GLP-1 receptor agonists (GLP-1 RAs) are increasingly evaluated for cardiovascular outcomes, including heart failure (HF), due to their weight-reducing and anti-inflammatory effects. Individual trials in HF have reported heterogeneous results, which appear to differ by HF subtype. No prior quantitative synthesis has systematically compared GLP-1 RA effects in heart failure with preserved (HFpEF) versus reduced ejection fraction (HFrEF) across a wide range of clinically relevant outcomes. This meta-analysis addresses this gap by evaluating subtype-specific efficacy across clinical, functional, biochemical, and hemodynamic domains to guide therapy and inform future research. Eight randomized controlled trials enrolling 11,234 patients were included following a systematic search of major databases per PRISMA 2020 guidelines. Risk of bias was assessed using the Cochrane ROB 2.0 tool. Data were pooled using random-effects models with Hartung-Knapp adjustment. Sensitivity analyses assessed robustness and certainty of evidence was rated using GRADE. In HFpEF, GLP-1 RAs significantly reduced HF worsening events (HR 0.67, 95% CI 0.50-0.89; I² = 9.9%, high-certainty) and improved NT-proBNP (ratio 0.85), six-minute walk distance (+17.6 m), Kansas City Cardiomyopathy Questionnaire score (+7.4 points), and systolic blood pressure (-3.6 mmHg). The composite of HF worsening events or cardiovascular death was also reduced (HR 0.76, 95% CI 0.64-0.90). In HFrEF, no benefit was observed for HF worsening events (HR 1.23, 95% CI 0.89-1.69; I² = 0%, moderate-certainty) or secondary outcomes. Gastrointestinal adverse events were the most frequent cause of drug discontinuation (RR 3.12, 95% CI 1.28-7.63). In conclusion, GLP-1 RAs improve clinical, functional, and biomarker outcomes in HFpEF but not in HFrEF, highlighting subtype-specific efficacy. Gastrointestinal intolerance remains a key limitation, emphasizing the need for careful patient selection to optimize adherence. PROSPERO Registration: CRD420251138529.
