Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus

Eri T. Kato, Michael G. Silverman, Ofri Mosenzon, Thomas A. Zelniker, Avivit Cahn, Remo H.M. Furtado, Julia Kuder, Sabina A. Murphy, Deepak L. Bhatt, Lawrence A. Leiter, Darren K McGuire, John P.H. Wilding, Marc P. Bonaca, Christian T. Ruff, Akshay S. Desai, Shinya Goto, Peter A. Johansson, Ingrid Gause-Nilsson, Per Johanson, Anna Maria LangkildeItamar Raz, Marc S. Sabatine, Stephen D. Wiviott

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

BACKGROUND: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. METHODS: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. RESULTS: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). CONCLUSIONS: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Original languageEnglish (US)
Pages (from-to)2528-2536
Number of pages9
JournalCirculation
Volume139
Issue number22
DOIs
StatePublished - May 28 2019

Fingerprint

Type 2 Diabetes Mellitus
Heart Failure
Mortality
Sodium-Glucose Transport Proteins
Hospitalization
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Stroke Volume
Cause of Death
Myocardial Infarction
Clinical Trials

Keywords

  • diabetes mellitus
  • heart failure
  • mortality
  • sodium-glucose transporter 2 inhibitors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kato, E. T., Silverman, M. G., Mosenzon, O., Zelniker, T. A., Cahn, A., Furtado, R. H. M., ... Wiviott, S. D. (2019). Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation, 139(22), 2528-2536. https://doi.org/10.1161/CIRCULATIONAHA.119.040130

Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. / Kato, Eri T.; Silverman, Michael G.; Mosenzon, Ofri; Zelniker, Thomas A.; Cahn, Avivit; Furtado, Remo H.M.; Kuder, Julia; Murphy, Sabina A.; Bhatt, Deepak L.; Leiter, Lawrence A.; McGuire, Darren K; Wilding, John P.H.; Bonaca, Marc P.; Ruff, Christian T.; Desai, Akshay S.; Goto, Shinya; Johansson, Peter A.; Gause-Nilsson, Ingrid; Johanson, Per; Langkilde, Anna Maria; Raz, Itamar; Sabatine, Marc S.; Wiviott, Stephen D.

In: Circulation, Vol. 139, No. 22, 28.05.2019, p. 2528-2536.

Research output: Contribution to journalArticle

Kato, ET, Silverman, MG, Mosenzon, O, Zelniker, TA, Cahn, A, Furtado, RHM, Kuder, J, Murphy, SA, Bhatt, DL, Leiter, LA, McGuire, DK, Wilding, JPH, Bonaca, MP, Ruff, CT, Desai, AS, Goto, S, Johansson, PA, Gause-Nilsson, I, Johanson, P, Langkilde, AM, Raz, I, Sabatine, MS & Wiviott, SD 2019, 'Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus', Circulation, vol. 139, no. 22, pp. 2528-2536. https://doi.org/10.1161/CIRCULATIONAHA.119.040130
Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM et al. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation. 2019 May 28;139(22):2528-2536. https://doi.org/10.1161/CIRCULATIONAHA.119.040130
Kato, Eri T. ; Silverman, Michael G. ; Mosenzon, Ofri ; Zelniker, Thomas A. ; Cahn, Avivit ; Furtado, Remo H.M. ; Kuder, Julia ; Murphy, Sabina A. ; Bhatt, Deepak L. ; Leiter, Lawrence A. ; McGuire, Darren K ; Wilding, John P.H. ; Bonaca, Marc P. ; Ruff, Christian T. ; Desai, Akshay S. ; Goto, Shinya ; Johansson, Peter A. ; Gause-Nilsson, Ingrid ; Johanson, Per ; Langkilde, Anna Maria ; Raz, Itamar ; Sabatine, Marc S. ; Wiviott, Stephen D. / Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. In: Circulation. 2019 ; Vol. 139, No. 22. pp. 2528-2536.
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title = "Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus",
abstract = "BACKGROUND: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. METHODS: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45{\%}. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. RESULTS: Of 17 160 patients, 671 (3.9{\%}) had HFrEF, 1316 (7.7{\%}) had HF without known reduced EF, and 15 173 (88.4{\%}) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95{\%} CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95{\%} CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95{\%} CI, 0.66-1.17]) and those without HF (HR, 0.88 [95{\%} CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95{\%} CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95{\%} CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95{\%} CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95{\%} CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95{\%} CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95{\%} CI, 0.86-1.10]; P for interaction=0.016). CONCLUSIONS: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.",
keywords = "diabetes mellitus, heart failure, mortality, sodium-glucose transporter 2 inhibitors",
author = "Kato, {Eri T.} and Silverman, {Michael G.} and Ofri Mosenzon and Zelniker, {Thomas A.} and Avivit Cahn and Furtado, {Remo H.M.} and Julia Kuder and Murphy, {Sabina A.} and Bhatt, {Deepak L.} and Leiter, {Lawrence A.} and McGuire, {Darren K} and Wilding, {John P.H.} and Bonaca, {Marc P.} and Ruff, {Christian T.} and Desai, {Akshay S.} and Shinya Goto and Johansson, {Peter A.} and Ingrid Gause-Nilsson and Per Johanson and Langkilde, {Anna Maria} and Itamar Raz and Sabatine, {Marc S.} and Wiviott, {Stephen D.}",
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issn = "0009-7322",
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TY - JOUR

T1 - Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus

AU - Kato, Eri T.

AU - Silverman, Michael G.

AU - Mosenzon, Ofri

AU - Zelniker, Thomas A.

AU - Cahn, Avivit

AU - Furtado, Remo H.M.

AU - Kuder, Julia

AU - Murphy, Sabina A.

AU - Bhatt, Deepak L.

AU - Leiter, Lawrence A.

AU - McGuire, Darren K

AU - Wilding, John P.H.

AU - Bonaca, Marc P.

AU - Ruff, Christian T.

AU - Desai, Akshay S.

AU - Goto, Shinya

AU - Johansson, Peter A.

AU - Gause-Nilsson, Ingrid

AU - Johanson, Per

AU - Langkilde, Anna Maria

AU - Raz, Itamar

AU - Sabatine, Marc S.

AU - Wiviott, Stephen D.

PY - 2019/5/28

Y1 - 2019/5/28

N2 - BACKGROUND: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. METHODS: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. RESULTS: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). CONCLUSIONS: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

AB - BACKGROUND: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. METHODS: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. RESULTS: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). CONCLUSIONS: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

KW - diabetes mellitus

KW - heart failure

KW - mortality

KW - sodium-glucose transporter 2 inhibitors

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