Retatrutide Achieves Up to 28.7% Weight Loss and Marked Knee Pain Reduction in Phase 3 TRIUMPH-4 Trial

Eli Lilly and Company has released positive topline results from TRIUMPH-4, a 68-week phase 3 trial evaluating the 2 highest investigational doses of its once-weekly "triagonist" retatrutide in adults with obesity or overweight and knee osteoarthritis (OA), without diabetes. Both the 9-mg and 12-mg doses met all primary and key secondary endpoints and produced clinically meaningful reductions in body weight and OA pain, according to the company announcement.¹

From an average baseline weight of 112.7 kg (248.5 lbs; BMI 40.4 kg/m²), participants receiving retatrutide lost up to 28.7% of their body weight (−32.3 kg; −71.2 lbs) at 68 weeks. Pain scores also improved substantially: retatrutide reduced Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores by as much as 4.5 points (−75.8%), compared with a 2.4-point (−40.3%) reduction with placebo. Most participants had severe obesity at baseline, with 84% entering the trial with BMI of 35 kg/m² or greater.¹

Obesity Compounds OA Pain

People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement," Kenneth Custer, PhD, executive vice president and president, Lilly Cardiometabolic Health, said in a statement.¹ Joint pain symptoms and severity increase with BMI values, according to the Obesity Action Coalition, with every 11 lbs of weight gained increasing the risk for OA by 36%.² The OAC also notes that the risk of disability from OA among those with obesity is 1.72 times greater than among normal weight individuals.²

"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."

A triple agonist, retatrutide combines a glucagon-like peptide 1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and a glucagon receptor agonist. The agent was recently described in an American Diabetes Association statemetn as "the next in the string of game-changing metabolic agents" that began with the GLP-1 receptor agonist semaglutide and continued with tirzepatide, a dual GLP-1/GIP receptor agonist.³

The Phase 3 TRIUMPH-4 Trial

TRIUMPH-4 randomly assgned 445 adults in a 1:1:1 ratio to retatrutide 9 mg, retatrutide 12 mg, or placebo. Participants escalated from 2 mg to their assigned dose in 4-week intervals. The trial enrolled individuals with BMI of 27 kg/m² or greater who met American College of Rheumatology criteria for knee OA.

Both retatrutide doses met the co-primary endpoints: percentage change in body weight and reduction in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 68. Improvements extended across secondary outcomes. A substantial proportion of participants achieved high levels of weight reduction; for example, nearly half of those receiving retatrutide achieved at least 25% weight loss, and a meaningful subset exceeded 30% or 35%, compared with minimal categorical weight loss in the placebo group. Measures of physical function also improved, with reductions in the WOMAC function subscale exceeding 70% for both retatrutide doses. In a post-hoc analysis, approximately 1 in 8 retatrutide-treated participants reported being completely free of knee pain at week 68, compared with just more than 4% of placebo recipients.

Looking at additional seconary endpoints, retatrutide also improved markers of cardiometabolic risk, lowering non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein. At the highest dose, systolic blood pressure decreased by 14.0 mm Hg.

Results from the treatment-regimen estimand supported these findings, showing sustained weight and pain reductions even when accounting for treatment adherence or initiation of prohibited therapies.

Safety Findings

The adverse-event profile reflected the gastrointestinal effects seen with other incretin-based therapies. Nausea, diarrhea, constipation, vomiting, and decreased appetite occurred more frequently with retatrutide than placebo. Dysesthesia was also reported, occurring in 8.8% of participants on 9 mg and 20.9% on 12 mg, compared with 0.7% on placebo; these events were generally mild and infrequently led to discontinuation. Overall discontinuation rates were similar between groups. Discontinuations attributed to adverse events occurred in 12.2% of those receiving 9 mg, 18.2% of those receiving 12 mg, and 4.0% of placebo recipients, with higher BMI at baseline associated with increased likelihood of discontinuation.

Lilly plans to present detailed TRIUMPH-4 data at an upcoming scientific meeting and submit them for publication. Seven additional phase 3 trials evaluating retatrutide in obesity, type 2 diabetes, osteoarthritis, sleep apnea, chronic low back pain, metabolic dysfunction–associated steatotic liver disease, and cardiometabolic outcomes are expected to report results in 2026, the company said.

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

2. Obesity and osteoarthritis fact sheet. Obesity Action Coalition. Accessed December 11, 2025. https://www.obesityaction.org/resources/obesity-and-osteoarthritis-fact-sheet/

3. Halsey G. “Triagonist” Therapy for Type 2 Diabetes and Comorbidities to be Previewed at 2023 ADA Scientific Sessions. Patient Care. June 23, 2023. Accesssed December 22, 2025. https://www.patientcareonline.com/view/-triagonist-therapy-for-type-2-diabetes-and-comorbidities-to-be-previewed-at-2023-ada-scientific-sessions