Liraglutide: short-lived effect on gastric emptying -- long lasting effects on body weight

Aim: Previous studies with the novel once daily glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide and the GLP‐1 receptor agonist exenatide have revealed profound insulinotrophic and antidiabetic effects, but also potent effects on gastric emptying (GE) and long‐term and lasting reductions in body weight. In this study, we examined the acute and chronic effects of two different GLP‐1 analogues with different pharmacokinetic profiles on GE, food intake and body weight. Methods: On the basis of a series of dose‐finding studies, the doses of exenatide and liraglutide with similar acute anorectic effects were identified. GE was assessed using a standard acetaminophen release assay. After the acute test, rats were dosed bi‐daily for 14 days in which period food intake and body weight was monitored. On day 14, the GE rate was reassessed. Results: While both compounds exerted robust acute reductions in GE, the effect was markedly diminished following 14 days of dosing with liraglutide. In contrast, exenatide‐treated rats still displayed a profound reduction in GE at the 14‐day time‐point. Both compounds exerted similar effects on body weight. Conclusion: The data suggest that the ‘gastric inhibitory’ GLP‐1 receptors in rats are subject to desensitization/tachyphylaxis but that this effect is dependent on full 24‐h exposure as obtained by liraglutide. The body weight‐lowering effects of GLP‐1 receptor stimulation are not subject to desensitization. These data indicate that regulation of appetite signals in the brain, and not GE, is the main mechanism for liraglutide‐induced weight loss.     

Primary‐care observational database study of the efficacy of GLP‐1 receptor agonists and insulin in the UK

Aims

We investigated use and efficacy of glucagon‐like peptide‐1 (GLP‐1) receptor agonists in UK practice.

Methods

People starting a GLP‐1 receptor agonist (exenatide, liraglutide) or insulin (glargine, detemir, NPH) after a regimen of two or three oral glucose‐lowering agents were identified from The Health Information Network observational primary care database (2007–2011). Mean change in HbA_1c and body weight were compared at 1 year between cohorts, adjusting for baseline characteristics.

Results

Baseline characteristics of GLP‐1 receptor agonist (n = 1123) vs. insulin (n = 1842) users were HbA_1c 78 vs. 84 mmol/mol (9.3 vs. 9.8%) and BMI 38.2 vs. 30.9 kg/m². The GLP‐1 receptor agonist cohort was younger, had shorter diabetes duration and follow‐up, less microvascular disease and heart failure, higher estimated glomerular filtration rate and more use of oral glucose‐lowering agents. Lower HbA_1c reduction on GLP‐1 receptor agonist [7 vs. 13 mmol/mol (0.6 vs. 1.2%) (n = 366 vs. 892)] was not statistically significant [adjusted mean difference ?1.4 (95% CI ?4.1, 1.2) mmol/mol], except in the highest HbA_1c quintile [>96 mmol/mol (>10.9%); adjusted mean difference ?17.8 (?28.6, ?7.0) mmol/mol]. GLP‐1 receptor agonist users lost weight [?4.5 vs. +1.5 kg; adjusted mean difference 4.7 (3.7, 5.8) kg; n = 335 vs. 634]. A UK 6‐month target reduction for GLP‐1 receptor agonists of 11 mmol/mol (1.0%) HbA_1c and 3% weight was reached by 24.9% of those continuing treatment.

Conclusions

Those starting GLP‐1 receptor agonists are heavier with better glycaemic control than those starting basal insulin. Subsequently, they have improved weight change, with similar HbA_1c reduction unless baseline HbA_1c is very high. The UK 6‐month GLP‐1 receptor agonist target is usually not reached.

     

Food intake in lean and obese mice after peripheral administration of glucagon-like peptide 2

We investigated the potential anorectic action of peripherally administered glucagon-like peptide 2 (GLP2) in lean and diet-induced obese (DIO) mice. Mice, fasted for 16?h, were injected i.p. with native GLP2 or [Gly2]GLP2, stable analog of GLP2, before or after GLP2 (3-33), a GLP2 receptor (GLP2R) antagonist, or exendin (9-39), a GLP1R antagonist. Food intake was measured at intervals 1, 2, 4, 8, and 24?h postinjection. In addition, we tested in lean mice the influence of [Gly2]GLP2 on gastric emptying and the effects of GLP1 alone or in combination with [Gly2]GLP2 on food intake. [Gly2]GLP2 dose dependently and significantly inhibited food intake in lean and DIO mice. The reduction of food intake occurred in the first hour postinjection and it was sustained until 4?h postinjection in lean mice while it was sustained until 2?h postinjection in DIO mice. GLP2 significantly inhibited food intake in both lean and DIO mice but only in the first hour postinjection. The efficiency of [Gly2]GLP2 or GLP2 in suppressing food intake was significantly weaker in DIO mice compared with lean animals. The [Gly2]GLP2 anorectic actions were blocked by the GLP2R antagonist GLP2 (3-33) or by the GLP1R antagonist exendin (9-39). The coadministration of [Gly2]GLP2 and GLP1 did not cause additive effects. [Gly2]GLP2 decreased the gastric emptying rate. Results suggest that GLP2 can reduce food intake in mice in the short term, likely acting at a peripheral level. DIO mice are less sensitive to the anorectic effect of the peptide.     

