Combination therapy of dipeptidyl peptidase‐4 inhibitors and metformin in type 2 diabetes: rationale and evidence

The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first‐line antidiabetic medication. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are novel oral hypoglycaemic agents that protect glucagon‐like peptide‐1 (GLP‐1) from degradation, maintain the bioactivity of endogenous GLP‐1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP‐4 inhibitors and metformin [as an add‐on, an initial combination or a fixed‐dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP‐1 by increasing GLP‐1 secretion, suppressing activity of DPP‐4 and upregulating the expression of GLP‐1 receptor in pancreatic β‐cells. Conversely, DPP‐4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP‐4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP‐4 inhibitors and metformin.     

The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus

Aim: To determine the efficacy and tolerability of PHX1149, a novel dipeptidyl peptidase‐4 (DPP4) inhibitor, in patients with type 2 diabetes. Methods: This is a multicentre, randomized, double‐blind, placebo‐controlled, 4‐week study in patients with type 2 diabetes with suboptimal metabolic control. Patients with a baseline haemoglobin A_1c (HbA_1c) of 7.3 to 11.0% were randomized 1 : 1 : 1 : 1 to receive once‐daily oral therapy with either PHX1149 (100, 200 or 400 mg) or placebo; patients were on a constant background therapy of either metformin alone or metformin plus a glitazone. Results: Treatment with 100, 200 or 400 mg of PHX1149 significantly decreased postprandial glucose area under the curve AUC_{0–2 h} by approximately 20% (+0.11 ± 0.50, ?2.08 ± 0.51, ?1.73 ± 0.49 and ?1.88 ± 0.48 mmol/l × h, respectively, for placebo and 100, 200 and 400 mg (p = 0.002, 0.008 and 0.004 vs. placebo). Postprandial AUC_{0–2 h} of intact glucagon‐like peptide‐1, the principal mediator of the biological effects of DPP4 inhibitors, was increased by 3.90 ± 2.83, 11.63 ± 2.86, 16.42 ± 2.72 and 15.75 ± 2.71 pmol/l × h, respectively, for placebo and 100, 200 and 400 mg (p = 0.053, 0.001 and 0.002 vs. placebo). Mean HbA_1c was lower in all dose groups; the placebo‐corrected change in the groups receiving 400 mg PHX1149 was ?0.28% (p = 0.02). DPP4 inhibition on day 28 was 53, 73 and 78% at 24 h postdose in the groups receiving 100, 200 and 400 mg PHX1149, respectively. There were no differences in adverse events between PHX1149‐treated and placebo subjects. Conclusions: Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.     

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.     

Glycemic Improvement with a Fixed‐dose combination of DPP‐4 inhibitor + metformin in patients with Type 2 diabetes (GIFT study)

This study investigates changes in A1C following a switch from dual therapy of metformin and DPP‐4 inhibitor to a fixed‐dose combination (FDC) of metformin + DPP‐4 inhibitor following the introduction of the FDC in the provincial formulary. The LMC Diabetes Registry was queried retrospectively for patients with type 2 diabetes, aged between 18 and 80 years with at least one A1C recorded prior and ≥3 months post‐switch. Five hundred and sixty‐eight subjects with mean age 64 ± 12 years and mean A1C 7.7% ± 1.2% met study criteria. Overall, A1C was 0.3% lower post‐switch to FDC (P < .01). In stratified analysis, subjects with baseline A1C between 7% and 10% had 0.4% lower A1C (P < .01), with 31% of these subjects reaching target A1C ≤7%, post‐switch. A1C reduction was greater among patients with a higher baseline pill burden: 0.4% among those using ≥10 pills/day vs. 0.1% for those with <10 pills/day (P = .02). In this real‐world study, switching to FDC of metformin + DPP‐4 inhibitor was associated with a significant improvement in A1C. Switching to FDC, especially in patients with high pill burden, can improve A1C goal achievement in clinical practice.     

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.     

Dipeptidyl‐peptidase IV inhibitor is effective in patients with type 2 diabetes with high serum eicosapentaenoic acid concentrations

