Retatrutide Once Weekly in Adults with Knee Osteoarthritis Pain and Obesity

BACKGROUND: Retatrutide, an investigational triple agonist of GIP, GLP-1, and glucagon receptors, may be useful for the treatment of painful knee osteoarthritis in persons with obesity. METHODS: In two phase 3 trials, adults without diabetes who had painful knee osteoarthritis and a body-mass index of at least 27 were randomly assigned to receive once-weekly subcutaneous retatrutide (9 or 12 mg in TRIUMPH-4 and 4, 9, or 12 mg in TRIUMPH-1-OA) or placebo. In TRIUMPH-4, the primary end points were the change in the WOMAC pain score (range, 0 to 10, with higher scores indicating worse pain) and the percent change in body weight at week 68. In TRIUMPH-1-OA, the primary end point was the change in the WOMAC pain score at week 80. For non-pain-related end points, intercurrent events were handled with a treatment-policy strategy. For pain-related end points, a hybrid-treatment estimand was applied, with a hypothetical strategy for intercurrent events that suggested treatment failure and a treatment-policy strategy elsewhere. We also report results for an intention-to-treat (ITT) estimand. RESULTS: A total of 445 participants underwent randomization in TRIUMPH-4 and 574 in TRIUMPH-1-OA. At 68 weeks, the mean changes in the WOMAC pain score (hybrid-treatment estimand) with retatrutide in TRIUMPH-4 were -3.96 (9 mg) and -3.74 (12 mg), versus -2.12 with placebo (difference vs. placebo, -1.83 [95% confidence interval {CI}, -2.37 to -1.30] and -1.61 [95% CI, -2.16 to -1.07], respectively). For the ITT estimand, the corresponding differences from placebo were -1.70 (95% CI, -2.19 to -1.22) and -1.38 (95% CI, -1.91 to -0.85) (P<0.001 for all comparisons). The mean percent changes in body weight with retatrutide were -20.0% (9 mg) and -23.7% (12 mg), versus -4.6% with placebo (difference vs. placebo, -15.4 percentage points [95% CI, -18.7 to -12.1] and -19.2 percentage points [95% CI, -22.4 to -15.9]; P<0.001 for both comparisons). At 80 weeks, the mean changes in the WOMAC pain score (hybrid-treatment estimand) with retatrutide in TRIUMPH-1-OA were -3.22 (4 mg), -3.48 (9 mg), and -3.64 (12 mg), versus -1.87 with placebo (difference vs. placebo, -1.35 [95% CI, -1.92 to -0.78], -1.61 [95% CI, -2.20 to -1.02], and -1.77 [95% CI, -2.34 to -1.20], respectively). For the ITT estimand, the corresponding differences from placebo were -0.96 (95% CI, -1.61 to -0.30), -1.41 (95% CI, -2.07 to -0.75), and -1.64 (95% CI, -2.26 to -1.02) (P≤0.005 for all comparisons). In both trials, serious adverse events were more common with retatrutide than with placebo, and the most common adverse events were gastrointestinal. CONCLUSIONS: In participants with painful knee osteoarthritis and obesity, treatment with retatrutide resulted in significantly greater reductions in both the WOMAC pain score and body weight than placebo. (Funded by Eli Lilly; TRIUMPH-4 and -1 ClinicalTrials.gov numbers, NCT05931367 and NCT05929066.).