The extra‐pancreatic effects of GLP‐1 receptor agonists: a focus on the cardiovascular,gastrointestinal and central nervous systems

The glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta‐cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP‐1 receptors are also expressed in extra‐pancreatic tissues and trial data suggest that GLP‐1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP‐1 or GLP‐1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP‐1RAs in both people with type 2 diabetes and obese people without diabetes. GLP‐1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP‐1RA‐induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP‐1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra‐pancreatic effects of GLP‐1RAs could provide multi‐factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP‐1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP‐1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future.     

Combination of the insulin sensitizer, pioglitazone, and the long-acting GLP-1 human analog, liraglutide, exerts potent synergistic glucose-lowering efficacy in severely diabetic ZDF rats

Objective: Severe insulin resistance and impaired pancreatic β‐cell function are pathophysiological contributors to type 2 diabetes, and ideally, antihyperglycaemic strategies should address both. Research Design and Methods: Therapeutic benefits of combining the long‐acting human glucagon‐like peptide‐1 (GLP‐1) analog, liraglutide (0.4 mg/kg/day), with insulin sensitizer, pioglitazone (10 mg/kg/day), were assessed in severely diabetic Zucker diabetic fatty rats for 42 days. Impact on glycaemic control was assessed by glycated haemoglobin (HbA_1C) at day 28 and by oral glucose tolerance test at day 42. Results: Liraglutide and pioglitazone synergistically improved glycaemic control as reflected by a marked decrease in HbA_1C (liraglutide + pioglitazone: 4.8 ± 0.3%; liraglutide: 8.8 ± 0.6%; pioglitazone: 7.9 ± 0.4%; vehicle: 9.7 ± 0.3%) and improved oral glucose tolerance at day 42 (area under the curve; liraglutide + pioglitazone: 4244 ± 445 mmol/l × min; liraglutide: 7164 ± 187 mmol/l × min; pioglitazone: 7430 ± 446 mmol/l × min; vehicle: 8093 ± 139 mmol/l × min). A 24‐h plasma glucose profile at day 38 was significantly decreased only in the liraglutide + pioglitazone group. In addition, 24‐h insulin profile was significantly elevated only in the liraglutide + pioglitazone group. Liraglutide significantly decreased food intake alone and in combination with pioglitazone, while pioglitazone alone increased cumulated food intake. As a result, rats on liraglutide alone gained significantly less weight than vehicle‐treated rats, whereas rats on pioglitazone alone gained significantly more body weight than vehicle‐treated rats. However, combination therapy with liraglutide and pioglitazone caused the largest weight gain, probably reflecting marked improvement of energy balance because of reduction of glucosuria. Conclusions: Combination therapy with insulinotropic GLP‐1 agonist liraglutide and insulin sensitizer, pioglitazone, improves glycaemic control above and beyond what would be expected from additive effects of the two antidiabetic agents.     

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.     

Diabetes and obesity treatment based on dual incretin receptor activation: ‘twincretins’

The gut incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion and regulate glucagon secretion. GLP‐1 also slows gastric emptying and suppresses appetite, whereas GIP seems to affect lipid metabolism. The introduction of selective GLP‐1 receptor (GLP‐1R) agonists for the treatment of type 2 diabetes and obesity has increased the scientific and clinical interest in incretins. Combining the body weight‐lowering and glucose‐lowering effects of GLP‐1 with a more potent improvement of β cell function through additional GIP action could potentially offer a more effective treatment of diabetes and obesity, with fewer adverse effects than selective GLP‐1R agonists; therefore, new drugs designed to co‐activate both the GIP receptor (GIPR) and the GLP‐1R simultaneously are under development. In the present review, we address advances in the field of GIPR and GLP‐1R co‐agonism and review in vitro studies, animal studies and human trials involving co‐administration of the two incretins, as well as results from a recently developed GIPR/GLP‐1R co‐agonist, and highlight promising areas and challenges within the field of incretin dual agonists.     

