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.

Baker Heart and Diabetes Institute 75 Commercial Rd Melbourne VIC 3004 Australia

Department of Cardiology Semmelweis University Hungarian Institute of Cardiology Üllői út 26 1085 Budapest Hungary

Department of Cardiovascular Surgery University Hospital Motol 5 Úvalu 84 150 06 Praha 5 Czech Republic

Department of Internal Medicine Latvijas Universitate Raiņa bulvāris 19 Centra rajons Riga LV 1586 Latvia

Department of Internal Medicine Universidad de La Frontera Francisco Salazar 1145 Temuco Araucanía Chile

Department of Medicine Institut Universitaire de Cardiologie et Pneumologie Université Laval Québec City QC Canada

Department of Medicine K2 Karolinska Institutet Solnavägen 1 Stockholm SE171 77 Sweden

Department of Medicine Li Ka Shing Knowledge Institute St Michael's Hospital University of Toronto 38 Shuter St Toronto ON M5B 1A6 Canada

Department of Medicine Oregon Health and Science University 3181 SW Sam Jackson Park Rd Portland OR 97239 USA

Department of Medicine RR 512 Health Sciences Building University of Washington Box 356420 1959 NE Pacific Street Seattle WA 98195 6420 USA

Department of Medicine Taichung Veterans General Hospital Rongguang Road Puli Township Nantou County Taichung 54552 Taiwan

Department of Medicine University of Cape Town Observatory Cape Town 7925 South Africa

Division of Cardiology Medical University of South Carolina 171 Ashley Ave Charleston SC 29425 USA

Division of Clinical Research and Training St John's Research Institute 100 Feet Rd John Nagar Koramangala Bengaluru Karnataka 560034 India

ECLA Estudios Clínicos Latinoamérica Instituto Cardiovascular de Rosario Paraguay 160 S2000 Rosario Santa Fe Argentina

Eli Lilly and Company 893 Delaware St Indianapolis IN 46225 USA

Institute of Genetics and Molecular Medicine University of Edinburgh Crewe Road Edinburgh EH4 2XU UK

Instituto Dante Pazzanese de Cardiologia and University Santo Amaro Av Dr Dante Pazzanese 500 Vila Mariana São Paulo SP 04012 909 Brazil

Masira Research Institute Medical School Universidad de Santander UDES Calle 70 No 55 210 Bucaramanga Colombia

Memphis Veterans Affairs Medical Center Preventive Medicine Section 1030 Jefferson Ave Memphis TN 38104 USA

National Medical Research Center of Cardiology Ulitsa Ostrovityanova 1 Moscow 117997 Russian Federation

Population Health Research Institute McMaster University and Hamilton Health Sciences 237 Barton Street East Hamilton ON L8L 2X2 Canada

Eur Heart J. 2021 Jul 8;42(26):2574-2576. doi: 10.1093/eurheartj/ehaa879. PubMed

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