Glucagon-like peptide-1 agonists (GLP-1 RAs) have produced substantial weight loss effects in type 2 diabetes mellitus (T2DM) cohorts, but these effects have not been thoroughly studied in patients with obesity and without diabetes. This review aimed to analyze direct comparative studies for semaglutide versus other GLP-1 RA (liraglutide and efinopegdutide) in facilitating weight loss and evaluating adverse events in patients with obesity. A systematic search following the guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was performed in PubMed, Embase, and Cochrane Library for direct comparative studies comparing semaglutide with other GLP-1 RA on weight loss in patients with obesity. A narrative synthesis and meta-analysis were performed to analyze the differences in weight loss between cohorts. A meta-analysis found that semaglutide produced a greater effect on mean weight loss compared to liraglutide, but did not produce a significant difference compared to efinopegdutide. Semaglutide, liraglutide, and efinopegdutide were well-tolerated and were associated with primarily minimal to moderate severity adverse effects, most of which were gastrointestinal. Future studies should continue to focus on conducting direct comparisons between GLP-1 RAs and emerging multi-receptor GLP-1 RAs, such as efinopegdutide, tirzepatide, and retratrutide, to determine clinical efficacy, long-term safety, and identifying the most effective regimens for clinical practice.
