SUN-654 Comparative Efficacy and Safety of Glucagon Receptor Agonists in Metabolic Outcomes: A Network Meta-Analysis of Randomized Controlled Trials

Abstract Disclosure: A. Abulehia: None. H. Ayesh: None. A. Itbaisha: None. D. Jaber: None. H. Abugharbieh: None. C.R. Andonie: None. Introduction: Obesity and type 2 diabetes mellitus (T2DM) are global health challenges associated with severe comorbidities, including cardiovascular disease and stroke. Glucagon-like peptide-1 (GLP-1) receptor agonists are a cornerstone of treatment, offering significant benefits in glycemic control and weight loss. The emergence of dual glucagon/GLP-1 receptor agonists, such as survodutide, cotadutide, retatrutide, and mazdutide, introduces a novel therapeutic paradigm. Despite promising outcomes, limited comparative evidence exists among these agents. This network meta-analysis evaluates the relative efficacy and safety of these agonists in improving weight loss and glycemic control. Methods: A systematic review identified 25 randomized controlled trials, with 15 trials meeting inclusion criteria. Random-effects models were applied to analyze mean differences (MD) in weight change, HbA1c, and treatment discontinuation rates due to adverse events. Heterogeneity was quantified using the I² statistic. Results: Retatrutide demonstrated the greatest efficacy in weight reduction, with a mean difference (MD) of -13.06 kg (95% CI [-17.50; -8.62], p < 0.0001), followed by survodutide (MD -10.72 kg, 95% CI [-15.06; -6.37], p < 0.0001). Mazdutide showed a moderate effect (MD -7.60 kg, 95% CI [-12.84; -2.36], p = 0.0045), while cotadutide had the smallest weight reduction (MD -3.35 kg, 95% CI [-10.65; 3.95], p = 0.3683). Regarding glycemic control, retatrutide achieved the most significant HbA1c reduction (MD -1.67%, 95% CI [-2.46; -0.88], p < 0.0001), followed by mazdutide (MD -0.90%, 95% CI [-1.50; -0.29], p = 0.0035) and survodutide (MD -0.74%, 95% CI [-1.27; -0.20], p = 0.0071). Cotadutide showed minimal improvement in HbA1c (MD -0.89%, 95% CI [-1.82; 0.04], p = 0.0605). Treatment discontinuation due to adverse events was notably higher with survodutide (RR 2.73, 95% CI [1.05; 7.09], p = 0.0516) and retatrutide (RR 2.43, 95% CI [0.61; 9.77], p = 0.1262), whereas cotadutide and mazdutide exhibited lower discontinuation rates, showing no significant differences from placebo. Conclusions: Retatrutide and survodutide demonstrate superior efficacy in weight loss and glycemic control among glucagon receptor agonists, though at the cost of higher adverse event-related discontinuation. Presentation: Sunday, July 13, 2025