Reactive hypoglycaemia following GLP‐1 infusion in pancreas transplant recipients

The aim of the study was to determine whether reactive hypoglycaemia in pancreas transplant recipients that followed administration of glucagon‐like peptide‐1 (GLP‐1) was associated with excessive insulin, insufficient glucagon, or both. Methodology involved six portally drained pancreas recipients who received GLP‐1 (1.5 pmol/kg/min) or placebo infusion on randomized occasions during glucose‐potentiated arginine testing. The second subject developed symptomatic hypoglycaemia [plasma glucose (PG) 42 mg/dl] 1 h after GLP‐1 administration; subsequent subjects received intravenous glucose following GLP‐1, but not placebo, infusion for PG levels <65 mg/dl. Following GLP‐1 vs. placebo infusion, PG was lower (58 ± 4 vs. 76 ± 5 mg/dl; p < 0.05) despite administration of intravenous glucose. During hypoglycaemia, insulin levels and the insulin‐to‐glucagon ratio were greater after GLP‐1 vs. placebo infusion (p < 0.05), while glucagon did not vary. It can be concluded from the study that GLP‐1 can induce reactive hypoglycaemia in pancreas transplant recipients through excessive insulin secretion associated with an increased insulin‐to‐glucagon ratio.     

Involvement of glucagon‐like peptide‐1 in the glucose‐lowering effect of metformin

Metformin is an oral antihyperglycaemic drug used in the first‐line treatment of type 2 diabetes. Metformin's classic and most well‐known blood glucose‐lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose‐lowering gut incretin hormone glucagon‐like peptide‐1 (GLP‐1), which may contribute to metformin's glucose‐lowering effect in patients with type 2 diabetes. The mechanisms behind metformin‐induced increments in GLP‐1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP‐1 secretion directly and/or indirectly and that metformin prolongs the half‐life of GLP‐1. Also, it has been suggested that metformin may potentiate the glucose‐lowering effects of GLP‐1 by increasing target tissue sensitivity to GLP‐1. The present article critically reviews the possible mechanisms by which metformin may affect GLP‐1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose‐lowering actions of metformin.     

Pharmacokinetic and pharmacodynamic properties of taspoglutide,a once‐weekly,human GLP‐1 analogue,after single‐dose administration in patients with Type 2 diabetes

Aims The study objectives were to evaluate the pharmacokinetic and pharmacodynamic properties, as well as safety and tolerability, of single doses of taspoglutide, a human glucagon‐like peptide‐1 (GLP‐1) analogue. Methods In a double‐blind, placebo‐controlled study, 48 patients with Type 2 diabetes [mean age 56 ± 7 years; mean body mass index (BMI) 30.4 ± 3.0 kg/m²] inadequately controlled with metformin (≤ 2 g/day) were enrolled in three sequential cohorts; 12 patients in each cohort were randomized to a single subcutaneous injection of taspoglutide (1, 8 or 30 mg) and four received placebo. Results Plasma concentrations peaked within 24 h after injection and were sustained for ≥ 14 days with all doses. In comparison with placebo, the 8‐ and 30‐mg doses of taspoglutide significantly reduced glycaemic parameters, including 24‐h blood glucose and 5‐h postprandial glucose areas under the curve (AUCs), for up to 14 days with the 30‐mg dose (P < 0.001). The most common adverse events, primarily gastrointestinal in nature, were dose‐dependent and transient. Conclusions A single dose of taspoglutide significantly improved glycaemic parameters in Type 2 diabetes patients for up to 14 days. The formulation was well tolerated and appears suitable for weekly administration.     

