• Stephen D Wiviott, Itamar Raz, Marc P Bonaca, Ofri Mosenzon, Eri T Kato, Avivit Cahn, Michael G Silverman, Thomas A Zelniker, Julia F Kuder, Sabina A Murphy, Deepak L Bhatt, Lawrence A Leiter, Darren K McGuire, WildingJohn P HJPHFrom the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital (S.D.W., M.P.B., T.A.Z., J.F.K., S.A.M., D.L.B., C.T.R., M.S.S.), and the Cardiology Division, Massachus, Christian T Ruff, Ingrid A M Gause-Nilsson, Martin Fredriksson, Peter A Johansson, Anna-Maria Langkilde, Marc S Sabatine, and DECLARE–TIMI 58 Investigators.
• From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital (S.D.W., M.P.B., T.A.Z., J.F.K., S.A.M., D.L.B., C.T.R., M.S.S.), and the Cardiology Division, Massachusetts General Hospital (M.G.S.) - both in Boston; the Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem (I.R., O.M., A.C.); the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (E.T.K.); Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.); the Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (D.K.M.); Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom (J.P.H.W.); and AstraZeneca Gothenburg, Mölndal, Sweden (I.A.M.G.-N., M.F., P.A.J., A.-M.L.).
• N. Engl. J. Med. 2019 Jan 24; 380 (4): 347-357.

BackgroundThe cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.MethodsWe randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.ResultsWe evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).ConclusionsIn patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

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