The effects of tirzepatide and semaglutide on clinical and metabolic outcomes in patients with heart failure with preserved ejection fraction and obesity: a systematic review and meta-analysis

BACKGROUND AND AIMS Heart failure with preserved ejection fraction (HFpEF) with obesity remains a therapeutic challenge with limited options. Glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin agonists may improve health status, functional capacity, and metabolic parameters. We evaluated the efficacy and safety of semaglutide and tirzepatide in this population. METHODS AND RESULTS We searched PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to June 2025. Mean differences (continuous outcomes) and risk ratios (worsening heart-failure events) were pooled using random-effects models; other outcomes were synthesised narratively. Four studies met the HFpEF-specific criteria (three randomized trials and one observational cohort); the primary analysis was restricted to the three randomized trials (n = 1876), with SELECT and FLOW retained as indirect supportive evidence. Semaglutide or tirzepatide improved KCCQ-CSS (+7.39 points; 95% CI 5.43-9.35) and 6-min walk distance (+17.18 m; 11.82-22.54), and reduced worsening heart-failure events (risk ratio 0.45; 0.31-0.66). Body weight decreased by -7.73% (-10.70 to -4.76; I2 = 93%). Findings were robust in sensitivity analysis; secondary outcomes showed consistent CRP and HbA1c reductions; gastrointestinal intolerance was the most common adverse event. CONCLUSIONS Semaglutide and tirzepatide were associated with improvements in health status, functional capacity, and body weight, and fewer worsening heart-failure events, in HFpEF with obesity, with an acceptable safety profile. They may have an adjunctive role, although larger, longer-term dedicated outcome trials are needed.