Hertzel C Gerstein1, Helen M Colhoun2, Gilles R Dagenais3, Rafael Diaz4, Mark Lakshmanan5, Prem Pais6, Jeffrey Probstfield7, Jeffrey S Riesmeyer5, Matthew C Riddle8, Lars Rydén9, Denis Xavier6, Charles Messan Atisso5, Leanne Dyal10, Stephanie Hall10, Purnima Rao-Melacini10, Gloria Wong10, Alvaro Avezum11, Jan Basile12, Namsik Chung13, Ignacio Conget14, William C Cushman15, Edward Franek16, Nicolae Hancu17, Markolf Hanefeld18, Shaun Holt19, Petr Jansky20, Matyas Keltai21, Fernando Lanas22, Lawrence A Leiter23, Patricio Lopez-Jaramillo24, Ernesto German Cardona Munoz25, Valdis Pirags26, Nana Pogosova27, Peter J Raubenheimer28, Jonathan E Shaw29, Wayne H-H Sheu30, Theodora Temelkova-Kurktschiev31. 1. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. Electronic address: gerstein@mcmaster.ca. 2. University of Edinburgh, Edinburgh, UK. 3. Institut Universitaire de Cardiologie et Pneumologie, Université Laval, Québec City, QC, Canada. 4. ECLA, Estudios Clínicos Latinoamérica, Rosario, Argentina. 5. Eli Lilly and Company, Indianapolis, IN, USA. 6. St John's Research Institute, Bangalore, India. 7. Department of Medicine, University of Washington, Seattle, WA, USA. 8. Department of Medicine, Oregon Health & Science University Portland, OR, USA. 9. Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden. 10. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. 11. Instituto Dante Pazzanese de Cardiologia and University Santo Amaro, São Paulo, Brazil. 12. Medical University of South Carolina, Charleston, SC, USA. 13. Yonsei University Health System, Seoul, South Korea. 14. Endocrinology and Nutrition Department, Hospital Clínic i Universitari, Barcelona, Spain. 15. Memphis Veterans Affairs Medical Center, Memphis, TN, USA. 16. Mossakowski Medical Research Centre, Polish Academy of Sciences and Central Clinical Hospital MSWiA, Warsaw, Poland. 17. Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania. 18. Department of Internal Medicine, Dresden Technical University, Dresden, Germany. 19. Victoria University of Wellington, Wellington, New Zealand. 20. University Hospital Motol, Prague, Czech Republic. 21. Semmelweis University, Hungarian Institute of Cardiology, Budapest, Hungary. 22. Universidad de La Frontera, Temuco, Chile. 23. Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, ON, Canada. 24. Research Institute, FOSCAL and Medical School, Universidad de Santander UDES, Bucaramanga, Colombia. 25. Universidad de Guadalajara Centro Universitario de Ciencias de la Salud, Guadalajara, Mexico. 26. Latvijas Universitate, Riga, Latvia. 27. National Medical Research Center of Cardiology, Moscow, Russia. 28. University of Cape Town, Cape Town, South Africa. 29. Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. 30. Taichung Veterans General Hospital, Taichung, Taiwan. 31. Robert Koch Medical Centre, Sofia, Bulgaria.
Abstract
BACKGROUND: Three different glucagon-likepeptide-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.
RCT Entities:
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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