Giulia Ferrannini1, Hertzel Gerstein2, Helen Martina Colhoun3, Gilles R Dagenais4, Rafael Diaz5, Leanne Dyal2, Mark Lakshmanan6, Linda Mellbin1, Jeffrey Probstfield7, Matthew Casey Riddle8, Jonathan Edward Shaw9, Alvaro Avezum10, Jan Neil Basile11, William C Cushman12, Petr Jansky13, Mátyás Keltai14, Fernando Lanas15, Lawrence Alan Leiter16, Patricio Lopez-Jaramillo17, Prem Pais18, Valdis Pīrāgs19, Nana Pogosova20, Peter Johann Raubenheimer21, Wayne Huey-Herng Sheu22, Lars Rydén1. 1. Department of Medicine K2, Karolinska Institutet, Solnavägen 1, Stockholm SE171 77, Sweden. 2. Population Health Research Institute, McMaster University and Hamilton Health Sciences, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada. 3. Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK. 4. Department of Medicine, Institut Universitaire de Cardiologie et Pneumologie, Université Laval, Québec City, QC, Canada. 5. ECLA, Estudios Clínicos Latinoamérica, Instituto Cardiovascular de Rosario, Paraguay 160, S2000 Rosario, Santa Fe, Argentina. 6. Eli Lilly and Company, 893 Delaware St, Indianapolis, IN 46225, USA. 7. Department of Medicine, RR-512, Health Sciences Building, University of Washington, Box 356420, 1959 NE Pacific Street, Seattle, WA 98195-6420, USA. 8. Department of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. 9. Baker Heart and Diabetes Institute, 75 Commercial Rd, Melbourne VIC 3004, Australia. 10. Instituto Dante Pazzanese de Cardiologia and University Santo Amaro, Av. Dr. Dante Pazzanese, 500 - Vila Mariana, São Paulo - SP, 04012-909, Brazil. 11. Division of Cardiology, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA. 12. Memphis Veterans Affairs Medical Center, Preventive Medicine Section, 1030 Jefferson Ave, Memphis, TN 38104, USA. 13. Department of Cardiovascular Surgery, University Hospital Motol, V Úvalu 84 150 06 Praha 5, Czech Republic. 14. Department of Cardiology, Semmelweis University, Hungarian Institute of Cardiology, Üllői út 26, 1085 Budapest, Hungary. 15. Department of Internal Medicine, Universidad de La Frontera, Francisco Salazar 1145, Temuco, Araucanía, Chile. 16. Department of Medicine, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, 38 Shuter St, Toronto, ON M5B 1A6, Canada. 17. Masira Research Institute, Medical School, Universidad de Santander UDES, Calle 70 No 55-210 Bucaramanga, Colombia. 18. Division of Clinical Research and Training, St. John's Research Institute, 100 Feet Rd, John Nagar, Koramangala, Bengaluru, Karnataka 560034, India. 19. Department of Internal Medicine, Latvijas Universitate, Raiņa bulvāris 19, Centra rajons, Riga LV-1586, Latvia. 20. National Medical Research Center of Cardiology, Ulitsa Ostrovityanova, 1, Moscow 117997, Russian Federation. 21. Department of Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa. 22. Department of Medicine, Taichung Veterans General Hospital, Rongguang Road, Puli Township, Nantou County, Taichung 54552, Taiwan.
Abstract
OBJECTIVE: Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. RESEARCH DESIGN AND METHODS: Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. RESULTS: Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81-1.05) vs. 0.78 (CI 0.61-0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. CONCLUSION: This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy. Published on behalf of the European Society of Cardiology. All rights reserved.
OBJECTIVE: Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. RESEARCH DESIGN AND METHODS: Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. RESULTS: Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81-1.05) vs. 0.78 (CI 0.61-0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. CONCLUSION: This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy. Published on behalf of the European Society of Cardiology. All rights reserved.