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

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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

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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.