Retatrutide Results Strengthen Lilly's Obesity Lead

Eli Lilly and Company said on Dec. 11, 2025, that retatrutide results from the TRIUMPH‑4 Phase 3 trial showed substantial mean weight loss and marked knee‑pain improvement in adults with obesity and knee osteoarthritis, reinforcing the company’s obesity‑drug program.

Weight Loss, Pain Relief, and Cardiometabolic Benefits

The TRIUMPH‑4 trial was a global Phase 3 registration study in adults with obesity or overweight and knee osteoarthritis, excluding those with diabetes. Participants had a body mass index (BMI) of at least 27.0 kg/m², with 84.0% starting at or above 35 kg/m². Over 68 weeks, patients received once‑weekly subcutaneous injections of retatrutide at 9 mg or 12 mg doses or placebo. Active arms began at 2 mg, increasing every four weeks to the assigned dose.

The study’s co‑primary endpoints were percent change in body weight and change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale at week 68. Under the efficacy estimand, retatrutide 12 mg achieved a mean weight loss of 28.7% (71.2 lbs) and a 4.5‑point improvement in WOMAC pain from a baseline of 6.0 points. The 9 mg dose produced a 26.4% weight loss and a 4.4‑point pain improvement, while placebo showed minimal changes. Lilly reported that both doses met all primary and key secondary endpoints.

Using the more conservative treatment‑regimen estimand, which accounts for nonadherence, the 12 mg dose yielded a 23.7% mean weight reduction. Secondary outcomes at 12 mg included responder rates of 58.6% for at least 25% weight loss, 39.4% for at least 30%, and 23.7% for at least 35%. Physical function improved by about 4.2 points on the WOMAC physical-function subscale, compared with 2.1 points for placebo. Post‑hoc analyses showed that 73.0% (9 mg) and 67.7% (12 mg) of participants achieved at least 70% pain reduction, and complete absence of knee pain was reported by 14.1% (9 mg) and 12.0% (12 mg), versus 4.2% with placebo.

Retatrutide also improved cardiometabolic markers, reducing non‑HDL cholesterol, triglycerides, and high‑sensitivity C‑reactive protein. The highest dose lowered systolic blood pressure by 14.0 mmHg.

Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health, said, "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."

Safety Profile and Development Outlook

Overall treatment discontinuation rates were similar between retatrutide and placebo arms, though adverse-event discontinuations were higher with active doses. The most common side effects were gastrointestinal, including nausea (38.1% at 9 mg, 43.2% at 12 mg versus 10.7% placebo), diarrhea, constipation, vomiting, and decreased appetite. Dysesthesia, an abnormal sensation, occurred in 8.8% (9 mg) and 20.9% (12 mg) of patients compared with 0.7% on placebo; it was generally mild and rarely led to stopping treatment.

Discontinuations due to adverse events were 12.2% at 9 mg, 18.2% at 12 mg, and 4.0% with placebo. Lilly noted these rates correlated strongly with baseline BMI and included some withdrawals for perceived excessive weight loss. Among participants with BMI at or above 35 kg/m², adverse-event discontinuations were lower but still elevated compared with placebo.

Lilly described the safety findings as consistent with other incretin-based therapies. Detailed TRIUMPH‑4 data will be presented at a future medical meeting and published in a peer-reviewed journal.

Retatrutide remains investigational and is part of Lilly’s broader TRIUMPH Phase 3 program, which includes four global registration trials in obesity and overweight with related complications such as obstructive sleep apnea and knee osteoarthritis. The program will expand into studies on type 2 diabetes, chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction-associated steatotic liver disease. Lilly expects seven additional Phase 3 trials in obesity and type 2 diabetes to complete in 2026, along with further TRIUMPH results, including data on a 4 mg maintenance dose.

Secondary reports have described retatrutide as outperforming Lilly’s approved obesity drug Zepbound in earlier trials and positioned it as a potential next-generation obesity treatment, highlighting the importance of the 2026 readouts for Lilly’s role in the growing obesity market.