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once‐daily human glucagon‐like peptide‐1 analogue liraglutide as add‐on to sulphonylurea in Japanese patients with type 2 diabetes

Aim: Sulphonylureas (SUs) are often used as first‐line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. Methods: The efficacy and safety of the once‐daily human glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m²; mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24‐week, double‐blind, parallel‐group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was ?1.56 (s.d. 0.84) and ?1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and ?0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference ?1.47 mmol/l and ?1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: ?0.37 kg), while mean body weight decreased in subjects receiving placebo (?1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose‐dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.     

Review of head‐to‐head comparisons of glucagon‐like peptide‐1 receptor agonists

Currently, six glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short‐acting exenatide twice daily and lixisenatide once daily; and longer‐acting liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP‐1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head‐to‐head trials and one large phase II study have compared the efficacy and safety of these seven GLP‐1RAs. All trials were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short‐acting GLP‐1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer‐acting agents, whereas the longer‐acting compounds reduced plasma glucose throughout the 24‐h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater than those with exenatide once weekly, albiglutide and dulaglutide. The most frequently observed AEs with GLP‐1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea. Nauseaoccurred less frequently, however, with exenatide once weekly and albiglutide than exenatide twice daily and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection‐site reactions than liraglutide and dulaglutide. GLP‐1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP‐1RAs and delivery methods may further expand future treatment options.     

Vildagliptin vs liraglutide as a second‐line therapy switched from sitagliptin‐based regimens in patients with type 2 diabetes: A randomized,parallel‐group study

Introduction

A step-up strategy for dipeptidyl peptidase (DPP)-4 inhibitor-based regimens has not yet been established. In addition, similarities and differences between DPP-4 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists remain to be elucidated in humans. We investigated the pleiotropic effects of vildagliptin vs liraglutide in patients with type 2 diabetes on sitagliptin-based regimens in an open-label, randomized, clinical trial.

Materials and Methods

A total of 122 patients with type 2 diabetes that was inadequately controlled by sitagliptin-based regimens were randomly assigned to either vildagliptin (50 mg, twice daily) or liraglutide treatment (0.9 mg, once daily) for 12 weeks. The primary outcomes were glycated hemoglobin and body mass index.

Results

Both vildagliptin and liraglutide significantly lowered glycated hemoglobin within 12 weeks after switching from sitagliptin, but liraglutide produced a greater reduction (−0.67 ± 0.12% vs −0.36 ± 0.53%). Liraglutide lowered body mass index, whereas vildagliptin did not affect body mass index. Vildagliptin lowered fasting C-peptide immunoreactivity, but liraglutide did not. Vildagliptin increased serum levels of adiponectin, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, whereas liraglutide had no effect on these levels. Quality of life, assessed using the diabetes treatment satisfaction questionnaire, was not impaired in either group. The most common adverse events were gastrointestinal symptoms, which occurred with similar frequencies in both groups.

Conclusions

Vildagliptin-mediated improvements in glycemic control did not correlate with indices for insulin secretion and insulin sensitivity. Switching from sitagliptin to liraglutide is useful in managing hyperglycemia and weight. Each agent exerts unique pleiotropic effects. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (no. 000004953).     

Anti-obesity effects of KR-66195, a synthetic DPP-IV inhibitor,in diet-induced obese mice and obese-diabetic ob/ob mice

Objective

We investigated whether KR-66195, a new synthetic dipeptidyl dipeptidase IV inhibitor, could prevent weight gain, as well as improving glycemic control in diet-induced obese (DIO) and ob/ob mice.

Materials/Methods

Male C57BL/6 mice were randomly assigned to the following groups: chow diet, high-fat diet, and high-fat diet with KR-66195. After KR-66195 treatment for eight weeks, intraperitoneal glucose tolerance tests were performed. A pair-feeding study was performed to investigate the mechanisms of the anti-obesity effects of KR-66195 in DIO mice. Female ob/ob mice were treated with KR-66195 for three weeks and compared to the vehicle-treated group.

Results

In DIO mice, KR-66195 treatment increased the plasma glucagon-like peptide (GLP)-1 levels and improved glucose tolerance. This treatment also reduced body weight gain (5.38 ± 0.94 g vs. 12.08 ± 0.55 g, P < 0.01) and food intake (2.41 ± 0.09 g vs. 2.79 ± 0.11 g, P < 0.05). In ob/ob mice, KR-66195 treatment for three weeks resulted in comparable effects in DIO mice. In the pair-feeding study, KR-66195-treated mice exhibited a 16% increase in energy expenditure (kcal/h/kg lean body mass) without significant differences in body weight or activities compared with pair-fed mice. These results suggest that KR-66195 prevented weight gain in DIO mice by decreasing food intake, as well as increasing energy expenditure.

