces Barriers to Insulin Therapy in Type 2 Diabetes

PubMed Central

Hermanns, Norbert; Lilly, Leslie C.; Mader, Julia K.; Aberer, Felix; Ribitsch, Anja; Kojzar, Harald; Warner, Jay; Pieber, Thomas R.

2015-01-01

Background: The PaQ® insulin delivery system is a simple-to-use patch-on device that provides preset basal rates and bolus insulin on demand. In addition to feasibility of use, safety, and efficacy (reported elsewhere), this study analyzed the impact of PaQ on patient-reported outcomes, including barriers to insulin treatment, diabetes-related distress, and attitudes toward insulin therapy in patients with type 2 diabetes on a stable multiple daily injection (MDI) regimen. Methods: This single-center, open-label, single-arm study comprised three 2-week periods: baseline (MDI), transition from MDI to PaQ, and PaQ treatment. Validated questionnaires were administered during the baseline and PaQ treatment periods: Barriers to Insulin Treatment questionnaire (BIT), Insulin Treatment Appraisal Scale (ITAS), and Problem Areas in Diabetes scale (PAID). Results: Eighteen patients (age 59 ± 5 years, diabetes duration 15 ± 7 years, 21% female, HbA1c 7.7 ± 0.7%) completed the questionnaires. There was a strong, significant effect of PaQ use in mean BIT total scores (difference [D] = −5.4 ± 0.7.7, P = .01, effect size [d] = 0.70). Patients perceived less stigmatization by insulin injection (D = −2.2 ± 6.2, P = .18, d = 0.35), increased positive outcome (D = 1.9 ± 6.6, P = .17, d = 0.29), and less fear of injections (1.3 ± 4.8, P = .55, d = 0.28). Mean change in ITAS scores after PaQ device use showed a nonsignificant improvement of 1.71 ± 5.63 but moderate effect size (d = 0.30, P = .14). No increase in PAID scores was seen. Conclusions: The results and moderate to large effects sizes suggest that PaQ device use has beneficial and clinically relevant effects to overcoming barriers to and negative appraisal of insulin treatment, without increasing other diabetes-related distress. PMID:25670847

A meta-analysis of rate ratios for nocturnal confirmed hypoglycaemia with insulin degludec vs. insulin glargine using different definitions for hypoglycaemia.

PubMed

Heller, S; Mathieu, C; Kapur, R; Wolden, M L; Zinman, B

2016-04-01

A prospective meta-analysis of phase 3 trials showed lower rates of nocturnal hypoglycaemia with insulin degludec vs. insulin glargine. We investigated the consistency of the results across different definitions of hypoglycaemia. This post-hoc, patient-level meta-analysis included six randomized, controlled, 26- or 52-week phase 3a trials in insulin-naïve participants with Type 2 diabetes mellitus (Type 2 diabetesinsulin naïve ), participants with Type 2 diabetes mellitus using basal-bolus therapy (Type 2 diabetesBB ) and those with Type 1 diabetes mellitus. We used three definitions of hypoglycaemia and different timescales for the nocturnal period. Rates were analysed for the entire core trial period, the 'maintenance period' only, and the extension trial set population. Analyses utilized a negative binomial regression model. In Type 2 diabetesinsulin naïve participants, risk of nocturnal hypoglycaemia was significantly lower with insulin degludec vs. insulin glargine for all hypoglycaemia definitions and trial periods. Risk was also lower for the timescale 21.59-05.59, but not 00.01-07.59. For Type 2 diabetesBB , nocturnal hypoglycaemia rates were lower with insulin degludec vs. insulin glargine across all definitions, timescales and trial periods, with one exception. For individuals with Type 1 diabetes mellitus, nocturnal hypoglycaemia risk was significantly lower with insulin degludec during the maintenance period for the original definition (plasma glucose < 3.1 mmol/l, timescale 00.01-05.59) and in the extension trial set population for all hypoglycaemia definitions except for the nocturnal timescale 00.01-07.59. Compared with insulin glargine, insulin degludec is associated with lower rates of nocturnal hypoglycaemia in people with Type 2 diabetes mellitus, and similar or lower rates in Type 1 diabetes mellitus, across different definitions. © 2015 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Association of hypoglycaemia severity with clinical, patient‐reported and economic outcomes in US patients with type 2 diabetes using basal insulin

PubMed Central

Lee, Lulu K.; Gupta, Shaloo; Preblick, Ron

2018-01-01

Aims To evaluate the clinical and patient‐reported outcomes and healthcare utilization and costs associated with patient‐reported hypoglycaemia in US adults with type 2 diabetes (T2D) treated with basal insulin. Materials and methods This was an observational, cross‐sectional, survey‐based study of adults with T2D on basal insulin ± oral antidiabetes drugs (OADs) or rapid‐acting/premixed insulin, who had in the past ever experienced hypoglycaemia, using US data from the National Health and Wellness Survey. Eligible patients were categorized as having no hypoglycaemia (38.7%), non‐severe hypoglycaemia (55.1%), or severe hypoglycaemia (6.2%) in the preceding 3 months. Outcomes included health‐related quality of life (HRQoL), work productivity and activity impairment, healthcare resource utilization, and estimated direct and indirect costs. Multivariable regression models were performed to control for patient characteristics. Results Patients who experienced severe hypoglycaemia had significantly (P < .05) lower HRQoL scores, greater overall impairment of work productivity and activity, greater healthcare resource utilization, and higher costs compared with those who experienced non‐severe or no hypoglycaemia. Patients with non‐severe hypoglycaemia also reported an impact on the number of provider visits, indirect costs, and HRQoL. Conclusions Patients with T2D using basal insulin ± OADs or rapid‐acting/premixed insulin in the United States who experienced severe hypoglycaemia had greater impairment of activity and work productivity, utilized more healthcare resources, and incurred higher associated costs than those with non‐severe or no hypoglycaemia. The study also demonstrated the impact that non‐severe hypoglycaemic events have on economic and HRQoL outcomes. Reducing the incidence and severity of hypoglycaemia could lead to clinically meaningful improvements in HRQoL and may result in lower healthcare utilization and associated costs

Clinical Evaluation of the Use of a Multifunctional Remotely Controlled Insulin Pump

PubMed Central

Pinget, Michel; Lachgar, Karim; Parkin, Christopher G.; Grulet, Hervé; Guillon-Metz, Françoise; Weissmann, Joerg

2014-01-01

Current insulin pumps now feature advanced functions for calculating insulin dosages, delivering insulin and analyzing data, however, the perceived usefulness of these functions in clinical settings has not been well studied. We assessed the use and patient perceptions of an insulin delivery system (Accu-Chek® Combo, Roche Diagnostics, Mannheim, Germany) that combines an insulin pump and a handheld multifunctional blood glucose meter with integrated remote control functions. This prospective, observational, multicenter study enrolled 74 type 1 diabetes patients within 13 weeks after starting use of the pump system. At 4 to 24 weeks, investigators collected usage data from the latest 14-day period. Seventy-two patients completed the evaluation, aged 39 ± 15 years, diabetes duration 16 ± 13 years, HbA1c 8.3 ± 1.6%. At follow-up, 62 (86.1%) patients used the remote control for ≥50% of all boluses, 20 (27.8%) used the bolus advisor for ≥50% of all boluses, and 42 (58.3%) viewed at least 1 of the e-logbook reports. More than 95% of users appraised the functions as easy-to-use and useful; median scores from VAS (0 = useless to 100 = indispensable) ranged from 72 to 85. A high percentage of study patients used the system’s advanced features, especially the remote control feature for bolusing. Overall, patients assessed the functions as useful and easy to use. Results support the implementation of these smart capabilities in further insulin pump developments. PMID:25107708

Continuous subcutaneous insulin infusion therapy and multiple daily insulin injections in type 1 diabetes mellitus: a comparative overview and future horizons.

PubMed

Thabit, Hood; Hovorka, Roman

2016-01-01

Continuous subcutaneous insulin infusion (CSII) therapy is currently accepted as a treatment strategy for type 1 diabetes. Transition from multiple daily injection therapy (MDI; including basal-bolus regimens) to CSII is based on expectations of better metabolic control and fewer hypoglycaemic events. Evidence to date has not been always conclusive. Evidence for CSII and MDI in terms of glycaemic control, hypoglycaemia and psychosocial outcomes is reviewed in the adult and paediatric population with type 1 diabetes. Findings from studies on threshold-based insulin pump suspension and predictive low glucose management (PLGM) are outlined. Limitations of current CSII application and future technological developments are discussed. Glycaemic control and quality of life (QOL) may be improved by CSII compared to MDI depending on baseline HbA1c and hypoglycaemia rates. Future studies are expected to provide evidence on clinical and cost effectiveness in those who will benefit the most. Training, structured education and support are important to benefit from CSII. Novel technological approaches linking continuous glucose monitoring (CGM) and CSII may help mitigate against frequent hypoglycaemia in those at risk. Development of glucose-responsive automated closed-loop insulin delivery systems may reduce the burden of disease management and improve outcomes in type 1 diabetes.

Combining insulins for optimal blood glucose control in type 1 and 2 diabetes: Focus on insulin glulisine

PubMed Central

Ulrich, Heather; Snyder, Benjamin; K Garg, Satish

2007-01-01

Normalization of blood glucose is essential for the prevention of diabetes mellitus (DM)-related microvascular and macrovascular complications. Despite substantial literature to support the benefits of glucose lowering and clear treatment targets, glycemic control remains suboptimal for most people with DM in the United States. Pharmacokinetic limitations of conventional insulins have been a barrier to achieving treatment targets secondary to adverse effects such as hypoglycemia and weight gain. Recombinant DNA technology has allowed modification of the insulin molecule to produce insulin analogues that overcome these pharmacokinetic limitations. With time action profiles that more closely mimic physiologic insulin secretion, rapid acting insulin analogues (RAAs) reduce post-prandial glucose excursions and hypoglycemia when compared to regular human insulin (RHI). Insulin glulisine (Apidra®) is a rapid-acting insulin analogue created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin. The quick absorption of insulin glulisine more closely reproduces physiologic first-phase insulin secretion and its rapid acting profile is maintained across patient subtypes. Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or RHI, respectively. Efficacy is maintained even when insulin glulisine is administered post-meal. In addition, glulisine appears to have a more rapid time action profile compared with insulin lispro across various body mass indexes (BMIs). The safety and tolerability profile of insulin glulisine is also comparable to that of insulin lispro or RHI in type 1 or 2 DM and it has been shown to be as safe and effective when used in a continuous subcutaneous insulin infusion (CSII). In summary, insulin glulisine is a safe, effective, and well tolerated rapid-acting insulin analogue across all BMIs and a worthy option for prandial

Novel simple insulin delivery device reduces barriers to insulin therapy in type 2 diabetes: results from a pilot study.

PubMed

Hermanns, Norbert; Lilly, Leslie C; Mader, Julia K; Aberer, Felix; Ribitsch, Anja; Kojzar, Harald; Warner, Jay; Pieber, Thomas R

2015-05-01

The PaQ® insulin delivery system is a simple-to-use patch-on device that provides preset basal rates and bolus insulin on demand. In addition to feasibility of use, safety, and efficacy (reported elsewhere), this study analyzed the impact of PaQ on patient-reported outcomes, including barriers to insulin treatment, diabetes-related distress, and attitudes toward insulin therapy in patients with type 2 diabetes on a stable multiple daily injection (MDI) regimen. This single-center, open-label, single-arm study comprised three 2-week periods: baseline (MDI), transition from MDI to PaQ, and PaQ treatment. Validated questionnaires were administered during the baseline and PaQ treatment periods: Barriers to Insulin Treatment questionnaire (BIT), Insulin Treatment Appraisal Scale (ITAS), and Problem Areas in Diabetes scale (PAID). Eighteen patients (age 59 ± 5 years, diabetes duration 15 ± 7 years, 21% female, HbA1c 7.7 ± 0.7%) completed the questionnaires. There was a strong, significant effect of PaQ use in mean BIT total scores (difference [D] = -5.4 ± 0.7.7, P = .01, effect size [d] = 0.70). Patients perceived less stigmatization by insulin injection (D = -2.2 ± 6.2, P = .18, d = 0.35), increased positive outcome (D = 1.9 ± 6.6, P = .17, d = 0.29), and less fear of injections (1.3 ± 4.8, P = .55, d = 0.28). Mean change in ITAS scores after PaQ device use showed a nonsignificant improvement of 1.71 ± 5.63 but moderate effect size (d = 0.30, P = .14). No increase in PAID scores was seen. The results and moderate to large effects sizes suggest that PaQ device use has beneficial and clinically relevant effects to overcoming barriers to and negative appraisal of insulin treatment, without increasing other diabetes-related distress. © 2015 Diabetes Technology Society.

Continuous versus bolus tube feeds: Does the modality affect glycemic variability, tube feeding volume, caloric intake, or insulin utilization?

PubMed

Evans, David C; Forbes, Rachel; Jones, Christian; Cotterman, Robert; Njoku, Chinedu; Thongrong, Cattleya; Tulman, David; Bergese, Sergio D; Thomas, Sheela; Papadimos, Thomas J; Stawicki, Stanislaw P

2016-01-01

Enteral nutrition (EN) is very important to optimizing outcomes in critical illness. Debate exists regarding the best strategy for enteral tube feeding (TF), with concerns that bolus TF (BTF) may increase glycemic variability (GV) but result in fewer nutritional interruptions than continuous TF (CTF). This study examines if there is a difference in GV, insulin usage, TF volume, and caloric delivery among intensive care patients receiving BTF versus CTF. We hypothesize that there are no significant differences between CTF and BTF when comparing the above parameters. Prospective, randomized pilot study of critically ill adult patients undergoing percutaneous endoscopic gastrostomy (PEG) placement for EN was performed between March 1, 2012 and May 15, 2014. Patients were randomized to BTF or CTF. Glucose values, insulin use, TF volume, and calories administered were recorded. Data were organized into 12-h epochs for statistical analyses and GV determination. In addition, time to ≥80% nutritional delivery goal, demographics, Acute Physiology and Chronic Health Evaluation II scores, and TF interruptions were examined. When performing BTF versus CTF assessments, continuous parameters were compared using Mann-Whitney U-test or repeated measures t-test, as appropriate. Categorical data were analyzed using Fisher's exact test. No significant demographic or physiologic differences between the CTF (n = 24) and BTF (n = 26) groups were seen. The immediate post-PEG 12-h epoch showed significantly lower GV and median TF volume for patients in the CTF group. All subsequent epochs (up to 18 days post-PEG) showed no differences in GV, insulin use, TF volume, or caloric intake. Insulin use for both groups increased when comparing the first 24 h post-PEG values to measurements from day 8. There were no differences in TF interruptions, time to ≥80% nutritional delivery goal, or hypoglycemic episodes. This study demonstrated no clinically relevant differences in GV, insulin use, TF

Classifying insulin regimens--difficulties and proposal for comprehensive new definitions.