Investigation of the effect of oral metformin on dipeptidylpeptidase‐4 (DPP‐4) activity in Type 2 diabetes1

Aims Glucagon‐like peptide‐1 (GLP‐1) is an insulinotropic hormone and major component of the enteroinsular axis. Its therapeutic potential in human diabetes is limited by rapid degradation and inactivation by the enzyme dipeptidylpeptidase‐4 (DPP‐4). We investigated the acute effects of metformin with and without food on DPP‐4 activity in Type 2 diabetes. Methods Ten subjects with Type 2 diabetes (6 male/4 female, age 65.8 ± 2.6 years, body mass index 30.0 ± 1.2 kg/m², glycated haemoglobin (HbA_1c) 6.3 ± 0.2%, mean ± sem ) received metformin 1 g orally or placebo together with a standard mixed meal (SMM) in a random crossover design. Six subjects re‐attended fasting and received metformin 1 g without a SMM. Results Following SMM (n = 10), DPP‐4 activity was not suppressed by metformin compared with placebo [area under curve (AUC)_{0–4 h} 1574 ± 4 vs. 1581 ± 8 μmol/ml/min, respectively]. Plasma glucose, insulin and active GLP‐1 were not different. However, DPP‐4 activity was suppressed with metformin following fasting compared with a SMM (n = 6) (AUC_{0–4 h} 1578 ± 4 vs. 1494 ± 9 μmol/min, P < 0.02). Metformin serum levels were significantly lower (P < 0.001) after SMM than fasting (AUC_{0–4 h} 350 ± 66 vs. 457 ± 55 mg/ml/min). Conclusion Metformin inhibits DPP‐4 activity in Type 2 diabetic patients in the fasting state but not when taken with a standard mixed meal. Metformin serum concentrations are lower if the drug is taken with food. These findings should be taken into account in establishing how to maximize efficacy of the drug.     

Twelve weeks treatment with the DPP‐4 inhibitor,sitagliptin, prevents degradation of peptide YY and improves glucose and non‐glucose induced insulin secretion in patients with type 2 diabetes mellitus

Aim: To examine the effects of 12 weeks of treatment with the DPP‐4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non‐glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes. Method: A double‐blinded, placebo‐controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add‐on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90‐min 20 mM hyperglycaemic clamp with 5 g of l ‐arginine infusion. Main outcome measure was postprandial total glucagon‐like peptide 1 (GLP‐1) concentration. Additional measures were insulin and C‐peptide, glycaemic control, intact and total peptide YY (PYY) and glucose‐dependent insulinotropic polypeptide (GIP), and intact glucagon‐like peptide 2 (GLP‐2) and GLP‐1. Results: All patients [sitagliptin n = 12, age: 59.5 (39–64) years, HbA1c: 8.0 (7.3–10.0)%, BMI: 33.2 (29.3–39.4); placebo n = 12, age: 60 (31–72) years, HbA1c: 7.7 (7.1–9.8)%, BMI: 30.7 (25.7–40.5)] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP‐1, GIP or intact GLP‐2, but reduced total PYY and PYY_{3‐ 36}, and increased PYY_{1‐ 36} and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group. Conclusion: The postprandial responses of total GLP‐1 and GIP and intact GLP‐2 were unaltered. PYY degradation was prevented. Glucose and non‐glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment.     

Chronic liraglutide therapy induces an enhanced endogenous glucagon‐like peptide‐1 secretory response in early type 2 diabetes

Sustained exogenous stimulation of a hormone‐specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon‐like peptide‐1 (GLP‐1) agonists on the endogenous GLP‐1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years’ duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP‐1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUC_GIP between the groups. By contrast, although fasting GLP‐1 was unaffected, the liraglutide arm had ~2‐fold higher AUC_{GLP ‐1} at 12 weeks ( P < .001), 24 weeks ( P < .001), 36 weeks ( P = .03) and 48 weeks ( P = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP‐1 response, highlighting the need for further study of the long‐term effects of incretin mimetics on L‐cell physiology.     

Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Background

Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are novel agents for type 2 diabetes treatment, offering glucose‐dependent insulinotropic effects, reduced glucagonemia and a neutral bodyweight or weight‐reducing profile. However, a short half‐life (minutes), secondary to rapid inactivation by dipeptidyl peptidase‐IV (DPP‐IV) and excretion, limits the therapeutic potential of the native GLP‐1 hormone. Recently, the GLP‐1 receptor agonist exenatide injected subcutaneously twice daily established a novel therapy class. Developing long‐acting and efficacious GLP‐1 analogues represents a pivotal research goal. We developed a GLP‐1 immunoglobulin G (IgG4) Fc fusion protein (LY2189265) with extended pharmacokinetics and activity.

