First Phase 3 retatrutide results: TRIUMPH-4 knee OA trial

On 11 December 2025 Lilly announced topline results from TRIUMPH-4, the first of retatrutide's Phase 3 trials to report. The trial enrolled 445 adults with obesity and painful knee osteoarthritis. Weight loss was the largest yet seen in a Phase 3 obesity trial, knee pain fell by about three-quarters, and a side effect not seen with earlier drugs in this class appeared for the first time.^[1]

What was announced

Lilly's headline was a loss of "up to an average of 71.2 lbs", which is the 12 mg efficacy-estimand figure translated into pounds. On the more conservative treatment-regimen estimand, which counts everyone randomised whether or not they stayed on the drug, the 12 mg arm lost 23.7% and placebo lost 4.6%.^[1] Both ways of counting are explained in how to read a trial.

Pain was the second primary outcome. On the WOMAC pain scale, scores fell by about three-quarters on retatrutide and by 40% on placebo. At 68 weeks 14.1% of the 9 mg group and 12.0% of the 12 mg group reported being pain-free, against 4.2% on placebo. Physical function improved by a similar margin. Systolic blood pressure fell by 14 mmHg on the top dose, and cholesterol, triglycerides and the inflammation marker hs-CRP all improved.^[1]

The side-effect picture

Stomach effects dominated, as with every drug in this class. Nausea affected 38.1% and 43.2% of the retatrutide arms versus 10.7% on placebo; diarrhoea 34.7% and 33.1% versus 13.4%; vomiting 20.4% and 20.9% versus none.^[1]

The new finding was dysesthesia: an altered, often unpleasant skin sensation such as tingling, burning or heightened sensitivity. It affected 8.8% of the 9 mg arm and 20.9% of the 12 mg arm, against 0.7% on placebo. Lilly described it as generally mild and said it rarely led to people stopping. It has not been reported with semaglutide or tirzepatide, and analysts flagged it as a genuine new safety signal.^[2] It has its own page.

Drop-out rates were also high: 12.2% and 18.2% stopped because of side effects, versus 4.0% on placebo. In the sub-group with a BMI of 35 or more the figures were lower (8.8% and 12.1% versus 4.8%). Lilly said some people with lower starting weights stopped because they felt they were losing too much weight.^[1] See discontinuation rates.

What is new versus what we knew

The Phase 2 trial in 2023 had shown 24.2% average loss at 48 weeks in 338 people, against 2.1% on placebo.^[3] TRIUMPH-4 confirmed that scale of effect in a larger group, over a longer period, and added a pain outcome. It also added something Phase 2 had not shown: a skin-sensation side effect in a fifth of people on the top dose, and a drop-out rate on that dose approaching one in five.

What it does not mean

• It does not mean retatrutide treats arthritis directly. The pain relief tracks the weight loss; the trial cannot separate the two.
• It does not mean these figures apply to everyone. Participants were heavy (average BMI 40) and had a painful joint. Lighter people dropped out more.
• It does not mean the drug is close to approval. This was one trial; Lilly said at the time that eight Phase 3 trials were running.^[1] The peer-reviewed paper is still to come.