117-OR: Effects of Triple-Hormone Receptor Agonist Retatrutide on Lipid Profiling in Participants with Obesity

In phase 2 (n=338), retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, reduced body weight, fasting glucose, triglycerides (TG), LDL and VLDL cholesterol in participants with obesity. To understand changes in energy metabolism, lipidomic profiling was conducted. Adult participants with obesity (BMI ≥30 kg/m2), or overweight (BMI ≥ 27 kg/m2) with a weight related comorbidity, were randomized to RETA 1, 4, 8, 12 mg or PBO for 48 wk. Fasting plasma collected at baseline, 24 and 48 wk, was used to measure acylcarnitines and complex lipid species using targeted mass spectrometry. Data were analyzed using a mixed model for repeated measures. An increase in 3-hydroxybutyrate (3-HB) was noted after 24 wk, accompanied by an increase in 3-hydroxybutyrylcarnitine (C4OH), acetylcarnitine-to-free carnitine ratio (C2/C0), and medium-chain ACs. The decrease of TGs at 48 wk was bias towards short-chain and saturated species. RETA 12 mg decreased total dihydroceramides (DhCers) at 48 wk by −20.1%, p-value 0.001. The increase in ketone body and C2/C0 observed after 24 wk is suggestive of adipose tissue lipolysis and reliance on fat oxidation. Inverse changes in TGs and DhCers were observed which associate with improved insulin sensitivity, reduced hepatic steatosis and systemic inflammation. Evaluation of potential benefits on cardiovascular events and MASLD may merit further investigation. Disclosure V. Pirro: Employee; Eli Lilly and Company. M.J. Pearson: Employee; Eli Lilly and Company. Y. Lin: Stock/Shareholder; Eli Lilly and Company, Pfizer Inc., AstraZeneca. M.L. Hartman: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. K.D. Roth: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. K.L. Duffin: Employee; Eli Lilly and Company. J. Willency: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly Diabetes. Stock/Shareholder; Lilly Diabetes. G. Ruotolo: None. Funding Eli Lilly and Company