BACKGROUND: Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.
METHODS: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of =30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).
RESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.
CONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).
| Discipline Area | Score |
|---|---|
| Endocrine |  |
| Special Interest - Obesity -- Physician | |
| Special Interest - Pain -- Physician |  |
| Rheumatology | |
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Internal Medicine | |
We do not know whether simaglutide's effects were solely due to weight loss or whether another mechanism such as an anti-inflammatory effect had a role. It would be interesting to match participants with similar weight loss. Another possibility would be to preform a study in persons with rheumatoid arthritis.
In this RCT, 407 patients with knee OA (mostly women, average 50s) were randomized to semaglutide or placebo. Not surprisingly, more weight loss and much better pain scores if in treatment arm. Most of the other treatments for OA target symptoms, but not causes. This is yet another reason why weight reduction in obese patients has benefits.
Seems to me this is all about the weight loss, so similar effects could be achieved with weight loss by other means. This is where semaglutide has the advantage: no other non-surgical treatment for obesity produces anything near the level of weight loss that semaglutide produces. Half the people lost 15% or more of their body weight, and this is in people who probably weighed > 300 pounds at the start. That is phenomenal weight loss.
The findings of this randomized trial demonstrate two things in my mind. First, the significant power of the placebo effect. The average change in WOMAC pain scores in the placebo arm alone met the bar for a clinically important difference! Second, the actual benefit of semaglutide, which led to an additional one out of every 3 treated patients experiencing a halving of their WOMAC pain scores! Combined with the other known health benefits of semaglutide in obese individuals, this is more compelling evidence that we should be prescribing and improving access to (and mitigating side effects of) these important medications for adults with obesity. The caveat here might be structured attention alone could also make a big difference, as demonstrated by the substantial placebo effect).
This double-blind, placebo-controlled RCT suggests that managing overweight in patients with knee osteoarthritis is easier.
