Based on decades of data from dietary and other lifestyle interventions, doctors have long known that significant weight loss can be an effective treatment for people who are overweight and have knee osteoarthritis (OA). One meta-analysis showed that OA pain, function and stiffness scores improved by 2% for every 1% in lost weight.1
But the disease can present a catch-22. “What’s particular about knee osteoarthritis is that it inhibits exercise to the degree where you can lose weight by exercising,” says Henning Bliddal, MD, a professor of rheumatology, an OA specialist and the head of the Parker Institute at Copenhagen University Hospital. “When your knees are affected to a certain extent, you cannot exercise the weight off. So you’ll have to do something else.”
Although reduced-calorie diets have been successful in helping some patients with obesity and knee OA lose weight, Dr. Bliddal has long sought a medical alternative that can yield similar results. After multiple studies began documenting the effectiveness of the drug semaglutide as an anti-obesity and anti-diabetic therapy, he and colleagues convinced the drug’s manufacturer, Bagsværd, Denmark-based Novo Nordisk, to set up a double-blind, randomized, placebo-controlled trial to test its potential for patients with obesity and knee OA as well. Dr. Bliddal received no compensation from Novo Nordisk for leading the study.
The Study
In a new study published in the New England Journal of Medicine, the researchers report that semaglutide may be more effective than lifestyle changes for promoting weight loss, reducing pain and improving function in patients who are overweight and have knee OA.2
“It was remarkable: even to us as old-school diet enthusiasts, this was a very, very strong signal,” Dr. Bliddal says. The weight loss, in fact, corresponded directly with the reduction in knee pain and increase in self-reported function. “It’s a substantial addition to our possibilities of interventions with this disease.”
The 68-week trial, dubbed the Semaglutide Treatment Effect in People with Obesity (STEP) 9 trial and funded by Novo Nordisk, enrolled 407 patients at 61 sites in 11 countries; two-thirds of the patients received once-weekly semaglutide injections while the other one-third received a placebo. All patients also received counseling on physical activity and a reduced-calorie diet.
After 68 weeks, the patients taking semaglutide lost 13.7% of their body weight, on average, while those taking a placebo lost only 3.2%. Those patients on semaglutide also reported a 41.7-point drop in the 0-to-100 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, in which higher scores reflect more pain. For those on a placebo, the pain score dropped by 27.5 points. Finally, patients taking semaglutide reported a 12-point improvement on the 36-question Short Form Health Survey (SF-36), which measures their quality of life. Those taking a placebo reported a 6.5-point improvement on the 0-to-100 scale, in which higher scores indicate greater well-being.
The improvement in pain, Dr. Bliddal says, suggests that semaglutide was considerably more effective for this patient group than standard, over-the-counter painkillers, at least by the end of the trial period. To participate in the trial, patients had to have a pain score of at least 40 on the WOMAC scale. With an average starting score of 72.8 for those assigned to the semaglutide arm, the major improvement after 68 weeks (by nearly 42 points, on average) would have knocked many of those participants out of eligibility. “If they had presented with the pain story that they ended up with, we would not have put them in the trial,” he says.
The observed incidence of adverse events, most commonly gastrointestinal disorders, was fairly low for both groups. Such events prompted 6.7% of participants in the semaglutide group and 3.0% in the placebo group to drop out of the trial; Dr. Bliddal says neither is a significant concern.
“We have learned how to use semaglutide and you have to start slow,” he says. “You have to increase the dose over a certain number of weeks to avoid most of this gastrointestinal trouble, and this works.” A bigger hurdle might be availability: The drug’s surging popularity for treating other weight-related conditions has led to shortages in some markets.
Another caveat is the well-known rebound effect in which patients who stop taking semaglutide can quickly regain lost weight. “There are two ways out of this,” Dr. Bliddal says. One is to gradually taper the drug dosage over time, paired with individual telephone or group-based support by providers to help ease the transition. The other is to provide patients who stop taking the drug with regular dietary consultations, preferably in supportive group settings.
Commentary
Two outside experts praised the STEP 9 trial’s design and methodology and agreed that its findings support the pivotal role of weight loss in improving patients’ pain and function, but urged caution given the absence of long-term data.
“The clinically meaningful improvements observed in the placebo group highlight the importance of structured counseling on diet and physical activity as foundational components of care,” says Zubeyir Salis, PhD, a public health researcher at the Centre for Big Data Research in Health at the University of New South Wales, Sydney. Regarding the study’s “compelling” results, he adds, “Semaglutide represents a promising pharmacological adjunct that may enhance these benefits, particularly for patients struggling to achieve sufficient weight loss through lifestyle changes alone.”
Even so, he says, “I remain cautious about immediate widespread adoption of semaglutide for knee OA, given the absence of long-term data on structural joint outcomes and the risk of weight regain after treatment cessation.”
Anita Wluka, PhD, FRACP, MBBS, a professor of public health and preventive medicine at Monash University, Melbourne, Australia, agrees that the trial helps fill some gaps in understanding how to achieve enough weight loss to yield a significant impact on pain in patients with knee OA. She questions, though, whether rapid weight gain after stopping semaglutide may affect joint pain more than gradual weight gain, given the reduced time available for a remodeling of the knees’ biomechanics. In other words, weight regained too rapidly may outpace the ability of the knee joints to adjust, exacerbating the pain. The rapid weight gain also may hurt patients’ morale, she cautions.
Given those limitations and the unknown long-term effects, Dr. Wluka says, “I may consider conservative therapy with exercise and dietary change in the first instance, despite their limited efficacy.”
Although the trial’s self-reported measures of pain and function didn’t allow for an investigation of semaglutide’s underlying mechanism of action, Dr. Bliddal maintains the results clearly point to weight loss as a key factor in alleviating patients’ knee pain. “We know that it makes a world of difference for the actual symptoms,” he says.
If used to achieve and maintain significant weight loss over a longer period, Dr. Bliddal says the drug may even help slow degradation of the knee joint. “By this, you would either avoid or postpone a possible replacement of the joint, which is a very important matter,” he says. Total knee replacements don’t last indefinitely and especially for younger patients with knee OA, delaying the replacement could prevent more complicated revisions in the future. Whether semaglutide can forestall that surgery, however, will require further research.
Bryn Nelson, PhD, is a medical journalist based in Seattle.
References
- Lim YZ, Wong J, Hussain SM, et al. Recommendations for weight management in osteoarthritis: A systematic review of clinical practice guidelines. Osteoarthr Cartil Open. 2022 Dec 1;4(4):100298.
- Bliddal H, Bays H, Czernichow S, et al. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. N Engl J Med. 2024 Oct 31;391(17):1573–1583.
