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In TRIUMPH-4, participants with obesity and knee osteoarthritis taking retatrutide 12 mg lost an average of 28.7% of their body weight at 68 weeks
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Retatrutide reduced WOMAC pain scores by up to an average of 4.5 points (75.8%) and significantly improved measures of physical function, with more than 1 out of 8 retatrutide-treated patients completely free from knee pain at the end of the trial
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Seven additional Phase 3 trials evaluating the investigational once-weekly treatment in obesity and type 2 diabetes are expected to complete in 2026
INDIANAPOLIS, Dec. 11, 2025 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced positive topline results from the Phase 3 TRIUMPH-4 clinical trial evaluating the safety and efficacy of the two highest investigational doses of retatrutide, a first-in-class GIP, GLP-1 and glucagon triple hormone receptor agonist, in adults with obesity or overweight and knee osteoarthritis, and without diabetes, as an adjunct to healthy diet and physical activity. In this global registration trial, where 84.0% of participants had a baseline BMI of ≥35 kg/m², each dose of retatrutide (9 mg and 12 mg) met all primary and key secondary endpoints, delivering significant weight loss and improvements in pain and physical function at 68 weeks using both the efficacy and treatment-regimen estimands.1,2 For the co-primary endpoints, retatrutide lowered weight by up to an average of 28.7% (71.2 lbs) and reduced pain by up to an average of 4.5 points (75.8%) using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score.3
"People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement," said Kenneth Custer, Ph.D., executive vice president and president, Lilly Cardiometabolic Health. "We are encouraged by the results of TRIUMPH-4, which highlight the powerful effect of retatrutide, a first-in-class triple agonist, on body weight, pain and physical function. With seven additional Phase 3 readouts expected in 2026, we believe retatrutide could become an important option for patients with significant weight loss needs and certain complications, including knee osteoarthritis."
About retatrutide
Retatrutide is an investigational once-weekly triple hormone receptor agonist. Retatrutide is a single molecule that activates the body's receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. Lilly is studying retatrutide in several Phase 3 clinical trials to evaluate its potential efficacy and safety in obesity and overweight with at least one weight-related medical problem, type 2 diabetes, knee osteoarthritis, moderate-to-severe obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction-associated steatotic liver disease.
About TRIUMPH-4 and the TRIUMPH clinical trial program
TRIUMPH-4 (NCT05931367) is a Phase 3, 68-week, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of retatrutide with placebo in adults with obesity or overweight and knee osteoarthritis. The study randomized 445 participants in a 1:1:1 ratio to receive either retatrutide 9 mg or 12 mg, or placebo. The objective of the study was to demonstrate that retatrutide is superior to placebo in WOMAC pain subscale score reduction and in body weight reduction from baseline to week 68 in people with a BMI ≥27.0 kg/m² and who met American College of Rheumatology Criteria (clinical and radiological) for knee osteoarthritis. Participants randomized to retatrutide initiated treatment with 2 mg once weekly and increased the dose in a step-wise approach every four weeks until reaching the target dose of 9 mg (via steps at 2 mg, 4 mg and 6 mg) or 12 mg (via steps at 2 mg, 4 mg, 6 mg and 9 mg).
The initial TRIUMPH Phase 3 global registrational clinical development program is evaluating the safety and efficacy of retatrutide for the treatment of obesity and overweight, obstructive sleep apnea and knee osteoarthritis in people with obesity and overweight across four global registrational trials. The program, which began in 2023, has enrolled more than 5,800 participants and additional results are anticipated next year. The TRIUMPH clinical trial program includes five doses of retatrutide: 2 mg, 4 mg, 6 mg, 9 mg and 12 mg. Across all studies, participants randomized to retatrutide initiated treatment with 2 mg once weekly and increased the dose every four weeks until reaching their target dose. The target doses in TRIUMPH-1 and TRIUMPH-2 are 4 mg, 9 mg and 12 mg, while target doses in TRIUMPH-3 and TRIUMPH-4 are 9 mg and 12 mg.
About Lilly
Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable.
Endnotes and References
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The efficacy estimand with weight management represents efficacy in all randomized participants who remained on the study intervention (with possible dose modifications) without initiating prohibited weight management treatments. The efficacy estimand with knee osteoarthritis pain represents efficacy in all randomized participants who remained on the study intervention (with possible dose modifications) without initiating prohibited weight management and/or pain treatments.
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The treatment-regimen estimand with weight management represents the estimated average treatment effect regardless of adherence to study intervention or initiation of prohibited weight management treatments. The treatment-regimen estimand with knee osteoarthritis pain represents the estimated average treatment effect regardless of adherence to study intervention assuming no treatment benefit should participants need significant actions associated with lack of efficacy.
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WOMAC is a patient-reported questionnaire validated in osteoarthritis for assessing pain, stiffness and physical function, with scores normalized to a 0–10 scale where higher values indicate worse symptoms.
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Not controlled for multiplicity.
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Percent change in the WOMAC pain and physical function subscale scores were not pre-specified and were estimated from a post-hoc analysis.