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

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.