The effect of glucagon-like peptide-1 receptor agonists on the course of gonarthrosis in obese patients with metabolic syndrome: a pilot randomized study

Objective: Evaluation of the efficacy and safety of glucagon-like peptide type 1 receptor agonists (GLP-1 RA) in combination with symptomatic slow acting drugs for osteoarthritis (SYSADOA) in patients with knee osteoarthritis (OA) and obesity and type 2 diabetes mellitus (DM2).

Materials and methods: The pilot phase of the randomized study included 117 patients aged 35 to 65 years with Kellgren-Lawrence stages I–III knee osteoarthritis (OA) and a body mass index (BMI) ≥30 kg/m² (74.4% were women). Group 1 included patients with knee osteoarthritis and obesity without DM2. Groups 2, 3, and 4 included patients with gonarthrosis, obesity, and DM2. Participants were randomly assigned to four groups matched for age, gender, BMI, and radiographic stage of knee OA: patients in group 1 (n=29) received diacerein therapy, patients in group 2 (n=29) received diacerein in combination with metformin, patients in group 3 (n=29) received diacerein in combination with semaglutide (SEMA), and patients in group 4 (n=30) received diacerein and semaglutide with subsequent dose escalation. Patients in Groups 3 and 4 treated with semaglutide underwent a standard stepwise titration: 0.25 mg once weekly for the first 4 weeks, then 0.5 mg once weekly for the next 4 weeks, and 1.0 mg once weekly for the final 4 weeks of follow-up. By week 12, all patients receiving semaglutide were receiving 1.0 mg once weekly. Higher doses of semaglutide were not used in this phase of the study. The follow-up period duration was 12 weeks. The primary endpoints were relative change in body weight and changes in the WOMAC pain subscale. Pain intensity was also assessed using a visual analog scale (VAS, 0–100 mm); C-reactive protein (CRP) levels, and adverse events (AEs) were also recorded.

Results: At baseline, the mean body weight of patients was 99.3±8.3 kg, the mean WOMAC pain subscale score was 11.0±3.4, pain intensity according to VAS was 60±17 mm, and the CRP level was 6.4±3.1 mg/l. After 12 weeks, the body weight of patients in group 1 remained virtually unchanged and was +0.2% compared to the baseline value. Patients in group 2 showed a moderate weight loss (-1.6%). In patients in groups 3 and 4, the weight loss was more pronounced and was 4.0% of the baseline level (-4.0% in group 3 and -4.1% in group 4). In patients in group 1, the pain reduction according to the WOMAC pain subscale was 10.9%, and in patients in group 2 - 12.7%. In patients of groups 3 and 4, pain reduction according to this subscale reached 26.4 and 27.3%, respectively. When assessing pain according to the VAS, pain intensity reduction in patients of groups 1 and 2 was 6.8 and 8.3%, while in patients of groups 3 and 4 it - 15.2 and 18.3%. The CRP level in patients of groups 1 and 2 remained virtually unchanged during the follow-up period (a decrease of 2.8 and 3.9%, respectively). Patients of groups 3 and 4 showed a more pronounced decrease in CRP by 13.6 and 14.9% compared to baseline values. Thus, patients who were prescribed diacerein in combination with semaglutide (groups 3 and 4) experienced a more significant decrease in body weight, pain severity, and CRP level compared to patients of groups 1 and 2 who received regimens without semaglutide, while maintaining an acceptable safety profile. Adverse events (AEs) were reported in 19 patients (16%), and only 2 (1.7%) led to treatment discontinuation.

Conclusion: In patients with knee OA, obesity, and DM2, the addition of semaglutide (Velgia) to diacerein for 12 weeks resulted in clinically significant weight loss, reduced pain scores (WOMAC and VAS), and decreased CRP levels compared to the semaglutide-free groups, with an acceptable safety profile. These data support the need for further, longer-term randomized trials, including those evaluating the efficacy and safety of higher semaglutide doses (Velgia 1.7 mg; 2.4 mg).