PubMed

Neu, A; Lange, K; Barrett, T; Cameron, F; Dorchy, H; Hoey, H; Jarosz-Chobot, P; Mortensen, H B; Robert, J-J; Robertson, K; de Beaufort, C

2015-09-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Monomeric insulins and their experimental and clinical implications.

PubMed

Brange, J; Owens, D R; Kang, S; Vølund, A

1990-09-01

Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier

Hospital protocols for targeted glycemic control: Development, implementation, and models for cost justification.

PubMed

Magee, Michelle F

2007-05-15

Evolving elements of best practices for providing targeted glycemic control in the hospital setting, clinical performance measurement, basal-bolus plus correction-dose insulin regimens, components of standardized subcutaneous (s.c.) insulin order sets, and strategies for implementation and cost justification of glycemic control initiatives are discussed. Best practices for targeted glycemic control should address accurate documentation of hyperglycemia, initial patient assessment, management plan, target blood glucose range, blood glucose monitoring frequency, maintenance of glycemic control, criteria for glucose management consultations, and standardized insulin order sets and protocols. Establishing clinical performance measures, including desirable processes and outcomes, can help ensure the success of targeted hospital glycemic control initiatives. The basal-bolus plus correction-dose regimen for insulin administration will be used to mimic the normal physiologic pattern of endogenous insulin secretion. Standardized insulin order sets and protocols are being used to minimize the risk of error in insulin therapy. Components of standardized s.c. insulin order sets include specification of the hyperglycemia diagnosis, finger stick blood glucose monitoring frequency and timing, target blood glucose concentration range, cutoff values for excessively high or low blood glucose concentrations that warrant alerting the physician, basal and prandial or nutritional (i.e., bolus) insulin, correction doses, hypoglycemia treatment, and perioperative or procedural dosage adjustments. The endorsement of hospital administrators and key physician and nursing leaders is needed for glycemic control initiatives. Initiatives may be cost justified on the basis of the billings for clinical diabetes management services and/or the return- on-investment accrued to reductions in hospital length of stay, readmissions, and accurate documentation and coding of unrecognized or uncontrolled

Effects of phenylalanine, histidine, and leucine on basal and GHRH-stimulated GH secretion and on PRL, insulin, and glucose levels in short children. Comparison with the effects of arginine.

PubMed

Bellone, J; Valetto, M R; Aimaretti, G; Segni, M; Volta, C; Cardimale, G; Baffoni, C; Pasquino, A M; Bernasconi, S; Bartolotta, E; Mucci, M; Ghigo, E

1996-01-01

Of the amino acids arginine is the most potent GH secretagogue in man. It potentiates the GH response to GHRH, exerts a weaker PRL-releasing effect, stimulates insulin and glucagon and induces a biphasic glucose variation. The potency and effects of other amino acids on pituitary and pancreatic hormones need to be clarified. In 43 children with normal short stature (5.3-14.0 yr; 30 M and 13 F) the effects of the infusion of phenylalanine (Phe, 0.08 g/kg), histidine (His, 0.1 g/kg), and leucine (Leu, 0.08 g/kg) on basal and GHRH-stimulated GH secretion and on PRL, insulin and glucose levels were studied and compared with those of arginine at high (hArg, 0.5 g/kg) or low dose (lArg, 0.2 g/kg). Phe increased basal (p < 0.05) but not GHRH-stimulated GH levels, induced PRL and insulin rises (p < 0.03 and p < 0.03), and did not change glycemia. Though a trend toward an increase in basal GH levels was found after His, His and Leu did not significantly modify either basal or GHRH-induced GH secretion nor basal PRL, insulin and glucose levels. Both hArg and lArg increased basal (p < 0.0001 and p < 0.05, respectively) and GHRH-stimulated GH levels (p < 0.006 and p < 0.006). hArg increased both PRL (p < 0.002) and insulin levels (p < 0.005) more (p < 0.0005 and p < 0.004) than lArg (p < 0.005 and p < 0.005), while glucose levels showed a similar increase followed by a similar decrease. We conclude that in childhood: a) Phe significantly increases GH secretion but, differently from Arg, does not potentiate the response to GHRH, suggesting different mechanisms of action of these amino acids; b) differently from His and Leu, Phe is a PRL and insulin secretagogue but is less potent than Arg; c) Arg has the highest stimulatory effect on pituitary and pancreatic hormones.

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled With Newly Initiated and Continuously Titrated Basal Insulin Glargine

PubMed Central

Riddle, Matthew C.; Forst, Thomas; Aronson, Ronnie; Sauque-Reyna, Leobardo; Souhami, Elisabeth; Silvestre, Louise; Ping, Lin; Rosenstock, Julio

2013-01-01

OBJECTIVE When oral therapy for type 2 diabetes is ineffective, adding basal insulin improves glycemic control. However, when glycated hemoglobin (HbA1c) remains elevated because of postprandial hyperglycemia, the next therapeutic step is controversial. We examined the efficacy and safety of lixisenatide in patients with HbA1c still elevated after initiation of insulin glargine. RESEARCH DESIGN AND METHODS This double-blind, parallel-group trial enrolled patients with HbA1c 7–10% despite oral therapy. Insulin glargine was added and systematically titrated during a 12-week run-in, after which candidates with fasting glucose ≤7.8 mmol/L and HbA1c 7–9% were randomized to lixisenatide 20 µg or placebo for 24 weeks while insulin titration continued. The primary end point was HbA1c change after randomization. RESULTS The randomized population (n = 446) had mean diabetes duration of 9.2 years, BMI 31.8 kg/m2, and daily glargine dosage of 44 units. HbA1c had decreased during run-in from 8.6 to 7.6%; adding lixisenatide further reduced HbA1c by 0.71 vs. 0.40% with placebo (least squares mean difference, –0.32%; 95% CI, –0.46 to –0.17; P < 0.0001). More participants attained HbA1c <7% with lixisenatide (56 vs. 39%; P < 0.0001). Lixisenatide reduced plasma glucose 2 h after a standardized breakfast (difference vs. placebo –3.2 mmol/L; P < 0.0001) and had a favorable effect on body weight (difference vs. placebo –0.89 kg; P = 0.0012). Nausea, vomiting, and symptomatic hypoglycemia <3.3 mmol/L were more common with lixisenatide. CONCLUSIONS Adding lixisenatide to insulin glargine improved overall and postprandial hyperglycemia and deserves consideration as an alternative to prandial insulin for patients not reaching HbA1c goals with recently initiated basal insulin. PMID:23564915

Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma glucose vs. insulin glargine: A meta-analysis of seven clinical trials.

PubMed

Russell-Jones, D; Gall, M-A; Niemeyer, M; Diamant, M; Del Prato, S

2015-10-01

Basal insulin analogues have a reduced risk of hypoglycaemia compared with NPH insulin, but hypoglycaemia still remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets in patients with diabetes. Insulin degludec (IDeg) is a new basal insulin that forms soluble multihexamers after subcutaneous injection resulting in an ultra-long duration of action and stable glucose-lowering effect. The aim of this analysis was to compare the effect of IDeg on FPG and nocturnal confirmed hypoglycaemia as compared to insulin glargine (IGlar). Data were included from seven phase 3a, randomised, open-label, treat-to-target clinical trials in which once-daily IDeg was compared with once-daily IGlar. Two trials included a total of 957 patients with type 1 diabetes (T1D) and five trials included a total of 3360 patients with type 2 diabetes (T2D); all trials were 26 or 52 weeks in duration. Confirmed hypoglycaemia was defined as plasma glucose <3.1 mmol/L or severe episodes requiring assistance, and nocturnal hypoglycaemia occurred between 00:01 and 05:59. In all trials, the mean end-of-trial FPG was lower for IDeg than IGlar, reaching statistical significance in three trials. Similarly, IDeg was associated with a lower rate of nocturnal confirmed hypoglycaemia vs. IGlar, which was statistically significant in three trials, regardless of type of diabetes or background therapy. This analysis shows that the lower rate of nocturnal confirmed hypoglycaemia seen with IDeg relative to IGlar is accompanied by a reduced mean FPG, in particular in patients with T2D. Copyright © 2015 Elsevier B.V. All rights reserved.

Acylated apelin-13 amide analogues exhibit enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties.

PubMed

O'Harte, Finbarr P M; Parthsarathy, Vadivel; Hogg, Christopher; Flatt, Peter R

2017-12-15

The adipokine, apelin has many biological functions but its activity is curtailed by rapid plasma degradation. Fatty acid derived apelin analogues represent a new and exciting avenue for the treatment of obesity-diabetes. This study explores four novel fatty acid modified apelin-13 analogues, namely, (Lys 8 GluPAL)apelin-13 amide, pGlu(Lys 8 GluPAL)apelin-13 amide, Lys 8 GluPAL(Tyr 13 )apelin-13 and Lys 8 GluPAL(Val 13 )apelin-13. Fatty acid modification extended the half-life of native apelin-13 to >24 h in vitro. pGlu(Lys 8 GluPAL)apelin-13 amide was the most potent insulinotropic analogue in BRIN-BD11 cells and isolated islets with maximal stimulatory effects of up to 2.7-fold (p < .001). (Lys 8 GluPAL)apelin-13 amide (1.9-fold) and Lys 8 GluPAL(Tyr 13 )apelin-13 (1.7-fold) were less effective, whereas Lys 8 GluPAL(Val 13 )apelin-13 had an inhibitory effect on insulin secretion. Similarly, pGlu(Lys 8 GluPAL)apelin-13 amide was most potent in increasing beta-cell intracellular Ca 2+ concentrations (1.8-fold, p < .001) and increasing glucose uptake in 3T3-L1 adipocytes (2.3-fold, p < .01). Persistent biological action was observed with both pGlu(Lys 8 GluPAL)apelin-13 amide and (Lys 8 GluPAL)apelin-13 amide significantly reducing blood glucose (39-43%, p < .01) and enhancing insulin secretion (43-56%, p < .001) during glucose tolerance tests in diet-induced obese mice. pGlu(Lys 8 GluPAL)apelin-13 amide and (Lys 8 GluPAL)apelin-13 amide also inhibited feeding (28-40%, p < .001), whereas Lys 8 GluPAL(Val 13 )apelin-13 increased food intake (8%, p < .05) in mice. These data indicate that novel enzymatically stable analogues of apelin-13 may be suitable for future development as therapeutic agents for obesity-diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

Estrogen Deprivation in Primate Pregnancy Leads to Insulin Resistance in Offspring

PubMed Central

Maniu, Adina; Aberdeen, Graham W.; Lynch, Terrie J.; Nadler, Jerry L.; Kim, Soon OK; Quon, Michael J.; Pepe, Gerald J.; Albrecht, Eugene D.

2016-01-01

This study tested the hypothesis that estrogen programs mechanisms within the primate fetus that promote insulin sensitivity and glucose homeostasis in offspring. Glucose tolerance tests were performed longitudinally in prepubertal offspring of baboons untreated or treated on days 100 to 165/175 of gestation (term is 184 days) with the aromatase inhibitor letrozole which decreased fetal estradiol levels by 95%. Basal plasma insulin levels were over 2-fold greater in offspring delivered to letrozole-treated than untreated animals. Moreover, the peak 1 min, average of the 1, 3 and 5 min, and area under the curve blood glucose and plasma insulin levels after an iv bolus of glucose were greater (P<0.05 and P<0.01, respectively) in offspring deprived of estrogen in utero than in untreated animals and partially or completely restored in letrozole plus estradiol-treated baboons. The value for the homeostasis model assessment of insulin resistance was 2.5-fold greater (P<0.02) and quantitative insulin sensitivity check index lower (P<0.01) in offspring of letrozole-treated versus untreated animals and returned to almost normal in letrozole plus estradiol-treated animals. The exaggerated rise in glucose and insulin levels after glucose challenge in baboon offspring deprived of estrogen in utero indicates that pancreatic beta cells had the capacity to secrete insulin, but that peripheral glucose uptake and/or metabolism were impaired, indicative of insulin resistance and glucose intolerance. We propose that estrogen normally programs mechanisms in utero within the developing primate fetus that lead to insulin sensitivity, normal glucose tolerance and the capacity to metabolize glucose after birth. PMID:27207093

Exponential increase in postprandial blood-glucose exposure with increasing carbohydrate loads using a linear carbohydrate-to-insulin ratio.

PubMed

Marran, K J; Davey, B; Lang, A; Segal, D G

2013-04-10

Postprandial glucose excursions contribute significantly to average blood glucose, glycaemic variability and cardiovascular risk. Carbohydrate counting is a method of insulin dosing that balances carbohydrate load to insulin dose using a fixed ratio. Many patients and current insulin pumps calculate insulin delivery for meals based on a linear carbohydrate-to-insulin relationship. It is our hypothesis that a non-linear relationship exists between the amounts of carbohydrate consumed and the insulin required to cover it. To document blood glucose exposure in response to increasing carbohydrate loads on fixed carbohydrate-to-insulin ratios. Five type 1 diabetic subjects receiving insulin pump therapy with good control were recruited. Morning basal rates and carbohydrate- to-insulin ratios were optimised. A Medtronic glucose sensor was used for 5 days to collect data for area-under-the-curve (AUC) analysis, during which standardised meals of increasing carbohydrate loads were consumed. Increasing carbohydrate loads using a fixed carbohydrate-to-insulin ratio resulted in increasing glucose AUC. The relationship was found to be exponential rather than linear. Late postprandial hypoglycaemia followed carbohydrate loads of >60 g and this was often followed by rebound hyperglycaemia that lasted >6 hours. A non-linear relationship exists between carbohydrates consumed and the insulin required to cover them. This has implications for control of postprandial blood sugars, especially when consuming large carbohydrate loads. Further studies are required to look at the optimal ratios, duration and type of insulin boluses required to cover increasing carbohydrate loads.

