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

REWIND Investigators

Research output: Contribution to journalArticle

119 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)121-130
Number of pages10
JournalThe Lancet
Volume394
Issue number10193
DOIs
StatePublished - Jul 13 2019

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Type 2 Diabetes Mellitus
Randomized Controlled Trials
Placebos
Cardiovascular Diseases
Incidence
Glycosylated Hemoglobin A
Subcutaneous Injections
Random Allocation
dulaglutide
Hypoglycemic Agents
Cause of Death
Hemoglobins
Stroke
Myocardial Infarction
Research Personnel
Mortality
Population

ASJC Scopus subject areas

  • Medicine(all)

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

In: The Lancet, Vol. 394, No. 10193, 13.07.2019, p. 121-130.

Research output: Contribution to journalArticle

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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.",
author = "{REWIND Investigators} and Gerstein, {Hertzel C.} and Colhoun, {Helen M.} and Dagenais, {Gilles R.} and Rafael Diaz and Mark Lakshmanan and Prem Pais and Jeffrey Probstfield and Riesmeyer, {Jeffrey S.} and Riddle, {Matthew C.} and Lars Ryd{\'e}n and Denis Xavier and Atisso, {Charles Messan} and Leanne Dyal and Stephanie Hall and Purnima Rao-Melacini and Gloria Wong and Alvaro Avezum and Jan Basile and Namsik Chung and Ignacio Conget and Cushman, {William C.} and Edward Franek and Nicolae Hancu and Markolf Hanefeld and Shaun Holt and Petr Jansky and Matyas Keltai and Fernando Lanas and Leiter, {Lawrence A.} and Patricio Lopez-Jaramillo and {Cardona Munoz}, {Ernesto German} and Valdis Pirags and Nana Pogosova and Raubenheimer, {Peter J.} and Shaw, {Jonathan E.} and Sheu, {Wayne H.H.} and Theodora Temelkova-Kurktschiev and Mercedes Abella and Andrea Alebuena and Sandra Almagro and Eduardo Amoroso and Paula Anadon and Elizabeth Andreu and Guillermo Aristimu{\~n}o and Maria Arzadun and Maria Barbieri and Raul Barcudi and Ines Bartolacci and Gabriel Bolobanich and Kyaw Soe",
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T1 - Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND)

T2 - a double-blind, randomised placebo-controlled trial

AU - REWIND Investigators

AU - Gerstein, Hertzel C.

AU - Colhoun, Helen M.

AU - Dagenais, Gilles R.

AU - Diaz, Rafael

AU - Lakshmanan, Mark

AU - Pais, Prem

AU - Probstfield, Jeffrey

AU - Riesmeyer, Jeffrey S.

AU - Riddle, Matthew C.

AU - Rydén, Lars

AU - Xavier, Denis

AU - Atisso, Charles Messan

AU - Dyal, Leanne

AU - Hall, Stephanie

AU - Rao-Melacini, Purnima

AU - Wong, Gloria

AU - Avezum, Alvaro

AU - Basile, Jan

AU - Chung, Namsik

AU - Conget, Ignacio

AU - Cushman, William C.

AU - Franek, Edward

AU - Hancu, Nicolae

AU - Hanefeld, Markolf

AU - Holt, Shaun

AU - Jansky, Petr

AU - Keltai, Matyas

AU - Lanas, Fernando

AU - Leiter, Lawrence A.

AU - Lopez-Jaramillo, Patricio

AU - Cardona Munoz, Ernesto German

AU - Pirags, Valdis

AU - Pogosova, Nana

AU - Raubenheimer, Peter J.

AU - Shaw, Jonathan E.

AU - Sheu, Wayne H.H.

AU - Temelkova-Kurktschiev, Theodora

AU - Abella, Mercedes

AU - Alebuena, Andrea

AU - Almagro, Sandra

AU - Amoroso, Eduardo

AU - Anadon, Paula

AU - Andreu, Elizabeth

AU - Aristimuño, Guillermo

AU - Arzadun, Maria

AU - Barbieri, Maria

AU - Barcudi, Raul

AU - Bartolacci, Ines

AU - Bolobanich, Gabriel

AU - Soe, Kyaw

PY - 2019/7/13

Y1 - 2019/7/13

N2 - 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.

AB - 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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U2 - 10.1016/S0140-6736(19)31149-3

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VL - 394

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EP - 130

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10193

ER -