Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity

BackgroundRetatrutide is a triple-receptor agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors. MethodsIn this phase 3, randomized, double-blind trial, we assigned adults with obesity without diabetes to receive a once-weekly subcutaneous injection of retatrutide (at a dose of 4 mg, 9 mg, or 12 mg) or placebo for 80 weeks. Primary outcomes (evaluated in the 9-mg and 12-mg groups each vs. placebo) were the percent change in body weight and the change in the WOMAC pain score (ranging from 1 to 10, with higher scores indicating worse pain) in the subgroup of 574 participants with knee osteoarthritis and the change in the apnea–hypopnea index in the 243 participants with obstructive sleep apnea. For weight-related end points, intercurrent events were handled by a treatment-regimen estimand (intention-to-treat [ITT]). For end points in participants with knee osteoarthritis or obstructive sleep apnea, a hybrid-treatment estimand was applied, with a hypothetical strategy for intercurrent events suggesting treatment failure; ITT results are also reported. ResultsA total of 2339 participants underwent randomization. The mean percent change in body weight in the retatrutide groups was −17.6% (4-mg dose), −23.7% (9-mg dose), and −25.0% (12-mg dose) versus −3.9% in the placebo group (differences, −19.8 and −21.0 percentage points, respectively; P<0.001 for both comparisons). Among the participants with knee osteoarthritis, the corresponding changes in the pain score in the retatrutide groups for the hybrid estimand were −3.2, −3.5, and −3.6 versus −1.9 with placebo (differences, −1.6 and −1.8 points; both P<0.001); the corresponding changes for the ITT estimand were −3.4, −3.9, and −4.1 versus −2.5 with placebo (differences, −1.4 and −1.6 points; both P<0.001). Among the participants with obstructive sleep apnea, the corresponding changes in events per hour in the retatrutide groups for the hybrid-treatment estimand were −22.9, −34.3, and 31.7 versus −9.9 (differences, −24.4 and −21.9; both P<0.001); the corresponding changes for the ITT estimand were −22.8, −34.3, and −32.1 versus −9.6 (differences, −24.7 and −22.5; both P<0.001). The most common adverse events were gastrointestinal. ConclusionsIn adults with obesity, retatrutide resulted in significant weight reduction, reduced pain in participants with knee osteoarthritis, and reduced apnea–hypopnea events in participants with obstructive sleep apnea. (Funded by Eli Lilly; TRIUMPH-1 ClinicalTrials.gov number, NCT05929066.)