학술논문
Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.
Document Type
Academic Journal
Author
Wiviott SD; 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.).; Raz I; 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.).; Bonaca MP; 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.).; Mosenzon O; 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.).; Kato ET; 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.).; Cahn A; 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.).; Silverman MG; 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.).; Zelniker TA; 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.).; Kuder JF; 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.).; Murphy SA; 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.).; Bhatt DL; 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.).; Leiter LA; 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.).; McGuire DK; 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.).; Wilding JPH; 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.).; Ruff CT; 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.).; Gause-Nilsson IAM; 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.).; Fredriksson M; 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.).; Johansson PA; 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.).; Langkilde AM; 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.).; Sabatine MS; 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.).
Source
Publisher: Massachusetts Medical Society Country of Publication: United States NLM ID: 0255562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1533-4406 (Electronic) Linking ISSN: 00284793 NLM ISO Abbreviation: N Engl J Med Subsets: MEDLINE
Subject
Language
English
Abstract
Background: The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.
Methods: We 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.
Results: We 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).
Conclusions: In 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 .).
Methods: We 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 m
Results: We 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).
Conclusions: In 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 .).