Sex-Based Differences in Clinical Outcomes Among Heart Failure Patients Treated With SGLT2 Inhibitors: Insights From a Multicenter Cohort Study

Abstract

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have emerged as a cornerstone in heart failure (HF) management across the spectrum of ejection fraction. However, evidence regarding potential sex-based differences in treatment response remains limited, particularly in real-world cohorts.

Methods: We conducted a retrospective cohort study including consecutive adult patients hospitalized with heart failure between 2019 and 2024 across five tertiary centers. Eligible patients initiated SGLT2i therapy (empagliflozin, dapagliflozin, or canagliflozin) within 90 days of index admission. Propensity score matching (1:1) was applied to balance baseline characteristics between men and women. The primary endpoint was all-cause mortality at two years. Secondary endpoints included heart failure rehospitalization, composite cardiovascular outcomes, and renal function trajectories. Kaplan–Meier survival analyses and multivariable Cox proportional hazards models were used to assess outcomes.

Results: A total of 4,286 patients were included (mean age 64 ± 12 years; 41% women). After matching, 1,512 men and 1,512 women were analyzed. Women demonstrated a significantly lower risk of all-cause mortality at two years compared to men (HR 0.78, 95% CI 0.65–0.92, p = 0.004). The reduction in HF rehospitalization was also more pronounced in women (HR 0.81, 95% CI 0.70–0.94, p = 0.006). No sex-based differences were observed in renal function decline. Sensitivity analyses across HF subtypes (HFrEF, HFpEF) yielded consistent findings.

Conclusion: In this large multicenter cohort, women with heart failure treated with SGLT2 inhibitors exhibited more favorable long-term outcomes compared to men, driven primarily by lower rates of mortality and rehospitalization. These results highlight the importance of sex-specific considerations in contemporary HF therapy and support tailored treatment strategies to optimize outcomes.