Aims/Introduction: Eicosapentaenoic acid (EPA) stimulates glucagon‐like peptide‐1 (GLP‐1) secretion in mice. We investigated the relationship between serum EPA concentrations and the efficacy of dipeptidyl‐peptidase IV (DPP‐4) inhibitor in patients with type 2 diabetes. Materials and Methods: Serum EPA concentrations were measured in 62 consecutive patients with type 2 diabetes who were newly given DPP‐4 inhibitor as a monotherapy or as an add‐on therapy to oral hypoglycemic agents. The dosage of oral hypoglycemic agents was maintained during the observation period. After 24 weeks of treatment with DPP‐4 inhibitor, we evaluated the relationships between a decrease in hemoglobin A1c from baseline and serum EPA concentrations, as well as age, sex, body mass index (BMI), hemoglobin A1c at baseline and usage of antidiabetic concomitant drugs. Results: Hemoglobin A1c was significantly decreased from 8.1 ± 1.1% to 7.2 ± 1.0% by DPP‐4 inhibitor. A decrease in hemoglobin A1c correlated with BMI (r = ?0.396, P = 0.0013), age (r = 0.275, P = 0.0032), hemoglobin A1c at baseline (r = 0.490, P < 0.0001) and log EPA (r = 0.285, P = 0.0246). Multiple regression analysis showed that BMI (β = ?0.419, P = 0.0002), hemoglobin A1c at baseline (β = 0.579, P < 0.0001) and log EPA (β = 0.220, P = 0.0228) were independent determinants of decrease in hemoglobin A1c. Conclusions: DPP‐4 inhibitor is effective in patients with type 2 diabetes with high serum EPA concentrations. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00220.x , 2012)     

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.     

Effect of exercise combined with glucagon‐like peptide‐1 receptor agonist treatment on cardiac function: A randomized double‐blind placebo‐controlled clinical trial

In patients with type 2 diabetes, both supervised exercise and treatment with the glucagon‐like peptide‐1 (GLP‐1) receptor agonist (GLP‐1RA) liraglutide may improve cardiac function. We evaluated cardiac function before and after 16 weeks of treatment with the GLP‐1RA liraglutide or placebo, combined with supervised exercise, in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (mean ± standard deviation [s.d.] ?7.1 ± 1.6 to ?7.7 ± 1.8 cm/s, P = .01), but not in the liraglutide group (?7.1 ± 1.4 to ?7.0 ± 1.4 cm/s, P = .60; between groups, P = .02). Similarly, the mean ± s.d. ratio of early and atrial mitral annular tissue velocities improved in the placebo group (1.0 ± 0.4 to 1.2 ± 0.4, P = .003), but not in the liraglutide group (1.0 ± 0.3 to 1.0 ± 0.3, P = .87; between groups, P = .03). We found no significant differences in heart rate, left ventricular (LV) structure or function within or between the groups. In conclusion, the addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect of exercise on LV diastolic function.     

Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes.

AIMS: Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important insulinotropic hormones that enhance the insulin secretory response to feeding. Their potential for treating Type 2 diabetes is limited by short biological half-life owing to degradation by dipeptidyl peptidase IV (DPP IV). We investigated the acute effects of metformin on DPP IV activity in Type 2 diabetes to elucidate inhibition of DPP IV as a possible mechanism of action. METHODS: Eight fasting subjects with Type 2 diabetes (5M/3F, age 53.1+/-4.2 years, BMI 36.8+/-1.8 kg/m2, glucose 8.9+/-1.2 mmol/l, HbA1c 7.8+/-0.6%) received placebo or metformin 1 g orally 1 week apart in a random, crossover design. RESULTS: Following metformin, DPP IV activity was suppressed compared with placebo (AUC0-6 h 3230+/-373 vs. 5764+/-504 nmol ml/l, respectively, P=0.001). Circulating glucose, insulin and total GLP-1 were unchanged. Metformin also concentration-dependently inhibited endogenous DPP IV activity in vitro in plasma from Type 2 diabetic subjects. CONCLUSION: Oral metformin effectively inhibits DPP IV activity in Type 2 diabetic patients, suggesting that the drug may have potential for future combination therapy with incretin hormones.     

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.     

Change in glycated haemoglobin levels after initiating second‐line therapy in type 2 diabetes: a primary care database study

