Sex-based differences in clinical outcomes among patients with obesity and heart failure with preserved ejection fraction treated with tirzepatide.

BackgroundSex-related differences are well recognized in heart failure with preserved ejection fraction (HFpEF), but real-world data describing clinical outcomes by sex among patients with obesity and HFpEF treated with tirzepatide remain limited.ObjectivesTo compare observed hospitalization, cardiovascular, and gastrointestinal outcomes between male and female patients with obesity and HFpEF treated with tirzepatide.DesignRetrospective, propensity score-matched, within-treatment cohort study.MethodsA retrospective study was conducted using TriNetX database which included 110 healthcare organizations. Adults with obesity, HFpEF, and taking tirzepatide between June 1, 2022 and January 1, 2025 were identified. Males and females were balanced using 1:1 propensity score matching (n=1,654 per group). Primary outcome assessed included all-cause hospitalization. Secondary outcomes were all-cause mortality, HF exacerbation, major adverse cardiovascular events (MACE), incident atrial fibrillation, nausea/vomiting and diarrhea. Two prespecified falsification endpoints were used.ResultsDuring 1-year follow-up, males had a lower hazard of all-cause hospitalization compared with females (HR 0.87, 95% CI 0.77-0.98). No significant differences were observed for all-cause mortality (HR 1.73, 95% CI 0.95-3.18), HF exacerbation (HR 1.14, 95% CI 0.90-1.44), MACE (HR 1.28, 95% CI 0.99-1.65), or incident atrial fibrillation (HR 1.21, 95% CI 0.61-2.43). Males experienced lower rates of nausea and vomiting (HR 0.50, 95% CI 0.37-0.67), while diarrhea was similar (HR 0.84, 95% CI 0.59-1.19). Falsification endpoints showed no significant associations.ConclusionAmong tirzepatide-treated patients with obesity and HFpEF, no statistically significant sex-associated differences were detected in major cardiovascular outcomes. Males had a modestly lower observed hazard of hospitalization and fewer coded nausea and vomiting events. Because this was a within-treatment observational comparison without an external comparator, these findings should not be interpreted as evidence of differential tirzepatide effectiveness by sex.