Lilly says retatrutide produced up to 71.2 pounds of weight loss in Phase 3 trial

Eli Lilly said on Dec. 11, 2025 that its investigational drug retatrutide helped adults with obesity and knee osteoarthritis lose an average of up to 71.2 pounds and reduce their knee pain substantially over 68 weeks in the Phase 3 TRIUMPH-4 trial ^[1]. Lilly said each dose tested met all primary and key secondary goals ^[1].

Retatrutide is not approved for any use. It is a once-weekly triple hormone receptor agonist — a single molecule that activates the body's receptors for GIP, GLP-1 and glucagon ^[1]. Lilly is also studying it in obesity, type 2 diabetes, obstructive sleep apnea, chronic low back pain, cardiovascular and kidney outcomes, and liver disease ^[1].

TRIUMPH-4 (NCT05869903) randomized 445 people with a BMI of at least 27 and knee osteoarthritis confirmed by American College of Rheumatology criteria; 84.0% had a starting BMI of 35 or higher ^[1]. Participants began at 2 mg weekly and increased the dose every four weeks until reaching 9 mg or 12 mg, or took a placebo ^[1]. Average starting weight was 112.7 kg (248.5 lbs) and average starting BMI was 40.4 ^[1].

On the efficacy measure, which counts participants who stayed on treatment, the 12 mg dose produced average weight loss of 28.7% (71.2 lbs) and the 9 mg dose 26.4% (64.2 lbs), compared with 2.1% (4.6 lbs) for placebo ^[1]. Weight loss of at least 30% was reached by 39.4% of people on 12 mg, 30.5% on 9 mg and 0.8% on placebo ^[1].

Pain was measured with the WOMAC scale, which runs from 0 to 10 and scores higher for worse symptoms ^[1]. From an average starting score of 6.0, pain fell by 4.5 points (75.8%) on 9 mg and 4.4 points (74.3%) on 12 mg, versus 2.4 points (40.3%) on placebo ^[1]. Physical function improved by 4.1 points on 9 mg and 4.2 points on 12 mg, versus 2.1 points on placebo ^[1]. 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 68 weeks, compared with 4.2% on placebo ^[1].

Using the treatment-regimen measure, which does not require people to stay on treatment, weight loss was 20.0% (50.5 lbs) at 9 mg and 23.7% (60.0 lbs) at 12 mg, versus 4.6% (11.7 lbs) for placebo ^[1]. Pain scores fell 4.0 points (67.2%) and 3.7 points (62.6%), versus 2.1 points (35.1%) ^[1]. Lilly said the percentage changes in pain and function scores were not pre-specified and came from a post-hoc analysis, and that some secondary measures were not controlled for multiple testing ^[1].

Side effects and tolerability

The most common side effects were nausea (38.1% at 9 mg, 43.2% at 12 mg, 10.7% on placebo), diarrhea (34.7%, 33.1%, 13.4%), constipation (21.8%, 25.0%, 8.7%), vomiting (20.4%, 20.9%, 0.0%) and reduced appetite (19.0%, 18.2%, 9.4%) ^[1]. Dysesthesia — unusual sensations such as tingling — was reported by 8.8% of people on 9 mg and 20.9% on 12 mg, compared with 0.7% on placebo; Lilly said these events were generally mild and rarely led to stopping treatment ^[1].

Discontinuation because of side effects was 12.2% at 9 mg and 18.2% at 12 mg, compared with 4.0% on placebo ^[1]. Lilly said those rates tracked with starting BMI and included people who stopped because they felt they had lost too much weight; among participants with a starting BMI of 35 or higher, the rates were 8.8% and 12.1% versus 4.8% ^[1].

Why it matters for patients

Most weight-loss medications are studied mainly for weight and blood sugar. This trial tested whether the same drug could also ease knee osteoarthritis pain and improve day-to-day function, which matters for people whose movement is limited by joint pain ^[1]. Kenneth Custer, president of Lilly Cardiometabolic Health, said people with obesity and knee osteoarthritis often live with pain and restricted mobility and "may eventually require total joint replacement" ^[1]. The trial also found reductions in non-HDL cholesterol, triglycerides and hsCRP, and a 14.0 mmHg drop in systolic blood pressure at the highest dose, though Lilly said these were not controlled for multiple testing ^[1].

Retatrutide remains investigational, so it is not available by prescription, and any timeline for a regulatory filing or approval decision has not been disclosed ^[1]. The two doses tested here are higher than the ones being tested in some other TRIUMPH trials, and the program includes a 4 mg maintenance dose ^[1]. How the pain benefit holds up over longer periods and after treatment stops has not been reported ^[1].

What happens next

Seven additional Phase 3 trials of retatrutide in obesity and type 2 diabetes are expected to complete in 2026 ^[1]. The broader TRIUMPH program began in 2023 and has enrolled more than 5,800 participants ^[1]. Full TRIUMPH-4 results will be presented at a future medical meeting and published in a peer-reviewed journal, but those dates have not been reported ^[1].