Lilly says retatrutide produced up to 28.7% weight loss and knee pain relief in Phase 3 trial

Eli Lilly said on December 11, 2025 that its investigational drug retatrutide helped adults with obesity and knee osteoarthritis lose an average of up to 28.7% of their body weight and reduced their knee pain in a Phase 3 trial called TRIUMPH-4 ^[1][2]. Retatrutide is a once-weekly triple hormone receptor agonist that acts on GIP, GLP-1 and glucagon receptors, and it is not approved by the FDA ^[1][2].

TRIUMPH-4 assigned 445 adults with a BMI of at least 27 kg/m² who met criteria for knee osteoarthritis, and who did not have diabetes, to retatrutide 9 mg, retatrutide 12 mg or placebo for 68 weeks ^[1][2]. Participants started at 2 mg once weekly and increased the dose every four weeks ^[1][2]. At the start, average weight was 112.7 kg (248.5 lbs), average BMI was 40.4, and 84.0% of participants had a BMI of 35 or higher ^[1][2].

On weight, using the efficacy estimand, which counts participants who stayed on treatment without starting other weight-management treatments, retatrutide 12 mg produced an average 28.7% loss (71.2 lbs) and 9 mg produced 26.4% (64.2 lbs), compared with 2.1% (4.6 lbs) on placebo ^[1][2]. Among secondary measures, 58.6% of the 12 mg group and 47.7% of the 9 mg group lost at least 25% of their body weight, versus 1.3% on placebo; 39.4% and 30.5% lost at least 30%, versus 0.8% ^[1][2].

On knee pain, measured with the WOMAC questionnaire, which runs from 0 to 10 with higher scores meaning worse symptoms, the average baseline was 6.0 points ^[1][2]. The 9 mg dose lowered pain by 4.5 points (75.8%) and the 12 mg dose by 4.4 points (74.3%), compared with 2.4 points (40.3%) on placebo ^[1][2]. Physical function scores improved by 4.1 and 4.2 points, versus 2.1 points on placebo ^[1][2]. In a post-hoc analysis, 14.1% of the 9 mg group and 12.0% of the 12 mg group reported no knee pain at all at 68 weeks, compared with 4.2% on placebo ^[1][2]. Lilly said the percentage changes in the pain and function scores were not pre-specified and came from post-hoc analysis ^[1][2].

A second set of numbers, the treatment-regimen estimand, counts everyone regardless of whether they stayed on the drug. It showed weight loss of 20.0% (9 mg) and 23.7% (12 mg) versus 4.6% on placebo, and pain reductions of 4.0 points and 3.7 points versus 2.1 points ^[1][2].

The most common side effects were nausea (38.1% on 9 mg and 43.2% on 12 mg, versus 10.7% on placebo), diarrhea (34.7% and 33.1% versus 13.4%), constipation (21.8% and 25.0% versus 8.7%), vomiting (20.4% and 20.9% versus 0.0%) and decreased appetite (19.0% and 18.2% versus 9.4%) ^[1][2]. Dysesthesia, or unusual skin sensations, occurred in 8.8% and 20.9% of treated participants versus 0.7% on placebo; Lilly described these events as generally mild and rarely leading to discontinuation ^[1][2]. Discontinuation because of side effects was 12.2% (9 mg) and 18.2% (12 mg) versus 4.0% on placebo, and among participants with a baseline BMI of 35 or higher the rates were 8.8% and 12.1% versus 4.8% ^[1][2]. The company said those rates included people who stopped because they felt they had lost too much weight ^[1][2].

Lilly also reported reductions in non-HDL cholesterol, triglycerides and high-sensitivity C-reactive protein, and a 14.0 mmHg drop in systolic blood pressure at the highest dose; it said those results were not controlled for multiplicity, a statistical adjustment for testing many measures at once ^[1][2].

Why it matters for patients

Obesity and knee osteoarthritis often occur together, and Lilly notes that people with both may eventually need total joint replacement ^[1][2]. GLP-1-based drugs already on the US market for weight loss are semaglutide (Ozempic, Wegovy, Rybelsus) and tirzepatide (Mounjaro, Zepbound); retatrutide is a different, unapproved molecule, so it is not an option patients can ask for today ^[1][2].

The results described here come from a company announcement, not a published study. Lilly said detailed results will be presented at a future medical meeting and published in a peer-reviewed journal, and no dates for those have been disclosed ^[1][2]. The gap between the two sets of numbers above is also worth noting: average weight loss and pain relief were smaller in the analysis that counted everyone, which reflects how many people stopped treatment. Head-to-head comparisons with approved drugs have not been reported.

The TRIUMPH-4 announcement lists a trial registry number of NCT05931367 in one version and NCT05869903 in another ^[1][2].

What happens next

Lilly said seven additional Phase 3 trials of retatrutide in obesity and type 2 diabetes are expected to complete in 2026, and that more TRIUMPH results, including a 4 mg maintenance dose, are expected next year ^[1][2]. The broader TRIUMPH program began in 2023 and has enrolled more than 5,800 participants ^[1][2]. Lilly has not disclosed a timeline for seeking FDA approval for retatrutide.