Written By: Pharmacally Medical News Desk
Lilly’s investigational triple agonist retatrutide has reported its first positive Phase 3 data from the TRIUMPH‑4 trial, demonstrating up to an average 28.7% weight loss and substantial reductions in knee osteoarthritis (OA) pain over 68 weeks in adults with obesity or overweight without diabetes. Both evaluated doses (9 mg and 12 mg once weekly) met all primary and key secondary endpoints, underscoring retatrutide’s potential as a disease‑modifying metabolic and musculoskeletal therapy.
Retatrutide (LY3437943) is a first‑in‑class once‑weekly injectable triple hormone receptor agonist targeting GIP, GLP‑1 and glucagon receptors to drive weight loss through appetite suppression, improved glucose and lipid metabolism, and increased energy expenditure. The molecule is being evaluated in the global TRIUMPH Phase 3 program across obesity, overweight with comorbidities, obstructive sleep apnea, knee OA, chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction‑associated steatotic liver disease.
TRIUMPH‑4 is the first registrational trial in this program to read out, focusing specifically on people with obesity or overweight and knee OA.
TRIUMPH‑4 trial
TRIUMPH4 is a 68-week, randomized, double-blind, placebo-controlled study evaluating once-weekly retatrutide at 9 mg and 12 mg. The trial enrolled adults with obesity or overweight who also had knee osteoarthritis, and most had severe obesity at baseline with a BMI of 35 kg/m² or higher.
Retatrutide produced large reductions in body weight. The 12 mg dose led to a 28.7 percent decrease, equal to about 32.3 kg (71.2 lbs), and the 9 mg dose led to a 26.4 percent decrease, equal to about 29.1 kg (64.2 lbs). The placebo group shows only about 2.1 kg (4.6 lbs) of weight loss.
The study’s main outcomes were percentage change in body weight and change in knee pain measured by the WOMAC pain score. Knee pain improved significantly in both retatrutide groups, with reductions of up to 4.5 points from a baseline of 6.0, representing pain decreases of up to about 75.8 percent in some analyses. Many participants reported near-complete or complete pain relief. Improvements in physical function, stiffness, and cardiometabolic markers were also seen.
Parameter (Week 68) | Retatrutide 9 mg | Retatrutide 12 mg | Placebo |
Mean body‑weight change (efficacy estimand) | −26.4% (−29.1 kg; −64.2 lbs) | −28.7% (−32.3 kg; −71.2 lbs | ~−2.1% (−2.1 kg; −4.6 lbs) |
Mean body‑weight change (treatment‑regimen) | −20.0% (−22.9 kg; −50.5 lbs) | −23.7% (−27.2 kg; −60.0 lbs) | −4.6% (−5.3 kg; −11.7 lbs) |
WOMAC pain change (from baseline 6.0) | Large reduction; met co‑primary endpoint | Large reduction; up to ~75.8% pain decrease in some analyses | Minimal improvement vs active arms |
Dysesthesia incidence | 8.8% of patients | 20.9% of patients | 0.7% of patients |
The safety profile of retatrutide in TRIUMPH4 was generally consistent with other incretin-based therapies. Gastrointestinal symptoms, including nausea, vomiting, and diarrhea, were the most common side effects. A notable finding was dysesthesia, described as tingling or abnormal sensations, which occurred in 8.8 percent of participants on the 9 mg dose and 20.9 percent on the 12 mg dose, compared with 0.7 percent on placebo. These events were usually mild and rarely led to stopping treatment. Ongoing Phase 3 studies, including cardiovascular and renal outcome trials, will help clarify long-term safety, especially at higher doses and in people with additional health conditions.
Kenneth Custer, Ph.D., Lilly’s executive vice president and president of Cardiometabolic Health, noted, “Adults with obesity and knee osteoarthritis often endure chronic pain, restricted mobility, and eventual need for joint replacement. TRIUMPH-4 results show retatrutide’s powerful effects as a first-in-class triple agonist on weight, pain, and function. With seven more Phase 3 readouts in 2026, it could become a key option for substantial weight loss and knee OA.”
These new data position retatrutide as one of the most potent late‑stage obesity candidates to date, with the added differentiation of clinically meaningful osteoarthritis pain relief in a high‑need population.
References
Lilly’s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial, 11 December 2025. Lilly’s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. | Eli Lilly and Company
A Study of Retatrutide (LY3437943) Once Weekly in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee (TRIUMPH-4), ClinicalTrials.gov ID NCT05931367, Study Details | NCT05931367 | A Study of Retatrutide (LY3437943) Once Weekly in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee | ClinicalTrials.gov