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.     

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.     

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.     

Efficacy and safety of canagliflozin as add‐on therapy to a glucagon‐like peptide‐1 receptor agonist in Japanese patients with type 2 diabetes mellitus: A 52‐week,open‐label,phase IV study

Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are antihyperglycaemic agents with weight‐lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add‐on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP‐1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and HDL cholesterol from baseline to week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (?0.70%; paired t test, P < .001). Significant changes were also observed in FPG (?34.7 mg/dL), body weight (?4.46%), SBP (?7.90 mm Hg), and HDL cholesterol (7.60%; all P < .001). The incidence of AEs, adverse drug reactions and hypoglycaemia was 71.8%, 32.4% and 9.9%, respectively. All hypoglycaemic events were mild. These findings suggest that the long‐term combination of canagliflozin with a GLP‐1RA is effective and well tolerated in Japanese patients with T2DM.     

Effect of single‐dose DPP‐4 inhibitor sitagliptin on β‐cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug‐naïve,well‐controlled type 2 diabetes subjects

To explore the effects of a single dose of the DPP‐4 inhibitor sitagliptin on glucose‐standardized insulin secretion and β‐cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug‐naïve, well‐controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). β‐cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β‐cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing β‐cell glucose sensitivity. Sitagliptin also increased active glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) and reduced total (reflecting the secretion) GIP, but not total GLP‐1 levels. We conclude that a single dose of DPP‐4 inhibition induces dissociated effects on different aspects of β‐cell function and incretin hormones after meal ingestion in both healthy and well‐controlled T2D subjects.     

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.     

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.     

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.     

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.     

GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self‐regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β‐cells by glucagon‐like peptide 1 receptor (GLP‐1R) agonists is known to be glucose‐dependent. GLP‐1R agonists potentiate glucose‐stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose‐regulated’ activity of GLP‐1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non‐regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP‐1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP‐1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP‐1R signalling promotes insulin secretion from pancreatic β‐cells via a glucose‐dependent process.     

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.     

Composite endpoints in trials of type‐2 diabetes

Composite endpoints (CEPs) are being used more frequently as outcomes for trials of drugs in type‐2 diabetes. We reviewed the literature to determine how CEPs have been used to date in trials of drugs for type‐2 diabetes. A systematic search was undertaken on Medline, Embase and Cochrane databases and Clinicaltrials.gov for randomized controlled trials of currently marketed agents including SGLT‐2 inhibitors (dapagliflozin), GLP‐1 agonists (exenatide, liraglutide) and DPP‐4 inhibitors (linagliptin, saxagliptin, sitagliptin and vildagliptin). CEPs used were identified as well as numbers and percentages of patients achieving each. Thirty‐six studies were identified that reported results on ≥1 CEP; 15 different CEPs were reported (7 with 2 components, 8 with 3 components). All CEPs addressed goals recommended by the American Diabetes Association (ADA). All included HbA1c<7%; other endpoints measured weight, blood pressure and hypoglycaemic events. Results were obtained for CEPs from 6 months to 2 years. Rates of achieving CEPs decreased with increasing numbers of components and outcomes assessed. CEPs are becoming used as indicators of clinical outcomes in type‐2 diabetes trials, but are still not common. More research is required to identify optimal CEPs. Standardization of outcomes and their reporting is needed.     

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.     

Role of γ‐aminobutyric acid signalling in the attenuation of counter‐regulatory hormonal responses after antecedent hypoglycaemia in healthy men

The attenuated counter‐regulatory response to hypoglycaemia after antecedent hypoglycaemic episodes has been observed in animals to be associated with an increase in γ‐aminobutyric acid (GABA) signalling. We therefore tested the hypothesis that the pharmacological suppression of GABAergic activity during a repeated hypoglycaemic episode enhances counter‐regulatory responses. Fourteen healthy men participated in two experimental sessions each comprising three insulin‐induced hypoglycaemic episodes. Before the third hypoglycaemic episode, participants received the GABA‐antagonistic drug modafinil (200 mg orally) and placebo, respectively. In the placebo condition, the secretion of norepinephrine, adrenocorticotropic hormone, cortisol and growth hormone, and the perception of neuroglycopenic symptoms were attenuated during the third as compared with the first hypoglycaemic episode (each p < 0.05). Modafinil reversed this effect for the noradrenergic response (p < 0.05), while not significantly altering the attenuation of other hormonal responses and symptom perception (p > 0.3). Our findings indicate that increased GABAergic transmission could contribute to aspects of the attenuated counter‐regulatory response after recurrent hypoglycaemia in humans.     

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.     

Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study

Aims: To evaluate the efficacy and safety of linagliptin 5 and 10 mg vs. placebo and voglibose in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: This study enrolled patients with inadequately controlled T2DM who were previously treated with one or two oral antidiabetics or were drug naÏve. After a 2 to 4‐week washout and placebo run‐in, 561 patients were randomized (2 : 2 : 2 : 1) to double‐blind treatment with linagliptin 5 or 10 mg qd, voglibose 0.2 mg tid or placebo. The primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) with linagliptin vs. placebo after 12 weeks and vs. voglibose after 26 weeks. Results: Baseline characteristics were well balanced across treatment groups (overall mean HbA1c was 8.01%). The adjusted mean (95% confidence interval) treatment differences at week 12 were ?0.87% (?1.04, ?0.70; p < 0.0001) and ?0.88% (?1.05, ?0.71; p < 0.0001) for linagliptin 5 and 10 mg vs. placebo and at week 26 were ?0.32% (?0.49, ?0.15; p = 0.0003) and ?0.39% (?0.56, ?0.21; p < 0.0001) for linagliptin 5 and 10 mg vs. voglibose. At week 12, mean HbA1c was 7.58, 7.48 and 8.34% in patients receiving linagliptin 5 mg, linagliptin 10 mg and placebo, respectively. At week 26, mean HbA1c was 7.63% with linagliptin 5 mg, 7.50% with linagliptin 10 mg and 7.91% with voglibose. Drug‐related adverse event rates were comparable across treatment groups over 12 weeks (9.4% linagliptin 5 mg, 8.8% linagliptin 10 mg and 10.0% placebo) and 26 weeks (11.3% linagliptin 5 mg, 10.6% linagliptin 10 mg and 18.5% voglibose). There were no documented cases of hypoglycaemia. Conclusions: Linagliptin showed superior glucose‐lowering efficacy and comparable safety and tolerability to both placebo and voglibose in Japanese patients with T2DM.     

The use of GLP‐1 receptor agonists in hospitalised patients: An untapped potential

In the outpatient setting, glucagon‐like peptide‐1 (GLP‐1) receptor agonists have proved to be highly efficacious drugs that provide glycaemic control with a low risk of hypoglycaemia. These characteristics make GLP‐1 receptor agonists attractive agents to treat dysglycaemia in perioperative or high‐dependency hospital settings, where glycaemic variability and hyperglycaemia are associated with poor prognosis. GLP‐1 also has a direct action on the myocardium and vasculature—which may be advantageous in the immediate aftermath of a vascular insult. This is a narrative review of the work in this area. The aim was to determine the populations of hospitalised patients being evaluated and the clinical and mechanistic end‐points tested, with the institution of GLP‐1 therapy in hospital. We searched the PubMed, Embase, and Google scholar databases, combining the term “glucagon‐like peptide 1” OR “GLP‐1” OR “incretin” OR “liraglutide” OR “exenatide” OR “lixisenatide” OR “dulaglutide” OR “albiglutide” AND “inpatient” OR “hospital” OR “perioperative” OR “postoperative” OR “surgery” OR “myocardial infarction” OR “stroke” OR “cerebrovascular disease” OR “transient ischaemic attack” OR “ICU” OR “critical care” OR “critical illness” OR “CCU” OR “coronary care unit.” Pilot studies were reported in the fields of acute stroke, cardiac resuscitation, coronary care, and perioperative care that showed advantages for GLP‐1 therapy, with normalisation of glucose, lower glucose variability, and lower risk of hypoglycaemia. Animal and human studies have reported improvements in myocardial performance when given acutely after vascular insult or surgery, but these have yet to be translated into randomised clinical trials.     

Glucose‐dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin‐1‐dependent manner in mice

Recently, glucagon‐like peptide‐1 (GLP‐1) levels have been found to be increased in response to inflammatory stimuli, leading to insulin secretion and prevention of hyperglycaemia during endotoxemia in mice. In the present study, we assess the relevance of the other incretin hormone, glucose‐dependent insulinotropic peptide (GIP), as a regulator of glucose metabolism under inflammatory conditions. We found that lipopolysaccharide (LPS) increased GIP secretion in a time‐ and dose‐dependent manner in C57BL/6J mice. To elucidate the underlying mechanisms, mice were injected with inflammatory cytokines known to be released by LPS. Circulating GIP levels significantly increased in response to interleukin (IL)‐1β but not IL‐6 or tumour necrosis factor (TNF)‐α administration. Using respective knockout mice we found that LPS‐mediated GIP secretion was selectively dependent on IL‐1 signalling. To evaluate the functional relevance of inflammatory GIP secretion we pretreated mice with the GIP‐receptor antagonist (Pro3)GIP. This blunted LPS‐induced TNF‐α and IL‐6 secretion but did not affect LPS‐induced insulin secretion or blood glucose‐lowering. In conclusion, GIP provides a novel link between the immune system and the gut, with proinflammatory‐immune modulatory function but minor glucose regulatory relevance in the context of acute endotoxemia.     

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.     

Similar risk of exercise‐related hypoglycaemia for insulin degludec to that for insulin glargine in patients with type 1 diabetes: a randomized cross‐over trial

We compared changes in blood glucose (BG) and risk of hypoglycaemia during and after exercise in 40 patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) or insulin glargine (IGlar) in a randomized, open‐label, two‐period, crossover trial. After individual titration and a steady‐state period, patients performed 30 min of moderate‐intensity cycle ergometer exercise (65% peak rate of oxygen uptake). BG, counter‐regulatory hormones and hypoglycaemic episodes were measured frequently during and for 24 h after exercise. BG changes during exercise were similar with IDeg and IGlar [estimated treatment difference (ETD) for maximum BG decrease: 0.14 mmol/l; 95% confidence interval (CI) ?0.15, 0.42; p = 0.34], as was mean BG (ETD ?0.16 mmol/l; 95% CI ?0.36, 0.05; p = 0.13). No hypoglycaemic episodes occurred during exercise. Post‐exercise mean BG, counter‐regulatory hormone response and number of hypoglycaemic episodes in 24 h after starting exercise were similar with IDeg (18 events in 13 patients) and IGlar (23 events in 15 patients). This clinical trial showed that, in patients with T1D treated with a basal‐bolus regimen, the risk of hypoglycaemia induced by moderate‐intensity exercise was low with IDeg and similar to that with IGlar.