Introduction The prevalence of diabetes has increased drastically over the last couple of decades. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) stimulate glucose-dependent insulin release and inhibit glucagon secretion from pancreatic islet cells, and have a recognized side effect of substantial weight loss. Weight loss has been associated with improved metabolic control and a reduction in comorbidities such as cardiovascular disease and the remission of type 2 diabetes. Therefore, pharmacological methodologies may become an attractive alternative to invasive surgical procedures. This systematic review analyzed semaglutide against alternative GLP-1 RAs in facilitating weight loss and evaluated their associated adverse effects (AEs) in diabetic patients.

Methods A systematic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was performed in PubMed, Embase, and Cochrane Library for studies comparing semaglutide against other GLP-1 RAs on weight loss. A narrative synthesis and meta-analysis using SPSS program version 29 were performed to analyze the differences in weight loss between cohorts.

Results Nine studies with 5,445 patients whose mean age was 60.01 years (range: 55.50-70.00) and mean follow-up of 32.5 weeks (4.0-58.7) were included. Three studies compared semaglutide against liraglutide, four studies compared semaglutide against dulaglutide, two studies compared semaglutide against tirzepatide, and one study compared semaglutide against exenatide. Meta-analysis showed that semaglutide (5.14% range: 4.95-5.80%) had a significantly greater mean weight loss compared to liraglutide (2.89% 2.00-3.35%), and dulaglutide (4.71% 2.07-6.81%). Tirzepatide (10.33% range: 8.22-11.90%) had a significantly greater mean weight loss compared to semaglutide (5.48% 4.88-6.08%). Common AEs included minor and moderate gastrointestinal (GI) events. 

Conclusions Semaglutide demonstrated increased weight loss compared to dulaglutide, liraglutide, and exenatide. However, newer dual agonists such as tirzepatide produced a greater weight loss compared to semaglutide, which may be attributed to its ability to act as a dual agonist of GLP-1 and gastric inhibitory polypeptide receptors. An important consideration is the high rate of AEs. GI AEs are the most commonly experienced AEs with semaglutide intervention, most specifically nausea and vomiting, with higher rates observed in patients with lower BMI. Additionally, there have been recently developed GLP-1 RAs acting on multiple receptors which may provide even greater weight loss and clinical outcomes for diabetic patients. Future studies should compare specific GLP-1 RAs to better outline the most efficacious and safe formulation of GLP-1 RAs for weight loss.