2565-P: Survodutide Induces Superior Weight Loss and Energy Expenditure Compared with Semaglutide in DIO Mice Housed at Thermoneutrality

Introduction and Objective: Standard rodent housing temperatures (20-22 °C) induce cold stress, elevating energy expenditure and potentially confounding anti-obesity drug efficacy. To better reflect human physiology, we evaluated survodutide and semaglutide effects in diet-induced obese (DIO) mice housed at thermoneutrality (28 °C). Methods: Male C57BL/6J mice (24 weeks old, >14 weeks on 60% high-fat diet, n=8/group) were acclimated to thermoneutrality for 2 weeks and then treated s.c. daily for 4 weeks with vehicle, semaglutide, or survodutide (both 20 nmol/kg). Body weight, food intake, energy expenditure, body composition, muscle weight, grip strength, and plasma amino acids were assessed. Results: Survodutide induced greater body weight loss than semaglutide (-27% or -18% vs. vehicle, p<0.001), with similar fat mass and lean mass reduction and no differences in muscle weight and grip strength between both treatments. Energy expenditure was significantly increased with survodutide, particularly during week 2 (0.34±0.03 kcal/h for vehicle, 0.33±0.05 kcal/h for semaglutide and 0.40±0.08 kcal/h for survodutide on day 10), while food intake suppression was comparable. Plasma amino acids (e.g. tyrosine and serin) were only reduced with survodutide when compared to vehicle. Conclusion: Under thermoneutral conditions, survodutide produced superior weight loss and transient energy expenditure elevation compared to semaglutide. The transient energy expenditure increase likely reflects glucagon receptor-driven hepatic thermogenesis and substrate oxidation, which diminish as weight loss and metabolic adaptation progress. At standard housing temperatures, cold-induced thermogenesis dominates energy expenditure and masks such effects, highlighting the importance of thermoneutral housing for accurate metabolic assessment. Disclosure M. Pereira: Employee; Ended; Boehringer Ingelheim International GmbH. W. Rist: Employee; Current; Boehringer Ingelheim International GmbH. B. Hamilton: Employee; Current; Boehringer Ingelheim International GmbH. T. Klein: Employee; Current; Boehringer Ingelheim International GmbH. Funding Boehringer Ingelheim