Long-Term Cardiovascular Outcomes of Glucagon-Like Peptide-1 Receptor Agonists in Non-diabetic Obesity: A Systematic Review and Meta-Analysis

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrate cardiovascular benefits in diabetic populations, yet evidence in non-diabetic obesity remains limited. We searched PubMed, Excerpta Medica database (Embase), Cochrane Controlled Register of Trials (CENTRAL), and Web of Science (January 2015-January 2025) for randomized controlled trials evaluating GLP-1 RAs in non-diabetic adults with obesity (BMI ≥30 kg/m²), with composite major adverse cardiovascular events (MACE) as the primary outcome using random-effects models with risk ratios (RRs) and 95% confidence intervals (CIs). Sixteen trials (23,467 participants, median 68 weeks follow-up) were included, demonstrating that GLP-1 RAs reduced MACE by 20% (RR 0.80, 95% CI 0.72-0.89), with strongest effects on stroke (RR 0.72), myocardial infarction (RR 0.84), and heart failure hospitalization (RR 0.82), alongside reductions in systolic blood pressure (4.2 mmHg), triglycerides (32 mg/dL), and high-sensitivity C-reactive protein (hsCRP) (38.6%), with 12.4% weight loss where mediation analyses showed 35%-55% of cardiovascular benefit was independent of weight reduction. GLP-1 RAs provide substantial cardiovascular protection in non-diabetic obesity through both weight loss-dependent and independent mechanisms, with acceptable safety profiles supporting their role in cardiovascular risk reduction.