Conclusions

KR-66195 markedly increased plasma levels of GLP-1, resulting in the probable improvement in glucose tolerance and reduced body weight and food intake. Thus, KR-66195 might be further developed as a therapeutic drug to treat obesity, as well as diabetes.     

Interactions of amylinergic and melanocortinergic systems in the control of food intake and body weight in rodents

Aims: Amylinergic and melanocortinergic systems have each been implicated in energy balance regulation. We examined the interactive effects of both systems using gene knockout and pharmacological approaches. Methods: Acute food consumption was measured in overnight fasted male wild‐type (WT) and melanocortin‐4 receptor (MC‐4R) deficient rats and in male and female WT and amylin knockout mice (AmyKO). Changes in food intake, body weight and composition in male WT and MC‐4R deficient rats and in male diet‐induced obese (DIO) rats. Pharmacological treatments included either rat amylin, murine leptin and/or the MC‐4R agonist, Ac‐R[CEH‐dF‐RWC]‐amide. Results: Amylin (10 µg/kg, IP) decreased food intake in WT but not in MC‐4R deficient rats (30 and 60 min post‐injection). Ac‐R[CEH‐dF‐RWC]‐amide (100 µg/kg, IP) suppressed food intake similarly in male WT and AmyKO, but was ineffective in female AmyKO. Amylin (50 µg/kg/day for 28 days) and leptin (125 µg/kg/day) synergistically reduced food intake and body weight in WT and MC‐4R deficient rats to a similar extent. Amylin (100 µg/kg) combined with Ac‐R[CEH‐dF‐RWC]‐amide (100 µg/kg, IP) decreased acute food intake over 3 h to a greater extent than either agent alone in fasted mice. In DIO rats, additive anorexigenic, weight‐ and fat‐lowering effects were observed over 12 days with the combination of rat amylin (50 µg/kg/day) and Ac‐R[CEH‐dF‐RWC]‐amide (2.3 mg/kg, SC injected daily). Conclusions: Although amylin's acute anorexigenic effects are somewhat blunted in MC‐4R deficiency and those of MC‐4R agonism in amylin deficiency, these effects are surmountable with pharmacological administration lending therapeutic potential to combined amylin/melanocortin agonism for obesity.     

Effects of 6 months glucagon‐like peptide‐1 receptor agonist treatment on endothelial function in type 2 diabetes mellitus patients

Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) are used for treatment in type 2 diabetes mellitus (T2DM). Little is known about their cardiovascular (CV) impact. We sought to determine the effects of chronic treatment on vascular function in T2DM. Brachial artery endothelial‐dependent flow‐mediated dilation (FMD) and endothelial‐independent glyceryl trinitrate (GTN) function and carotid intima‐medial thickness (cIMT) were assessed in 11 severely obese T2DMs (4 females, 7 males: 55 ± 8 years, diabetes duration 8.3 ± 4.7 years mean ± s.d.) before and after 6 months GLP‐1 RA. Body weight (5.3 ± 1.2 kg; p < 0.05) and magnetic resonance imaging determined total and subcutaneous fat, but not visceral fat, decreased. Glycaemic control improved. There were no significant changes in FMD, GTN and cIMT (?1.1 ± 0.4%, 0.3 ± 3.0% and 0.00 ± 0.04 mm, respectively). Despite significant improvements in body composition and glycaemic control, 6 months GLP‐1 RA treatment did not modulate vascular function. Alternative strategies may therefore be needed to reduce the burden of CV risk in severely obese patients with long‐standing T2DM.     

Short‐acting glucagon‐like peptide‐1 receptor agonists as add‐on to insulin therapy in type 1 diabetes: A review

A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol) and, furthermore, an increasing number of patients with type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy, which is associated with well‐described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because of their glucagonostatic and extrapancreatic effects. So far, the focus has mainly been on the long‐acting GLP‐1RAs, but the risk–benefit ratio emerging from studies evaluating the effect of long‐acting GLP‐1RAs as adjunctive therapy to insulin therapy in patients with type 1 diabetes has been disappointing. This might be attributable to a lack of glucagonostatic effect of these long‐acting GLP‐1RAs in type 1 diabetes, alongside development of tachyphylaxis to GLP‐1‐induced retardation of gastric emptying. In contrast, the short‐acting GLP‐1RAs seem to have a preserved and sustained effect on glucagon secretion and gastric emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short‐acting GLP‐1RAs are all derived from small open‐label trials and should thus be interpreted with caution. In the present paper we review the potential role of GLP‐1RAs, in particular short‐acting GLP‐1RAs, as add‐on to insulin in the treatment of type 1 diabetes.     

