Metformin shows knee OA pain-relieving potential

Metformin, a common medication for diabetes, appears to produce a moderate reduction in knee pain and stiffness for overweight or obese individuals with symptomatic knee osteoarthritis (OA), as shown in the results of a randomized clinical trial.

After 6 months of treatment, the primary outcome of mean knee pain scores on a 100-mm visual analogue scale (VAS) decreased by 31.3 mm with metformin vs 18.9 mm with placebo from baseline. [JAMA 2025;doi:10.1001/jama.2025.3471]

While the between-group difference of −11.4 mm (95 percent confidence interval [CI], −20.1 to −2.6; p=0.01) in VAS pain score fell below the 15-mm minimally clinically important difference, it translated to a moderate effect on pain (effect size, 0.43, 95 percent CI, 0.02–0.83). This effect size, according to the investigators, was higher than what was observed with nonsteroidal anti-inflammatory drugs over 6 to 12 weeks in a study of patients with hip and knee OA (effect size, 0.32, 95 percent CI, 0.24–0.39). [Osteoarthritis Cartilage 2007;15:981-1000]

Furthermore, relative to placebo, metformin was associated with significant reductions in the secondary endpoints of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for knee pain (−113.9 vs −68.2; adjusted difference, −42.4, 95 percent CI, −83.9 to −1.0; p=0.045), knee stiffness (−56.9 vs −26.7; adjusted difference, −23.0, 95 percent CI, −40.4 to −5.7; p=0.01), and knee function (−426.1 vs −221.7; adjusted difference, −179.8, 95 percent CI, −313.0 to −46.6; p=0.009).

No significant difference between the metformin and placebo groups were seen in health-related quality of life (adjusted difference in AQoL-8D* score, 0.01, 95 percent CI, −0.02 to 0.05; p=0.47), the percentage of participants who met the criteria for OMERACT-OARSI** response (65 percent vs 45 percent, respectively; odds ratio, 2.21, 95 percent CI, 0.92–5.31; p=0.07), and 3-month VAS pain score change (adjusted difference, −2.5 mm, 95 percent CI, −11.7 to 6.6; p=0.58).

The current study builds on previous findings from animal and preclinical studies showing that metformin helps improve pain and joint structural outcomes in OA. Beyond its well-known effects on blood sugar, metformin also reduces insulin resistance, endogenous hyperinsulinaemia, and inflammation, and promotes modest weight loss. [Curr Obes Rep 2019;8:156-164; Front Pharmacol 2022;13:952560; Arthritis Res Ther 2019;21:127; PLoS One 2018;13:e0191242; JAMA Netw Open 2023;6:e233646]

“The pleiotropic mechanisms of metformin, including its effects on inflammation and glucose and lipid metabolism, suggest that the benefits may take longer than 3 months in humans to manifest. This may explain why an effect was not observed at 3 months but was observed at 6 months,” the investigators noted. [Front Pharmacol 2022;13:952560; Osteoarthritis Cartilage 2022;30:1434-1442]

Trial population

For the trial, 107 Individuals (mean age 58.8 years, 68 percent female) with knee pain for at least 6 months, a VAS pain score of >40 mm, and BMI of at least 25 kg/m² (mean 32.7 kg/m²) were recruited from the community through local and social media advertisements in Victoria, Australia, between June 2021 and August 2023. These patients were randomly assigned to receive oral metformin 2,000 mg/d (n=54) or identical placebo (n=53) for 6 months.

A total of 88 participants (82 percent), including 45 in the metformin group and 43 in the placebo group, completed the primary outcome assessment at 6 months. Over 6 months, telemedicine-assessed medication adherence was more than 80 percent in 81 percent of participants in the metformin group and 74 percent in the placebo group. Most participants achieved the 2,000-mg/day dose of metformin (80 percent) or the full placebo dose (74 percent). Mean weight change over 6 months was −1.8 kg with metformin and −1.2 kg with placebo.

Subgroup analyses indicated that metformin yielded significantly greater reduction in VAS pain scores at 6 months compared with placebo in females (adjusted difference, −12.9 mm; p=0.02) but not in males (adjusted difference, −5.4 mm; p=0.51), in participants with mild to moderate pain (<70 mm: adjusted difference, −15.8 mm; p=0.001) but not those with severe pain (≥70 mm: adjusted difference, −4.3 mm; p=0.59), and regardless of joint space narrowing grade (grade 0 to 1: adjusted difference, −11.0 mm; p=0.045; grade 2: adjusted difference, −14.2 mm; p=0.03).

In terms of safety, adverse events (AEs) occurred in 16 participants (30 percent) in the metformin group and in 10 participants (19 percent) in the placebo group. The most common AEs were diarrhoea (15 percent vs 8 percent, respectively) and abdominal discomfort (13 percent vs 9 percent, respectively).

“The findings [of the present study] support a potential role of metformin in improving symptoms in individuals with knee OA and overweight or obesity. However, given the relatively small sample size, a confirmatory study is needed,” the investigators said.