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OBJECTIVE -This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metforminsulfonylurea combination therapy. RESULTS -Week 30 A1C changes from baseline (ϮSE) were Ϫ0.8 Ϯ 0.1% (10 g), Ϫ0.6 Ϯ 0.1% (5 g), and ϩ0.2 Ϯ 0.1% (placebo; adjusted P Ͻ 0.0001 vs. placebo), yielding placeboadjusted reductions of Ϫ1.0% (10 g) and Ϫ0.8% (5 g). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C Յ7% than placebo-treated subjects (34% [10 g], 27% [5 g], and 9% [placebo]; P Ͻ 0.0001). Both exenatide arms demonstrated significant weight loss (Ϫ1.6 Ϯ 0.2 kg from baseline each exenatide arm, Ϫ0.9 Ϯ 0.2 kg placebo; P Յ 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 g), 19% (5 g), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. RESEARCH DESIGN AND METHODSCONCLUSIONS -Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.

OBJECTIVE -In patients with type 2 diabetes, exenatide reduces A1C, postprandial and fasting glucose, and weight. In this study we investigated the effects of continuous exenatide administration from a long-acting release (LAR) formulation.RESEARCH DESIGN AND METHODS -In this randomized, placebo-controlled phase 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously once weekly for 15 weeks to subjects with type 2 diabetes (n ϭ 45) suboptimally controlled with metformin (60%) and/or diet and exercise (40%): 40% female, A1C (mean Ϯ SD) 8.5 Ϯ 1.2%, fasting plasma glucose 9.9 Ϯ 2.3 mmol/l, weight 106 Ϯ 20 kg, and diabetes duration 5 Ϯ 4 years.RESULTS -From baseline to week 15, exenatide LAR reduced mean Ϯ SE A1C by Ϫ1.4 Ϯ 0.3% (0.8 mg) and Ϫ1.7 Ϯ 0.3% (2.0 mg), compared with ϩ0.4 Ϯ 0.3% with placebo LAR (P Ͻ 0.0001 for both). A1C of Յ7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting plasma glucose was reduced by Ϫ2.4 Ϯ 0.9 mmol/l (0.8 mg) and Ϫ2.2 Ϯ 0.5 mmol/l (2.0 mg) compared with ϩ1.0 Ϯ 0.7 mmol/l with placebo LAR (P Ͻ 0.001 for both). Exenatide LAR reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had body weight reductions (Ϫ3.8 Ϯ 1.4 kg) (P Ͻ 0.05), whereas body weight was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event.No subjects treated with exenatide LAR withdrew from the study.CONCLUSIONS -Exenatide LAR offers the potential of 24-h glycemic control and weight reduction with a novel once-weekly treatment for type 2 diabetes.

Aims There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS trial assessed the efficacy, safety, and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. Materials and Methods Participants with PWS (12–65 years) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib, or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Coprimary endpoints were the changes in hyperphagia (measured by Hyperphagia Questionnaire for Clinical Trials [HQ-CT]; possible score 0–36) and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. Results 107 were included in the intention-to-treat analysis: placebo (n=34), 1.8 mg beloranib (n=36), or 2.4 mg beloranib (n=37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference −6.3, 95% CI −9.6 to −3.0; p=0.0003) and 2.4 mg beloranib groups (−7.0, 95% CI −10.5 to −3.6; p=0.0001) vs placebo. Compared to placebo, weight change was greater with 1.8 mg (mean difference −8.2%, 95% CI −10.8 to −5.6; p<0.0001) and 2.4 mg beloranib (−9.5%, 95% CI −12.1 to −6.8; p<0.0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (two fatal events of pulmonary embolism and two events of deep vein thrombosis) compared to placebo. Conclusions MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviors and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

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Treatment with split-dose ionizing radiation at an early age and chronic exposure to a residential power frequency MF were found to produce small but significant increases in body weight.

Aims/hypothesis This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m 2 ) and type 2 diabetes (HbA 1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). Methods Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. Results In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was −3.1 ± 1.2% with placebo (n = 22) vs −13.5 ± 1.1% and −12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA 1c (baseline 67 mmol/mol [8.3%]) was −6.6 ± 2.2 mmol/mol (−0.6 ± 0.2%) with placebo vs −21.9 ± 2.2 mmol/mol (−2.0 ± 0.2%) or −21.9 ± 3.3 mmol/mol (−2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4677-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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