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

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.