Lilly's Retatrutide Eases Knee Osteoarthritis Pain and Improves Function in Two Phase 3 Trials, NEJM Reports

Eli Lilly's experimental weight-loss drug retatrutide significantly reduced knee pain and improved physical function in people with obesity and knee osteoarthritis in two late-stage trials, according to results published in the New England Journal of Medicine.

Once-weekly retatrutide significantly reduced WOMAC pain scores and body weight versus placebo in adults with painful knee osteoarthritis and obesity in two phase 3 trials, TRIUMPH-4 and TRIUMPH-1-OA. The results were published Nov. 8, 2026, in the New England Journal of Medicine and presented at ACR Convergence 2026, held Nov. 6-11 in Orlando, Florida.

What is retatrutide?

Retatrutide works differently from current obesity drugs. It is an investigational triple agonist of the GIP, GLP-1 and glucagon receptors. By comparison, existing medicines such as semaglutide target one hormone pathway, and tirzepatide targets two.

The drug has not been approved by U.S. regulators.

The trials

The studies enrolled people with both conditions. Adults without diabetes who had painful knee osteoarthritis and a body-mass index of at least 27 were randomly assigned to receive once-weekly retatrutide or placebo.

A total of 445 participants were randomized in TRIUMPH-4 and 574 in TRIUMPH-1-OA.

The trials measured pain using a standard arthritis scale. The WOMAC pain score ranges from 0 to 10, with higher scores indicating worse pain. Participants' average baseline WOMAC pain score was 5.95.

Pain and function results

Pain improved substantially compared with placebo. At 68 weeks, mean changes in WOMAC pain scores with retatrutide in TRIUMPH-4 were −3.96 for the 9 mg dose and −3.74 for 12 mg, versus −2.12 with placebo.

The reduction in pain scores was significant by week 16 and sustained through week 68.

Physical function also improved. WOMAC physical function scores decreased 4.14 points in the 9 mg group and 4.20 in the 12 mg group, versus 2.06 in the placebo group.

Many patients saw major relief. In a pooled analysis, 63.2% to 69.6% of retatrutide-treated participants achieved at least a 50% reduction in WOMAC pain at week 68, compared with 37.8% with placebo.

Some became pain-free. In a post-hoc analysis, 14.1% of patients on the 9 mg dose and 12.0% on 12 mg were completely free of knee pain at 68 weeks, compared with 4.2% on placebo.

Weight loss

The drug also produced large weight reductions. In topline TRIUMPH-4 results, body weight fell 20.0% with 9 mg and 23.7% with 12 mg, versus 4.6% with placebo. Lilly reported weight loss of up to 28.7% using a different statistical approach.

Other benefits

Secondary endpoints also improved, including average pain intensity, lipid levels and inflammation measured by high-sensitivity C-reactive protein, which fell more than 50% with both doses.

Why it matters

Excess weight places extra stress on the knees and is one of the strongest risk factors for osteoarthritis, a common cause of pain and disability. Current treatments largely focus on pain relief, exercise and, in advanced cases, joint replacement.

The findings suggest a drug that targets weight could also ease symptoms. One analysis noted that retatrutide's pain reduction numerically exceeded results seen for semaglutide in osteoarthritis trials, though differences in trial design preclude direct comparison.

What's next

Lilly has more data coming. The company said seven additional phase 3 readouts were expected in 2026.

The trials were funded by Lilly. Retatrutide remains investigational, and patients should talk with their doctors about approved treatment options.