Differential Outcomes with Empagliflozin and Dapagliflozin in Heart Failure with Mildly Reduced Ejection Fraction

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure (HF), yet comparative effectiveness between individual agents in heart failure with mildly reduced ejection fraction (HFmrEF) remains limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network electronic health record database. Adults (≥18 years) with HF and left ventricular ejection fraction (LVEF) 41-49% initiating empagliflozin or dapagliflozin between September 2021 and December 2025 were included. Propensity score matching (1:1) balanced demographics, comorbidities, medications, and laboratory values, yielding 1,466 patients per group. Outcomes were assessed over 1 year after treatment initiation and included all-cause mortality, hospitalization, HF exacerbation, and urinary tract infection (UTI). Risk analyses and Kaplan-Meier survival analyses with hazard ratios (HRs) were performed. Results: In the matched cohort, empagliflozin was associated with lower all-cause mortality (HR 0.75, 95% CI 0.59-0.96), substantially fewer hospitalizations (HR 0.61, 95% CI 0.55-0.67), and HF exacerbations (HR 0.64, 95% CI 0.57-0.73) compared to dapagliflozin. Rates of UTI were similar between groups (HR 0.81, 95% CI 0.65-1.01). Conclusions: In this large real-world HFmrEF population, empagliflozin was associated with lower mortality, hospitalization, and HF exacerbation compared with dapagliflozin, with no significant difference in UTI risk. These findings suggest potential heterogeneity in clinical effectiveness among SGLT2 inhibitors in HFmrEF and warrant confirmation in prospective comparative studies.