Cerebrovascular outcomes of semaglutide in patients with type 2 diabetes mellitus or obesity: a systematic review and meta-analysis

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated favourable cardiovascular effects, yet whether this benefit extends to cerebrovascular outcomes remains unclear. This study aims to investigate the cerebrovascular outcomes of semaglutide in patients with type 2 diabetes mellitus (T2DM) or obesity. PubMed, Embase, the Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov were systematically searched from inception to September 23, 2025, using predefined semaglutide terms. Randomized controlled trials (RCTs) ≥ 26 weeks of oral or subcutaneous semaglutide in adults with T2DM or obesity were included. Prespecified cerebrovascular outcomes included ischemic stroke, hemorrhagic stroke, and transient ischemic attack (TIA). Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled under a random-effects model, with subgroup and sensitivity analyses. Risk of bias was assessed via RoB 2 and evidence certainty via GRADE. 27 RCTs (40,878 participants) were included. Semaglutide was associated with a reduced risk of overall cerebrovascular events (RR 0.88, 95% CI 0.78-1.00, P = 0.045). A numerically lower risk of TIA was also observed, though it did not reach the conventional threshold for statistical significance (RR 0.84, 95% CI 0.70-1.00, P = 0.055). As the 95% CIs for both effect estimates abutted the null value of 1.00, these borderline findings should be interpreted with caution. No statistically significant associations were identified for ischemic cerebrovascular events or hemorrhagic cerebrovascular events. Prespecified exploratory subgroup analyses stratified by age, dose, and treatment duration showed a significantly reduced TIA risk among patients treated for ≥ 52 weeks (RR 0.83, 95% CI 0.69–0.99, P = 0.042) and among those without T2DM (RR 0.69, 95% CI 0.52–0.92, P = 0.011). Primary findings were robust in sensitivity analyses; GRADE certainty was moderate. Our findings suggest that semaglutide may be associated with a lower risk of overall cerebrovascular events and TIA in patients with T2DM or obesity. However, the observed differences across treatment duration and diabetes status were exploratory and should be interpreted cautiously. Further studies are needed to confirm these findings.