Safety and efficacy of a basal-plus regimen with insulin glargine and insulin glulisine for elderly patients with high cardiovascular risk and type 2 diabetes mellitus.

PubMed

Gómez-Huelgas, R; Sabán-Ruiz, J; García-Román, F J; Quintela-Fernández, N; Seguí-Ripoll, J M; Bonilla-Hernández, M V; Romero-Meliá, G

2017-05-01

To assess the safety and efficacy of a basal-plus (BP) regimen with insulin glargine (as basal insulin) and insulin glulisine (as prandial insulin) with the main meal for elderly patients with type 2 diabetes mellitus (DM2) and high cardiovascular risk, following standard clinical practice. An observational, retrospective study was conducted in 21 centres of internal medicine in Spain. The study included patients aged 65 years or older with DM2, undergoing treatment with a BP regimen for 4 to 12 months before inclusion in the study and a diagnosis of cardiovascular disease or high cardiovascular risk. The primary endpoint was the change in glycated haemoglobin (HbA1c) from the introduction of the glulisine to inclusion in the study. The study included 198 patients (mean age, 74±6.4 years; males, 52%). After at least 4 months of treatment with the BP regimen, started with the addition of glulisine, the mean HbA1c value decreased significantly (9±1.5% vs. 7.7±1.1%; P<.001), and almost 24% of the patients reached HbA1c levels of 7.5-8%. Furthermore, blood glucose levels under fasting conditions decreased significantly (190.6±73.2mg/dl vs. 138.9±38.2mg/dl; P<.001). A total of 35 patients (17.7%) had some hypoglycaemia during the month prior to the start of the study, and 2 cases (1.01%) of severe hypoglycaemia were detected. The BP strategy could significantly improve blood glucose control in patients 65 years of age or older with DM2 and high cardiovascular risk and is associated with a low risk of severe hypoglycaemia. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Impact of Bromocriptine-QR Therapy on Glycemic Control and Daily Insulin Requirement in Type 2 Diabetes Mellitus Subjects Whose Dysglycemia Is Poorly Controlled on High-Dose Insulin: A Pilot Study.

PubMed

Roe, Erin D; Chamarthi, Bindu; Raskin, Philip

2015-01-01

The concurrent use of a postprandial insulin sensitizing agent, such as bromocriptine-QR, a quick release formulation of bromocriptine, a dopamine D2 receptor agonist, may offer a strategy to improve glycemic control and limit/reduce insulin requirement in type 2 diabetes (T2DM) patients on high-dose insulin. This open label pilot study evaluated this potential utility of bromocriptine-QR. Ten T2DM subjects on metformin (1-2 gm/day) and high-dose (TDID ≥ 65 U/day) basal-bolus insulin were enrolled to receive once daily (morning) bromocriptine-QR (1.6-4.8 mg/day) for 24 weeks. Subjects with at least one postbaseline HbA1c measurement (N = 8) were analyzed for change from baseline HbA(1c), TDID, and postprandial glucose area under the curve of a four-hour mixed meal tolerance test (MMTT). Compared to the baseline, average HbA1c decreased 1.76% (9.74 ± 0.56 to 7.98 ± 0.36, P = 0.01), average TDID decreased 27% (199 ± 33 to 147 ± 31, P = 0.009), and MMTT AUC(60-240) decreased 32% (P = 0.04) over the treatment period. The decline in HbA(1c) and TDID was observed at 8 weeks and sustained over the remaining 16-week study duration. In this study, bromocriptine-QR therapy improved glycemic control and meal tolerance while reducing insulin requirement in T2DM subjects poorly controlled on high-dose insulin therapy.

Effectiveness of basal-supported oral therapy (BOT) using insulin glargine in patients with poorly controlled type 2 diabetes.

PubMed

Suzuki, Daisuke; Umezono, Tomoya; Miyauchi, Masaaki; Kimura, Moritsugu; Yamamoto, Naoyuki; Tanaka, Eitaro; Kuriyama, Yusuke; Sato, Hiroki; Miyatake, Han; Kondo, Masumi; Toyoda, Masao; Fukagawa, Masafumi

2012-07-20

To determine the clinical usefulness of basal-supported oral therapy (BOT) using insulin glargine in Japanese patients with type 2 diabetes. We compared HbA1c levels, body weight, and insulin doses before the introduction of BOT and in the final month of the observation period in 122 patients with type 2 diabetes who received BOT with insulin glargine between October 2007 and July 2009. To exclude the possible effects of seasonal changes in glycemic control, 57 of the 122 patients were followed-up for one year and examined for changes in HbA1c levels, body weight, and insulin dose. Examination of all cases (n=122) showed a significant decrease in HbA1c (before BOT: 8.7±1.8, after: 7.1±1.1%), but no significant change in body weight (before: 63.1±16.1, after: 63.8±17.0 kg). The mean observation period was 10.5±6.4 months. Insulin doses were significantly increased during the study. HbA1c levels improved significantly in patients on non-insulin-secreting drugs (biguanide, α-glucosidase inhibitor and thiazolidine derivatives) than those on insulin-secreting drugs (SU agents and glinides). BOT with insulin glargine is a useful strategy that can achieve good glycemic control in clinical practice without causing serious hypoglycemia. The introduction of BOT before exhaustion of pancreatic β cells may increase its effectiveness.

Long-term safety and efficacy of tofogliflozin as add-on to insulin in patients with type 2 diabetes: Results from a 52-week, multicentre, randomized, double-blind, open-label extension, Phase 4 study in Japan (J-STEP/INS).

PubMed

Terauchi, Yasuo; Tamura, Masahiro; Senda, Masayuki; Gunji, Ryoji; Kaku, Kohei

2018-05-01

To evaluate the long-term safety and efficacy of tofogliflozin as an add-on treatment to insulin over 52 weeks. This 52-week, multicentre, Phase 4 study consisted of a 16-week, randomized, double-blind, placebo-controlled phase and a 36-week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus, aged 20 to 75 years, with suboptimal glycaemic control (7.5%-10.5%) receiving insulin monotherapy (basal-bolus, bolus, premix [low and high] and basal) or receiving combination therapy with basal insulin and dipeptidyl peptidase-4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as the 'tofo-tofo group' and patients who received placebo and tofogliflozin (36 weeks) were referred to as the 'pla-tofo group'. A total of 210 patients received treatment per randomization. Hypoglycaemia was the most common treatment-emergent adverse event (AE) (42.9% in the tofo-tofo group and 29.4% in the pla-tofo group). Patients reported genital infection, urinary tract infection, excessive urination and AEs related to volume depletion (2.1%, 2.1%, 7.1% and 10.0% of patients in the tofo-tofo group, and 0%, 1.5%, 2.9% and 7.4% of patients in the pla-tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo-tofo and pla-tofo groups were 8.53% (-0.76% ± 0.077) and 8.40% (-0.73% ± 0.102); 68.84 kg (-1.52 kg ± 0.207) and 72.24 kg (-2.13 kg ± 0.313), respectively. This study demonstrates the safety and efficacy of tofogliflozin as add-on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

A cross-sectional survey among patients and prescribers on insulin dosing irregularities and impact of mild (self-treated) hypoglycemia episodes in Spanish patients with type 2 diabetes as compared to other European patients.

PubMed

Ampudia-Blasco, Francisco J; Galán, Manuel; Brod, Meryl

2014-10-01

In Spain, data suggest that 13.8% of adults have diabetes. Two important aspects in diabetes management are mild hypoglycemic episodes and poor treatment adherence. This study assesses the impact of missed insulin doses and prevalence of mistimed and reduced insulin doses and mild hypoglycemia in patients with type 2 diabetes treated with basal insulin analogues in Spain, and compares the data collected to pooled data from 8 other European countries (OECs). GAPP2 was an international, online, cross-sectional study of diabetic patients aged ≥40 years treated with long-acting insulin analogues and their healthcare professionals. Patients and healthcare professionals were recruited from online research panels. Data reported in Spain are compared to pooled data from 8 OECs. In Spain, 1-3% of patients reported they had reduced, missed, or mistimed at least one insulin does in the previous month. Significantly more OEC patients reported dosing irregularities (15-23%; all P<0.01). In Spain, 77% of patients were worried and 59% felt guilty for missing a dose of basal insulin, while 24% reported that they were very worried about nocturnal hypoglycemia. Significantly fewer OEC patients reported worrying (47%; P<0.01) and feeling guilty (37%; P<0.01) about missing an insulin dose, or worry about nocturnal hypoglycemia (12%; P<0.01). In Spain, patients with type 2 diabetes report fewer dosing irregularities and hypoglycemic episodes as compared to patients from OECs. However, Spanish patients appear to have a reduced quality of life related to hypoglycemia as well as worry and guilt related to insulin dosing irregularities. Copyright © 2014 SEEN. Published by Elsevier Espana. All rights reserved.

When Intensive Insulin Therapy (MDI) Fails in Patients With Type 2 Diabetes: Switching to GLP-1 Receptor Agonist Versus Insulin Pump.

PubMed

Cohen, Ohad; Filetti, Sebastiano; Castañeda, Javier; Maranghi, Marianna; Glandt, Mariela

2016-08-01

Treatment with insulin, alone or with oral or injectable hypoglycemic agents, is becoming increasingly common in patients with type 2 diabetes. However, approximately 40% of patients fail to reach their glycemic targets with the initially prescribed regimen and require intensification of insulin therapy, which increases the risks of weight gain and hypoglycemia. Many of these patients eventually reach a state in which further increases in the insulin dosage fail to improve glycemic control while increasing the risks of weight gain and hypoglycemia. The recently completed OpT2mise clinical trial showed that continuous subcutaneous insulin infusion (CSII) is more effective in reducing glycated hemoglobin (HbA1c) than intensification of multiple daily injection (MDI) insulin therapy in patients with type 2 diabetes who do not respond to intensive insulin therapy. CSII therapy may also be useful in patients who do not reach glycemic targets despite multidrug therapy with basal-bolus insulin and other agents, including glucagon-like peptide (GLP)-1 receptor agonists; current guidelines offer no recommendations for the treatment of such patients. Importantly, insulin and GLP-1 receptor agonists have complementary effects on glycemia and, hence, can be used either sequentially or in combination in the initial management of diabetes. Patients who have not previously failed GLP-1 receptor agonist therapy may show reduction in weight and insulin dose, in addition to moderate improvement in HbA1c, when GLP-1 receptor agonist therapy is added to MDI regimens. In subjects with long-standing type 2 diabetes who do not respond to intensive insulin therapies, switching from MDI to CSII and/or the addition of GLP-1 receptor agonists to MDI have the potential to improve glycemic control without increasing the risk of adverse events. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for

Cost-Effectiveness of Insulin Degludec Versus Insulin Glargine U100 in Patients with Type 1 and Type 2 Diabetes Mellitus in Serbia.

PubMed

Lalić, Nebojša; Russel-Szymczyk, Monika; Culic, Marina; Tikkanen, Christian Klyver; Chubb, Barrie

2018-04-26

This study investigates the cost-effectiveness of insulin degludec versus insulin glargine U100 in patients with type 1 and type 2 diabetes mellitus in Serbia. A cost-utility analysis, implementing a simple short-term model, was used to compare treatment costs and outcomes with degludec versus glargine U100 in patients with type 1 (T1DM) and type 2 diabetes (T2DM). Cost-effectiveness was analysed in a 1-year setting, based on data from clinical trials. Costs were estimated from the healthcare payer perspective, the Serbian Health Insurance Fund (RFZO). The outcome measure was the incremental cost-effectiveness ratio (ICER) or cost per quality-adjusted life-year (QALY) gained. Degludec is highly cost-effective compared with glargine U100 for people with T1DM and T2DM in Serbia. The ICERs are estimated at 417,586 RSD/QALY gained in T1DM, 558,811 RSD/QALY gained in T2DM on basal oral therapy (T2DM BOT ) and 1,200,141 RSD/QALY gained in T2DM on basal-bolus therapy (T2DM B/B ). All ICERs fall below the commonly accepted thresholds for cost-effectiveness in Serbia (1,785,642 RSD/QALY gained). In all three patient groups, insulin costs are higher with degludec than with glargine U100, but these costs are partially offset by savings from a lower daily insulin dose in T1DM and T2DM BOT , a reduction in hypoglycaemic events in all three patient groups and reduced costs of SMBG testing in the T2DM groups with degludec versus glargine U100. Degludec is a cost-effective alternative to glargine U100 for patients with T1DM and T2DM in Serbia. Degludec may particularly benefit those suffering from hypoglycaemia or where the patient would benefit from the option of flexible dosing. Novo Nordisk.

Efficacy and Safety of Vildagliptin as an Add-On Therapy in Inadequately Controlled Type 2 Diabetes Patients Treated With Basal Insulin.

PubMed

Saito, Daisuke; Kanazawa, Akio; Shigihara, Nayumi; Sato, Fumihiko; Uchida, Toyoyoshi; Sato, Junko; Goto, Hiromasa; Miyatsuka, Takeshi; Ikeda, Fuki; Ogihara, Takeshi; Ohmura, Chie; Watada, Hirotaka

2017-03-01

The aim of this study was to investigate the efficacy and safety of vildagliptin as an add-on therapy for patients with type 2 diabetes mellitus inadequately controlled with basal insulin. Twenty-four patients treated with basal insulin and oral anti-diabetes drugs were randomly allocated into two groups: the control group (did not receive any add-on drugs) and vildagliptin group (received vildagliptin 100 mg/day for 6 months). The primary outcome was changes in hemoglobin A1c (HbA1c) from baseline to end of study. Treatment with vildagliptin significantly reduced HbA1c from 8.1±0.7% at baseline to 7.1±0.7% (P < 0.01), while there was no significant change of HbA1c in the control group. Vildagliptin group showed significant reduction of HbA1c compared with control group (-1.0±0.3% vs. 0.2±0.8%, P < 0.01). In addition, vildagliptin group showed a significant increase in 1,5-anhydroglucitol compared with the control group (4.5 ± 3.4 vs. 0.5 ± 4.1 μg/mL, P < 0.05). Mild hypoglycemia was reported in one patient of the vildagliptin group and two patients of the control group. Vildagliptin improved glycemic control without increasing hypoglycemia in Japanese type 2 diabetes inadequately controlled with basal insulin treatment and other oral anti-diabetes drugs. This study was registered with UMIN (University Hospital Medical Information Network ID#000010849).

