Cardiovascular and functional outcomes of glucagon-like peptide−1 receptor agonists in heart failure with preserved or mildly reduced ejection fraction: a systematic review and meta-analysis of randomized controlled trials

Heart failure with preserved (HFpEF) or mildly reduced ejection fraction (HFmrEF) accounts for more than half of heart failure (HF) cases and is strongly associated with obesity and metabolic dysfunction. Glucagon-like peptide−1 receptor agonists (GLP-1RA) provide cardiometabolic benefits, yet their impact on heart-failure outcomes remains uncertain. We aim to evaluate the effects of GLP-1RA on cardiovascular (CV) outcomes, HF events, and functional status in patients with HFpEF and HFmrEF. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines. PubMed, Scopus, Web of Science, and CENTRAL were searched from inception to 15 April 2026 for randomized controlled trials (RCTs) comparing GLP-1RA with placebo in adults with HFpEF or HFmrEF (EF ≥40%). The primary outcome was a composite of CV death or worsening HF. Secondary outcomes included worsening HF events, all-cause mortality, CV mortality, Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), 6-min walk distance (6MWD), and body-weight change. Random-effects models were used. Seven RCTs involving 6,525 patients were included. GLP-1RA significantly reduced the composite outcome of CV death or worsening HF (RR 0.72, 95% CI 0.60–0.85) and the outcome of worsening HF alone (RR 0.62, 95% CI 0.47–0.83). No significant differences were observed in all-cause mortality or CV mortality. GLP-1RA significantly improved KCCQ-CSS (MD 7.38 points, 95% CI 5.51–9.26), 6MWD (MD 17.60 m, 95% CI 11.86–23.35), and body weight (MD −9.56, 95% CI −12.71 to −6.41). The signal of benefit was numerically stronger in obesity-enriched populations. In HFpEF/HFmrEF, GLP-1RA improves symptoms and functional capacity and reduces worsening HF events, without a significant reduction in mortality. The signal of benefit was numerically stronger in obesity-enriched populations, supporting the need for further phenotype-targeted trials to clarify long-term clinical benefits.