TRIUMPH-4: Retatrutide Delivers Weight Loss, Knee Osteoarthritis Pain Relief

Eli Lilly and Company has announced positive topline results from the phase 3 TRIUMPH-4 clinical trial assessing the safety and efficacy of the 2 largest investigational doses of retatrutide in adults with obesity or overweight and knee osteoarthritis, and without diabetes, as an adjunct to healthy diet and physical activity.1

According to a December 11, 2025, release from the Company, both the 9 mg and 12 mg doses of the first-in-class GIP, GLP-1, and glucagon triple hormone receptor agonist 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

"People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement," said Kenneth Custer, PhD, executive vice president and president, Lilly Cardiometabolic Health.1 "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."

An investigational once-weekly triple hormone receptor agonist, retatrutide is a single molecule that activates the body's receptors for GIP, GLP-1, and glucagon. Lilly is studying retatrutide in several phase 3 clinical trials to evaluate its potential efficacy and safety across several indications, including obesity and overweight with ≥ 1 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.1,2,3

TRIUMPH-4 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 randomly assigned 445 participants in a 1:1:1 ratio to receive either retatrutide 9 mg or 12 mg, or placebo. 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).1

The objective of the study is to demonstrate superiority to placebo in Western Ontario and McMaster Universities Osteoarthritis Index (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 clinical and radiological American College of Rheumatology Criteria for knee osteoarthritis.1

In TRIUMPH-4, 84% of participants had a baseline BMI of ≥35 kg/m². For the co-primary endpoints, retatrutide reduced 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 WOMAC pain score.1

In additional secondary endpoints, retatrutide reduced known markers of cardiovascular risk, including non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein (hsCRP), and at the highest dose lowered systolic blood pressure by 14.0 mmHg, using the efficacy estimand. In an additional post-hoc analysis, 14.1% of patients on retatrutide 9 mg and 12.0% patients on retatrutide 12 mg were completely free of knee pain at 68 weeks compared to 4.2% on placebo.1

For the treatment-regimen estimand, each dose level of retatrutide led to statistically significant improvements in both co-primary and all secondary endpoints. The treatment-regimen estimand results for the co-primary endpoints were:

• Percent change in body weight: -20.0% (-22.9 kg; -50.5 lbs; 9 mg); -23.7% (-27.2 kg; -60.0 lbs; 12 mg) and -4.6% (-5.3 kg; -11.7 lbs; placebo)
• Change in WOMAC pain subscale score: -4.0 points (-67.2%; 9 mg), -3.7 points (-62.6%; 12 mg) and -2.1 points (-35.1%; placebo)

Adverse events were consistent with those observed in other clinical trials for other incretins, the most common among participants treated with retatrutide (9 mg and 12 mg, respectively) being nausea (38.1% and 43.2% vs 10.7% with placebo), diarrhea (34.7% and 33.1% vs 13.4% with placebo), constipation (21.8% and 25.0% vs 8.7% with placebo), vomiting (20.4% and 20.9% vs 0.0% with placebo), and decreased appetite (19.0% and 18.2% vs 9.4% with placebo). Dysesthesia occurred in 8.8% and 20.9% of patients treated with retatrutide compared to 0.7% with placebo.1

Overall treatment discontinuation rates were similar across the retatrutide and placebo treatment arms. Discontinuation rates due to adverse events (12.2% and 18.2% vs 4.0% with placebo) were highly correlated with baseline BMI and included discontinuations for perceived excessive weight loss.1

As described in the release from Lilly, detailed TRIUMPH-4 results will be presented at a future medical meeting and published in a peer-reviewed journal, and additional results from the TRIUMPH program including a 4 mg maintenance dose are expected in 2026.1

References

1. Lilly. 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. December 11, 2025. Accessed December 11, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average

2. Kunzmann K. Retatrutide Clears Fatty Liver Disease in >85% of Patients with Obesity. HCPLive. November 13, 2023. Accessed December 11, 2025. https://www.hcplive.com/view/retatrutide-clears-fatty-liver-disease-patients-obesity

3. Campbell P. Retatrutide Showcases Historic Weight-Lowering, Glycemic Control Benefits in Phase 2 Data. HCPLive. June 27, 2023. Accessed December 11, 2025. https://www.hcplive.com/view/retatrutide-showcases-weight-lowering-glycemic-control-benefits-in-phase-2-data