Effects of short-acting exenatide added three times daily to insulin therapy on bone metabolism in type 1 diabetes.

AIM: To evaluate the efficacy of the short-acting glucagon-like peptide-1 receptor agonist, exenatide, added to insulin therapy in type 1 diabetes on bone mineral density and bone turnover markers. MATERIALS AND METHODS: In a randomized, double-blinded, parallel-group trial, 108 individuals with type 1 diabetes aged 18 years or older on basal-bolus therapy with HbA1c 59-88 mmol/mol (7.5%-10.0%) and body mass index of more than 22.0 kg/m2 were randomized (1:1) to preprandial subcutaneous injection of 10 µg exenatide (Byetta) before breakfast, lunch, and dinner over 26 weeks as add-on treatment to insulin therapy. RESULTS: Exenatide elicited a body weight reduction of 4.4 kg compared with placebo, but no between-group differences in bone mineral density, as assessed by whole-body, hip, lumbar, and forearm dual-energy X-ray absorptiometry following 26 weeks of treatment, were observed. Fasting plasma levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, and amino-terminal propeptide of type I procollagen, a marker of bone formation, were unchanged by exenatide compared with placebo after 26 weeks. CONCLUSIONS: Despite an exenatide-induced body weight reduction, no changes in bone metabolism were observed with exenatide added to insulin therapy in type 1 diabetes after 26 weeks.

Effect of short-acting exenatide administered three times daily on markers of cardiovascular disease in type 1 diabetes: A randomized double-blind placebo-controlled trial.

AIMS: To investigate the effect of adding the short-acting glucagon-like peptide 1 receptor agonist (GLP-1RA) exenatide to insulin treatment on markers of cardiovascular risk in type 1 diabetes. MATERIALS AND METHODS: In a randomized, double-blind, parallel-group trial, 108 individuals with type 1 diabetes aged ≥18 years on multiple daily injection therapy with a body mass index >22.0 kg/m2 and glycated haemoglobin concentration of 59 to 88 mmol/mol (7.5%-10.0%) were randomized (1:1) to preprandial subcutaneous injection of 10 µg exenatide (Byetta®) or placebo three times daily over 26 weeks as add-on treatment to existing insulin therapy. Reported markers of cardiovascular risk were secondary endpoints and were analyzed in a baseline-adjusted linear mixed model in the intention-to-treat population. The primary results of this study, the MAG1C (Meal-time Administration of exenatide for Glycaemic control in type 1 diabetes Cases) trial, were previously reported. RESULTS: Exenatide changed total fat mass by -2.6 kg (95% confidence interval [CI] -3.6; -1.6; P < 0.0001) and lean body mass by -1.1 kg (95% CI -1.9; -0.4; P = 0.01) compared with placebo, as assessed by dual-energy X-ray absorptiometry. Fat mass reductions were similar for central and peripheral fat mass. Exenatide did not change levels of interleukin-2 or -6; tumour necrosis factor-α; C-reactive protein; N-terminal prohormone of brain natriuretic peptide; or 8-oxo-7,8-dihydroguanosine (RNA oxidation marker) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (DNA oxidation marker). CONCLUSIONS: Exenatide added to insulin therapy in type 1 diabetes for 26 weeks resulted in body weight loss primarily from fat mass reduction, but had no effect on biomarkers of cardiovascular disease risk.

