Background: [media] 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.
Method: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (BMI ≥30) and a clinical and radiological 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 0–100, 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 0–100, 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.
Conclusion: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in statistically-significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo.
(Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.)
[The decrease in pain over time looks proportional to the weight loss over time, so it may be mediated through weight loss, although they don’t analyze where the benefit comes from.]
…The results of subgroup analysis indicated greater improvements in WOMAC pain scores with semaglutide than with placebo in all subgroups defined according to BMI at baseline (Table S4). Semaglutide resulted in greater reductions over a 68-week period than placebo in pain intensity according to the score on the numerical rating scale for daily knee pain (difference, −1.0 point; 95% CI, −1.6 to −0.5) (Figure S6).
Semaglutide resulted in greater reductions over a period of 68 weeks than placebo in the WOMAC stiffness score (estimated difference, −15.9 points; 95% CI, −23.2 to −8.6) and WOMAC total score (estimated difference, −14.9 points; 95% CI, −20.5 to −9.3) (Figure S7 & S8). Greater improvements from baseline to week 68 in the 6-minute walk distance were reported in the semaglutide group than in the placebo group (mean change, 56.8 meters and 14.2 m, respectively; estimated difference, 42.6 m; 95% CI, 25.6–59.7).
The percentage of participants who were using nonsteroidal antiinflammatory drugs (NSAIDs) or acetaminophen decreased during the trial in both groups, although to a greater extent in the semaglutide group (Figure 3). Acetaminophen use was more prevalent at baseline in the semaglutide group but reached a level similar to that in the placebo group by ~week 36. NSAID use was similarly prevalent at baseline in the two groups but was lower in the semaglutide group by ~week 16. Only 23 participants (8.5%) in the semaglutide group and 13 (9.6%) in the placebo group reported taking opioids at any time during the trial; of these participants, 12 in the semaglutide group and 7 in the placebo group reported codeine use.
…The trial was not designed to investigate the mechanism of action of semaglutide on knee osteoarthritis, so mechanistic conclusions cannot be drawn. Weight reduction is most likely a major contributor, as a result of reduced mechanical stress on the knee joints; previous studies have shown that weight reduction through various strategies can lead to considerable alleviation of knee pain and joint stiffness.9 However, preclinical studies have shown that GLP-1 receptor agonists have antiinflammatory and antidegradative effects.34, 35
The severity of obesity varied among the enrolled participants, and subgroup analyses indicated a benefit of semaglutide with respect to pain regardless of BMI values at baseline. However, overall mean BMI and pain scores at baseline were higher than in previous studies involving persons with knee osteoarthritis,15, 16, 19 and a high percentage of participants (41%) had severe obesity (BMI ≥40) at baseline. Future studies could further explore the applicability of these findings to wider populations.