New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 2).

PubMed

Terauchi, Y; Koyama, M; Cheng, X; Takahashi, Y; Riddle, M C; Bolli, G B; Hirose, T

2016-04-01

To compare the efficacy and safety of insulin glargine 300 U/ml (Gla-300) with glargine 100 U/ml (Gla-100) in Japanese people with type 2 diabetes using basal insulin plus oral antihyperglycaemic drug(s) [OAD(s)]. The EDITION JP 2 study (NCT01689142) was a 6-month, multicentre, open-label, phase III study. Participants (n = 241, male 61%, mean diabetes duration 14 years, mean weight 67 kg, mean body mass index 25 kg/m(2), mean glycated haemoglobin (HbA1c) 8.02 %, mean basal insulin dose 0.24 U/kg/day) were randomized to Gla-300 or Gla-100, while continuing OAD(s). Basal insulin was titrated to target fasting self-monitored plasma glucose 4.4-5.6 mmol/l. The primary efficacy endpoint was HbA1c change over 6 months. Safety endpoints included hypoglycaemia and weight change. Gla-300 was non-inferior to Gla-100 for HbA1c reduction [least squares (LS) mean difference 0.10 (95% confidence interval [CI] -0.08, 0.27) %]. The mean HbA1c at month 6 was 7.56 and 7.52 % with Gla-300 and Gla-100, respectively. Nocturnal confirmed (≤3.9 mmol/l) or severe hypoglycaemia risk was 38% lower with Gla-300 versus Gla-100 [relative risk 0.62 (95% CI 0.44, 0.88)]; annualized rates were 55% lower at night [rate ratio 0.45 (95% CI 0.21, 0.96)] and 36% lower at any time [24 h; rate ratio 0.64 (95% CI 0.43, 0.96)]. Severe hypoglycaemia was infrequent. A significant between-treatment difference in weight change favoured Gla-300 [LS mean difference -1.0 (95% CI -1.5, -0.5) kg; p = 0.0003]. Adverse event rates were comparable between groups. Japanese people with type 2 diabetes using basal insulin plus OAD(s) experienced less hypoglycaemia with Gla-300 than with Gla-100, while glycaemic control did not differ. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese adults with type 1 diabetes using basal and mealtime insulin: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 1)

PubMed Central

Koyama, M.; Cheng, X.; Takahashi, Y.; Riddle, M. C.; Bolli, G. B.; Hirose, T.

2016-01-01

Aim To compare efficacy and safety of new insulin glargine 300 U/ml (Gla‐300) with that of insulin glargine 100 U/ml (Gla‐100) in Japanese adults with type 1 diabetes. Methods The EDITION JP 1 study (NCT01689129) was a 6‐month, multicentre, open‐label, phase III study. Participants (n = 243) were randomized to Gla‐300 or Gla‐100 while continuing mealtime insulin. Basal insulin was titrated with the aim of achieving a fasting self‐monitored plasma glucose target of 4.4–7.2 mmol/l. The primary endpoint was change in glycated haemoglobin (HbA1c) over 6 months. Safety measures included hypoglycaemia and change in body weight. Results Gla‐300 was non‐inferior to Gla‐100 for the primary endpoint of HbA1c change over the 6‐month period {least squares [LS] mean difference 0.13 % [95 % confidence interval (CI) −0.03 to 0.29]}. The annualized rate of confirmed (≤3.9 mmol/l) or severe hypoglycaemic events was 34 % lower with Gla‐300 than with Gla‐100 at night [rate ratio 0.66 (95 % CI 0.48–0.92)] and 20 % lower at any time of day [24 h; rate ratio 0.80 (95 % CI 0.65–0.98)]; this difference was most pronounced during the first 8 weeks of treatment. Severe hypoglycaemia was infrequent. The basal insulin dose increased in both groups (month 6 dose: Gla‐300 0.35 U/kg/day, Gla‐100 0.29 U/kg/day). A between‐treatment difference in body weight change over 6 months favouring Gla‐300 was observed [LS mean difference −0.6 kg (95 % CI −1.1 to −0.0); p = 0.035]. Adverse event rates were comparable between the groups. Conclusions In Japanese adults with type 1 diabetes using basal plus mealtime insulin, less hypoglycaemia was observed with Gla‐300 than with Gla‐100, particularly during the night, while glycaemic control did not differ. PMID:26662964

New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese adults with type 1 diabetes using basal and mealtime insulin: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 1).

PubMed

Matsuhisa, M; Koyama, M; Cheng, X; Takahashi, Y; Riddle, M C; Bolli, G B; Hirose, T

2016-04-01

To compare efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with that of insulin glargine 100 U/ml (Gla-100) in Japanese adults with type 1 diabetes. The EDITION JP 1 study (NCT01689129) was a 6-month, multicentre, open-label, phase III study. Participants (n = 243) were randomized to Gla-300 or Gla-100 while continuing mealtime insulin. Basal insulin was titrated with the aim of achieving a fasting self-monitored plasma glucose target of 4.4-7.2 mmol/l. The primary endpoint was change in glycated haemoglobin (HbA1c) over 6 months. Safety measures included hypoglycaemia and change in body weight. Gla-300 was non-inferior to Gla-100 for the primary endpoint of HbA1c change over the 6-month period {least squares [LS] mean difference 0.13 % [95 % confidence interval (CI) -0.03 to 0.29]}. The annualized rate of confirmed (≤3.9 mmol/l) or severe hypoglycaemic events was 34 % lower with Gla-300 than with Gla-100 at night [rate ratio 0.66 (95 % CI 0.48-0.92)] and 20 % lower at any time of day [24 h; rate ratio 0.80 (95 % CI 0.65-0.98)]; this difference was most pronounced during the first 8 weeks of treatment. Severe hypoglycaemia was infrequent. The basal insulin dose increased in both groups (month 6 dose: Gla-300 0.35 U/kg/day, Gla-100 0.29 U/kg/day). A between-treatment difference in body weight change over 6 months favouring Gla-300 was observed [LS mean difference -0.6 kg (95 % CI -1.1 to -0.0); p = 0.035]. Adverse event rates were comparable between the groups. In Japanese adults with type 1 diabetes using basal plus mealtime insulin, less hypoglycaemia was observed with Gla-300 than with Gla-100, particularly during the night, while glycaemic control did not differ. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Is the current standard of care leading to cost-effective outcomes for patients with type 2 diabetes requiring insulin? A long-term health economic analysis for the UK.

PubMed

Valentine, W J; Curtis, B H; Pollock, R F; Van Brunt, K; Paczkowski, R; Brändle, M; Boye, K S; Kendall, D M

2015-07-01

The aim of the analysis was to investigate whether insulin intensification, based on the use of intensive insulin regimens as recommended by the current standard of care in routine clinical practice, would be cost-effective for patients with type 2 diabetes in the UK. Clinical data were derived from a retrospective analysis of 3185 patients with type 2 diabetes on basal insulin in The Health Improvement Network (THIN) general practice database. In total, 48% (614 patients) intensified insulin therapy, defined by adding bolus or premix insulin to a basal regimen, which was associated with a reduction in HbA1c and an increase in body mass index. Projections of clinical outcomes and costs (2011 GBP) over patients' lifetimes were made using a recently validated type 2 diabetes model. Immediate insulin intensification was associated with improvements in life expectancy, quality-adjusted life expectancy and time to onset of complications versus no intensification or delaying intensification by 2, 4, 6, or 8 years. Direct costs were higher with the insulin intensification strategy (due to the acquisition costs of insulin). Incremental cost-effectiveness ratios for insulin intensification were GBP 32,560, GBP 35,187, GBP 40,006, GBP 48,187 and GBP 55,431 per QALY gained versus delaying intensification 2, 4, 6 and 8 years, and no intensification, respectively. Although associated with improved clinical outcomes, insulin intensification as practiced in the UK has a relatively high cost per QALY and may not lead to cost-effective outcomes for patients with type 2 diabetes as currently defined by UK cost-effectiveness thresholds. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Challenges constraining insulin access in Nepal-a country with no local insulin production.

PubMed

Sharma, Abhishek; Bhandari, Parash Mani; Neupane, Dipika; Kaplan, Warren A; Mishra, Shiva Raj

2018-05-01

Nepal is facing an increasing burden of diabetes and relies almost entirely on insulin imported through India. We employed a modified version of the WHO/Health Action International standard survey to assess insulin availability and prices, along with qualitative interviews with insulin retailers (pharmacists) and wholesalers in the Kathmandu Valley, Nepal. The mean availability of the two human insulins listed on the 2011 Nepal Essential Medicine List were 14.3% and 42.85% in the surveyed private- and public-sector pharmacies, respectively, compared with the WHO target of 80% availability. The median consumer price of human insulin cartridges, analogue insulin cartridges and pens was, respectively, 2.1, 4.6 and 5.3 times that of human insulin vials (US$5.54). The insulin cartridges made in India were less expensive (p<0.001) than those made elsewhere. The lowest-paid worker would need to spend between 3 and 17 days' wages to purchase a monthly insulin supply out of pocket. Insulin access is limited in Kathmandu owing to low availability and the highly unaffordable price. Insulin access could improve with the government exploring additional suppliers, pooling insulin tenders, auditing insulin utilization and developing independent prescribing guidelines. Furthermore, there is a need to educate physicians and develop a consensus statement on insulin initiation to curb the growing analogue use and promote rational use.

The effect of a long-acting somatostatin analogue (SMS 201-995) on intermediary metabolism and gut hormones after a test meal in normal subjects.

PubMed

Fuessl, H S; Burrin, J M; Williams, G; Adrian, T E; Bloom, S R

1987-08-01

SMS 201-995 is an octapeptide analogue of somatostatin. The effect of a single subcutaneous (s.c.) injection of 50 micrograms SMS 201-995 on post-prandial intermediary metabolism was investigated in normal subjects. In spite of a long-lasting post-prandial suppression of insulin secretion, there were no significant changes in the plasma concentration of alanine, glycerol, 3-OH-butyrate or lactate. However, SMS 201-995 impairs carbohydrate tolerance, probably due to inhibition of insulin secretion. Basal and post-prandial plasma concentrations of the gut regulatory peptides pancreatic glucagon, motilin, pancreatic polypeptide, gastric inhibitory polypeptide, enteroglucagon, gastrin and peptide YY were suppressed up to 5 hours after subcutaneous administration of a single dose of SMS 201-995.

Insulin Pump Malfunction During Hospitalization: Two Case Reports.

PubMed

Faulds, Eileen R; Wyne, Kathleen L; Buschur, Elizabeth O; McDaniel, Jodi; Dungan, Kathleen

2016-06-01

Insulin pump malfunctions and failures continue to occur; however, more severe malfunctions such as the "runaway pump" phenomenon are rarely reported. This article describes two cases of pump malfunction in which pump users appear to have received an unsolicited bolus of insulin resulting in severe episodes of hypoglycemia during hospitalization. Both cases of insulin pump malfunction occurred in the inpatient setting at a large academic medical center in the United States. An analysis of the corresponding insulin pump downloads was performed. The Food and Drug Administration's (FDA's) Manufacturer and User Facility Device Experience (MAUDE) database was searched for similar cases involving Medtronic (Northridge, CA) insulin pumps using the terms "pump," "infusion," "insulin AND malfunction AND Medtronic." The two cases described show remarkable similarities, each demonstrating a severe hypoglycemic event preceded by an infusion site change followed by an alarm. In both cases a rapid spraying of insulin was reported. The insulin pump downloads validated much of the patients' and medical staff's descriptions of events. The FDA's MAUDE database search revealed 425 cases meeting our search term criteria. All cases were reviewed. Seven cases were identified involving independent movement of the reservoir piston. The cases detailed are the first to describe an insulin pump malfunction of this nature in the hospital setting involving unsolicited insulin boluses leading to severe hypoglycemia. The cases are particularly compelling in that they were witnessed by medical personnel. Providers and patients should receive instruction education on the recognition and management of insulin pump malfunction.

Influence of Unweighting on Insulin Signal Transduction in Muscle

NASA Technical Reports Server (NTRS)

Tischler, Marc E.

2002-01-01

Unweighting of the juvenile soleus muscle is characterized by an increased binding capacity for insulin relative to muscle mass due to sparing of the receptors during atrophy. Although carbohydrate metabolism and protein degradation in the unweighted muscle develop increased sensitivity to insulin in vivo, protein synthesis in vivo and system A amino acid transport in vitro do not appear to develop such an enhanced response. The long-term goal is to identify the precise nature of this apparent resistance in the insulin signal transduction pathway and to consider how reduced weight-bearing may elicit this effect, by evaluating specific components of the insulin signalling pathway. Because the insulin-signalling pathway has components in common with the signal transduction pathway for insulin-like growth factor (IGF-1) and potentially other growth factors, the study could have important implications in the role of weight-bearing function on muscle growth and development. Since the insulin signalling pathway diverges following activation of insulin receptor tyrosine kinase, the immediate specific aims will be to study the receptor tyrosine kinase (IRTK) and those branches, which lead to phosphorylation of insulin receptor substrate-1 (IRS-1) and of Shc protein. To achieve these broader objectives, we will test in situ, by intramuscular injection, the responses of glucose transport, system A amino acid transport and protein synthesis to insulin analogues for which the receptor has either a weaker or much stronger binding affinity compared to insulin. Studies will include: (1) estimation of the ED(sub 50) for each analogue for these three processes; (2) the effect of duration (one to four days) of unweighting on the response of each process to all analogues tested; (3) the effect of unweighting and the analogues on IRTK activity; and (4) the comparative effects of unweighting and analogue binding on the tyrosine phosphorylation of IRTK, IRS-1, and Shc protein.

