In a 68-week, double-blind randomized controlled trial, once-weekly subcutaneous semaglutide 2.4 mg demonstrated superior outcomes in both weight reduction and knee osteoarthritis pain compared with placebo. The STEP 9 trial, published in The New England Journal of Medicine, enrolled 407 participants across 61 sites in 11 countries.

The study found that participants receiving semaglutide achieved a mean body weight reduction of 13.7% compared with 3.2% in the placebo group. Pain scores, measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), decreased by 41.7 points with semaglutide versus 27.5 points with placebo.

The trial enrolled adults who met the American College of Rheumatology criteria for knee osteoarthritis: knee pain plus three or more factors (age >50 years, morning stiffness <30 minutes, crepitus, bony tenderness, bony enlargement, no palpable warmth). Participants had Kellgren-Lawrence grade 2 or 3 radiographic changes and baseline WOMAC pain scores of at least 40 on a scale of 0 to 100.

The study population had a mean age of 56 years, a mean BMI of 40.3, and a mean WOMAC pain score of 70.9. Women comprised 81.6% of participants. Baseline comorbidities included hypertension (48.2%), dyslipidemia (30.5%), gastroesophageal reflux disease (11.3%), asthma (9.3%), and cardiovascular disease (5.2%).

Participants underwent block randomization in groups of six without stratification factors. The protocol required a 72-hour analgesic washout period before randomization. During washout periods, a maximum of 4 g of acetaminophen was permitted per day, but no pain medication was allowed within 24 hours before visits. Participants maintained electronic pain diaries recording their worst daily knee pain on a 0-10 scale.

The semaglutide dose was initiated at 0.24 mg with escalation to reach 2.4 mg by week 16. Dose reduction to 1.7 mg was permitted for unacceptable side effects, with at least one recommended re-attempt at reaching the 2.4 mg target dose.

Secondary endpoints showed significant improvements with semaglutide with 87.0% of semaglutide recipients achieving ≥ 5% weight loss versus 29.2% with placebo, and 70.4% achieving ≥ 10% weight loss versus 9.2% with placebo. WOMAC physical function scores improved by 41.5 points for the semaglutide recipients versus 26.7 points for the placebo, and SF-36 physical function scores increased by 12.0 points for semaglutide recipients versus 6.5 points for the placebo.

Other outcomes of the study included semaglutide recipients improving their six-minute walk distance by 56.8 meters versus 14.2 meters for the placebo, and reducing waist circumference by an average of 6.9 cm. Semaglutide recepients also showed WOMAC stiffness score improvement of -15.9 points, WOMAC total score improvement of -14.9 points, and daily knee pain numerical rating scale reduction of -1.0 point.

Opioid use during the trial was 8.5% in the semaglutide group versus 9.6% in the placebo group, with codeine specifically used by 12 semaglutide versus 7 placebo patients. NSAID and acetaminophen use decreased more substantially in the semaglutide group. Acetaminophen use equalized between groups by week 36, while NSAID use became lower in the semaglutide group by week 16.

Serious adverse events occurred in 10.0% of semaglutide recipients versus 8.1% of placebo recipients, including:

• Neoplasms: 3.3% vs 2.2%
• Gastrointestinal disorders: 1.5% vs 0.7%
• Acute gallbladder disease: 1.1% vs 0.7%
• Cardiovascular disorders: 1.1% vs 1.5%
• COVID-19: 19.0% vs 23.7%

Blood pressure reductions in the semaglutide group were -8±15/-3±9 mm Hg compared with -0±13/-1±9 mm Hg in the placebo group.

Treatment completion rates were 86.7% in the semaglutide group and 77.9% in the placebo group, with overall trial completion rates of 90.8% and 89.7%, respectively. Among the 235 semaglutide recipients completing treatment, 89.8% achieved the full 2.4-mg dose, 3.8% received 1.7 mg to < 2.4 mg, and 4.7% received < 1.7 mg, with 1.7% not reporting dosing.

The trial included a 7-week follow-up period after the 68-week treatment phase during which participants did not receive study medication.

A conflict of interest disclosure can be found in the study.