Efficacy and safety of Tirzepatide in patients with heart failure with preserved ejection fraction: A systematic review and meta-analysis

BACKGROUND Obesity-related heart failure with preserved ejection fraction (HFpEF) is associated with high morbidity and limited therapeutic options. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has demonstrated reductions in cardiovascular mortality and worsening heart failure events in a recent randomized controlled trial. However, pooled evidence for tirzepatide's cardiovascular and clinical effects in HFpEF remains limited. Moreover, head-to-head comparisons of tirzepatide with semaglutide, another incretin-mimetic therapy shown to be beneficial in HFpEF, are sparse. This meta-analysis aims to systematically analyze the efficacy and safety of tirzepatide in patients with HFpEF. METHODS We conducted a systematic review by searching multiple databases up to December 5, 2025 evaluating tirzepatide versus standard therapy and semaglutide for cardiovascular outcomes in patients with obesity-related HFpEF. Statistical analysis was performed using RevMan 5.4, with an inverse variance random effects model to calculate hazard ratios (HR) and odds ratios (OR). Heterogeneity was assessed using the Higgins I² test. The study protocol is registered in PROSPERO (CRD420251170117). RESULTS Our final analysis included five studies, including RCTs and observational studies with a total of 47,710 patients with HFpEF and BMI ≥ 30 kg/m2, a mean age of 64.7 years, and follow-up ranging from 52 to 146 weeks. Tirzepatide was associated with a significant reduction in the composite outcome of cardiovascular mortality and worsening heart failure events compared with standard therapy (HR 0.50; 95% CI: 0.42-0.60; p < 0.001). A significant reduction in heart failure exacerbation events alone was also observed with tirzepatide versus standard therapy (HR 0.75; p = 0.04), whereas no significant difference was seen when compared with semaglutide (HR 0.95; p = 0.31). Heart failure hospitalization and all-cause mortality did not differ significantly between tirzepatide and either standard therapy or semaglutide. No statistically significant difference in adverse drug reactions was observed. CONCLUSION In this meta-analysis, tirzepatide was associated with a significant reduction in the composite outcome of cardiovascular mortality and worsening heart failure events in patients with HFpEF and obesity. When compared to semaglutide, there were no significant differences in heart failure hospitalization or all-cause mortality.