Dasiglucagon Treatment for Postprandial Hypoglycemia After Gastric Bypass: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Postbariatric hypoglycemia affects >50% of individuals who have undergone Roux-en-Y gastric bypass surgery. Despite the often debilitating nature of this complication, existing treatment options are limited and often inefficient. Dasiglucagon is a stable glucagon analog available in a ready-to-use formulation and was recently shown to mitigate postbariatric hypoglycemia in experimental settings. Here, we aimed to evaluate the hypoglycemic hindering potential of dasiglucagon in an outpatient trial. RESEARCH DESIGN AND METHODS: We conducted a randomized, double-blind, placebo-controlled, crossover, proof-of-concept study at the Center for Clinical Metabolic Research at Gentofte Hospital in Denmark. The study included 24 individuals who had undergone Roux-en-Y gastric bypass surgery (n = 23 women) with continuous glucose monitor-verified postbariatric hypoglycemia (≥15 min at <3.9 mmol/L three or more times per week) randomly assigned to two treatment periods of 4 weeks of self-administered subcutaneous dasiglucagon at 120 µg or placebo. The primary and key secondary outcomes were continuous glucose monitor-captured percentage of time in level 1 and 2 hypoglycemia (<3.9 and <3.0 mmol/L), respectively. RESULTS: Compared with placebo, treatment with dasiglucagon significantly reduced time in level 1 hypoglycemia by 33% (-1.2 percentage points; 95% CI -2.0 to -0.5; P = 0.002) and time in level 2 hypoglycemia by 54% (-0.4 percentage points; 95% CI -0.6 to -0.2; P < 0.0001). Furthermore, dasiglucagon corrected hypoglycemia within 15 min in 401 of 412 self-administrations, compared with 104 of 357 placebo self-administrations (97.3% vs. 29.1% correction of hypoglycemia rate; P < 0.001). Dasiglucagon was generally well tolerated, with mostly mild to moderate adverse events of nausea. CONCLUSIONS: Compared with placebo, 4 weeks of self-administered dasiglucagon effectively reduced clinically relevant hypoglycemia in individuals who had undergone Roux-en-Y gastric bypass surgery.

Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In type 2 diabetes, long-acting GLP-1 receptor agonists lower fasting plasma glucose and improve glycaemic control via their insulinotropic and glucagonostatic effects. In type 1 diabetes, their efficacy as an add-on treatment to insulin therapy is modest. Short-acting GLP-1 receptor agonists also lower postprandial glucose excursions in type 2 diabetes by decelerating gastric emptying rate. We aimed to test the efficacy of a short-acting GLP-1 receptor agonist in type 1 diabetes. METHODS: In the single-centre, parallel-group, randomised, double-blind, placebo-controlled MAG1C trial, patients with type 1 diabetes on multiple daily injection therapy aged 18 years and older with HbA1c 59-88 mmol/mol (7·5-10·0%) and a BMI of more than 22·0 kg/m2 were randomly assigned (1:1) through a computer-generated randomisation list to preprandial subcutaneous injection of 10 µg exenatide (Byetta) or placebo three times daily for 26 weeks as an add-on treatment to usual insulin therapy. Clinically assessed insulin titration was done by study staff. Participants and investigators were masked to treatment allocation. The primary endpoint was between-group difference in HbA1c after 26 weeks. Data were analysed with a baseline-adjusted linear mixed model in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03017352, and is completed. FINDINGS: Between Jan 4, 2017, and Jan 16, 2019, 108 participants were randomly assigned, 54 to exenatide and 54 to placebo; 23 participants discontinued treatment (17 in the exenatide group and six in the placebo group). From a baseline-adjusted mean of 66·4 mmol/mol (95% CI 64·9-67·8 [8·2%, 8·1-8·4]), HbA1c changed by -3·2 mmol/mol (-5·0 to -1·4 [-0·3%, -0·5 to -0·1]) with exenatide and -2·1 mmol/mol (-3·7 to -0·6 [-0·2%, -0·3 to -0·1]) with placebo after 26 weeks (estimated treatment difference of -1·1 mmol/mol (-3·4 to 1·2 [-0·1%, -0·3 to 0·1]; p=0·36). Exenatide increased the number of self-reported gastrointestinal adverse events (primarily nausea [48 events among 37 patients with exenatide, nine with placebo among 9 patients]). Two serious adverse events occurred in the exenatide group, and six occurred in the placebo group (none were considered to be related to the study drug). INTERPRETATION: Short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes. FUNDING: AstraZeneca.

The efficacy and safety of exenatide once weekly in patients with type 2 diabetes.

INTRODUCTION: Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D). Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit-risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide. Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.