Metformin for Knee Osteoarthritis in Patients With Overweight or Obesity

Importance: Preclinical and preliminary human evidence suggests that metformin, a first-line treatment for type 2 diabetes, reduces inflammation, preserves cartilage, and improves knee pain in knee osteoarthritis. Objective: To evaluate the effects of metformin on knee pain at 6 months in participants with symptomatic knee osteoarthritis and overweight or obesity. Design, Setting, and Participants: Community-based randomized, parallel-group, double-blind, placebo-controlled clinical trial that used telemedicine to recruit and follow up participants remotely. Individuals with knee pain for 6 months or longer, a pain score greater than 40 mm on a 100-mm visual analog scale (VAS), and body mass index of 25 or higher were recruited from the community through local and social media advertisements in Victoria, Australia, between June 16, 2021, and August 1, 2023. Final follow-up occurred on February 8, 2024. Interventions: Participants were randomly assigned to receive either oral metformin, 2000 mg/d (n = 54), or identical placebo (n = 53) for 6 months. Main Outcomes and Measures: The primary outcome was change in knee pain, measured using a 100-mm VAS (score range, 0-100; 100 = worst; minimum clinically important difference = 15) at 6 months. Results: Of 225 participants assessed for eligibility, 107 (48%) were randomized (mean age, 58.8 SD, 9.5 years; 68% female) and assigned to receive metformin or placebo. Eighty-eight participants (82%) completed the trial. At 6 months, the mean change in VAS pain was -31.3 mm in the metformin group and -18.9 mm in the placebo group (between-group difference, -11.4 mm; 95% CI, -20.1 to -2.6 mm; P = .01), corresponding to an effect size (standardized mean difference) of 0.43 (95% CI, 0.02-0.83). The most common adverse events were diarrhea (8 15% in the metformin group and 4 8% in the placebo group) and abdominal discomfort (7 13% in the metformin group and 5 9% in the placebo group). Conclusions and Relevance: These results support use of metformin for treatment of symptomatic knee osteoarthritis in people with overweight or obesity. Because of the modest sample size, confirmation in a larger clinical trial is warranted. Trial Registration: ANZCTR Identifier: ACTRN12621000710820.