OR09-08 Muscle Loss With Weight Loss Is Modulated by Age, Sex, and Protein Intake and May Affect Glucose Homeostasis in Adults With Obesity

Abstract Disclosure: M.S. Haines: BioAge. L.E. Dichtel: Perspectum, Lumos Pharma, Recordati, Novo Nordisk, Third Rock Ventures, Merida Biosciences, Marea Therapeutics, Flare Therapeutics. C. Dobbie: None. S. Wasserman: None. A. Bader: None. M. Mirgorodsky: None. C.V. Anekwe: None. G. Curtis: None. W.P. Dutton: None. G. O'Brien: None. F.C. Stanford: Eli Lilly & Company, Novo Nordisk, Amgen Inc, Pfizer, Inc., AstraZeneca, Doximity, GoodRx, Sweetch, Clearmind Medicine, Apnimed, LifeForce, Mellicell, Currax, Vida Health, Ilant Health, Empros Pharma, Dox Health, Calibrate. K.K. Miller: Amgen Inc, Bristol-Myers Squibb, General Electric, Boston Scientific, Becton Dickinson. Loss of muscle mass is a consequence of weight loss in adults with obesity and may have unintended consequences on metabolic and bone health because muscle is responsible for most post-prandial glucose disposal and is a critical determinant of bone mineral density (BMD). About 40% of the weight lost secondary to semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is lean mass. However, predictors of muscle loss in this population are unknown, as are the effects of muscle loss on glucose and bone homeostasis. This observational prospective study aimed to identify risk factors for, and factors that protect against, loss of muscle mass due to weight loss with semaglutide, and to investigate whether muscle loss impacts glucose and bone homeostasis. We studied 39 adults with obesity and prescribed either semaglutide (n=22) or a diet and lifestyle intervention for weight loss [Healthy Habits for Life (HHL)] (n=17) for 3 months. The primary outcome was change in lean mass by DXA. Mean age [46 ± 13 y (SD)], BMI (37.7 ± 5.0 kg/m2), HbA1c (5.4 ± 0.3%), % female (72%, n=28) and race (77% White, n=30) were similar between groups. Mean weight loss was 6.7 ± 2.9 vs. 2.5 ± 3.2% in the semaglutide vs. HHL groups (p=0.002). Among those who lost weight, 47.5 ± 25.9% of the weight loss was lean mass in the semaglutide vs. 34.8 ± 41.6% in the HHL group (p=0.19). Change in lean mass was more strongly correlated with change in weight in the HHL (R=0.93, p<0.0001) vs. semaglutide (R=0.55, p=0.01) group (intervention arm * change in lean mass interaction, p=0.03). Lower protein intake at 3 months in the semaglutide group (R=0.52, p=0.02) and older age in the HHL group (R= -0.53, p=0.03) were associated with a greater decrease in lean mass. After adjusting for change in weight, older age (p=0.046), female sex (p=0.02), and lower protein intake at 3 months (p=0.03) were associated with a greater decrease in lean mass in the semaglutide, but not the HHL, group. In the same adjusted model, a greater decrease in lean mass was associated with less improvement in HbA1c in the semaglutide group (p=0.03) only. The bone resorption marker C-terminal telopeptide (CTX) (15 ± 29%, p=0.03) and total body BMD (1.9 ± 1.5%, p<0.0001) increased in the semaglutide, but not HHL, group. The bone formation marker procollagen type 1 N-terminal propeptide (P1NP) did not change in either group. In conclusion, older age and female sex may be associated with greater muscle loss, while higher protein intake may be relatively protective against muscle loss, in adults with obesity prescribed semaglutide. Greater muscle loss was independently associated with less improvement in glucose homeostasis with semaglutide. Therefore, maintaining muscle mass with weight loss in individuals with obesity on semaglutide may be essential to mitigate insulin resistance and frailty. The association between semaglutide and bone metabolism warrants further investigation. Presentation: Saturday, July 12, 2025