Comparative Efficacy and Tolerability of Incretin-Based Medication for Weight Loss in Adults with Overweight or Obesity: A Meta-Analysis of Randomized Controlled Trials

Introduction and Objective: Glucagon-like peptide-1 receptor-agonists (GLP-1 RAs) and the dual GIP/GLP-1 receptor agonist tirzepatide, when used for the pharmacological treatment of obesity, have become substantially more effective (tirzepatide > semaglutide > liraglutide) regarding weight reduction. We wanted to systematically study the impact on adverse events. Methods: We conducted a meta-analysis of randomized, placebo-controlled trials evaluating liraglutide 3 mg once daily, semaglutide 2.4 mg once weekly, and tirzepatide 15 mg once weekly in adults with overweight or obesity. Outcomes included placebo-subtracted body weight reduction and odds ratios for gastrointestinal adverse events, treatment discontinuation, and hypoglycemia. Results: Nineteen RCT including 13,508 participants were analyzed. Mean weight loss was −5.3% (95% CI −5.6 to −4.9) with liraglutide, −12.0% (−12.4 to −11.5) with semaglutide, and −14.6% (−15.5 to −13.8) with tirzepatide (all p<0.0001). Weight reduction with semaglutide and tirzepatide was dose-dependent across the full dose range. Odds ratios for nausea were 4.0 (95% CI 3.4-4.6), 2.7 (2.3-3.1), and 3.9 (3.2-5.0), and for vomiting 4.5 (3.6-5.7), 3.5 (2.9-4.3), and 6.0 (4.1-8.8) for liraglutide, semaglutide, and tirzepatide, respectively. Treatment discontinuation occurred in 8.4% (L), 3.7% (S), and 2.8% (T). Hypoglycemia was rare and severe events were not reported. Conclusion: Marked and significant differences in weight-reducing efficacy exist among incretin-based therapies, whereas risks of gastrointestinal AE, treatment discontinuation, and hypoglycemia are broadly comparable, likely reflecting dose-escalation strategies that improve tolerability. Disclosure: S. Al Basri: None. M.A. Nauck: Advisory Panel; Current; Boehringer Ingelheim International GmbH, Eli Lilly and Company. Speaker's Bureau; Current; Novo Nordisk. Advisory Panel; Current; Pfizer Inc., Regor. Consultant; Current; Structure Therapy. Speaker's Bureau; Current; Eli Lilly and Company, Novo Nordisk, Medscape, Medical Learning Institute. Advisory Panel; Current; Sun Pharmaceutical Industries Ltd. W. Fenske: Advisory Panel; Current; Lilly Global Health Partnership, Boehringer Ingelheim International GmbH, Novo Nordisk. Other - Speaker; Current; Amgen Inc.