Retatrutide And Lipid And Metabolite Profiles In Participants With Obesity With Or Without Type 2 Diabetes.

“Retatrutide And Lipid And Metabolite Profiles In Participants With Obesity With Or Without Type 2 Diabetes. Pearson MJ(1), Willency JA(1), Lin Y(1), Abadi A(1), Hartman ML(1), Coskun T(1), Ruotolo G(1), Duffin KL(1), Haupt A(1), Newgard CB(2)(3)(4), Pirro V(1). Author information: (1)Eli Lilly and Company, Indianapolis, IN, USA. (2)Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, NC, USA. (3)Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University School of Medicine, Durham, NC, USA. (4)Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA. CONTEXT: In phase 2 trials, retatrutide reduced body weight, hemoglobin A1c, and improved the lipid profiles of participants living with obesity, with and without T2D. OBJECTIVE: Assess plasma metabolome and lipidome changes associated with retatrutide treatment. DESIGN: Metabolomics and lipidomics were performed in fasting samples from two randomized, placebo-controlled phase 2 trials. Participants living with obesity with and without T2D were treated for 36 and 48 weeks, respectively. SETTING: Post-hoc exploratory analysis. PARTICIPANTS: 282 and 213 participants in the obesity and T2D trials, respectively. INTERVENTION(S): Obesity trial; retatrutide (1, 4, 8, 12 mg) or placebo. T2D trial: retatrutide (0.5, 4, 8, 12 mg) or placebo or dulaglutide (1.5 mg). MAIN OUTCOME MEASURE(S): Changes in metabolite and lipid levels with retatrutide treatment against baseline levels and placebo using multiplicity correction. RESULTS: At both primary and study endpoints for both populations, higher doses of retatrutide were associated with changes in a cluster of metabolites comprising 3-hydroxybutyrate, acetylcarnitine, free carnitine and fatty acid-derived long-chain acylcarnitines. Mediation analyses suggested that changes in these biomarkers mediated 23.2% of the weight-reduction response in participants without T2D and that this mediation was blunted to 12.7% in participants with T2D. Retatrutide treatment was also associated with changes in metabolites associated with insulin resistance, including branched-chain amino acids and their catabolic products, 2-aminoadipic acid, 2-hydroxybutyrate, urate, and triglycerides enriched in short-chain and saturated acyl side chains. These changes were found in both study populations and sustained across study endpoints. CONCLUSIONS: Retatrutide was associated with changes in two metabolic clusters related to fatty acid oxidation and insulin resistance in a direction associated with improved metabolic health and reduced cardiovascular risk. © The Author(s) 2026. Published by Oxford University Press on behalf of the Endocrine Society.”