V-Go Insulin Delivery System Versus Multiple Daily Insulin Injections for Patients With Uncontrolled Type 2 Diabetes Mellitus.

PubMed

Winter, Abigail; Lintner, Michaela; Knezevich, Emily

2015-04-21

Type 2 diabetes mellitus affects over 29.1 million Americans, diagnosed and undiagnosed. Achieving and maintaining glycemic control for these patients is of extreme importance when working to prevent complications and improve quality of life for patients. The V-Go is a newly developed insulin delivery system. The push of a button inserts a needle into the patient once daily and remains attached for 24 hours. The V-Go is designed to release a set basal rate throughout the day, while allowing patients to provide up to 36 units of on-demand bolus insulin with the manual click of 2 buttons. It is a spring-loaded device filled daily with rapid-acting insulin that runs without the use of batteries or computer software. The main objective of this prospective active comparator study was to observe the A1C lowering effects of multiple daily insulin injections (MDII) versus the use of the V-Go insulin delivery system for patients with uncontrolled type 2 diabetes mellitus over a 3-month period. In addition, the effect on insulin requirement for these patients was assessed with secondary comparisons of weight, blood pressure, prevalence of hypoglycemic events, and quality of life before and after 3 months of intensified insulin therapy with regular monitoring by a clinical pharmacist at an internal medicine clinic. The average A1C lowering experienced by the 3 patients in the V-Go group was 1.5%, while the average A1C change in the 3 patients in the MDII group was an increase of 0.2%. All patients in the V-Go group experienced a decrease in insulin total daily dose (TDD), with an average decrease of 26.3 units. All patients in the MDII group experienced an increase in insulin TDD with an average of 15 units daily to achieve therapeutic goals individualized for each patient. All patients who underwent intensification of insulin therapy experienced an increase in subjective quality of life (QOL) as determined using the Diabetes-39 (D-39) questionnaire, though QOL results lacked

The potential for improvement of outcomes by personalized insulin treatment of type 1 diabetes as assessed by analysis of single-patient data from a randomized controlled cross-over insulin trial.

PubMed

Pedersen-Bjergaard, Ulrik; Kristensen, Peter L; Beck-Nielsen, Henning; Nørgaard, Kirsten; Perrild, Hans; Christiansen, Jens S; Jensen, Tonny; Parving, Hans-Henrik; Thorsteinsson, Birger; Tarnow, Lise

2017-01-01

The evidence for optimal insulin treatment in type 1 diabetes is mainly based on randomised controlled trials applying a parallel-group design. Such trials yield robust general results but crucial individual treatment effects cannot be extracted. We aimed to assess the potential for further improvement of outcomes by personalized insulin therapy by analyzing data from a cross-over trial at individual level. Post hoc analysis of data from a two-year multicentre, prospective, randomised, open, blinded endpoint (PROBE) trial (the HypoAna trial). In a cross-over design 114 patients with type 1 diabetes and recurrent severe hypoglycemia were treated with basal-bolus therapy based on analog (detemir/aspart) or human (NPH/regular) insulin aiming at maintenance of baseline HbA1c levels. For each patient a superior outcome was defined as fewer events of severe hypoglycemia defined by need for third party treatment assistance or a more than 0.4% (4.4mmol/mol) lower HbA1c. Only one quarter had comparable outcome of the two treatments in terms of rate of severe hypoglycemia or HbA1c. Twice as many patients had superior outcome of analog-based as compared to human insulin-based insulin treatment. The rate of severe hypoglycemia with the superior treatment was lower compared to the rates obtained with analog insulin and with human insulin (0.67, 1.09, and 1.57 episode per patient-year, respectively (p<0.0001)). Personalized insulin treatment of type 1 diabetes based on single-patient evidence may improve outcomes significantly compared to a general treatment approach. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Rational steering of insulin binding specificity by intra-chain chemical crosslinking

NASA Astrophysics Data System (ADS)

Viková, Jitka; Collinsová, Michaela; Kletvíková, Emília; Buděšínský, Miloš; Kaplan, Vojtěch; Žáková, Lenka; Veverka, Václav; Hexnerová, Rozálie; Aviñó, Roberto J. Tarazona; Straková, Jana; Selicharová, Irena; Vaněk, Václav; Wright, Daniel W.; Watson, Christopher J.; Turkenburg, Johan P.; Brzozowski, Andrzej M.; Jiráček, Jiří

2016-01-01

Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the CuI-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone’s B-chain C-terminus for its IR-B specificity.

The new era of biotech insulin analogues.

PubMed

Brange, J

1997-07-01

Many of the structural properties of insulin have evolved in response to the requirements of biosynthesis, processing, transport and storage in the pancreatic beta cells, properties that are not necessary for the biological action of the hormone. It is therefore not surprising that wild-type insulin has far from optimal characteristics for replacement therapy. For example, native human insulin self-associates to hexameric units, which limits the possibilities for the absorption of the molecule by various routes. During the last decade new techniques of molecular design have emerged and recombinant DNA technology offers new and exciting opportunities for rational protein drug design. This review describes examples of recent advances in insulin engineering aimed at optimizing the hormone for therapy. Such approaches focus on improvements in the pharmacokinetic properties, storage stability, and feasibility for less intrusive routes of administration.

Impact of Bromocriptine-QR Therapy on Glycemic Control and Daily Insulin Requirement in Type 2 Diabetes Mellitus Subjects Whose Dysglycemia Is Poorly Controlled on High-Dose Insulin: A Pilot Study

PubMed Central

Roe, Erin D.; Chamarthi, Bindu; Raskin, Philip

2015-01-01

Background. The concurrent use of a postprandial insulin sensitizing agent, such as bromocriptine-QR, a quick release formulation of bromocriptine, a dopamine D2 receptor agonist, may offer a strategy to improve glycemic control and limit/reduce insulin requirement in type 2 diabetes (T2DM) patients on high-dose insulin. This open label pilot study evaluated this potential utility of bromocriptine-QR. Methods. Ten T2DM subjects on metformin (1-2 gm/day) and high-dose (TDID ≥ 65 U/day) basal-bolus insulin were enrolled to receive once daily (morning) bromocriptine-QR (1.6–4.8 mg/day) for 24 weeks. Subjects with at least one postbaseline HbA1c measurement (N = 8) were analyzed for change from baseline HbA1c, TDID, and postprandial glucose area under the curve of a four-hour mixed meal tolerance test (MMTT). Results. Compared to the baseline, average HbA1c decreased 1.76% (9.74 ± 0.56 to 7.98 ± 0.36, P = 0.01), average TDID decreased 27% (199 ± 33 to 147 ± 31, P = 0.009), and MMTT AUC60–240 decreased 32% (P = 0.04) over the treatment period. The decline in HbA1c and TDID was observed at 8 weeks and sustained over the remaining 16-week study duration. Conclusion. In this study, bromocriptine-QR therapy improved glycemic control and meal tolerance while reducing insulin requirement in T2DM subjects poorly controlled on high-dose insulin therapy. PMID:26060825

Studies on the mechanism of salicylate-induced increase of insulin secretion in man.

PubMed

Giugliano, D; Cozzolino, D; Ceriello, A; Cerciello, T; Varano, R; Saccomanno, F; Torella, R

1988-01-01

Salicylate compounds are known to increase basal and stimulated insulin secretion in man. In our studies, infusion of lysine acetylsalicylate (72 mg/min) increased basal insulin levels and amplified insulin responses to glucose (5 g i.v.), arginine (5 g i.v.) and tolbutamide (1 g i.v.). Verapamil, an organic calcium antagonist, did not modify LAS-induced increase of basal insulin levels, but reduced the effect of LAS on glucose-induced insulin secretion. Calcitonin and somatostatin, two agents that inhibit basal and glucose-stimulated insulin secretion, inhibited the insulin response to glucose in presence of LAS infusion. The ability of salicylate compounds to augment insulin secretion might be due to multiple sites of action in the Beta-cells.

Characterization of swallow modulation in response to bolus volume in healthy subjects accounting for catheter diameter.

PubMed

Ferris, Lara; Schar, Mistyka; McCall, Lisa; Doeltgen, Sebastian; Scholten, Ingrid; Rommel, Nathalie; Cock, Charles; Omari, Taher

2018-06-01

Characterization of the pharyngeal swallow response to volume challenges is important for swallowing function assessment. The diameter of the pressure-impedance recording catheter may influence these results. In this study, we captured key physiological swallow measures in response to bolus volume utilizing recordings acquired by two catheters of different diameter. Ten healthy adults underwent repeat investigations with 8- and 10-Fr catheters. Liquid bolus swallows of volumes 2.5, 5, 10, 20, and 30 mL were recorded. Measures indicative of distension, contractility, and flow timing were assessed. Pressure-impedance recordings with pressure-flow analysis were used to capture key distension, contractility, and pressure-flow timing parameters. Larger bolus volumes increased upper esophageal sphincter distension diameter (P < .001) and distension pressures within the hypopharynx and upper esophageal sphincter (P < .05). Bolus flow timing measures were longer, particularly latency of bolus propulsion ahead of the pharyngeal stripping wave (P < .001). Use of a larger-diameter catheter produced higher occlusive pressures, namely upper esophageal sphincter basal pressure (P < .005) and upper esophageal sphincter postdeglutitive pressure peak (P < .001). The bolus volume swallowed changed measurements indicative of distension pressure, luminal diameter, and pressure-flow timing; this is physiologically consistent with swallow modulation to accommodate larger, faster-flowing boluses. Additionally, catheter diameter predominantly affects lumen occlusive pressures. Appropriate physiological interpretation of the pressure-impedance recordings of pharyngeal swallowing requires consideration of the effects of volume and catheter diameter. NA. Laryngoscope, 128:1328-1334, 2018. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

[Usefulness of Bolus Administration Using the FLEX Mode(Bolus Infusion Mode)for Baclofen Tolerance].

PubMed

Tanaka, Kazunori

2017-02-01

Intrathecal baclofen(ITB)is used to treat intractable spasticity of various etiologies and can provide better control of spasticity through the adjustment of the dose administered through the pump. However, in patients who develop tolerance to baclofen with the standard simple continuous mode, a sharp increase in dose becomes necessary, and spasticity can become harder to control. We investigated whether switching from the simple continuous mode to the bolus infusion mode was effective in controlling spasticity in patients with baclofen tolerance. We reported four patients undergoing ITB therapy at our facility who were considered to have developed baclofen tolerance. We observed the number of bolus infusions and total dose suitable for maintaining spasticity control after switching from the simple continuous mode to the bolus infusion mode. After switching to the bolus infusion mode, the total dose could be reduced in the short term; however, in the long term, the frequency of bolus infusions had to be increased to maintain spasticity control. Two years after changing to bolus infusion six times a day, the total dose was higher than that in the simple continuous mode for two of the four patients, and was the same level in the other two patients. Our four cases suggest that bolus infusion is effective in patients with baclofen tolerance during ITB therapy. Therefore, the conditions of bolus infusion should be further investigated.

Current state of type 2 diabetes management.

PubMed

Molitch, Mark E

2013-06-01

Type 2 diabetes mellitus (T2DM) and its associated comorbidities are a major public health issue in the United States. Although a sizable pharmacotherapeutic armamentarium exists to combat this disease and several sources have published evidence-based management guidelines, the management of patients with T2DM remains complex and suboptimal. Currently available medications target various organs in an attempt to normalize hyperglycemia; however, newer agents targeting additional organ systems are in development. Among these, a class of medications that inhibit the sodium glucose cotransporter 2 (SGLT2) in the kidney show promise in their ability to decrease glucose reabsorption and increase glucose excretion. In particular, one of these compounds, canagliflozin, recently was approved by the US Food and Drug Administration. Despite such advances, the natural course of T2DM often eventually leads to the initiation of insulin therapy. A working knowledge of management guidelines, particularly concerning when and how to initiate monotherapies, combination therapies, and complex insulin regimens, is essential for optimal patient management. Insulin therapies should mimic normal physiologic levels of insulin through the use of both basal and bolus insulin analogues. Recognition of the various factors influencing therapeutic choices is also critical for improved patient management.

Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Cost-Utility Analysis.

PubMed

Dawoud, Dalia; Fenu, Elisabetta; Higgins, Bernard; Wonderling, David; Amiel, Stephanie A

2017-12-01

To assess the cost-effectiveness of basal insulin regimens for adults with type 1 diabetes mellitus in England. A cost-utility analysis was conducted in accordance with the National Institute for Health and Care Excellence reference case. The UK National Health Service and personal and social services perspective was used and a 3.5% discount rate was applied for both costs and outcomes. Relative effectiveness estimates were based on a systematic review of published trials and a Bayesian network meta-analysis. The IMS CORE Diabetes Model was used, in which net monetary benefit (NMB) was calculated using a threshold of £20,000 per quality-adjusted life-year (QALY) gained. A wide range of sensitivity analyses were conducted. Insulin detemir (twice daily) [iDet (bid)] had the highest mean QALY gain (11.09 QALYs) and NMB (£181,456) per patient over the model time horizon. Compared with the lowest cost strategy (insulin neutral protamine Hagedorn once daily), it had an incremental cost-effectiveness ratio of £7844/QALY gained. Insulin glargine (od) [iGlarg (od)] and iDet (od) were ranked as second and third, with NMBs of £180,893 and £180,423, respectively. iDet (bid) remained the most cost-effective treatment in all the sensitivity analyses performed except when high doses were assumed (>30% increment compared with other regimens), where iGlarg (od) ranked first. iDet (bid) is the most cost-effective regimen, providing the highest QALY gain and NMB. iGlarg (od) and iDet (od) are possible options for those for whom the iDet (bid) regimen is not acceptable or does not achieve required glycemic control. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

In vivo assessment of cardiac insulin resistance by nuclear probes using an iodinated tracer of glucose transport.