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.     

Twincretin as a potential therapeutic for the management of type 2 diabetes with obesity

Unimolecular peptide‐based dual agonists against glucagon‐like peptide‐1 receptor (GLP‐1R) and glucose‐dependent insulinotropic polypeptide receptor (GIPR) have been gaining much attention recently as novel antidiabetic agents that can potentially control glycemia and bodyweight. Although GLP‐1 and GIP both enhance insulin secretion and subsequently ameliorate postprandial glucose excursion, most research has focused on GLP‐1R as a therapeutic target for type 2 diabetes. This is partly because the effects of GIPR activation on glycemia and bodyweight have been controversial. GIPR‐deficient mice showed impaired glucose tolerance with reduced β‐cell function and resistance to high‐fat diet‐induced obesity, whereas GIPR agonists improved glycemia and prevented high‐fat diet‐induced obesity in mice. Conflicting results in mice might be explained by pharmacological levels of GIP signal in the central nervous systems decreasing food intake and overcoming the obesogenic effects of GIP at physiological levels in adipose tissues. Thus, GIPR activation at pharmacological levels might result in bodyweight reduction. Indeed, bodyweight reduction by GIPR/GLP‐1R dual agonists was greater than GLP‐1R single agonists in individuals with type 2 diabetes. Thus, GLP‐1R/GIPR dual agonists can add additional therapeutic efficacy to tailored diabetes care, especially among obese individuals with type 2 diabetes. However, caution should be exercised as to whether or not these drugs are appropriate for the management of Asian type 2 diabetes patients, which are primarily characterized by non‐obesity and impaired β‐cell function, as well as in that of elderly adults with type 2 diabetes, who tend to develop sarcopenia and frailty as a result of poor energy intake.     

Incretin therapies: highlighting common features and differences in the modes of action of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors

Over the last few years, incretin‐based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon‐like peptide 1 (GLP‐1), which is partly responsible for augmenting glucose‐dependent insulin secretion in response to nutrient intake (the ‘incretin effect’). In patients with T2D, pharmacological doses/concentrations of GLP‐1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose‐dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin‐based glucose‐lowering medications. Two classes of incretin‐based therapies are available: GLP‐1 receptor agonists (GLP‐1RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors. GLP‐1RAs promote GLP‐1 receptor (GLP‐1R) signalling by providing GLP‐1R stimulation through ‘incretin mimetics’ circulating at pharmacological concentrations, whereas DPP‐4 inhibitors prevent the degradation of endogenously released GLP‐1. Both agents produce reductions in plasma glucose and, as a result of their glucose‐dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non‐glycaemic benefits such as weight loss, improvements in β‐cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin‐based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.     

Efficacy and safety of liraglutide,a once‐daily human glucagon‐like peptide‐1 analogue,in Latino/Hispanic patients with type 2 diabetes: post hoc analysis of data from four phase III trials

The aim of the present analysis was to evaluate the efficacy of the glucagon‐like peptide‐1 receptor agonist liraglutide in Latino/Hispanic individuals with type 2 diabetes, in addition to comparing its treatment effects with those observed in non‐Latino/Hispanic individuals. Analyses were performed on patient‐level data from a subset of individuals self‐defined as Latino/Hispanic from four phase III studies, the LEAD‐3, LEAD‐4, LEAD‐6 and 1860‐LIRA‐DPP‐4 trials. Endpoints included change in glycated haemoglobin (HbA1c) and body weight from baseline. In Latino/Hispanic patients (n = 505; 323 treated with liraglutide) after 26 weeks, mean HbA1c reductions were significantly greater with both liraglutide 1.2 and 1.8 mg versus comparator or placebo in the LEAD‐3 and LEAD‐4 studies, and with 1.8 mg liraglutide in the 1860‐LIRA‐DPP‐4 trial. In LEAD‐3 both doses led to significant differences in body weight change among Latino/Hispanic patients versus the comparator. With 1.8 mg liraglutide, difference in weight change was significant only in the 1860‐LIRA‐DPP‐4 trial versus sitagliptin. For both endpoints Latino/Hispanic and non‐Latino/Hispanic patients responded to liraglutide similarly. In summary, liraglutide is efficacious for treatment of type 2 diabetes in Latino/Hispanic patients, with a similar efficacy to that seen in non‐Latino/Hispanic patients.