Dapagliflozin and cardiovascular outcomes in type 2 diabetes

DECLARE–TIMI 58 Investigators

Research output: Contribution to journalArticle

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; DECLARETIMI 58 ClinicalTrials.gov number, NCT01730534,

Original languageEnglish (US)
Pages (from-to)347-357
Number of pages11
JournalNew England Journal of Medicine
Volume380
Issue number4
DOIs
StatePublished - Jan 24 2019

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Type 2 Diabetes Mellitus
Confidence Intervals
Placebos
Hospitalization
Heart Failure
Cardiovascular Diseases
Kidney
Safety
Cause of Death
Sodium-Glucose Transport Proteins
Diabetic Ketoacidosis
Mortality
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Body Surface Area
Glomerular Filtration Rate
Chronic Kidney Failure
Stroke
Myocardial Infarction
Infection

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Dapagliflozin and cardiovascular outcomes in type 2 diabetes. / DECLARE–TIMI 58 Investigators.

In: New England Journal of Medicine, Vol. 380, No. 4, 24.01.2019, p. 347-357.

Research output: Contribution to journalArticle

DECLARE–TIMI 58 Investigators. / Dapagliflozin and cardiovascular outcomes in type 2 diabetes. In: New England Journal of Medicine. 2019 ; Vol. 380, No. 4. pp. 347-357.
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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; DECLARETIMI 58 ClinicalTrials.gov number, NCT01730534,",
author = "{DECLARE–TIMI 58 Investigators} and Wiviott, {S. D.} and I. Raz and Bonaca, {M. P.} and O. Mosenzon and Kato, {E. T.} and A. Cahn and Silverman, {M. G.} and Zelniker, {T. A.} and Kuder, {J. F.} and Murphy, {S. A.} and Bhatt, {D. L.} and Leiter, {L. A.} and McGuire, {D. K.} and Wilding, {J. P.H.} and Ruff, {C. T.} and Nilsson, {G. I.} and M. Fredriksson and Johansson, {P. A.} and Langkilde, {A. M.} and Sabatine, {M. S.} and S. Bansilal and R. Furtado and Fish, {M. P.} and D. Gabovitch and A. Jevne and S. Ahern and K. Im and Goodrich, {E. L.} and C. Lowe and N. Fisher and J. Gannon and S. Trindade and A. Towarowski and Y. Fox and E. Johnsson and S. Ranft and B. Faber and M. Wallander and A. Weiss and A. Buskila and Abola, {M. T.B.} and D. Ardissino and O. Averkov and P. Aylward and C. Bode and F. Bonnici and E. Bonora and Budaj, {A. J.} and S. Cernea and Anderson, {Robert J.}",
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TY - JOUR

T1 - Dapagliflozin and cardiovascular outcomes in type 2 diabetes

AU - DECLARE–TIMI 58 Investigators

AU - Wiviott, S. D.

AU - Raz, I.

AU - Bonaca, M. P.

AU - Mosenzon, O.

AU - Kato, E. T.

AU - Cahn, A.

AU - Silverman, M. G.

AU - Zelniker, T. A.

AU - Kuder, J. F.

AU - Murphy, S. A.

AU - Bhatt, D. L.

AU - Leiter, L. A.

AU - McGuire, D. K.

AU - Wilding, J. P.H.

AU - Ruff, C. T.

AU - Nilsson, G. I.

AU - Fredriksson, M.

AU - Johansson, P. A.

AU - Langkilde, A. M.

AU - Sabatine, M. S.

AU - Bansilal, S.

AU - Furtado, R.

AU - Fish, M. P.

AU - Gabovitch, D.

AU - Jevne, A.

AU - Ahern, S.

AU - Im, K.

AU - Goodrich, E. L.

AU - Lowe, C.

AU - Fisher, N.

AU - Gannon, J.

AU - Trindade, S.

AU - Towarowski, A.

AU - Fox, Y.

AU - Johnsson, E.

AU - Ranft, S.

AU - Faber, B.

AU - Wallander, M.

AU - Weiss, A.

AU - Buskila, A.

AU - Abola, M. T.B.

AU - Ardissino, D.

AU - Averkov, O.

AU - Aylward, P.

AU - Bode, C.

AU - Bonnici, F.

AU - Bonora, E.

AU - Budaj, A. J.

AU - Cernea, S.

AU - Anderson, Robert J.

PY - 2019/1/24

Y1 - 2019/1/24

N2 - 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; DECLARETIMI 58 ClinicalTrials.gov number, NCT01730534,

AB - 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; DECLARETIMI 58 ClinicalTrials.gov number, NCT01730534,

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U2 - 10.1056/NEJMoa1812389

DO - 10.1056/NEJMoa1812389

M3 - Article

VL - 380

SP - 347

EP - 357

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 4

ER -