The aim of the present study was to compare the absolute reduction in glycated haemoglobin (HbA1c) levels at 6 months after initiating second‐line glucose‐lowering therapy in patients with type 2 diabetes treated with metformin monotherapy in general practices. A total of 7009 patients were identified (Disease Analyser Germany: January 2004 to December 2014). The patients' mean ± standard deviation (s.d.) age was 63 ± 11 years, 55.5% were male and their mean ± s.d. HbA1c level was 8.0 ± 1.6%. The initiated second‐line therapies included: dipeptidyl peptidase‐4 (DPP‐4) inhibitors (38.7%); sulphonylureas (36.3%); insulin (13.3%); glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs; 2.5%); thiazolidinediones (5%); and other agents (glinides, aldose‐reductase inhibitors; 4.1%). The mean absolute HbA1c change from baseline was ?0.9% (DPP‐4 inhibitors, ?0.9%; sulphonylureas, ?0.9%; insulin, ?1.1%; GLP‐1RAs, ?0.7%; thiazolidinediones, ?0.9%; and other, ?0.7%; all p < 0.001). Overall, 58% of patients reached the HbA1c target of <7% (DPP‐4 inhibitors, 61.7%; sulphonylureas, 56.7%; insulin, 45.6%; GLP‐1RAs, 62.2%; thiazolidinediones, 69.7%; and other, 57.5%). Compared with sulphonlyureas, DPP‐4 inhibitors, GLP‐1RAs and thiazolidinediones were associated with an increased odds of reaching HbA1c <7% [odds ratio (OR) 1.24, 95% confidence interval (CI) 1.09–1.40; OR 1.43, 95% CI 1.01–2.04; and OR 1.70, 95% CI 1.30–2.23, respectively], whereas insulin was related to a lower odds (0.66, 95% CI 0.55–0.78). In conclusion, in patients with type 2 diabetes very similar reductions in HbA1c after 6 months of second‐line therapy were achieved regardless of the type of therapy.     

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.     

DPP‐4 inhibition and islet function

During recent years, dipeptidyl peptidase‐4 (DPP‐4) inhibition has been included in the clinical management of type 2 diabetes, both as monotherapy and as add‐on to several other therapies. DPP‐4 inhibition prevents the inactivation of the incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1). This results in stimulation of insulin secretion and inhibition of glucagon secretion, and there is also a potential β‐cell preservation effect, as judged from rodent studies; that is, it might target the key islet dysfunction in the disease. In type 2 diabetes. This reduces 24‐h glucose levels and reduces HbA_1c by ≈ 0.8–1.1% from baseline levels of 7.7–8.5%. DPP‐4 inhibition is safe, with a very low risk for adverse events including hypoglycemia, and it prevents weight gain. The present review summarizes the studies on the influence of DPP‐4 inhibition on islet function. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00184.x, 2012)     

Chronic administration of DSP‐7238, a novel,potent, specific and substrate‐selective DPP IV inhibitor,improves glycaemic control and β‐cell damage in diabetic mice

Aims: The purpose of this study is to assess the in vitro enzyme inhibition profile of DSP‐7238, a novel non‐cyanopyrrolidine dipeptidyl peptidase (DPP) IV inhibitor and to evaluate the acute and chronic effects of this compound on glucose metabolism in two different mouse models of type 2 diabetes. Methods: The in vitro enzyme inhibition profile of DSP‐7238 was assessed using plasma and recombinant enzymes including DPP IV, DPP II, DPP8, DPP9 and fibroblast activation protein α (FAPα) with fluorogenic substrates. The inhibition type was evaluated based on the Lineweaver–Burk plot. Substrate selectivity of DSP‐7238 and comparator DPP IV inhibitors (vildagliptin, sitagliptin, saxagliptin and linagliptin) was evaluated by mass spectrometry based on the changes in molecular weight of peptide substrates caused by release of N‐terminal dipeptides. In the in vivo experiments, high‐fat diet‐induced obese (DIO) mice were subjected to oral glucose tolerance test (OGTT) following a single oral administration of DSP‐7238. To assess the chronic effects of DSP‐7238 on glycaemic control and pancreatic β‐cell damage, DSP‐7238 was administered for 11 weeks to mice made diabetic by a combination of high‐fat diet (HFD) and a low‐dose of streptozotocin (STZ). After the dosing period, HbA1c was measured and pancreatic damage was evaluated by biological and histological analyses. Results: DSP‐7238 and sitagliptin both competitively inhibited recombinant human DPP IV (rhDPP IV) with K_i values of 0.60 and 2.1 nM respectively. Neither vildagliptin nor saxagliptin exhibited competitive inhibition of rhDPP IV. DSP‐7238 did not inhibit DPP IV‐related enzymes including DPP8, DPP9, DPP II and FAPα, whereas vildagliptin and saxagliptin showed inhibition of DPP8 and DPP9. Inhibition of glucagon‐like peptide‐1 (GLP‐1) degradation by DSP‐7238 was apparently more potent than its inhibition of chemokine (C‐X‐C motif) ligand 10 (IP‐10) or chemokine (C‐X‐C motif) ligand 12 (SDF‐1α) degradation. In contrast, vildagliptin and saxagliptin showed similar degree of inhibition of degradation for all the substrates tested. Compared to treatment with the vehicle, single oral administration of DSP‐7238 dose‐dependently decreased plasma DPP IV activity and improved glucose tolerance in DIO mice. In addition, DSP‐7238 significantly decreased HbA1c and ameliorated pancreatic damage following 11 weeks of chronic treatment in HFD/STZ mice. Conclusions: We have shown in this study that DSP‐7238 is a potent DPP IV inhibitor that has high specificity for DPP IV and substrate selectivity against GLP‐1. We have also found that chronic treatment with DSP‐7238 improves glycaemic control and ameliorates β‐cell damage in a mouse model with impaired insulin sensitivity and secretion. These findings indicate that DSP‐7238 may be a new therapeutic agent for the treatment of type 2 diabetes.     