PubMed

Briat, Arnaud; Slimani, Lotfi; Perret, Pascale; Villemain, Danièle; Halimi, Serge; Demongeot, Jacques; Fagret, Daniel; Ghezzi, Catherine

2007-11-01

Insulin resistance, implying depressed cellular sensitivity to insulin, is a risk factor for type 2 diabetes and cardiovascular disease. This study is the first step towards the development of a technique of insulin resistance measurement in humans with a new tracer of glucose transport, [(123)I]6-deoxy-6-iodo-D-glucose (6DIG). We investigated 6DIG kinetics in anaesthetised control rats and in three models of insulin-resistant rats: fructose fed, Zucker and ZDF. The study of myocardial 6DIG activity was performed under two conditions: first, 6DIG was injected under the baseline condition and then it was injected after a bolus injection of insulin. After each injection, radioactivity was measured over 45 min by external detection via NaI probes, in the heart and blood. A tri-compartment model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the heart. These coefficients were significantly increased with insulin in control rats and did not change significantly in insulin-resistant rats. The ratio of the coefficient obtained under insulin to that obtained under basal conditions gave an index of cardiac insulin resistance for each animal. The mean values of these ratios were significantly lower in insulin-resistant than in control rats: 1.16 +/- 0.06 vs 2.28 +/- 0.18 (p < 0.001) for the fructose-fed group, 0.92 +/- 0.05 vs 1.62 +/- 0.25 (p < 0.01) for the Zucker group and 1.34 +/- 0.06 vs 2.01 +/- 0.26 (p < 0.05) for the ZDF group. These results show that 6DIG could be a useful tracer to image cardiac insulin resistance.

Reduction of Sulfonylurea with the Initiation of Basal Insulin in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Undergoing Long-Term Sulfonylurea-Based Treatment.

PubMed

Yang, Yeoree; Shin, Jeong Ah; Yang, Hae Kyung; Lee, Seung Hwan; Ko, Seung Hyun; Ahn, Yu Bae; Yoon, Kun Ho; Cho, Jae Hyoung

2016-12-01

There were a limited number of studies about β-cell function after insulin initiation in patients exposed to long durations of sulfonylurea treatment. In this study, we aimed to evaluate the recovery of β-cell function and the efficacy of concurrent sulfonylurea use after the start of long-acting insulin. In this randomized controlled study, patients with type 2 diabetes mellitus (T2DM), receiving sulfonylurea for at least 2 years with glycosylated hemoglobin (HbA1c) >7%, were randomly assigned to two groups: sulfonylurea maintenance (SM) and sulfonylurea reduction (SR). Following a 75-g oral glucose tolerance test (OGTT), we administered long-acting basal insulin to the two groups. After a 6-month follow-up, we repeated the OGTT. Among 69 enrolled patients, 57 completed the study and were analyzed: 31 in the SM and 26 in the SR group. At baseline, there was no significant difference except for the longer duration of diabetes and lower triglycerides in the SR group. After 6 months, the HbA1c was similarly reduced in both groups, but there was little difference in the insulin dose. In addition, insulin secretion during OGTT was significantly increased by 20% to 30% in both groups. A significant weight gain was observed in the SM group only. The insulinogenic index was more significantly improved in the SR group. Long-acting basal insulin replacement could improve the glycemic status and restore β-cell function in the T2DM patients undergoing sulfonylurea-based treatment, irrespective of the sulfonylurea dose reduction. The dose reduction of the concurrent sulfonylurea might be beneficial with regard to weight grain.

High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation.

PubMed

Pauly, Marion; Assense, Allan; Rondon, Aurélie; Thomas, Amandine; Dubouchaud, Hervé; Freyssenet, Damien; Benoit, Henri; Castells, Josiane; Flore, Patrice

2017-03-03

Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21-5% FiO 2 , 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy.

High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation

PubMed Central

Pauly, Marion; Assense, Allan; Rondon, Aurélie; Thomas, Amandine; Dubouchaud, Hervé; Freyssenet, Damien; Benoit, Henri; Castells, Josiane; Flore, Patrice

2017-01-01

Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21–5% FiO2, 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy. PMID:28255159

Clinical performance of three bolus calculators in subjects with type 1 diabetes mellitus: a head-to-head-to-head comparison.

PubMed

Zisser, Howard; Wagner, Robin; Pleus, Stefan; Haug, Cornelia; Jendrike, Nina; Parkin, Chris; Schweitzer, Matthias; Freckmann, Guido

2010-12-01

Insulin pump systems now provide automated bolus calculators (ABCs) that electronically calculate insulin boluses to address carbohydrate intake and out-of-range blood glucose (bG) levels. We compared the efficacy of three ABCs (Accu-Chek(®) Combo [Roche Insulin Delivery Systems (IDS), Inc., Fishers, IN, a member of the Roche Group], Animas(®) 2020 [Animas Corp., West Chester, PA, a Johnson and Johnson company], and MiniMed Paradigm Bolus Wizard(®) [Medtronic MiniMed, Northridge, CA]) to safely reduce postprandial hyperglycemia in type 1 diabetes mellitus (T1DM). T1DM subjects (n = 24) were recruited at a single center for a prospective, triple crossover study. ABCs with the programmed target range (80-140 mg/dL) were used in random order. Postprandial hyperglycemia was induced by reducing the calculated bolus by 25%. Two hours after test meals, the ABCs were allowed to determine whether a correction bolus was needed. Differences between 6-h bG values after test meals that achieved 2-h postprandial hyperglycemia and the mean of the target range (110 mg/dL) were determined. The mean difference between 6-h bG levels following test meals and the 110 mg/dL bG target with the MiniMed device (47.4 ± 31.8 mg/dL) was significantly higher than the Animas (17.3 ± 30.9 mg/dL) and Roche IDS (18.8 ± 33.8 mg/dL) devices (P = 0.0022 and P = 0.0049, respectively). The number of meals with 2-h postprandial hyperglycemia and bG levels at 2 h was similar. Roche IDS and Animas devices recommended correction boluses significantly (P = 0.0001 and P = 0.0002, respectively) more frequently than the MiniMed device. ABC use was not associated with severe hypoglycemia. There was no significant difference in the rate of mild hypoglycemia (bG <60 mg/dL not requiring assistance) among the three groups (Roche IDS and Animas, n = 2; MiniMed, n = 0). In this study, the Roche IDS and Animas devices were more efficacious in controlling

Home Use of Day-and-Night Hybrid Closed-Loop Insulin Delivery in Suboptimally Controlled Adolescents With Type 1 Diabetes: A 3-Week, Free-Living, Randomized Crossover Trial.

PubMed

Tauschmann, Martin; Allen, Janet M; Wilinska, Malgorzata E; Thabit, Hood; Acerini, Carlo L; Dunger, David B; Hovorka, Roman

2016-11-01

This study evaluated the feasibility, safety, and efficacy of day-and-night hybrid closed-loop insulin delivery in adolescents with type 1 diabetes under free-living conditions. In an open-label randomized crossover study, 12 suboptimally controlled adolescents on insulin pump therapy (mean ± SD age 14.6 ± 3.1 years; HbA 1c 69 ± 8 mmol/mol [8.5 ± 0.7%]; duration of diabetes 7.8 ± 3.5 years) underwent two 21-day periods in which hybrid closed-loop insulin delivery was compared with sensor-augmented insulin pump therapy in random order. During the closed-loop intervention, a model predictive algorithm automatically directed insulin delivery between meals and overnight. Participants used a bolus calculator to administer prandial boluses. The proportion of time that sensor glucose was in the target range (3.9-10 mmol/L; primary end point) was increased during the closed-loop intervention compared with sensor-augmented insulin pump therapy by 18.8 ± 9.8 percentage points (mean ± SD; P < 0.001), the mean sensor glucose level was reduced by 1.8 ± 1.3 mmol/L (P = 0.001), and the time spent above target was reduced by 19.3 ± 11.3 percentage points (P < 0.001). The time spent with sensor glucose levels below 3.9 mmol/L was low and comparable between interventions (median difference 0.4 [interquartile range -2.2 to 1.3] percentage points; P = 0.33). Improved glucose control during closed-loop was associated with increased variability of basal insulin delivery (P < 0.001) and an increase in the total daily insulin dose (53.5 [39.5-72.1] vs. 51.5 [37.6-64.3] units/day; P = 0.006). Participants expressed positive attitudes and experience with the closed-loop system. Free-living home use of day-and-night closed-loop in suboptimally controlled adolescents with type 1 diabetes is safe, feasible, and improves glucose control without increasing the risk of hypoglycemia. Larger and longer studies are warranted. © 2016 by the American Diabetes Association.

Basal measures of insulin sensitivity and insulin secretion and simplified glucose tolerance tests in dogs.

PubMed

Verkest, K R; Fleeman, L M; Rand, J S; Morton, J M

2010-10-01

There is need for simple, inexpensive measures of glucose tolerance, insulin sensitivity, and insulin secretion in dogs. The aim of this study was to estimate the closeness of correlation between fasting and dynamic measures of insulin sensitivity and insulin secretion, the precision of fasting measures, and the agreement between results of standard and simplified glucose tolerance tests in dogs. A retrospective descriptive study using 6 naturally occurring obese and 6 lean dogs was conducted. Data from frequently sampled intravenous glucose tolerance tests (FSIGTTs) in 6 obese and 6 lean client-owned dogs were used to calculate HOMA, QUICKI, fasting glucose and insulin concentrations. Fasting measures of insulin sensitivity and secretion were compared with MINMOD analysis of FSIGTTs using Pearson correlation coefficients, and they were evaluated for precision by the discriminant ratio. Simplified sampling protocols were compared with standard FSIGTTs using Lin's concordance correlation coefficients, limits of agreement, and Pearson correlation coefficients. All fasting measures except fasting plasma glucose concentration were moderately correlated with MINMOD-estimated insulin sensitivity (|r| = 0.62-0.80; P < 0.03), and those that combined fasting insulin and glucose were moderately closely correlated with MINMOD-estimated insulin secretion (r = 0.60-0.79; P < 0.04). HOMA calculated using the nonlinear formulae had the closest estimated correlation (r = 0.77 and 0.74) and the best discrimination for insulin sensitivity and insulin secretion (discriminant ratio 4.4 and 3.4, respectively). Simplified sampling protocols with half as many samples collected over 3 h had close agreement with the full sampling protocol. Fasting measures and simplified intravenous glucose tolerance tests reflect insulin sensitivity and insulin secretion derived from frequently sampled glucose tolerance tests with MINMOD analysis in dogs. Copyright 2010 Elsevier Inc. All rights reserved.

Patient safety and minimizing risk with insulin administration - role of insulin degludec.

PubMed

Aye, Myint M; Atkin, Stephen L

2014-01-01

Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long

Insulin and Glucagon-Like Peptide 1 Receptor Agonist Combination Therapy in Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PubMed

Maiorino, Maria Ida; Chiodini, Paolo; Bellastella, Giuseppe; Capuano, Annalisa; Esposito, Katherine; Giugliano, Dario

2017-04-01

The combination of basal insulin plus a glucagon-like peptide 1 receptor agonist (GLP-1RA) has been proposed as a treatment option to intensify insulin therapy in type 2 diabetes. We performed a meta-analysis of randomized controlled trials (RCTs) comparing this combination strategy to other injectable antidiabetes treatments on metabolic control in adult patients with type 2 diabetes. We conducted an electronic search until November 2016 on many electronic databases to identify RCTs assessing changes in HbA 1c , proportion of patients at HbA 1c target ≤7% (53 mmol/mol), hypoglycemia, and weight change. We used a random-effect model to calculate the weighted mean difference (WMD) or relative risk (RR) with the 95% CI. We identified 26 RCTs, lasting 12-52 weeks, and involving 11,425 patients. When the combination strategy was compared with other injectable treatments (overall data), there were reductions in HbA 1c (WMD = -0.47%, 95% CI -0.59 to -0.35), more patients at HbA 1c target (RR = 1.65, 95% CI 1.44-1.88), similar hypoglycemic events (RR = 1.14, 95% CI 0.93-1.39) and a reduction in weight (WMD = -2.5 kg, 95% CI -3.3 to -1.7), with high heterogeneity ( I 2 > 89%, P < 0.001) and a significant publication bias for three outcomes. In preplanned subgroup analyses, the combination treatment was similar to basal-bolus insulin regimens for glycemic control, with less hypoglycemia (RR = 0.66, 95% CI 0.46-0.93) and reduced weight (WMD = -4.7 kg, 95% CI -6.9 to -2.4). Fixed-ratio combinations yielded results similar to the overall analysis (HbA 1c WMD = -0.56%, 95% CI -0.72 to -0.40). GLP-1RAs alone or as titratable fixed-ratio combinations with basal insulin may represent a promising option to advance basal insulin therapy or to initiate injectable therapy in patients with type 2 diabetes inadequately controlled on oral agents. Longer studies are needed to assess durability and tolerability. © 2017 by the American Diabetes Association.

The Effects of Basal Insulin Suspension at the Start of Exercise on Blood Glucose Levels During Continuous Versus Circuit-Based Exercise in Individuals with Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion.

PubMed

Zaharieva, Dessi; Yavelberg, Loren; Jamnik, Veronica; Cinar, Ali; Turksoy, Kamuran; Riddell, Michael C

2017-06-01

Exercise causes glycemic disturbances in individuals with type 1 diabetes (T1D). Continuous moderate-intensity aerobic exercise (CON) generally lowers blood glucose (BG) levels and often leads to hypoglycemia. In comparison, circuit-based exercise (CIRC) may attenuate the drop in BG. The goal of this study is to contrast the effects of basal insulin suspension at the onset of two different forms of exercise (CON vs. CIRC). Twelve individuals (six men and six women) with T1D on insulin pump therapy were recruited for the study. All participants completed a maximal aerobic fitness test and two 40-min exercise sessions, consisting of either continuous treadmill walking or a circuit workout. Basal insulin infusion was stopped at the onset of exercise and resumed in recovery. After providing an initial reference value, volunteers were blinded to their [BG] and were asked to estimate their levels during exercise. Oxygen consumption (47.5 ± 7.5 vs. 54.5 ± 13.5 mL·kg -1 ·min -1 , P = 0.03) and heart rate (122 ± 20 vs. 144 ± 20 bpm, P = 0.003) were lower in CON vs. CIRC. Despite the lower workload, BG levels dropped more with CON vs. CIRC (delta BG = -3.8 ± 1.5 vs. -0.5 ± 3.0 mmol/L for CON vs. CIRC, respectively, P = 0.001). Participants were able to estimate their BG more accurately during CON (r = 0.83) vs. CIRC (r = 0.33) based on a regression analysis. Despite a lower intensity of exercise, with full basal insulin suspension at the start of exercise, CON results in a larger drop in BG vs. CIRC. These findings have implications for single hormone-based artificial pancreas development for exercise. While this study does not negate the importance of frequent capillary BG monitoring during exercise, it does suggest that if persons are knowledgeable about their pre-exercise BG levels, they can accurately perceive the changes in BG during CON, but not during CIRC.

