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 HbA(1c) 59-88 mmol/mol (7.5-10.0%) and a BMI of more than 22.0 kg/m(2) were randomly assigned (1:1) through a computer-generated randomisation list to preprandial subcutaneous injection of 10 mu g 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 HbA(1c) 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]), HbA(1c) 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]; 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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.