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

Circulation. 2019 May 28;139(22):2528-2536. doi: 10.1161/CIRCULATIONAHA.119.040130. Epub 2019 Mar 18.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / therapeutic use*
  • Cardiovascular Agents / adverse effects
  • Cardiovascular Agents / therapeutic use*
  • Cause of Death
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / mortality
  • Double-Blind Method
  • Female
  • Glucosides / adverse effects
  • Glucosides / therapeutic use*
  • Heart Failure / diagnosis
  • Heart Failure / drug therapy*
  • Heart Failure / mortality
  • Heart Failure / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Risk Assessment
  • Risk Factors
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
  • Stroke Volume / drug effects*
  • Time Factors
  • Treatment Outcome
  • Ventricular Function, Left / drug effects*

Substances

  • 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
  • Benzhydryl Compounds
  • Cardiovascular Agents
  • Glucosides
  • Sodium-Glucose Transporter 2 Inhibitors

Associated data

  • ClinicalTrials.gov/NCT01730534