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 A1c (HbA1c) 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 HbA1c 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. FUNDING: Eli Lilly and Company.

Baker Heart and Diabetes Institute Melbourne VIC Australia

Department of Internal Medicine Dresden Technical University Dresden Germany

Department of Medicine K2 Karolinska Institutet Stockholm Sweden

Department of Medicine Oregon Health and Science University Portland OR USA

Department of Medicine University of Washington Seattle WA USA

ECLA Estudios Clínicos Latinoamérica Rosario Argentina

Eli Lilly and Company Indianapolis IN USA

Endocrinology and Nutrition Department Hospital Clínic i Universitari Barcelona Spain

Institut Universitaire de Cardiologie et Pneumologie Université Laval Québec City QC Canada

Instituto Dante Pazzanese de Cardiologia and University Santo Amaro São Paulo Brazil

Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca Romania

Latvijas Universitate Riga Latvia

Li Ka Shing Knowledge Institute St Michael's Hospital University of Toronto Toronto ON Canada

Medical University of South Carolina Charleston SC USA

Memphis Veterans Affairs Medical Center Memphis TN USA

Mossakowski Medical Research Centre Polish Academy of Sciences and Central Clinical Hospital MSWiA Warsaw Poland

National Medical Research Center of Cardiology Moscow Russia

Population Health Research Institute McMaster University and Hamilton Health Sciences Hamilton ON Canada

Research Institute FOSCAL and Medical School Universidad de Santander UDES Bucaramanga Colombia

Robert Koch Medical Centre Sofia Bulgaria

Semmelweis University Hungarian Institute of Cardiology Budapest Hungary

St John's Research Institute Bangalore India

Taichung Veterans General Hospital Taichung Taiwan

Universidad de Guadalajara Centro Universitario de Ciencias de la Salud Guadalajara Mexico

Universidad de La Frontera Temuco Chile

University Hospital Motol Prague Czech Republic

University of Cape Town Cape Town South Africa

University of Edinburgh Edinburgh UK

Victoria University of Wellington Wellington New Zealand

Yonsei University Health System Seoul South Korea

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ClinicalTrials.gov
NCT01394952