127-OR: The Effect of Tirzepatide during Weight Loss on Metabolic Adaption, Fat Oxidation, and Food Intake in People with Obesity

We hypothesized that tirzepatide (TZP) causes body weight loss by reducing food intake and, according to pre-clinical studies, decreasing metabolic adaptation during weight loss. In a randomized blinded clinical trial in people with obesity (PWO) undergoing caloric restriction, we investigated the effect of TZP vs Placebo (PBO) on energy metabolism after targeting a 10% (±2%) weight loss. In this 18wk phase 1 study, 55 PWO, were randomized (1:1) to TZP 15 mg or PBO (mean baseline body weight 102.5 vs 103.1 kg, respectively). The primary objective was to investigate the change from baseline in sleeping metabolic rate (SMR) measured by whole-room indirect calorimetry. Secondary measures were changes in 24-hr sedentary energy expenditure, 24-hr respiratory quotient (RQ), sleeping RQ, substrate utilization, body composition (BC) and food intake. TZP caused greater weight loss than PBO (-16.7 kg vs -8.3 kg; p<0.001). The decreases in SMR and 24-hr energy expenditure were not different between groups after adjusting for changes in body weight and BC. However, TZP significantly reduced 24-hr RQ and sleeping RQ compared to PBO; thus, significantly increasing fat oxidation while decreasing carbohydrate and protein oxidation rates. TZP also significantly reduced food intake. Overall, TZP did not affect metabolic adaptation but significantly increased fat oxidation. Disclosure E.Ravussin: Advisory Panel; Novartis, Research Support; Eli Lilly and Company, Novartis AG. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. G.Sanchez-delgado: Research Support; Eli Lilly and Company, Novo Nordisk, Abbott, Maastricht instruments, Vyaire Medical, ParvoMedics, Cosmed, Speaker's Bureau; Eli Lilly and Company. C.K.Martin: Board Member; EHE Health, Wondr Health, Other Relationship; ABGIL, Research Support; Pack Health, Evidation Health, Lilly, WW International, Inc. H.Nishiyama: None. J.Li: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. S.Urva: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. E.J.Pratt: Employee; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Z.Milicevic: Employee; Eli Lilly and Company. Funding Eli Lilly and Company