The effect of dipeptidyl peptidase-4 inhibition on gastric volume, satiation and enteroendocrine secretion in type 2 diabetes: a double-blind, placebo-controlled crossover study

Objectives The incretin hormone glucagon‐like peptide‐1 (GLP‐1) retards gastric emptying and decreases caloric intake. It is unclear whether increased GLP‐1 concentrations achieved by inhibition of the inactivating enzyme dipeptidyl peptidase‐4 (DPP‐4) alter gastric volumes and satiation in people with type 2 diabetes. Methods In a double‐blind, placebo‐controlled crossover design, 14 subjects with type 2 diabetes received vildagliptin (50 mg bid) or placebo for 10 days in random order separated by a 2‐week washout. On day 7, fasting and postmeal gastric volumes were measured by a ^99mTc single‐photon emission computed tomography (SPECT) method. On day 8, a liquid Ensure® meal was consumed at 30 ml/min, and maximum tolerated volume (MTV) and symptoms 30 min later were measured using a visual analogue scale (VAS) to assess effects on satiation. On day 10, subjects ingested water until maximum satiation was achieved. The volume ingested was recorded and symptoms similarly measured using a VAS. Results Vildagliptin raised plasma GLP‐1 concentrations. However, fasting (248 ± 21 vs. 247 ± 19 ml, P = 0·98) and fed (746 ± 28 vs. 772 ± 26 ml, P = 0·54) gastric volumes did not differ when subjects received vildagliptin or placebo. Treatment with vildagliptin did not alter the MTV of Ensure® (1657 ± 308 vs. 1389 ± 197 ml, P = 0·15) or water compared to placebo (1371 ± 141 vs. 1172 ± 156 ml, P = 0·23). Vildagliptin was associated with decreased peptide YY (PYY) concentrations 60 min after initiation of the meal (166 ± 27 vs. 229 ± 34 pmol/l, P = 0·01). Conclusions Vildagliptin does not alter satiation or gastric volume in people with type 2 diabetes despite elevated GLP‐1 concentrations. Compensatory changes in enteroendocrine secretion could account for the lack of gastrointestinal symptoms.     

Differential effects of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide and metformin on pancreatic β‐cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes

This substudy of the AWARD‐3 trial evaluated the effects of the once‐weekly glucagon‐like peptide‐1 receptor agonist, dulaglutide, versus metformin on glucose control, pancreatic function and insulin sensitivity, after standardized test meals in patients with type 2 diabetes. Meals were administered at baseline, 26 and 52 weeks to patients randomized to monotherapy with dulaglutide 1.5 mg/week (n = 133), dulaglutide 0.75 mg/week (n = 136), or metformin ≥1500 mg/day (n = 140). Fasting and postprandial serum glucose, insulin, C‐peptide and glucagon levels were measured up to 3 h post‐meal. β‐cell function and insulin sensitivity were assessed using empirical variables and mathematical modelling. At 26 weeks, similar decreases in area under the curve for glucose [AUC_glucose (0–3 h)] were observed among all groups. β‐cell function [AUC_insulin/AUC_glucose (0–3 h)] increased with dulaglutide and was unchanged with metformin (p ≤ 0.005, both doses). Dulaglutide improved insulin secretion rate at 9 mmol/l glucose (p ≤ 0.04, both doses) and β‐cell glucose sensitivity (p = 0.004, dulaglutide 1.5 mg). Insulin sensitivity increased more with metformin versus dulaglutide. In conclusion, dulaglutide improves postprandial glycaemic control after a standardized test meal by enhancing β‐cell function, while metformin exerts a greater effect on insulin sensitivity.     