21 CFR 520.1158 - Iodochlorhydroxyquin boluses.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Iodochlorhydroxyquin boluses. (a) Specifications. Each bolus contains 10 grams of iodochlorhydroxyquin. (b) Sponsor. See No. 053501 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. 1 bolus (10 grams...

21 CFR 520.1158 - Iodochlorhydroxyquin boluses.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Iodochlorhydroxyquin boluses. (a) Specifications. Each bolus contains 10 grams of iodochlorhydroxyquin. (b) Sponsor. See No. 053501 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. 1 bolus (10 grams...

21 CFR 520.1158 - Iodochlorhydroxyquin boluses.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Iodochlorhydroxyquin boluses. (a) Specifications. Each bolus contains 10 grams of iodochlorhydroxyquin. (b) Sponsor. See No. 053501 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. 1 bolus (10 grams...

21 CFR 520.1158 - Iodochlorhydroxyquin boluses.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Iodochlorhydroxyquin boluses. (a) Specifications. Each bolus contains 10 grams of iodochlorhydroxyquin. (b) Sponsor. See No. 053501 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. 1 bolus (10 grams...

Renal function preservation with pioglitazone or with basal insulin as an add-on therapy for patients with type 2 diabetes mellitus.

PubMed

Chang, Yu-Hung; Hwu, Der-Wei; Chang, Dao-Ming; An, Ling-Wang; Hsieh, Chang-Hsun; Lee, Yau-Jiunn

2017-06-01

Clinical outcome may differ owing to the distinct pharmacological characteristics of insulin sensitizers and insulin. This study was performed to compare the metabolic and renal function changes with add-on pioglitazone treatment versus basal insulin in patients with type 2 diabetes mellitus (DM) in whom sulfonylurea and metformin regimens failed. Patients who were consecutively managed in the diabetes comprehensive program with add-on pioglitazone or detemir/glargine treatment for at least 2 years following sulfonylurea and metformin treatment failure were included. A total of 1002 patients were enrolled (pioglitazone: 559, detemir: 264, glargine: 179). After propensity score matching, there were 105 patients with matchable baseline characteristics in each group. After a mean of 3.5 years of follow-up, the pioglitazone group showed a greater HbA1c reduction than the detemir group and the glargine group. Despite patients in all three groups exhibiting significant body weight gain, those in the pioglitazone group and the glargine group showed greater body weight increases than the patients in the detemir group (2.1, 1.6 and 0.8 kg, respectively, p < 0.05). Interestingly, Cox regression analysis indicated that patients under detemir or glargine treatment had a higher probability of CKD progression as compared with the pioglitazone group, with hazard ratios of 2.63 (95% CI 1.79-3.88) and 3.13 (95% CI 2.01-4.87), respectively. Our study first showed that treatment with both pioglitazone and basal insulin improved glycemic control, while only pioglitazone treatment was observed to be advantageous in terms of preserving renal function when used as an add-on therapy for patients with type 2 DM in whom sulfonylurea and metformin regimens failed.

Efficacy of Additional Canagliflozin Administration to Type 2 Diabetes Patients Receiving Insulin Therapy: Examination of Diurnal Glycemic Patterns Using Continuous Glucose Monitoring (CGM).

PubMed

Matsumura, Mihoko; Nakatani, Yuki; Tanka, Seiichi; Aoki, Chie; Sagara, Masaaki; Yanagi, Kazunori; Suzuki, Kunihiro; Aso, Yoshimasa

2017-08-01

The efficacy of administering a sodium-glucose cotransporter 2 inhibitor during insulin therapy has not been established. In this study, we examined its effects based on diurnal glycemic patterns using continuous glucose monitoring (CGM). The subjects were 15 patients who had received insulin therapy for 1 year or more. A CGM device was attached to all subjects for 1 week. The administration of canagliflozin at 100 mg was started 4 days after attachment. The mean glucose concentrations, standard deviation (SD), mean amplitude of glycemic excursions (MAGE), mean of daily difference of blood glucose (MODD), and area under the curve (AUC) (≥180, <70 mg h/dL) after the start of administration were compared with the pretreatment values. In addition, we compared changes in the number of insulin units between basal and bolus insulin. Furthermore, we investigated the influence of canagliflozin on oxidative stress markers and cytokines using 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), and adiponectin as parameters. The mean glucose concentrations decreased from 161.1 to 139.1 mg/dL (P < 0.01). The SD decreased from 36.5 to 29.6 mg/dL (P = 0.05). The MAGE decreased from 89.2 to 77.4 mg/dL (P < 0.01), and the MODD decreased from 34.3 to 25.5 mg/dL (P < 0.05). All parameters showed significant improvements in diurnal changes. AUC of ≥180, i.e., the total area of blood glucose levels at or above 180 on the blood glucose curve of CGM, decreased from 339.1 to 113.6 mg/dL (P < 0.05). AUC of <70, i.e., the total area of blood glucose levels below 70 on the blood glucose curve of CGM, slightly decreased from 1.6 to 0.3 mg/dL (P = 0.08). The total number of basal insulin units decreased from 128 to 76, and that of bolus insulin decreased from 266 to 154; the dose of insulin could be markedly decreased. In addition, the mean 8-OHdG level decreased from 11.4 to 10.8 ng/mg Cre (P < 0.05), and the mean TNF-α level decreased

β-Cells with relative low HIMP1 overexpression levels in a transgenic mouse line enhance basal insulin production and hypoxia/hypoglycemia tolerance.

PubMed

Zhang, Xiaoping; Degenstein, Linda; Cao, Yun; Stein, Jeffrey; Osei, Kwame; Wang, Jie

2012-01-01

Rodent pancreatic β-cells that naturally lack hypoglycemia/hypoxia inducible mitochondrial protein 1 (HIMP1) are susceptible to hypoglycemia and hypoxia influences. A linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 is suggested in a recent study using transformed β-cells lines. To further illuminate this linkage, we applied mouse insulin 1 gene promoter (MIP) to control HIMP1-a isoform cDNA and have generated three lines (L1 to L3) of heterozygous HIMP1 transgenic (Tg) mice by breeding of three founders with C57BL/6J mice. In HIMP1-Tg mice/islets, we performed quantitative polymerase chain reaction (PCR), immunoblot, histology, and physiology studies to investigate HIMP1 overexpression and its link to β-cell function/survival and body glucose homeostasis. We found that the HIMP1 level increased steadily in β-cells of L1 to L3 heterozygous HIMP1-Tg mice. HIMP1 overexpression at relatively lower levels in L1 heterozygotes results in a negligible decline in blood glucose concentrations and an insignificant elevation in blood insulin levels, while HIMP1 overexpression at higher levels are toxic, causing hyperglycemia in L2/3 heterozygotes. Follow-up studies in 5-30-week-old L1 heterozygous mice/islets found that HIMP1 overexpression at relatively lower levels in β-cells has enhanced basal insulin biosynthesis, basal insulin secretion, and tolerances to low oxygen/glucose influences. The findings enforced the linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 in β-cells, and show a potential value of HIMP1 overexpression at relatively lower levels in modulating β-cell function and survival.

[Diagnosis of insulin resistance by indirect methods in obese school children].

PubMed

Angulo, Nerkis; de Szarvas, Sobeida Barbella; Mathison, Yaira; Hadad, Erika; González, Dora; Hernández, Ana; Guevara, Harold

2013-06-01

Obesity leads to a deterioration of glucose tolerance and the action of insulin. The purpose of this study was to determine insulin resistance (IR) by indirect methods, and its correlation with clinical, anthropometric and biochemical variables in obese normoglycemic school children. This was a descriptive-correlational study of 72 school prepubescent children, who attended the ambulatory "El Concejo" of the University of Carabobo (UC) and at the Gastroenterology and Pediatric Nutrition service of the city hospital "Enrique Tejera" (CHET), in Valencia, Venezuela, between January-April 2011. exogenous obesity. We assessed personal and family history, presence of Acanthosis Nigricans and nutritional and biochemical status. We found a higher percentage of IR, through the use of the QUICKI method (66.7%), followed by the HOMA (55.6%) and basal insulin (45.9%). The mean (chi) indexes of body mass and waist circumference were significantly greater (p < 0.05) in patients with IR, by HOMA and QUICKI techniques. The QUICKI method detected significant differences (p < 0.05) in the values of glycemia, basal insulin and postprandial insulin, among patients with diminished and normal insulin sensitivities. While HOMA, detected these differences (p < 0.05) in the values of glycemia and basal insulin. A statistically significant relationship was observed (p < 0.05), between the presence of Acanthosis Nigricans and IR, by the HOMA, QUICKI and basal insulin methods. In conclusion, the evaluated techniques, QUICKI, HOMA and basal insulin indexes, were most effective for detecting the IR.

Three-year efficacy of complex insulin regimens in type 2 diabetes.

PubMed

Holman, Rury R; Farmer, Andrew J; Davies, Melanie J; Levy, Jonathan C; Darbyshire, Julie L; Keenan, Joanne F; Paul, Sanjoy K

2009-10-29

Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited. In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. Median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens (P=0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, P=0.006) or in the basal group (43.2%, P=0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (P=0.002). [corrected] Median rates of hypoglycemia per patient per year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (P<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups. Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin. (Current Controlled Trials number, ISRCTN51125379.) 2009 Massachusetts Medical Society

Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial.

PubMed

Aroda, Vanita R; Rosenstock, Julio; Wysham, Carol; Unger, Jeffrey; Bellido, Diego; González-Gálvez, Guillermo; Takami, Akane; Guo, Hailing; Niemoeller, Elisabeth; Souhami, Elisabeth; Bergenstal, Richard M

2016-11-01

This study was conducted to demonstrate the efficacy and safety of LixiLan (iGlarLixi), a novel, titratable, fixed-ratio combination of insulin glargine (iGlar) (100 units) and lixisenatide, compared with iGlar in patients with type 2 diabetes inadequately controlled on basal insulin with or without up to two oral glucose-lowering agents. After a 6-week run-in when iGlar was introduced and/or further titrated, and oral antidiabetic drugs other than metformin were stopped, 736 basal insulin-treated patients (mean diabetes duration 12 years, BMI 31 kg/m 2 ) were randomized 1:1 to open-label, once-daily iGlarLixi or iGlar, both titrated to fasting plasma glucose <100 mg/dL (<5.6 mmol/L) up to a maximum dose of 60 units/day. The primary outcome was change in HbA 1c levels at 30 weeks. HbA 1c decreased from 8.5% (69 mmol/mol) to 8.1% (65 mmol/mol) during the run-in period. After randomization, iGlarLixi showed greater reductions in HbA 1c from baseline compared with iGlar (-1.1% vs. -0.6%, P < 0.0001), reaching a mean final HbA 1c of 6.9% (52 mmol/mol) compared with 7.5% (58 mmol/mol) for iGlar. HbA 1c <7.0% (53 mmol/mol) was achieved in 55% of iGlarLixi patients compared with 30% on iGlar. Mean body weight decreased by 0.7 kg with iGlarLixi and increased by 0.7 kg with iGlar (1.4 kg difference, P < 0.0001). Documented symptomatic hypoglycemia (≤70 mg/dL) was comparable between groups. Mild gastrointestinal adverse effects were very low but more frequent with iGlarLixi. Compared with iGlar, a substantially higher proportion of iGlarLixi-treated patients achieved glycemic targets with a beneficial effect on body weight, no additional risk of hypoglycemia, and low levels of gastrointestinal adverse effects in inadequately controlled, basal insulin-treated, long-standing type 2 diabetes. © 2016 by the American Diabetes Association.

Insulin Pump and Continuous Glucose Monitor Initiation in Hospitalized Patients with Type 2 Diabetes Mellitus.

PubMed

Levitt, David L; Spanakis, Elias K; Ryan, Kathleen A; Silver, Kristi D

2018-01-01

Insulin pumps and continuous glucose monitoring (CGM) are commonly used by patients with diabetes mellitus in the outpatient setting. The efficacy and safety of initiating inpatient insulin pumps and CGM in the nonintensive care unit setting is unknown. In a prospective pilot study, inpatients with type 2 diabetes were randomized to receive standard subcutaneous basal-bolus insulin and blinded CGM (group 1, n = 5), insulin pump and blinded CGM (group 2, n = 6), or insulin pump and nonblinded CGM (group 3, n = 5). Feasibility, glycemic control, and patient satisfaction were evaluated among groups. Group 1 had lower mean capillary glucose levels, 144.5 ± 19.5 mg/dL, compared with groups 2 and 3, 191.5 ± 52.3 and 182.7 ± 59.9 mg/dL (P 1 vs. 2+3  = 0.05). CGM detected 19 hypoglycemic episodes (glucose <70 mg/dL) among all treatment groups, compared with 12 episodes detected by capillary testing, although not statistically significant. No significant differences were found for the total daily dose of insulin or percentage of time spent below target glucose range (<90 mg/dL), in target glucose range (90-180 mg/dL), or above target glucose range (>180 mg/dL). On the Diabetes Treatment Satisfaction Questionnaire-Change, group 3 reported increased hyperglycemia and decreased hypoglycemia frequency compared with the other two groups, although the differences did not reach statistical significance. Insulin pump and CGM initiation are feasible during hospitalization, although they are labor intensive. Although insulin pump initiation may not lead to improved glycemic control, there is a trend toward CGM detecting a greater number of hypoglycemic episodes. Larger studies are needed to determine whether use of this technology can lower inpatient morbidity and mortality.

