Semaglutide and major adverse cardiovascular events in patients with and without DM: A systematic review and meta-analysis.

Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), has been associated with cardiovascular benefits, whereas the consistency of its effect across various clinical settings, as well as its safety-economic profile, remains uncertain. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were searched up to January 2025 and identified 11 randomized controlled trials (12 comparisons; 25,067 participants) comparing semaglutide with placebo or active control. Using a DerSimonian-Laird random-effects model, semaglutide reduced major adverse cardiovascular events by 32% [pooled odds ratio (OR)=0.68; 95%; confidence interval 0.52-0.91; 95% prediction interval 0.44-1.04]. Point estimates remained unchanged after censoring all STEP obesity trials (OR=0.70) or both heart-failure trials (OR=0.66), indicating a negligible institution-level effect. Mixed-effects meta-regression analysis revealed greater benefit with lower body weight, LDL- and total cholesterol levels, and lesser benefit with higher age, HbA1c and blood pressure (all P<0.01). Safety pooling found higher risks of any gastrointestinal (GI) disorder [relative risk (RR)=1.47], gallbladder events (RR=2.37), and discontinuation due to GI intolerance (RR 2.32). A total of seven out of 11 trials enrolled ≥75% White patients, none of whom were from low-income countries, limiting generalizability. Besides, U.S. cost-utility models published in the literature report incremental cost-effectiveness ratios of US$ 180,000-260,000 per quality-adjusted life-year, above conventional willingness-to-pay thresholds. Overall, semaglutide demonstrated marked cardiovascular risk reduction at all doses and across all populations, with low statistical heterogeneity. However, this benefit must be weighed against GI intolerance, limited racial and geographic representation and uncertain cost-effectiveness outside high-income regions. Future trials must oversample underrepresented minorities, extend to low- and middle-income regions, and include formal economic evaluations to further refine population-specific benefit-risk profiles and value estimates.