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:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01730534.