Weight Loss Efficacy of Tirzepatide Compared to Placebo or GLP-1 Receptor Agonists in Adults With Obesity or Overweight: A Meta-Analysis of Randomized Controlled Trials With ≥ 20 Weeks Treatment Duration.

Introduction: Tirzepatide, a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like Peptide 1 (GLP-1) analogue, is a novel medication with comparable pharmacological characteristics and has demonstrated promising weight reduction outcomes in its antidiabetic trials following the approval of liraglutide and semaglutide for long-term weight control. Nonetheless, this efficacy has not been fully explored, so this meta-analysis was aimed to measure the weight loss efficacy and safety of tirzepatide in adults with overweight or obesity. Methods: We searched the PubMed, Cochrane, and Embase databases for RCTs of once-weekly tirzepatide vs. placebo or GLP-1 receptor agonists. We included studies involving adult participants who were overweight or obese despite T2DM or OHA use, with a trial duration of at least 20 weeks. The primary outcomes accounted for the mean difference in weight from baseline in the three doses of tirzepatide compared to placebo and GLP-1 receptor agonists, separately. The secondary outcomes included safety profiles and achievement of categorical weight loss of 5%, 10% and 15%. We performed the statistical analysis on RevMan 5.4, GRADE assessment using GRADEpro GDT and the quality of the included studies assessed using the Cochrane risk-of-bias (Version 2) tool. Results: We identified six RCTs in which the data of 6266 subjects were analysed. Once-weekly doses (5, 10 and 15 mg) of tirzepatide were more effective than placebo and GLP-1 RAs. Also, the proportion of patients achieving categorical weight loss goals was higher in the tirzepatide groups than in others. GRADE assessment also indicated high-certainty evidence for ≥ 15% weight loss with tirzepatide and moderate-to-low certainty for lower thresholds. Gastrointestinal side effects appeared similar between the three doses of tirzepatide and GLP-1 RAs, but they were significantly higher than placebo might impact tolerability for certain patients. Conclusion: A dose-dependent tirzepatide was superior to placebo and GLP-1 RAs in weight reduction. However, the lean mass reduction and tolerability require further investigation. Trial Registration: ClinicalTrials.gov identifier: NCT04255433.