Methods

In vitro and in vivo activity of LY2189265 was characterized in rodent and primate cell systems and animal models.

Results

LY2189265 retained full receptor activity in vitro and elicited insulinotropic activity in islets similar to native peptide. Half‐life in rats and cynomolgus monkeys was 1.5–2 days, and serum immunoreactivity representing active compound persisted > 6 days. In rats, LY2189265 enhanced insulin responses during graded glucose infusion 24 h after one dose. LY2189265 increased glucose tolerance in diabetic mice after one dose and lowered weight and delayed hyperglycaemia when administered twice weekly for 4 weeks. In monkeys, LY2189265 significantly increased glucose‐dependent insulin secretion for up to a week after one dose, retained efficacy when administered subchronically (once weekly for 4 weeks) and was well tolerated.

Conclusions

LY2189265 retains the effects of GLP‐1 with increased half‐life and efficacy, supporting further evaluation as a once‐weekly treatment of type 2 diabetes. Copyright © 2010 John Wiley & Sons, Ltd.     

The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes*(†)

Background: The present study was conducted to evaluate the efficacy, safety and tolerability of sitagliptin added to ongoing metformin therapy in Chinese patients with type 2 diabetes (T2DM) who failed to achieve adequate glycemic control with metformin monotherapy. Methods: After a metformin titration/stabilization period and a 2‐week, single‐blind, placebo run‐in period, 395 Chinese patients with T2DM aged 25–77 years (baseline HbA1c 8.5%) were randomized (1:1) to double‐blind placebo or sitagliptin 100 mg q.d. added to ongoing open‐label metformin (1000 or 1700 mg/day) for 24 weeks. Results: Significant (P < 0.001) changes from baseline in HbA1c (?0.9%), fasting plasma glucose (?1.2 mmol/L), and 2‐h post‐meal plasma glucose (?1.9 mmol/L) were seen with sitagliptin compared with placebo. There were no significant differences between sitagliptin and placebo in the incidence of hypoglycemia or gastrointestinal adverse events. A small decrease from baseline body weight was observed in the placebo group compared with no change in the sitagliptin group (between‐group difference 0.5 kg; P = 0.018). Conclusions: The addition of sitagliptin 100 mg to ongoing metformin therapy significantly improved glycemic control and was generally well tolerated in Chinese patients with T2DM who had inadequate glycemic control on metformin alone.     

Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on beta-cell function in patients with type 2 diabetes: a model-based approach

Purpose: The purpose of this exploratory analysis was to assess the effect of sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on pancreatic beta‐cell function using a model‐based analysis. Methods: Data for this analysis were from three large, placebo‐controlled clinical studies that examined sitagliptin 100 mg q.d. as add‐on to metformin therapy or as monotherapy over 18 or 24 weeks. In these studies, subsets of patients consented to undergo extensive blood sampling as part of a nine‐point meal tolerance test performed at baseline and study end‐point. Blood samples were collected at ?10, 0, 10, 20, 30, 60, 90, 120 and 180 min relative to the start of a meal and subsequently were assayed for plasma glucose and serum C‐peptide concentrations. Parameters for beta‐cell function were calculated using the C‐peptide minimal model, which estimates insulin secretion rate (ISR) and partitions the ISR into basal (Φ_b; ISR at basal glucose concentrations), static (Φ_s; ISR at above basal glucose concentrations following a meal) and dynamic (Φ_d; ISR in response to the rate of increase in above basal glucose concentrations following a meal) components. The total responsivity index (Φ_total; average ISR over the average glucose concentration) is calculated as a function of Φ_s, Φ_d and Φ_b. Insulin sensitivity was assessed with a validated composite index (ISI). Disposition indices (DI), which assess insulin secretion in the context of changes in insulin sensitivity, were calculated as the product of Φand ISI. Results: When administered in combination with ongoing metformin therapy or as monotherapy, sitagliptin was associated with substantial reductions in postprandial glycaemic excursion following a meal challenge relative to placebo. Sitagliptin produced significant (p < 0.05 vs. placebo) improvements in Φ_s and Φ_total, regardless of treatment regimen (add‐on to metformin or as monotherapy). For Φ_d, there was a numerical, but not statistically significant, improvement with sitagliptin relative to placebo. Treatment with sitagliptin increased Φ_b, but the difference relative to placebo was only significant with monotherapy. ISI was not significantly different between sitagliptin and placebo. The DIs for the static, dynamic and total measures were significantly (p < 0.05) increased with sitagliptin treatment relative to placebo. Conclusions: In this model‐based analysis, sitagliptin improved beta‐cell function relative to placebo in both fasting and postprandial states in patients with type 2 diabetes.     

Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects

Aims: Albiglutide is a glucagon‐like peptide‐1 (GLP‐1) mimetic generated by genetic fusion of a dipeptidyl peptidase‐IV‐resistant GLP‐1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP‐1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/tolerability profile of albiglutide in non‐diabetic volunteers. Methods: In this single‐blind, randomized, placebo‐controlled trial, 39 subjects (18–60 years, body mass index 19.9–35.0 kg/m²) received placebo (n = 10) or escalating doses of albiglutide (n = 29) on days 1 and 8 in the following sequential cohorts: cohort 1: 0.25 + 1 mg; cohort 2: 3 + 6 mg; cohort 3: 16 + 24 mg; cohort 4: 48 + 60 mg; and cohort 5: 80 + 104 mg. Dose proportionality was evaluated based on area under the plasma drug concentration versus time curve [area under the curve (AUC_{(0–7 days)})] and maximum plasma drug concentration (C_max) for cohorts 2–5 during week 1. Results: Albiglutide had a terminal elimination half‐life (T_1/2) of 6–8 days and time to maximum observed plasma drug concentration (T_max) of 3–4 days. A greater‐than‐dose proportional increase in albiglutide exposure was observed. Albiglutide demonstrated a dose‐dependent trend in reductions of glucose weighted mean AUC and fructosamine levels in healthy subjects. The incidence and severity of adverse events (AEs) was similar between placebo and albiglutide groups. Headache was the most frequent drug‐related AE, followed by constipation, flatulence and nausea. Conclusions: Albiglutide has a half‐life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non‐diabetic subjects.     

Plasma gastric inhibitory polypeptide and glucagon‐like peptide‐1 levels after glucose loading are associated with different factors in Japanese subjects

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are major incretins that potentiate insulin secretion from pancreatic β‐cells. The factors responsible for incretin secretion have been reported in Caucasian subjects, but have not been thoroughly evaluated in Japanese subjects. We evaluated the factors associated with incretin secretion during oral glucose tolerance test (OGTT) in Japanese subjects with normal glucose tolerance (NGT). Materials and Methods: We measured plasma GIP and GLP‐1 levels during OGTT in 17 Japanese NGT subjects and evaluated the factors associated with GIP and GLP‐1 secretion using simple and multiple regression analyses. Results: GIP secretion (AUC‐GIP) was positively associated with body mass index (P < 0.05), and area under the curve (AUC) of C‐peptide (P < 0.05) and glucagon (P < 0.01), whereas GLP‐1 secretion (AUC‐GLP‐1) was negatively associated with AUC of plasma glucose (P < 0.05). The insulinogenic index was most strongly associated with GIP secretion (P < 0.05); homeostasis model assessment β‐cell was the most the strongly associated factor in GLP‐1 secretion (P < 0.05) among the four indices of insulin secretion and insulin sensitivity. Conclusions: Several distinct factors might be associated with GIP and GLP‐1 secretion during OGTT in Japanese subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00078.x, 2011)     

Effect of Metformin on Intact Proinsulin and des 31,32 Proinsulin Concentrations in Subjects with Non-insulin-dependent (Type 2) Diabetes Mellitus

