Retatrutide's first Phase 3 win: 28.7% weight loss plus knee pain relief in TRIUMPH-4

Eli Lilly reported topline results on December 11, 2025 from TRIUMPH-4, the first Phase 3 trial of retatrutide to read out. In 445 adults with obesity or overweight plus knee osteoarthritis and no diabetes, the highest dose produced an average 28.7% weight loss at 68 weeks and cut knee pain scores by as much as 75.8% ^[1].

Retatrutide is an investigational once-weekly injection that acts on three hormone receptors at once: GIP, GLP-1 and glucagon ^[1]. That is one more target than tirzepatide (Mounjaro/Zepbound), which hits GIP and GLP-1, and two more than semaglutide (Ozempic/Wegovy/Rybelsus), which acts on GLP-1 alone. Retatrutide is not approved by the FDA for any use.

What the trial measured

TRIUMPH-4 randomized participants 1:1:1 to retatrutide 9 mg, retatrutide 12 mg, or placebo for 68 weeks ^[1]. Everyone started at 2 mg weekly and stepped up every four weeks to their assigned target dose ^[1]. Participants needed a BMI of at least 27 and had to meet American College of Rheumatology clinical and radiological criteria for knee osteoarthritis ^[1]. This was a heavy-baseline group: average starting weight was 112.7 kg (248.5 lbs) with an average BMI of 40.4, and 84.0% of participants started with a BMI of 35 or higher ^[1].

Using the efficacy estimand — which reflects people who stayed on treatment — weight fell 26.4% on 9 mg (64.2 lbs), 28.7% on 12 mg (71.2 lbs) and 2.1% on placebo (4.6 lbs) ^[1]. Some 58.6% of the 12 mg group lost at least 25% of their body weight, 39.4% lost at least 30%, and 23.7% lost at least 35%, versus 1.3%, 0.8% and 0.0% on placebo ^[1].

On the second co-primary endpoint, WOMAC pain scores (a 0–10 patient-reported scale where higher is worse) dropped 4.5 points on 9 mg and 4.4 points on 12 mg from a baseline of 6.0, versus 2.4 points on placebo ^[1]. Physical function scores improved by a similar amount ^[1]. In a post-hoc analysis, 14.1% of the 9 mg group and 12.0% of the 12 mg group were completely free of knee pain at 68 weeks, compared with 4.2% on placebo ^[1]. Lilly notes the percentage-change figures for WOMAC and the pain-free analysis were not pre-specified ^[1].

Under the stricter treatment-regimen estimand, which counts everyone regardless of whether they stayed on the drug, weight loss was 20.0% (9 mg) and 23.7% (12 mg) versus 4.6% on placebo, and pain scores fell 4.0 and 3.7 points versus 2.1 ^[1].

Side effects

The most common adverse events were gastrointestinal, in line with other incretin drugs: nausea in 38.1% (9 mg) and 43.2% (12 mg) versus 10.7% on placebo; diarrhea in 34.7% and 33.1% versus 13.4%; constipation in 21.8% and 25.0% versus 8.7%; and vomiting in 20.4% and 20.9% versus 0.0% ^[1].

One finding stands out: dysesthesia — abnormal or unpleasant skin sensations — occurred in 8.8% of the 9 mg group and 20.9% of the 12 mg group, versus 0.7% on placebo. Lilly says these events were generally mild and rarely led to stopping treatment ^[1].

Discontinuations due to adverse events were 12.2% (9 mg) and 18.2% (12 mg) versus 4.0% on placebo. Lilly says those rates tracked closely with starting BMI and included people who stopped because of "perceived excessive weight loss"; among participants with baseline BMI of 35 or higher, the rates were 8.8% and 12.1% versus 4.8% ^[1].

Why it matters for patients

Knee osteoarthritis is common in people with obesity, and Lilly frames severe cases as eventually leading to joint replacement ^[1]. TRIUMPH-4 is designed to test whether a weight-loss drug can also move pain and function — endpoints that matter for daily life and for insurance coverage arguments. But placebo groups in pain trials often improve too, and here placebo pain scores fell 2.4 points ^[1], so the drug's added benefit is smaller than the headline 75.8% figure suggests.

These are topline company numbers, not peer-reviewed data. Full results will be presented at a medical meeting and published later ^[1]. How retatrutide compares head-to-head against tirzepatide or semaglutide is not known — no such trial is described in these sources. Pricing, insurance coverage and a possible FDA filing date are also not yet known.

What happens next

Lilly says seven additional Phase 3 readouts are expected in 2026, including trials that test a lower 4 mg maintenance dose alongside 9 mg and 12 mg ^[1]. The broader TRIUMPH program began in 2023 and has enrolled more than 5,800 participants across obesity, obstructive sleep apnea and knee osteoarthritis, with other studies underway in type 2 diabetes, chronic low back pain, cardiovascular and kidney outcomes, and fatty liver disease ^[1].

One small discrepancy: Lilly's investor page lists TRIUMPH-4 as NCT05931367, while the PR Newswire version of the same release lists NCT05869903 ^[1][2].