Uniform efficacy of SGLT2 inhibitors across the ejection fraction spectrum and in high-risk patients with HFpEF: a prespecified pooled analysis

Background Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases and imposes a high symptom burden. Although SGLT2 inhibitors are guideline-recommended, it remains uncertain whether their efficacy is uniform across the entire LVEF spectrum and in high-risk populations like recently hospitalized patients. Objective To definitively assess the consistency of SGLT2 inhibitor efficacy and safety across LVEF subgroups and in extended, high-risk HFpEF populations through a prespecified pooled analysis. Methods This trial-level pooled analysis included 12,251 HFpEF patients (LVEF >40%) from the EMPEROR-Preserved and DELIVER trials. Prespecified subgroups were defined by baseline LVEF (<50%, 50-59%, ≥60%), hospitalization status, and HFimpEF. The primary endpoint was cardiovascular death or heart failure hospitalization. Treatment effect consistency was assessed using an inverse-variance weighted fixed-effects model, with heterogeneity quantified by I 2 and interaction tested. Results SGLT2 inhibitors significantly reduced the risk of the primary endpoint by 20% vs. placebo (HR 0.80, 95% CI 0.73–0.87, P < 0.001). This benefit was consistent across all LVEF subgroups (<50%: HR 0.76; 50-59%: HR 0.79; ≥60%: HR 0.82; interaction P = 0.690) and extended to key high-risk subgroups: recently hospitalized patients in DELIVER (HR 0.74) and those with HFimpEF (HR 0.71). No new safety signals were identified. Conclusion This analysis confirms a uniform class effect of SGLT2 inhibitors in HFpEF, with consistent cardiovascular protection regardless of LVEF or high-risk clinical status. These findings solidify their role as foundational therapy and support a universal treatment strategy across the ejection fraction spectrum. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261277529 , PROSPERO CRD420261277529.