Abstract Body (Do not enter title and authors here): Background:
This updated systematic review and meta-analysis was conducted to provide comprehensive and reliable conclusions regarding the cardiovascular safety of semaglutide, with particular attention to outcome variations by sex, race, and estimated glomerular filtration rate (eGFR).
Methods:
A systematic search was conducted in accordance with PRISMA guidelines to identify randomized controlled trials (RCTs) evaluating the impact of semaglutide on major adverse cardiovascular events (MACE) and expanded MACE. The databases PubMed, Cochrane Library, and ClinicalTrials.gov were searched for studies published between 2016 and April 2025. Study quality was assessed using the Cochrane Risk of Bias tool, and data were synthesized using RevMan 5.4. The protocol for this review was registered on PROSPERO (CRD420251066136).

Results:
Out of 5,439 screened records, 5 RCTs comprising a total of 37,267 participants were included. Semaglutide was associated with a significant reduction in the risk of MACE (RR 0.83; 95% CI 0.78–0.88; p < 0.00001) and expanded MACE (RR 0.82; 95% CI 0.78–0.87; p < 0.00001). The cardiovascular benefit was consistent across sexes—males (RR 0.82) and females (RR 0.85)—and across most ethnic groups, including Asians and Whites. However, the benefit was not statistically significant in Black or Afro-Caribbean populations (RR 0.82; 95% CI 0.49–1.38; p = 0.46).
Conclusion:
Semaglutide significantly reduces the risk of MACE and expanded MACE, suggesting its potential role as a therapeutic option in cardiovascular risk management. The observed benefit is consistent across sexes and most racial subgroups. However, further research is needed to confirm its effectiveness in Black or Afro-Caribbean populations.