An experimental weekly injection from Eli Lilly sharply reduced knee pain in adults with obesity and knee osteoarthritis while helping them lose about a quarter of their body weight, according to two phase 3 trials published Nov. 8 in the New England Journal of Medicine and presented the same day at the American College of Rheumatology’s annual meeting in Orlando, Florida.
The drug, retatrutide, is not approved by the U.S. Food and Drug Administration for any use. In a pooled analysis of the two studies, which together enrolled more than 1,000 people, about two-thirds of participants who received retatrutide reported at least a 50% reduction in knee pain, compared with 38% of those who received a placebo, Northwestern University said in announcing the results.
“If you lose a significant amount of weight with this treatment, there is a good chance that you’re going to get a meaningful reduction in your knee pain,” said Dr. Thomas Schnitzer, the corresponding author and a professor at Northwestern University Feinberg School of Medicine. “A major factor is that you’re loading your knees less and therefore, there’s less pain and it allows you to increase your function.”
What did the retatrutide knee osteoarthritis trials find?
In the first trial, TRIUMPH-4, 445 adults with painful knee osteoarthritis and a body-mass index of 27 or higher were randomly assigned to weekly retatrutide at 9 mg or 12 mg, or to a placebo, for 68 weeks. Participants started with an average weight of about 248 pounds and an average pain score of about 6 on a 0-to-10 scale, according to the study abstract.
By week 68, pain scores fell by an average of 4.48 points on the 9 mg dose and 4.41 points on the 12 mg dose, compared with 2.43 points on placebo. Body weight fell by an average of 26.4% and 28.7% on the two doses, compared with 2.1% on placebo.
The second trial, TRIUMPH-1-OA, tested three doses (4, 9 and 12 mg) in 574 participants for 80 weeks. Pain scores fell by 3.66 to 4.30 points across the retatrutide groups, compared with 2.24 points on placebo, and weight loss ranged from 18.6% to 28.7%, compared with 1.5% on placebo, the abstract reported.
Lilly has said that in TRIUMPH-4, more than 1 in 8 participants on retatrutide were completely free of knee pain at the end of the study in a post-hoc analysis, compared with 4.2% on placebo. The highest dose also lowered systolic blood pressure by 14 mmHg, the company reported.
How is retatrutide different from Ozempic and Zepbound?
Semaglutide (Ozempic, Wegovy) acts on one gut-hormone receptor, GLP-1, and tirzepatide (Mounjaro, Zepbound) acts on two. Retatrutide is a single molecule that activates three: GLP-1, GIP and glucagon. Northwestern noted that currently available GLP-1 drugs typically produce 10% to 20% weight loss, while retatrutide produced 20% to 25% in these studies. HNC previously reported on retatrutide’s head-to-head diabetes trial results.
Why does weight loss matter for knee arthritis?
About 5% of the U.S. population, roughly 15 million people, have painful knee osteoarthritis, according to Northwestern. Current treatments include physical therapy, topical treatments, anti-inflammatory pills such as ibuprofen, short-acting steroid injections and, in some cases, opioids. Research has shown that losing 5% to 10% of body weight can ease symptoms, but Schnitzer said it is hard to lose more than 10% through diet and exercise alone, and hard to exercise when your knees hurt.
What were the side effects?
The most common side effects were gastrointestinal and mostly mild to moderate, occurring mainly as the dose was increased. In TRIUMPH-4, nausea affected 38.1% and 43.2% of people on the 9 mg and 12 mg doses, compared with 10.7% on placebo, and vomiting affected about 20% on retatrutide versus none on placebo. An abnormal skin sensation called dysesthesia was reported in 8.8% and 20.9% of the two dose groups. Discontinuation due to adverse events was 12.2% and 18.2% on retatrutide versus 4.0% on placebo, and included people who stopped because of what was perceived as excessive weight loss, Lilly said. In TRIUMPH-1-OA, the 4 mg group had fewer gastrointestinal side effects and fewer dropouts.
What questions remain?
People who needed a knee replacement were excluded. The biggest unknown, Schnitzer said, is whether the drug slows the disease enough to reduce the need for joint replacement. The trials also did not include people with knee osteoarthritis who are not overweight. Schnitzer said diet, exercise and lifestyle changes remain the first step, noting that GLP-1-type drugs can cause stomach problems and muscle loss, which matters because muscle helps stabilize the knee. The studies were funded by Eli Lilly, and Lilly scientists are co-authors.
Key Takeaways
- Two phase 3 trials published Nov. 8 in NEJM found weekly retatrutide reduced knee osteoarthritis pain and body weight compared with placebo.
- Pooled, about two-thirds of people on retatrutide had at least a 50% cut in knee pain, vs. 38% on placebo.
- Average weight loss reached 28.7% on the highest dose.
- Nausea, diarrhea, vomiting and a skin-sensation side effect were common; more people stopped the drug than stopped placebo.
- Retatrutide is not FDA-approved. Whether it slows joint damage or prevents knee replacement is unknown.
Frequently Asked Questions
Is retatrutide FDA-approved?
No. Retatrutide is an investigational drug and is not approved by the FDA for any use, including obesity or knee osteoarthritis. Products sold online as retatrutide are not FDA-approved medicines.
Who was in the knee trials?
Adults with moderate to severe knee osteoarthritis pain and a body-mass index of 27 or higher, without diabetes. People who needed knee replacement were excluded.
How much did knee pain improve?
In TRIUMPH-4, pain scores fell by about 4.4 to 4.5 points on a 0-to-10 scale on retatrutide, compared with about 2.4 points on placebo, over 68 weeks.
Should I stop my current arthritis treatment?
No. Talk with your doctor before changing any treatment. Researchers said diet, exercise and physical therapy remain the foundation of care for knee osteoarthritis.
Sources: New England Journal of Medicine (Schnitzer et al., Nov. 8, 2026); Northwestern University news release (Nov. 8, 2026); ACR Convergence 2026 abstracts for TRIUMPH-4 and TRIUMPH-1-OA; Eli Lilly TRIUMPH-4 topline release.
Photo: A U.S. Navy hospital corpsman works with a sailor during a knee physical therapy session aboard USS George Washington. U.S. Navy photo by Mass Communication Specialist 2nd Class William Pittman, public domain, via Wikimedia Commons.
