Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial

  • Lancet. 2019 Jul 13;394(10193):121-130. doi: 10.1016/S0140-6736(19)31149-3.
Hertzel C Gerstein  1 ,  Helen M Colhoun  2 ,  Gilles R Dagenais  3 ,  Rafael Diaz  4 ,  Mark Lakshmanan  5 ,  Prem Pais  6 ,  Jeffrey Probstfield  7 ,  Jeffrey S Riesmeyer  5 ,  Matthew C Riddle  8 ,  Lars Rydén  9 ,  Denis Xavier  6 ,  Charles Messan Atisso  5 ,  Leanne Dyal  10 ,  Stephanie Hall  10 ,  Purnima Rao-Melacini  10 ,  Gloria Wong  10 ,  Alvaro Avezum  11 ,  Jan Basile  12 ,  Namsik Chung  13 ,  Ignacio Conget  14 ,  William C Cushman  15 ,  Edward Franek  16 ,  Nicolae Hancu  17 ,  Markolf Hanefeld  18 ,  Shaun Holt  19 ,  Petr Jansky  20 ,  Matyas Keltai  21 ,  Fernando Lanas  22 ,  Lawrence A Leiter  23 ,  Patricio Lopez-Jaramillo  24 ,  Ernesto German Cardona Munoz  25 ,  Valdis Pirags  26 ,  Nana Pogosova  27 ,  Peter J Raubenheimer  28 ,  Jonathan E Shaw  29 ,  Wayne H-H Sheu  30 ,  Theodora Temelkova-Kurktschiev  31 ,  REWIND Investigators
PMID: 31189511 DOI: 10.1016/S0140-6736(19)31149-3
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 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.

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