Once-weekly retatrutide reduced WOMAC pain and body weight vs placebo in two phase 3 trials, with up to 69.6% of participants halving knee pain at week 68.
Once-weekly retatrutide significantly reduced Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores and body weight vs placebo in adults with painful
Retatrutide is an investigational triple agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors.1 The trials follow the phase 3 STEP 9 trial, in which semaglutide reduced knee osteoarthritis pain in persons with obesity, and topline TRIUMPH-4 results announced in December 2025.3,4
TRIUMPH-4 (NCT05931367) randomized 445 adults without diabetes with a body-mass index (BMI) of at least 27 and a baseline WOMAC pain score of 4 to 9 to retatrutide 9 mg, 12 mg, or placebo once weekly for 68 weeks.1 TRIUMPH-1-OA (NCT05929066) randomized 574 participants to retatrutide 4 mg, 9 mg, 12 mg, or placebo for 80 weeks.1 Approximately 80% of participants in both trials had a BMI above 35.1
In TRIUMPH-4, the mean change in WOMAC pain score at week 68 was −3.96 with 9 mg and −3.74 with 12 mg vs −2.12 with placebo (difference, −1.83 [95% CI, −2.37 to −1.30] and −1.61 [95% CI, −2.16 to −1.07]; P < .001 for both).1 Mean body weight changed by −20.0% and −23.7% vs −4.6% with placebo (difference, −15.4 and −19.2 percentage points; P < .001 for both).1
In TRIUMPH-1-OA, differences from placebo in WOMAC pain at week 80 were −1.35 (95% CI, −1.92 to −0.78) with 4 mg, −1.61 (95% CI, −2.20 to −1.02) with 9 mg, and −1.77 (95% CI, −2.34 to −1.20) with 12 mg (P < .001 for all).1 Pain results used a prespecified hybrid-treatment estimand; with the intention-to-treat estimand, differences were smaller but remained significant, ranging from −0.96 (P = .005) with 4 mg to −1.64 with 12 mg.1
In pooled analyses at week 68, 69.6% (189/248) of participants receiving 9 mg and 63.2% (167/236) receiving 12 mg achieved at least a 50% reduction in WOMAC pain vs 37.8% (86/185) with placebo.1 At least a 50% reduction in WOMAC physical function score occurred in 64.6% (176/246) and 63.5% (168/235) vs 33.1% (73/183), respectively.1
WOMAC physical function improved significantly vs placebo in both trials, and results in participants with a BMI of at least 35 were similar to those in the overall populations.1 In TRIUMPH-1-OA, mean weight change at week 80 ranged from −17.5% with 4 mg to −24.8% with 12 mg vs −4.3% with placebo.1
Retatrutide is a once-weekly injectable agonist of the GIP, GLP-1, and glucagon receptors, producing substantial weight reduction and lowering mechanical load on weight-bearing joints.
Retatrutide at 4 mg, 9 mg, and 12 mg significantly reduced WOMAC pain and body weight vs placebo, with mean weight loss of up to 24.8% and pooled 50% pain responder rates of up to 69.6% vs 37.8% with placebo.
Gastrointestinal events, most commonly nausea, diarrhea, and constipation, were the most frequent adverse events (AEs) and occurred mainly during dose escalation.1 Discontinuation due to AEs occurred in 12.8% and 18.2% of the 9-mg and 12-mg groups vs 4.0% with placebo in TRIUMPH-4, and in 2.8% to 15.3% of retatrutide groups vs 6.2% with placebo in TRIUMPH-1-OA.1
Serious AEs were more common with retatrutide, occurring in 9.5% and 10.8% of retatrutide groups vs 2.0% with placebo in TRIUMPH-4.1 Dysesthesia occurred in 6.3% to 20.9% of retatrutide-treated participants vs 0.7% with placebo, and one death in each TRIUMPH-4 retatrutide group was assessed as unrelated to treatment.1
"A major factor is that you're loading your knees less and therefore, there's less pain and it allows you to increase your function," said Thomas J. Schnitzer, MD, PhD, professor of physical medicine and rehabilitation, anesthesiology, and medicine (rheumatology), Northwestern University Feinberg School of Medicine.2
The trials excluded patients requiring knee replacement and were not designed to assess osteoarthritis progression or avoidance of joint replacement.1,2 Both trials were funded by Eli Lilly, which participated in trial design, data analysis, and manuscript preparation.1