We have investigated the effects of metformin treatment on concentrations of proinsulin-like molecules in subjects with Type 2 (non-insulin-dependent) diabetes mellitus. Metformin was given for 12 weeks in an increasing dose up to 850 mg three times daily in a double-blind placebo-controlled cross-over design to 27 subjects (age 53.0 ± 9.9 years; 19 male, 8 female). Concentrations of insulin and proinsulin-like molecules were measured by highly specific enzymoimmunometric assays. The end of metformin treatment was compared with end of placebo treatment. Metformin lowered fasting plasma glucose concentrations (at 12 weeks, metformin: 8.0 ± 2.5 vs placebo: 12.0 ± 2.3 mmol l⁻¹, p r2 0.001;). Concentrations of intact (median change −2.9 (range −28.4 to +2.5 pmol l⁻¹), p =0.02) and des 31,32 proinsulin (median change −1.6 (range −14.1 to +5.4 pmol l⁻¹), p = 0.07) and percentage of proinsulin-like molecules were reduced by metformin treatment (median change −6 % (range −16 % to +6 %), p = 0.02). Changes in the ratio of proinsulin-like molecules were significantly related with those in fasting plasma glucose (r_s = 0.69, p < 0.001). Changes in concentrations of intact and des 31,32 proinsulin on metformin were not related to changes in body mass index or fasting glucose concentration or changes in concentrations of total triglyceride, cholesterol, and plasminogen activator inhibitor-1. Therefore, metformin treatment in subjects with Type 2 diabetes mellitus significantly reduced concentrations of proinsulin-like molecules over a 12-week period. However, these changes were not related to changes in cardiovascular risk factors seen during metformin treatment. We conclude that short-term effects of metformin treatment on proinsulin-like molecules are similar to those previously observed with dietary treatment in subjects with Type 2 diabetes but opposite to those of sulphonylurea treatment. The effect of long-term treatment with metformin on proinsulin-like molecules needs to be assessed.     

Exenatide effects on gastric emptying rate and the glucose rate of appearance in plasma: A quantitative assessment using an integrative systems pharmacology model

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonist (GLP‐1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food‐related factors on postprandial plasma glucose (PPG) stabilization under GLP‐1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP‐1 and exenatide plasma concentration‐time profiles; (2) GER estimates under placebo, GLP‐1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice‐daily 5‐ and 10‐μg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%‐49%), whereas the midday GluRA peak is affected to a lesser degree (5%‐30%) due to lower plasma drug concentrations. This effect was dose‐dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.     

Efficacy of Metformin in Type II Diabetes: Results of a Double-Blind, Placebo-controlled, Dose-Response Trial

PURPOSE: To study the efficacy and safety of various dosages of metformin as compared with placebo in patients with type II diabetes mellitus.PATIENTS AND METHODS: A 14-week, multicenter, double-blind, dose-response study was conducted. After a 3-week, single-blind, placebo-controlled washout, 451 patients with fasting plasma glucose levels of at least 180 mg/dL were randomized to receive an 11-week course of placebo or metformin given at 500, 1000, 1500, 2000, or 2500 mg daily.RESULTS: Metformin improved glucose variables as compared with placebo. The adjusted mean changes in fasting plasma glucose from baseline associated with each metformin group at week 7, 11, or at endpoint exceeded those associated with placebo by 19 to 84 mg/dL at dosages of 500 to 2000 mg daily, respectively. The corresponding between-group differences in glycated hemoglobin (HbA_1c) ranged from 0.6% to 2.0% at dosages of 500 to 2000 mg daily, respectively. All between-group differences were significant (P < 0.05) for both fasting plasma glucose and HbA_1c at week 7, week 11, and endpoint, except for the difference between placebo and metformin 500 mg in fasting plasma glucose at endpoint (P = 0.054). Treatment-related adverse events occurred in 15% of patients in the placebo group and in 28% in the metformin group (P = 0.02); these were primarily manifested as digestive disturbances, such as diarrhea.CONCLUSIONS: Metformin lowered fasting plasma glucose and HbA_1c generally in a dose-related manner. Benefits were observed with as little as 500 mg of metformin; maximal benefits were observed at the upper limits of the recommended daily dosage. All dosages were well tolerated. Metformin appears to be a useful therapeutic option for physicians who wish to titrate drug therapy to achieve target glucose concentrations.     

