SUN-659 Comparative Efficacy and Safety of Tirzepatide vs Retatrutide in Weight Loss: A Network Meta-Analysis of Clinical Trials

Abstract Disclosure: A. Salhab: None. H. Maraqah: None. Y. Habes: None. M. Abusabha: None. H. Ayesh: None. Background: The global rise in obesity poses a significant public health challenge, contributing to an increased burden of comorbidities such as cardiovascular disease, type 2 diabetes, and certain cancers. Dual and triple agonists targeting GLP-1, GIP, and glucagon receptors have emerged as promising therapies for achieving substantial weight loss. Tirzepatide, a dual GLP-1 and GIP receptor agonist, and Retatrutide, a triagonist targeting GLP-1, GIP, and glucagon receptors, have demonstrated remarkable efficacy. However, comparative evidence between these therapies remains limited. This network meta-analysis evaluates the efficacy and safety of tirzepatide versus retatrutide in achieving weight loss, providing insights for clinical decision-making and guiding future research. Methods: A systematic search across PubMed, Cochrane, Scopus, Web of Science, and ClinicalTrials.gov identified 132 studies, with 12 meeting inclusion criteria. Random-effects models were used to calculate mean differences (MD) and relative risk (RR) with 95% confidence intervals (CI). Outcomes included absolute and percentage weight change and adverse events. Results: Retatrutide demonstrated greater absolute weight reduction compared to tirzepatide (Retatrutide: MD -16.34 kg, 95% CI [-22.11; -10.56], p < 0.0001; Tirzepatide: MD -11.82 kg, 95% CI [-15.08; -8.56], p < 0.0001). Percentage weight loss was similarly greater for retatrutide (Retatrutide: MD -23.77%, 95% CI [-29.16; -18.38], p < 0.0001; Tirzepatide: MD -16.79%, 95% CI [-19.62; -13.95], p < 0.0001). Adverse events were more frequent with retatrutide (RR 4.10, 95% CI [1.42; 11.84], p = 0.0092) compared to tirzepatide (RR 2.78, 95% CI [1.98; 3.91], p < 0.0001). Both agents showed significant efficacy compared to placebo in weight reduction and safety profiles, with retatrutide achieving superior outcomes in weight loss parameters. Conclusions: Retatrutide demonstrates superior efficacy in both absolute and percentage weight reduction compared to tirzepatide, albeit with a higher frequency of adverse events. These findings underscore the potential of retatrutide in achieving substantial weight loss and highlight the need for further direct comparisons in head-to-head trials to assess long-term safety and efficacy. Presentation: Sunday, July 13, 2025