Comparative efficacy and safety of semaglutide 2.4 mg and tirzepatide 5-15 mg in obesity with or without type 2 diabetes: A systematic review of Phase 3 clinical trials.

BACKGROUND AND AIMS: Both semaglutide 2.4 mg and tirzepatide have been recently approved for chronic use in obesity. There is a lack of literature comparing the efficacy and safety of both these agents in people with obesity/overweight with or without type 2 diabetes (T2D). We systematically reviewed Phase 3 randomized controlled trials (RCTs) conducted with two agents to synthesize the comparative efficacy and safety outcomes. METHODS: We systematically searched PubMed electronic databases until December 15, 2024, using selected keywords and Boolean "AND." Subsequently, we compared the most closely matched trials conducted with semaglutide 2.4 mg and tirzepatide through an adjusted (if baseline imbalance in treatment outcome modifiers present) or unadjusted (in the absence of baseline imbalance) indirect treatment comparison method. RESULTS: We identified one trial each of semaglutide 2.4 mg (STEP-1) and tirzepatide 5, 10, and 15 mg (SURMOUNT-1) in obese or overweight people without T2D and one trial each of semaglutide 2.4 mg (STEP-2) and tirzepatide 10 and 15 mg (SURMOUNT-2) in overweight people with T2D that were almost entirely comparable concerning baseline outcome modifier characteristics. Our unadjusted analysis without individual patients' data found relatively higher (4 and 5.4 % additional) weight loss, HbA1c (-0.4 % additional) reduction, and fewer gastrointestinal side effects (GI S/E) with tirzepatide 10 and 15 mg, respectively, than with semaglutide 2.4 mg, in the intention-to-treat analysis. CONCLUSION: Tirzepatide 10 and 15 mg are more effective and have fewer GI S/E than semaglutide 2.4 mg. A well-powered head-to-head RCT is currently needed to confirm these findings.