LY2189265, a long‐acting glucagon‐like peptide‐1 analogue,showed a dose‐dependent effect on insulin secretion in healthy subjects

Aim: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics and potential immunogenicity of single, escalating subcutaneous injections of a once‐weekly glucagon‐like peptide‐1 analogue in healthy subjects. Methods: This phase 1, three‐period, crossover, double‐blind, placebo‐controlled study investigated single, escalating subcutaneous doses of LY2189265 (LY) ranging from 0.1 to 12 mg; approximately six subjects were randomized to each dose. Parameters of safety, including adverse events, were assessed. The pharmacokinetic profile was assessed over 14 days. Pharmacodynamic parameters (glucose and insulin concentrations) were measured following a step‐glucose infusion (day 3) and as part of an oral glucose tolerance test (OGTT) (day 5). Results: LY was generally well tolerated with some increase in gastrointestinal symptoms with escalating doses. There were small dose‐dependent increases in pulse rate with doses ≥1.0 mg and diastolic blood pressure with doses ≥3.0 mg. The half‐life of LY was approximately 90 h, with C_max occurring between 24 and 48 h in most subjects. Evidence of increase in glucose‐dependent insulin secretion and suppression of serum glucose excursions were observed during an OGTT at all doses compared to placebo; no episodes of hypoglycaemia occurred. No subjects developed antibodies to LY2189265. Conclusions: LY showed an acceptable safety profile and exhibited the expected glucagon‐like peptide‐1 pharmacological effects on glucose suppression and insulin secretion with a half‐life that supports once‐weekly dosing.     

Lixisenatide,a novel GLP‐1 receptor agonist: efficacy,safety and clinical implications for type 2 diabetes mellitus

Recent advances in therapies for the treatment of type 2 diabetes mellitus (T2DM) have led to the development of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), which, unlike insulin and sulphonylurea, are effective, with a low risk of hypoglycaemia. Lixisenatide is recommended as a once‐daily GLP‐1 RA for the treatment of T2DM. In persons with T2DM, lixisenatide 20 µg once‐daily given by bolus subcutaneous injection improves insulin secretion and suppresses glucagon secretion in a glucose‐dependent manner. Compared with the longer‐acting GLP‐1 RA liraglutide, lixisenatide achieved a significantly greater reduction in postprandial plasma glucose (PPG) during a standardized test breakfast in persons with T2DM otherwise insufficiently controlled on metformin alone. This is primarily due to the greater inhibition of gastric motility by lixisenatide compared with liraglutide. The efficacy and safety of lixisenatide was evaluated across a spectrum of T2DM in a series of phase III, randomized, placebo‐controlled trials known as the GetGoal programme. Lixisenatide monotherapy or as add‐on to oral antidiabetic agents or basal insulin achieved significant reductions in glycated haemoglobin, PPG and fasting plasma glucose, with either weight loss or no weight gain. The most frequent adverse events were gastrointestinal and transient in nature. Lixisenatide provides an easy, once‐daily, single‐dose, add‐on treatment to oral antidiabetic agents or basal insulin for the management of T2DM, with little or no increased risk of hypoglycaemia and a potential beneficial effect on body weight.     

Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas

Aims: Prolonged exposure of pancreatic beta‐cells in vitro to the sulphonylureas tolbutamide and glibenclamide induces subsequent desensitization of insulinotropic pathways. Clinically, the insulin‐sensitizing biguanide drug metformin is often administered alongside sulphonylurea as antidiabetic therapy. The present study examines the functional effects of metformin (200 µM) on tolbutamide‐ and glibenclamide‐induced desensitisation. Methods: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin‐secreting BRIN‐BD11 cells. Results: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2–1.7‐fold; p < 0.001) the insulin‐releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide‐induced insulin release at all concentrations (50–400 µM) examined, but tolbutamide‐stimulated insulin secretion was only augmented at higher concentrations (300–400 µM). Exposure for 18 h to 100 µM tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 µM) prevented or partially reversed many of the adverse effects on K_ATP channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP‐1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co‐culture with metformin, but cellular insulin content was depressed. Conclusions: The results suggest that metformin can prevent the aspects of sulphonylurea‐induced beta‐cell desensitization.     

Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients

Aims: Imeglimin is the first in a new tetrahydrotriazine‐containing class of oral antidiabetic agents, the glimins. It has been shown to act on the liver, muscle and pancreatic β‐cells to uniquely target the key defects of type 2 diabetes. Two studies were performed to compare the safety and efficacy of imeglimin with metformin and placebo on glycaemic control in type 2 diabetes patients. Methods: In a 4‐week phase IIa, three‐arm parallel group study, patients were randomized to imeglimin 2000 mg once daily (od), imeglimin 1000 mg twice daily (bid) or metformin 850 mg bid and responses to an oral glucose tolerance test (OGTT) were measured. In an 8‐week phase IIa, four‐arm controlled multi‐centre study, patients were randomized to imeglimin 500 mg bid, imeglimin 1500 mg bid, metformin 850 mg bid or placebo. Glycaemic assessments included area under the curve (AUC) up to 6 h (AUC_0?6h) for glucose during a prolonged meal, fasting plasma glucose (FPG) and HbA1c. Safety and tolerability were assessed in both studies through adverse event recording and laboratory parameters, vital signs and electrocardiogram. Results: Imeglimin was found to be as effective as metformin at reducing the AUC_PG and AUC_0?6h, FPG and HbA1c. Imeglimin exhibited a favourable tolerability profile in comparison to metformin. Conclusions: The results from both studies confirm that imeglimin displays a superior benefit : risk profile compared with metformin in type 2 diabetes patients. The encouraging tolerability profile of imeglimin could make it suitable for combination with other classes of antidiabetic agents and may increase availability to a wider patient population.     

Combination treatment with alogliptin and voglibose increases active GLP‐1 circulation,prevents the development of diabetes and preserves pancreatic beta‐cells in prediabetic db/db mice

Aim: Alogliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, and voglibose, an alpha‐glucosidase inhibitor, have different but complementary mechanisms of action on glucagon‐like peptide‐1 (GLP‐1) regulation and glucose‐lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice. Methods: Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice. Results: After 3 weeks, voglibose treatment increased GLP‐1 secretion (voglibose alone, 1.6‐fold; alogliptin plus voglibose, 1.5‐fold), while it decreased plasma glucose‐dependent insulinotropic polypeptide (GIP) (voglibose alone, ?30%; alogliptin plus voglibose, ?29%). Alogliptin, voglibose and combination treatment decreased plasma DPP‐4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP‐1 levels by 4.5‐, 1.8‐ and synergistically by 9.1‐fold respectively. Combination treatment increased plasma insulin by 3.6‐fold (alogliptin alone, 1.3‐fold; voglibose alone, 1.8‐fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6‐, 3.4‐ and synergistically by 8.5‐fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha‐cell distribution in the pancreatic islet. Conclusions: Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP‐1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta‐cells and islet structure in prediabetic db/db mice.     

Blood pressure and cardiac autonomic nervous system in obese type 2 diabetic patients: effect of metformin administration

BACKGROUND: Hyperinsulinemia/insulin resistance and elevated plasma free fatty acids (FFA) levels are involved in the hypertension and cardiac sympathetic overactivity. Metformin improves insulin action and lower plasma FFA concentrations. We investigate the possible effect of metformin on arterial blood pressure (BP) and cardiac sympathetic nervous system. METHODS: One hundred twenty overweight type 2 diabetic patients were treated by placebo (n = 60) + diet or metformin (850 mg twice daily) (n = 60) + diet for 4 months, to evaluate the effect of metformin treatment on the cardiac autonomic nervous system. Insulin resistance was measured by the Homeostasis Model Assessment (HOMA) index. Heart rate variability (HRV) assessed cardiac sympathovagal balance. RESULTS: Metformin treatment, but not placebo treatment, was associated with a decrease in fasting plasma glucose (P <.05), insulin (P <.05), triglyceride (P <.05), and FFA (P <.03) concentrations and HOMA index (P <.03). Metformin treatment was also associated with a significant improvement in cardiac sympathovagal balance but not in mean arterial BP. Furthermore, in a multivariate analysis, delta change in sympathovagal balance index (LF/HF ratio) were associated with delta change in plasma FFA concentrations and HOMA index independently of gender and delta change in plasma triglyceride and HbA1c concentrations. CONCLUSIONS: Our study demonstrated that metformin treatment might be useful for improving cardiac sympathovagal balance in obese type 2 diabetic patients.