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.
Bibliographical noteFunding Information:
The trial was sponsored and funded by Eli Lilly and Company led by an international steering committee coordinated by the Population Health Research Institute in Hamilton, Canada, which also did all data analyses. Site management and data collection were provided by ICON Clinical Research. Scientists employed by the funder were on the steering committee and contributed to trial design, trial implementation, and data interpretation. All authors and the sponsor jointly made the decision to submit for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk, and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Janssen, Sanofi, Kowa, and Cirius. HMC reports research grants from Eli Lilly, AstraZeneca, Regeneron, Pfizer, Roche, Sanofi, and Novo Nordisk; honoraria for speaking from Eli Lilly and Regeneron; consulting fees from Eli Lilly, Novartis, Regeneron, Sanofi, and Novo Nordisk; and shares in Bayer and Roche. RD reports research grants from the Population Health Research Institute, Duke Clinical Research Institute, Montreal Health Innovations Coordinating Center, CPC Clinical Research, DalCor, Amgen, Lepetit, and Cirius; honoraria for speaking from Sanofi; and consulting fees from Sanofi and Cirius. MCR reports grants to his institution from Eli Lilly, AstraZeneca, and Novo Nordisk; honoraria for consulting from Adocia, DalCor, GlaxoSmithKline, and Theracos; and honoraria for speaking from Sanofi. LR reports grants from the Swedish Heart Lung Foundation, Stockholms Läns Landsting, and Boehringer Ingelheim, and fees for consulting and speaking from Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Merck, and Bayer. ML is employed by Eli Lilly, owns stock, and has a patent pending, JSR is employed by Eli Lilly and has a patent pending. CMA is employed by Eli Lilly and owns stock. DX reports grants from Cadila, Boehringer Ingelheim, AstraZeneca, Sanofi-Aventis, Pfizer, Bristol-Myers Squibb, the UK Medical Research Council, and the Wellcome Trust. JB reports consulting fees from Eli Lilly, ReCor, and Medtronic. WCC reports grants from Eli Lilly. EF reports consulting and speaking fees from AstraZeneca, Boehringer Ingelheim, Bioton, Mundipharma, MSD, Novartis, Novo Nordisk, and Servier. MH reports honoraria for speaking from Sanofi, Novo Nordisk, Amgen, MSD, and AstraZeneca. FL reports grants from the Population Health Research Institute. LAL reports grants from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Novo Nordisk, Sanofi, and GSK; honoraria for speaking from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, and Sanofi; and consulting fees from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Sanofi, and Servier. JES reports grants from Eli Lilly, and consulting fees or speaking honoraria from AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi, Mylan, Boehringer Ingelheim, Merck Sharp and Dohme, and Abbott. TT-K reports consulting fees from Bayer, AstraZeneca, and Hamilton Health Sciences. All other authors declare no competing interests.
The trial was funded by Eli Lilly and Company. We gratefully acknowledge the contribution of all participants. The names of the REWIND investigators, coordinators, committee members, and staff are listed in the appendix (pp 2–11) . Their contributions, as well as those of ICON Clinical Research, which provided site management and collected the data, are gratefully acknowledged.
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