Abstract

Background Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A 1c (HbA 1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. Methods This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1: 1) to either weekly subcutaneous injection of dulaglutide (1.5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66.2 years [SD 6.5], median HbA 1c 7.2% [IQR 6.6-8.1], 4589 [46.3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5.4 years (IQR 5.1-5.9), the primary composite outcome occurred in 594 (12.0%) participants at an incidence rate of 2.4 per 100 person-years in the dulaglutide group and in 663 (13.4%) participants at an incidence rate of 2.7 per 100 person-years in the placebo group (hazard ratio [HR] 0.88, 95% CI 0.79-0.99; p=0.026). All-cause mortality did not differ between groups (536 [10.8%] in the dulaglutide group vs 592 [12.0%] in the placebo group; HR 0.90, 95% CI 0.80-1.01; p=0.067). 2347 (47.4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34.1%) participants assigned to placebo (p 0.0001). Interpretation Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. Copyright (c) 2019 Elsevier Ltd. All rights reserved.