ANALGESIC EFFECT OF INTRATHECAL BACLOFEN BOLUS ON NEUROPATHIC PAIN IN SPINAL CORD INJURY PATIENTS.

PubMed

Kumru, Hatice; Benito-Penalva, Jesus; Kofler, Markus; Vidal, Joan

2018-05-18

GABA-ergic neurons are widely distributed throughout the central nervous system, including the spinal cord which is important for the transmission of pain impulses to the brain. Here we hypothesized that intrathecal baclofen (ITB) which is a GABA analogue might exert analgesic effects on neuropathic pain, which could be related to subtypes of pain in spinal cord injury (SCI). SCI patients with a cervical or thoracic lesion and neuropathic pain were randomized to receive either a single ITB bolus or placebo. Numerical Rating Scale (NRS), Neuropathic Pain Symptom Inventory (NPSI), and Brief Pain Inventory (BPI) were obtained for assessment of neuropathic pain. Spasticity was assessed using Modified Ashworth Scale and visual analogue scale. Evaluations were performed at baseline, and 4, 8, and 24 hours after application of ITB or placebo. Eight patients received ITB, 5 placebo. Neuropathic pain improved significantly in the ITB group based on NRS, BPI, and NPSI, which revealed an effect on all subtypes of pain. Spasticity declined significantly. In the placebo group, there was neither significant change in pain nor in spasticity. An ITB bolus exerted a significant analgesic effect on all subtypes of neuropathic pain in SCI patients. ITB has analgesic effects on all subtypes of neuropathic pain and can improve interference of neuropathic pain with activities of daily living. ITB might be a promising analgesic treatment to control neuropathic pain. Copyright © 2018. Published by Elsevier Inc.

Insulin detemir in the management of type 2 diabetes in non-Western countries: safety and effectiveness data from the A₁chieve observational study.

PubMed

Zilov, Alexey; El Naggar, Nabil; Shah, Siddharth; Shen, Chunduo; Haddad, Jihad

2013-09-01

This subgroup analysis of the A₁chieve study examined data from 15,545 people who started treatment with insulin detemir ± oral glucose-lowering drugs in routine clinical care. A₁chieve was a 24-week, international, prospective, non-interventional study of people with type 2 diabetes from non-Western nations starting treatment with basal insulin detemir, bolus insulin aspart or biphasic insulin aspart 30, alone or in combination, to evaluate their safety and effectiveness in routine clinical practice. HbA₁c for the global cohort improved after 24 weeks from 9.5 ± 1.6% by -2.0 ± 1.6% [80 ± 17 by -22 ± 17 mmol/mol] (-2.1 ± 1.6% [-23 ± 17 mmol/mol] for insulin-naïve participants; -1.6 ± 1.7% [-17 ± 19 mmol/mol] for prior insulin users). Fasting plasma glucose and postprandial plasma glucose were also significantly reduced (p<0.001), irrespective of prior therapy or geographical region. The incidence of major hypoglycaemia decreased significantly over 24 weeks in both the insulin-naïve and insulin-experienced groups (p<0.0001). Mean body weight decreased overall by -0.4 ± 4.0 kg and blood pressure, lipid profiles, and self-reported quality of life improved over 24 weeks for all people starting treatment with insulin detemir. People with type 2 diabetes in poor glycaemic control starting treatment with insulin detemir reported significant improvements in glycaemic control with improved treatment tolerability, irrespective of prior treatment and geographical region, after 24 weeks. Copyright © 2013. Published by Elsevier Ireland Ltd.

One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin: the EDITION 1 12-month randomized trial, including 6-month extension.

PubMed

Riddle, M C; Yki-Järvinen, H; Bolli, G B; Ziemen, M; Muehlen-Bartmer, I; Cissokho, S; Home, P D

2015-09-01

To evaluate the maintenance of efficacy and safety of insulin glargine 300 U/ml (Gla-300) versus glargine 100 U/ml (Gla-100) in people with type 2 diabetes mellitus (T2DM) using basal plus meal-time insulin for 12 months in the EDITION 1 trial. EDITION 1 was a multicentre, randomized, open-label, two-arm, phase IIIa study. Participants completing the initial 6-month treatment period continued to receive Gla-300 or Gla-100, as previously randomized, once daily for a further 6-month open-label extension phase. Changes in glycated haemoglobin (HbA1c) and fasting plasma glucose concentrations, insulin dose, hypoglycaemic events and body weight were assessed. Of 807 participants enrolled in the initial phase, 89% (359/404) assigned to Gla-300 and 88% (355/403) assigned to Gla-100 completed 12 months. Glycaemic control was sustained in both groups (mean HbA1c: Gla-300, 7.24%; Gla-100, 7.42%), with more sustained HbA1c reduction for Gla-300 at 12 months: least squares mean difference Gla-300 vs Gla-100: HbA1c -0.17 [95% confidence interval (CI) -0.30 to -0.05]%. The mean daily basal insulin dose at 12 months was 1.03 U/kg for Gla-300 and 0.90 U/kg for Gla-100. Lower percentages of participants had ≥1 confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemic event with Gla-300 than Gla-100 at any time of day [24 h; 86 vs 92%; relative risk 0.94 (95% CI 0.89-0.99)] and during the night [54 vs 65%; relative risk 0.84 (95% CI 0.75-0.94)], while the annualized rates of such hypoglycaemic events were similar. No between-treatment differences in adverse events were apparent. During 12 months of treatment of T2DM requiring basal and meal-time insulin, glycaemic control was better sustained and fewer individuals reported hypoglycaemia with Gla-300 than with Gla-100. The mean basal insulin dose was higher with Gla-300 compared with Gla-100, but total numbers of hypoglycaemic events and overall tolerability did not differ between treatments. © 2015 The Authors. Diabetes

Long‐term safety and efficacy of tofogliflozin as add‐on to insulin in patients with type 2 diabetes: Results from a 52‐week, multicentre, randomized, double‐blind, open‐label extension, Phase 4 study in Japan (J‐STEP/INS)

PubMed Central

Tamura, Masahiro; Senda, Masayuki; Gunji, Ryoji; Kaku, Kohei

2018-01-01

Aims To evaluate the long‐term safety and efficacy of tofogliflozin as an add‐on treatment to insulin over 52 weeks. Materials and methods This 52‐week, multicentre, Phase 4 study consisted of a 16‐week, randomized, double‐blind, placebo‐controlled phase and a 36‐week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus, aged 20 to 75 years, with suboptimal glycaemic control (7.5%‐10.5%) receiving insulin monotherapy (basal‐bolus, bolus, premix [low and high] and basal) or receiving combination therapy with basal insulin and dipeptidyl peptidase‐4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as the ‘tofo‐tofo group’ and patients who received placebo and tofogliflozin (36 weeks) were referred to as the ‘pla‐tofo group’. Results A total of 210 patients received treatment per randomization. Hypoglycaemia was the most common treatment‐emergent adverse event (AE) (42.9% in the tofo‐tofo group and 29.4% in the pla‐tofo group). Patients reported genital infection, urinary tract infection, excessive urination and AEs related to volume depletion (2.1%, 2.1%, 7.1% and 10.0% of patients in the tofo‐tofo group, and 0%, 1.5%, 2.9% and 7.4% of patients in the pla‐tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo‐tofo and pla‐tofo groups were 8.53% (−0.76% ± 0.077) and 8.40% (−0.73% ± 0.102); 68.84 kg (−1.52 kg ± 0.207) and 72.24 kg (−2.13 kg ± 0.313), respectively. Conclusions This study demonstrates the safety and efficacy of tofogliflozin as add‐on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management. PMID:29316236

[Cloning, expressing of exendin-4 analogue and bioactivity analysis in vivo].

PubMed

Li, Taiming; Gu, Chunjiao; Ge, Xiaoyu; Li, Zhezhe; Wang, Dan; Ma, Yanhong; Liu, Tao; Zhang, Meiyou; Li, Li; Liu, Jingjing

2012-07-01

To construct, express and purify Exendin-4 analogue and detect its biological activity in vivo. Insert gene sequence into fusion partner ofpED plasmid which is helped to purification, entitled the new recombinant plasmid 5 Exendin-4 analogue polypeptide gene and fusion partner gene was linked by acid hydrolysisgene, transformed to E. coli BL21 and the fusion protein was induced by lactose. After acid hydrolysis, the Exendin-4 analogue polypeptide separated from fusion chaperon. Anion charge chromatography were used to further purification. 6 to 8 week-old ICR mice were injected (s.c) with Exendin-4 analogue, blood glucose and plasma insulin level was detected in different period after oral glucose tolerance test. The results show that high expression of inclusion body was induced by lactose, which accounted for 40% of germ proteins, the Exendin-4 analogue was obtained with the purity of 91.8% after being purified by anion charge chromatography. Bioactivity assay showed that the level of blood glucose of mouse which treated with exendin-4 analogue was obviously decreased to normal (P < 0.01), and the level of plasma insulin was increased obviously (P < 0.01).

Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single-dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs.

PubMed

Lankisch, M R; Ferlinz, K C; Leahy, J L; Scherbaum, W A

2008-12-01

To investigate whether the addition of a single bolus of insulin glulisine (glulisine), administered at either breakfast or main mealtime, in combination with basal insulin glargine (glargine) and oral antidiabetic drugs (OADs), provides equivalent glycaemic control in patients with type 2 diabetes, irrespective of the time of glulisine injection. A national, multicentre, randomized, open-label, parallel-group study of 393 patients with type 2 diabetes who were suboptimally controlled [haemoglobin A(1c) (HbA(1c)) > 6.5-9.0% and fasting blood glucose (BG) 7.0% at baseline and who reached HbA(1c)bolus of glulisine, added to glargine and OADs, resulted in significantly improved HbA(1c) levels, irrespective of whether glulisine was administered at breakfast or at main mealtime. These results may represent a simplified and effective approach to

A European, multicentre, retrospective, non‐interventional study (EU‐TREAT) of the effectiveness of insulin degludec after switching basal insulin in a population with type 1 or type 2 diabetes

PubMed Central

Tentolouris, Nikolaos; Knudsen, Søren T.; Lapolla, Annunziata; Prager, Rudolf; Phan, Tra‐Mi; Wolden, Michael L.; Schultes, Bernd

2017-01-01

Aims To evaluate the clinical effectiveness of switching to insulin degludec (IDeg) in insulin‐treated patients with either type 1 diabetes (T1DM) or type 2 diabetes (T2DM) under conditions of routine clinical care. Materials and Methods This was a multicentre, retrospective, chart review study. In all patients, basal insulin was switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3‐month period before first prescription of IDeg. Values are presented as mean [95%CI]. Results T1DM (n = 1717): HbA1c decreased by −2.2 [−2.6; −2.0] mmol/mol (−0.20 [−0.24; −0.17]%) at 6 months vs baseline (P < .001). Rate ratio of overall (0.79 [0.69; 0.89]), non‐severe nocturnal (0.54 [0.42; 0.69]) and severe (0.15 [0.09; 0.24]) hypoglycaemia was significantly lower in the 6‐month post‐switch period vs the pre‐switch period (P < .001 for all). Total daily insulin dose decreased by −4.88 [−5.52; −4.24] U (−11%) at 6 months vs baseline (P < .001). T2DM (n = 833): HbA1c decreased by −5.6 [−6.3; −4.7] mmol/mol (−0.51 [−0.58; −0.43] %) at 6 months vs baseline (P < .001). Rate ratio of overall (0.39 [0.27; 0.58], P < .001), non‐severe nocturnal (0.10 [0.06; 0.16], P < .001) and severe (0.075 [0.01; 0.43], P = .004) hypoglycaemia was significantly lower in the 6‐month post‐switch period vs the pre‐switch period. Total daily insulin dose decreased by −2.48 [−4.24; −0.71] U (−3%) at 6 months vs baseline (P = .006). Clinical outcomes for T1DM and T2DM at 12 months were consistent with results at 6 months. Conclusions This study demonstrates that switching patients to IDeg from other basal insulins improves glycaemic control and significantly reduces the risk of hypoglycaemia in routine clinical practice. PMID:29106039

Benchmarking Insulin Treatment Persistence Among Patients with Type 2 Diabetes Across Different U.S. Payer Segments.

PubMed

Wei, Wenhui; Jiang, Jenny; Lou, Youbei; Ganguli, Sohini; Matusik, Mark S

2017-03-01

Treatment persistence with basal insulins is crucial to achieving sustained glycemic control, which is associated with a reduced risk of microvascular disease and other complications of type 2 diabetes (T2D). However, studies suggest that persistence with basal insulin treatment is often poor. To measure and benchmark real-world basal insulin treatment persistence among patients with T2D across different payer segments in the United States. This was a retrospective observational study of data from a national pharmacy database (Walgreen Co., Deerfield, IL). The analysis included patients with T2D aged ≥ 18 years who filled ≥ 1 prescription for basal insulins between January 2013 and June 2013 (the index prescription) and who had also filled prescriptions for ≥ 1 oral antidiabetes drug in the database. Patients with claims for premixed insulin were excluded. Treatment persistence was defined as remaining on the study medication(s) during the 1-year follow-up period. Patients were stratified according to treatment history (existing basal insulin users vs. new insulin users), payer segments (commercially insured, Medicare, Medicaid, or cash-pay), type of basal insulin (insulin glargine, insulin detemir, or neutral protamine Hagedorn insulin [NPH]), and device for insulin administration (pen or vial/syringe). A total of 274,102 patients were included in this analysis, 82% of whom were existing insulin users. In terms of payer segments, 45.3% of patients were commercially insured, 47.8% had Medicare, 5.9% had Medicaid, and 1.1% were cash-pay. At the 1-year follow-up, basal insulin treatment persistence rate was 66.8% overall, 61.7% for new users, and 67.9% for existing users. In general, for both existing and new basal insulin users, higher persistence rate and duration were associated with Medicare versus cash-pay patients, use of insulin pens versus vial/syringe, and use of insulin glargine versus NPH. This large-scale study provides a benchmark of basal insulin