1711-P: Menopausal Hormonal Status and Estradiol Use Modulate Semaglutide-Associated Weight Loss in Women: Analyses from STEP1 and SELECT

Introduction and Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) induce substantial weight loss (WL) in both sexes; however, post hoc analyses indicate women achieve ~40% greater WL reductions than men. We aimed to investigate the underlying mechanisms. Methods: We analyzed data from the STEP 1 (n=1482) and SELECT (n=17,604) trials in adults with overweight/obesity without T2D randomized to semaglutide 2.4 mg or placebo. We assessed the influence of drug exposure and age on WL trajectories. SomaScan proteomic profiling was used to explore associations between endogenous sex hormones and WL. A subgroup of STEP 1 participants >55 years (yrs) receiving exogenous estradiol via hormone replacement therapy (HRT; n=30) was evaluated. Results: WL differences between sexes were not fully explained by drug exposure. In SELECT, men showed consistent WL across ages 45-90 yrs, whereas WL in women decreased with age. Circulating FSH and LH delineated menopausal status and predicted WL magnitude, particularly during perimenopause (p<0.05; Fig. A). HRT significantly augmented WL in women >55 yrs vs matched controls (20% vs 16%, p=0.009; Fig. B). Conclusion: Multiple factors contribute to sex-related differences in GLP-1RA-induced WL. Analyses implicate menopausal status as a key determinant, with HRT highlighting a specific hormonal role. Larger studies are warranted to confirm these findings. Disclosure M. Dermit: None. F. Capelluto: Employee; Current; Novo Nordisk. E. Huvinen: Speaker's Bureau; Current; Lilly. Advisory Panel; Current; Vivus BV. Speaker's Bureau; Current; Vivus BV. Consultant; Current; Lilly. Speaker's Bureau; Current; Novo Nordisk. Consultant; Current; Novo Nordisk. Research Support; Current; Novo Nordisk. Speaker's Bureau; Current; Exeltis, Navamedic. Speaker's Bureau; Ended; Orion pharma, Novartis Pharmaceuticals Corporation. B. McGowan: Advisory Panel; Current; Novo Nordisk. Speaker's Bureau; Current; Novo Nordisk. Advisory Panel; Current; Lilly. Speaker's Bureau; Current; Lilly. Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH. Stock/Shareholder; Current; Reset Health. Board Member; Current; Reset Health. D. Rubino: Other - Advisory panel, research support, shareholder; Current; AbbVie Inc. Other - steering committee, research support; Current; Amgen Inc. Other - advisory panel, steering committee, research support; Current; AstraZeneca. Other - advisory panel, research support; Current; Boehringer Ingelheim International GmbH. Other - advisory panel, speaker, research support,; Current; Novo Nordisk. Consultant; Current; Lilly, Shionogi & Co., Ltd. Advisory Panel; Current; Neurocrine Biosciences, Inc., Regeneron Pharmaceuticals Inc. Consultant; Current; Pfizer Inc., Roche Pharmaceuticals, Cytoki. Other - advisory, research support; Current; Terns Pharmaceutical. Advisory Panel; Current; Neuraly Inc. Consultant; Current; Ferring Pharmaceuticals. Consultant; Ended; NodThera. M. Quiroga: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Eli Lilly and Company, Genmab, Coloplast, Novo Nordisk. D.M. Belmont-Rausch: Employee; Current; Novo Nordisk A/S. Stock/Shareholder; Current; Viking Therapeutics. Stock/Shareholder; Ended; Madrigal Pharmaceuticals, Inc. L. Bjerre Knudsen: Employee; Current; Novo Nordisk. P. Richards: Employee; Current; Novo Nordisk A/S.