Abstract
INTRODUCTION: Semaglutide and tirzepatide are newly approved glucagon-like peptide-1 receptor agonists for weight management in adults without diabetes. However, safety concerns regarding gastrointestinal (GI) adverse outcomes have been raised. This review comprehensively evaluates their GI safety profile in randomized controlled trials (RCTs). METHODS: Thirteen RCTs involving 26 894 obese participants without diabetes were analyzed. Pooled analysis assessed the risks for GI, biliary, hepatic, and pancreatic adverse events. RESULTS: Overall GI adverse events were 1.86 times higher with *both* agents (95% CI=1.56, 2.21), with tirzepatide showing a greater risk (RR 2.94, 95% CI=2.61, 3.32) than semaglutide (RR 1.68, 95% CI=1.46, 1.94). Semaglutide increased gallbladder-related disorders, particularly cholelithiasis, by over 2.6 times (95% CI=1.40, 4.82), while tirzepatide showed no significant biliary risk. Neither agent significantly increased hepatic or pancreatic adverse events. CONCLUSION: Compared to placebo, both Semaglutide and tirzepatide are associated with increased GI adverse outcomes, with most cases being mild. Clinicians should carefully monitor patients for potential adverse outcomes.