Semaglutide extends benefits in obesity-associated knee OA

In individuals with obesity and moderate-to-severe pain due to knee osteoarthritis (OA), treatment with the GLP-1 RA* semaglutide led to significantly greater reductions in body weight and pain related to knee OA as opposed to placebo, findings from the STEP** 9 trial suggest.

At week 68, the mean change in body weight from baseline was greater in the semaglutide vs placebo arm (−13.7 percent vs −3.2 percent), as were the mean changes in WOMAC*** pain score (−41.7 vs −27.5 points) and SF-36^# physical function score (12 vs 6.5 points; p<0.001 for all). [N Engl J Med 2024;391:1573-1583]

Other efficacy endpoints

Semaglutide also trumped placebo in terms of changes in waist circumference (WC; difference, −6.9 cm) and 6MWD^## (mean change, 56.8 vs 14.2 m), as well as the proportion of participants losing ≥5 (85.2 percent vs 33.6 percent), ≥10 (68.1 percent and 12.9 percent), ≥15 (45.6 percent vs 4.5 percent) and ≥20 percent (22.3 percent vs 1.3 percent) of body weight by week 68.

Week 68 also saw greater drops in WOMAC physical function (estimated difference, −14.9 points; p<0.001), stiffness (estimated difference, −15.9 points), and total scores (estimated difference, −14.9 points) with semaglutide vs placebo.

Analgesic use, safety

The fraction of participants using NSAIDs or acetaminophen during the trial dropped in both arms, more so in the semaglutide arm. “[This] confirms that pain reduction with semaglutide was not due to increased use of analgesic agents, [suggesting] an NSAID-sparing effect of semaglutide, potentially limiting the adverse effects of NSAIDs and reducing polypharmacy,” the researchers said.

The most frequently reported serious adverse events (AEs) were neoplasms (benign, malignant, or unspecified; n=9 vs 3 events in the respective semaglutide and placebo arms) and gastrointestinal disorders (n=5 events vs 1 event).

About 7 percent of semaglutide recipients and 3 percent of those on placebo permanently discontinued their regimen due to AEs. Blood pressure drops were greater in the semaglutide vs placebo arm (mean 8 vs 0 mm Hg [systolic] and 3 vs 1 mm Hg [diastolic]).

Semaglutide STEPs into realm of knee OA

“There remains an unmet need for weight management medications that can facilitate nonsurgical, sustained weight reduction and reduce pain in individuals with obesity-related knee OA,” said the researchers.

The team set out to evaluate whether semaglutide 2.4 mg would be superior to placebo as an adjunct to lifestyle modifications in reducing body weight and knee OA-related pain in obese individuals diagnosed with moderate knee OA, with at least moderately severe pain.

A total of 407 participants (mean age 56 years, 81.6 percent women) were randomized 2:1 to once-weekly SC semaglutide 2.4 mg or placebo, on top of counselling on physical activity and a reduced-calorie diet. Among semaglutide recipients who completed the treatment period, about 90 percent were receiving the full 2.4-mg dose at the last treatment visit.

At baseline, mean body weight was 108.6 kg, mean BMI 40.3 kg/m², mean WC 118.7 cm, and mean WOMAC pain score 70.9. Forty-one percent of patients had severe obesity (BMI ≥40 kg/m²).

“The findings support the use of once-weekly SC semaglutide 2.4 mg for weight management and treatment of pain in individuals with obesity and moderate-to-severe pain due to knee OA,” said the researchers.

However, they underlined that mechanistic conclusions cannot be drawn as the study was not designed to assess the drug’s mechanism of action on knee OA. “Weight reduction is most likely a major contributor [due to] 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.”

The effects may also be attributed to the perceived anti-inflammatory and antidegradative effects of GLP-1 RAs. [Am J Transl Res 2019;11:4800-4808; Sci Rep 2022;12:1567]

“Regardless of the mechanism by which semaglutide leads to reduced pain in OA, the findings … open the door to more effective treatments than have heretofore been available. The findings confirm that substantial weight loss causes an often dramatic reduction in pain,” said Dr David Felson from Boston University School of Medicine in Massachusetts, US, in an editorial. [N Engl J Med 2024;391:1643-1644]

Felson noted that if the observed effects are mediated by factors other than weight loss alone, new therapeutic avenues may be available. “It will be important to obtain data on whether semaglutide is similarly effective in individuals with OA without obesity, as well as better data on whether GLP-1 RAs prevent progressive structural deterioration of the joint in OA.”