260 efficacy of sglt2 inhibitors in patients with and without heart failure and across the spectrum of left ventricular ejection fraction: a systematic review and meta-analysis of randomized controlled trials

Abstract Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have demonstrated to reduce heart failure (HF) and renal outcomes irrespective of diabetes status. The cardiovascular efficacy and the mortality benefit of these agents in patients without HF and across the spectrum of left ventricular ejection fraction (EF) are a matter of debate. Methods This study-level meta-analysis included 11 controlled randomized trials and 76,520 patients randomized to a SGLT-2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) or placebo in different clinical settings including diabetes, HF with reduced or preserved EF and chronic kidney disease. Data were stratified by history of HF, HF with reduced EF (≤40%), mid-range EF (40-49%) and preserved EF (≥50%). The incidence of the following outcomes, when available, was evaluated: HF composite outcome, defined as cardiovascular death or hospitalization/urgent visit for HF, its individual components and all-cause mortality. An additional sensitivity analysis tested the efficacy of SGLT-2 inhibitors in patients with extremely reduced EF (≤30%). Results Overall, there were 22,653 patients with HF (33.8%) and 44,304 patients without HF (66.2%). In patients without history of HF, SGLT-2 inhibitors significantly reduced the risk of HF outcomes (HR 0.76, 95% CI 0.68-0.86) and all-cause mortality (HR 0.84, 95% CI 0.73-0.95). In patients with HF, a significant reduction in the composite of cardiovascular death and HF events was consistently observed in those with reduced EF (HR 0.71, 95% CI 0.65-0.78), mid-range EF (HR 0.68, 95% CI 0.57-0.81) and preserved EF (HR 0.78, 95% CI 0.69-0.89; Figure). There was a significant reduction in all-cause mortality also in patients with HF treated with SGLT-2 inhibitors (HR 0.87, 95% CI 0.80-0.95). Conclusions SGLT-2 inhibitors demonstrated cardiovascular and mortality benefits irrespective from history of HF and across the spectrum of left ventricular EF.