The once‐daily human glucagon‐like peptide‐1 analog,liraglutide, improves β‐cell function in Japanese patients with type 2 diabetes

Aims/Introduction: β‐cell function was evaluated by homeostasis model assessment of β‐cell function (HOMA‐B) index, proinsulin:insulin and proinsulin:C‐peptide ratios in adult, Japanese type 2 diabetes patients receiving liraglutide. Materials and Methods: Data from two randomized, controlled clinical trials (A and B) including 664 Japanese type 2 diabetes patients (mean values: glycated hemoglobin [HbA_1c] 8.61–9.32%; body mass index [BMI] 24.4–25.3 kg/m²) were analyzed. In two 24‐week trials, patients received liraglutide 0.9 mg (n = 268) or glibenclamide 2.5 mg (n = 132; trial A), or liraglutide 0.6, 0.9 mg (n = 176) or placebo (n = 88) added to previous sulfonylurea therapy (trial B). Results: Liraglutide was associated with improved glycemic control vs sulfonylurea monotherapy or placebo. In liraglutide‐treated groups in trials A and B, area under the curve (AUC) _{insulin 0–3 h} was improved (P < 0.001 for all) and the AUC_{insulin 0–3 h}:AUC_{glucose 0–3 h} ratio was increased (estimated treatment difference [liraglutide–comparator] 0.058 [0.036, 0.079]). HOMA‐B significantly increased with liraglutide relative to comparator in trial B (P < 0.05), but not in trial A. The reduction in fasting proinsulin:insulin ratio was 50% greater than in comparator groups. Conclusions: In Japanese type 2 diabetes patients, liraglutide was associated with effective glycemic control, restoration of prandial insulin response and indications of improved β‐cell function. This trial was registered with Clinicaltrials.gov (trial A: no. NCT00393718/JapicCTI‐060328 and trial B: no. NCT00395746/JapicCTI‐060324). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00193.x, 2012)     

Synergistic effect of α‐glucosidase inhibitors and dipeptidyl peptidase 4 inhibitor treatment

Monotherapy of α‐glucosidase inhibitor (α‐GI) or dipeptidyl peptidase 4 (DPP4) inhibitor does not sufficiently minimize glucose fluctuations in the diabetic state. In the present study, we evaluated the combined effects of various of α‐GI inhibitors (acarbose, voglibose or miglitol) and sitagliptin, a DPP4 inhibitor, on blood glucose fluctuation, insulin and active glucagon‐like peptide‐1 (GLP‐1) levels after nutriment loading in mice. Miglitol and sitagliptin elicited a 47% reduction (P < 0.05) of the area under the curve of blood glucose levels for up to 2 h after maltose‐loading, a 60% reduction (P < 0.05) in the range of blood glucose fluctuation, and a 32% decrease in plasma insulin compared with the control group. All three of the combinations elicited a 2.5–4.9‐fold synergistic increase in active GLP‐1 (P < 0.05 vs control). Thus, combined treatment with the α‐GI miglitol, which more strongly inhibits the early phase of postprandial hyperglycemia, and DPP4 inhibitor yields both complementary and synergistic effects, and might represent a superior anti‐hyperglycemic therapy. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00081.x, 2011)     

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.     

Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes

Aims/hypothesis We assessed the effects of vildagliptin, a novel dipeptidyl peptidase IV inhibitor, on postprandial lipid and lipoprotein metabolism in patients with type 2 diabetes.Subjects, materials and methods This was a single-centre, randomised, double-blind study in drug-naive patients with type 2 diabetes. Patients received vildagliptin (50 mg twice daily, n=15) or placebo (n=16) for 4 weeks. Triglyceride, cholesterol, lipoprotein, glucose, insulin, glucagon and glucagon-like peptide-1 (GLP-1) responses to a fat-rich mixed meal were determined for 8 h postprandially before and after 4 weeks of treatment.Results Relative to placebo, 4 weeks of treatment with vildagliptin decreased the AUC_0–8h for total trigyceride by 22±11% (p=0.037), the incremental AUC_0–8h (IAUC_0–8h) for total triglyceride by 85±47% (p=0.065), the AUC_0–8h for chylomicron triglyceride by 65±19% (p=0.001) and the IAUC_0–8h for chylomicron triglyceride by 91±28% (p=0.002). This was associated with a decrease in chylomicron apolipoprotein B-48 (AUC_0–8h, −1.0±0.5 mg l⁻¹ h, p=0.037) and chylomicron cholesterol (AUC_0–8h, −0.14±0.07 mmol l⁻¹ h, p=0.046). Consistent with previous studies, 4 weeks of treatment with vildagliptin also increased intact GLP-1, suppressed inappropriate glucagon secretion, decreased fasting and postprandial glucose, and decreased HbA_1c from a baseline of 6.7% (change, −0.4±0.1%, p<0.001), all relative to placebo.Conclusions/interpretation Treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal. The mechanisms underlying the effects of this dipeptidyl peptidase IV inhibitor on postprandial lipid metabolism remain to be explored.