An experimental weight-loss injection may offer more than a way to shed pounds, with clinical trials suggesting it could also ease the burden of painful knee arthritis.
Losing weight can help relieve knee osteoarthritis, yet the condition often makes weight loss difficult in the first place. When walking, climbing stairs, or simply standing up from a chair causes pain, getting enough exercise can become a challenge.
For the roughly 15 million Americans living with painful knee osteoarthritis, treatment options remain limited. Physical therapy, topical medications, anti-inflammatory drugs such as ibuprofen and Voltaren, opioids, and corticosteroid injections can help manage symptoms, although steroid injections typically provide only short-term relief.
Previous research has shown that losing just 5% to 10% of body weight through diet and exercise can improve symptoms. Losing more than 10%, however, is difficult through lifestyle changes alone, particularly for people whose knees already limit their movement.
An experimental weight-loss injection called retatrutide may offer another way to address this problem. In two large clinical trials led by Northwestern University, participants who were overweight or had obesity experienced substantial weight loss alongside significant reductions in knee pain.
Knee pain dropped as weight fell
The phase 3 trials, published in the New England Journal of Medicine, involved more than 1,000 participants combined. Those receiving the highest dose of retatrutide lost approximately 25% of their body weight on average. A pooled analysis found that about two-thirds of participants receiving the drug reported at least a 50% reduction in knee pain, compared with 38% of those given a placebo.
Researchers tracked these changes using the Western Ontario and McMaster Universities Arthritis Index (WOMAC), which asks patients to rate their pain from 0 to 10. Participants also recorded their daily pain levels through an app.
“The findings are really saying for people who are overweight and have OA, 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 corresponding author Dr. Thomas Schnitzer, a professor of physical medicine and rehabilitation, anesthesiology and medicine (rheumatology) 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.”
A drug that targets three hormones
Developed by Eli Lilly, retatrutide is a once-weekly injection that activates receptors for three naturally occurring hormones involved in metabolism. Existing weight-loss medications such as semaglutide and tirzepatide target one or two receptors and typically produce weight reductions of 10% to 20%. Retatrutide produced losses of approximately 20% to 25% in these trials.
“Participants had remarkable responses,” Schnitzer said. “Many of the people in this study lost considerable amounts of weight, with a few losing up to a hundred pounds or more.”
The improvements also extended beyond body weight and joint pain. Participants experienced lower blood pressure, reduced blood lipid levels, and less systemic inflammation, suggesting broader metabolic benefits.
Scientists from Eli Lilly were among the study’s co-authors. Philip Conaghan, professor of musculoskeletal medicine at the University of Leeds in the United Kingdom, presented results from the TRIUMPH-4 trial at the American College of Rheumatology annual meeting in Orlando, Florida. Findings from the second trial, TRIUMPH-1-OA, were presented separately during a poster session.
Pain relief leaves unanswered questions
Despite the promising results, retatrutide remains experimental and would require approval from the U.S. Food and Drug Administration before becoming a treatment option. Schnitzer emphasized that diet, exercise, and lifestyle changes should remain the first approach because they are less expensive and avoid potential side effects associated with GLP-1 medications, including gastrointestinal problems and muscle loss. Preserving muscle is especially important for patients with knee osteoarthritis because it helps stabilize the joint.
The trials also left a crucial question unanswered. Although retatrutide significantly reduced pain, researchers do not yet know whether it slows the underlying progression of osteoarthritis or could help patients avoid knee replacement surgery. People who already needed knee replacements were excluded from the studies.
“That would be the goal here to say you can reduce people’s pain, and you can stop the progression of their osteoarthritis,” Schnitzer said.
Further research must also determine whether retatrutide could benefit people with knee osteoarthritis who are not overweight, since they were not included in the trials. Scientists are particularly interested in whether the drug’s potential anti-inflammatory effects contribute to pain relief independently of weight loss.
“These drugs are believed to have significant anti-inflammatory activity, but the mechanism is not entirely known,” Schnitzer said. “Whether cutting down inflammation in the joint is also important in addition to reducing load needs more research, so this is still a first step, in my view. I’ve been working in the OA field for a long time, and I think this opens up opportunities to do a lot more studies to understand the condition better.”
Reference: “Retatrutide Once Weekly in Adults with Knee Osteoarthritis Pain and Obesity” by Thomas J. Schnitzer, David J. Hunter, Philip G. Conaghan, Arya M. Sharma, Sue D. Pedersen, Kaiyi Chen, So Young Park, Nune Makarova, Kathryn Giblin and Tammy Forrester, 7 November 2026, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2610676
Funding for the study was provided by Eli Lilly and Company.
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