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

, Hertzel C. Gerstein (Lead / Corresponding author), Helen M. Colhoun, Gilles R. Dagenais, Rafael Diaz, Mark Lakshmanan, Prem Pais, Jeffrey Probstfield, Jeffrey S. Riesmeyer, Matthew C. Riddle, Lars Rydén, Denis Xavier, Charles Messan Atisso, Leanne Dyal, Stephanie Hall, Purnima Rao-Melacini, Gloria Wong, Alvaro Avezum, Jan Basile, Namsik ChungIgnacio Conget, William C. Cushman, Edward Franek, Nicolae Hancu, Markolf Hanefeld, Shaun Holt, Petr Jansky, Matyas Keltai, Fernando Lanas, Lawrence A. Leiter, Patricio Lopez-Jaramillo, Ernesto German Cardona Munoz, Valdis Pirags, Nana Pogosova, Peter J. Raubenheimer, Jonathan E Shaw, Wayne H.-H. Sheu, Theodora Temelkova-Kurktschiev

    Research output: Contribution to journalArticle

    59 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 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.

    Original languageEnglish
    Pages (from-to)121-130
    Number of pages10
    JournalLancet
    Volume394
    Issue number10193
    Early online date7 Jun 2019
    DOIs
    Publication statusPublished - 13 Jul 2019

    Fingerprint

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

    Cite this

    , Gerstein, H. C., Colhoun, H. M., Dagenais, G. R., Diaz, R., Lakshmanan, M., ... Temelkova-Kurktschiev, T. (2019). Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet, 394(10193), 121-130. https://doi.org/10.1016/S0140-6736(19)31149-3
    Gerstein, Hertzel C. ; Colhoun, Helen M. ; Dagenais, Gilles R. ; Diaz, Rafael ; Lakshmanan, Mark ; Pais, Prem ; Probstfield, Jeffrey ; Riesmeyer, Jeffrey S. ; Riddle, Matthew C. ; Rydén, Lars ; Xavier, Denis ; Atisso, Charles Messan ; Dyal, Leanne ; Hall, Stephanie ; Rao-Melacini, Purnima ; Wong, Gloria ; Avezum, Alvaro ; Basile, Jan ; Chung, Namsik ; Conget, Ignacio ; Cushman, William C. ; Franek, Edward ; Hancu, Nicolae ; Hanefeld, Markolf ; Holt, Shaun ; Jansky, Petr ; Keltai, Matyas ; Lanas, Fernando ; Leiter, Lawrence A. ; Lopez-Jaramillo, Patricio ; Cardona Munoz, Ernesto German ; Pirags, Valdis ; Pogosova, Nana ; Raubenheimer, Peter J. ; Shaw, Jonathan E ; Sheu, Wayne H.-H. ; Temelkova-Kurktschiev, Theodora. / Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND) : a double-blind, randomised placebo-controlled trial. In: Lancet. 2019 ; Vol. 394, No. 10193. pp. 121-130.
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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 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.",
    author = "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 Rory McCrimmon",
    note = "Copyright {\circledC} 2019 Elsevier Ltd. All rights reserved.",
    year = "2019",
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    day = "13",
    doi = "10.1016/S0140-6736(19)31149-3",
    language = "English",
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    Gerstein, HC, Colhoun, HM, Dagenais, GR, Diaz, R, Lakshmanan, M, Pais, P, Probstfield, J, Riesmeyer, JS, Riddle, MC, Rydén, L, Xavier, D, Atisso, CM, Dyal, L, Hall, S, Rao-Melacini, P, Wong, G, Avezum, A, Basile, J, Chung, N, Conget, I, Cushman, WC, Franek, E, Hancu, N, Hanefeld, M, Holt, S, Jansky, P, Keltai, M, Lanas, F, Leiter, LA, Lopez-Jaramillo, P, Cardona Munoz, EG, Pirags, V, Pogosova, N, Raubenheimer, PJ, Shaw, JE & Sheu, WH-H & Temelkova-Kurktschiev, T 2019, 'Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial', Lancet, vol. 394, no. 10193, pp. 121-130. https://doi.org/10.1016/S0140-6736(19)31149-3

    Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND) : a double-blind, randomised placebo-controlled trial. /; Gerstein, Hertzel C. (Lead / Corresponding author); Colhoun, Helen M.; Dagenais, Gilles R.; Diaz, Rafael; Lakshmanan, Mark; Pais, Prem; Probstfield, Jeffrey; Riesmeyer, Jeffrey S.; Riddle, Matthew C.; Rydén, Lars; Xavier, Denis; Atisso, Charles Messan; Dyal, Leanne; Hall, Stephanie; Rao-Melacini, Purnima; Wong, Gloria; Avezum, Alvaro; Basile, Jan; Chung, Namsik; Conget, Ignacio; Cushman, William C.; Franek, Edward; Hancu, Nicolae; Hanefeld, Markolf; Holt, Shaun; Jansky, Petr; Keltai, Matyas; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Cardona Munoz, Ernesto German; Pirags, Valdis; Pogosova, Nana; Raubenheimer, Peter J.; Shaw, Jonathan E; Sheu, Wayne H.-H.; Temelkova-Kurktschiev, Theodora.

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

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND)

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

    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 - McCrimmon, Rory

    N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

    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 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.

    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 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.

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