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INCHEON, South Korea — The diabetes drug metformin may reduce the pain of knee osteoarthritis (OA) in patients with overweight or obese, independent of weight loss, according to results from a randomized placebo-controlled study presented at the World Congress on Osteoarthritis (OARSI) 2025 Annual Meeting.

The double-blind trial, which was simultaneously published on April 24, 2025, in JAMA, involved 107 patients with symptomatic radiologic knee OA and a body mass index > 25, who were randomly assigned to receive either 2000 mg/d metformin or a placebo for 6 months.

This treatment was associated with a mean change in the visual analog scale for pain of −31.3 mm in the treatment group compared with −18.9 mm in the placebo group at 6 months, which represented a significant adjusted between-group difference of −11.4 mm (P = .01).

While this did not achieve the minimum clinically important difference of 15 mm, Flavia Cicuttini, MD, a rheumatologist at the Alfred Hospital and Monash University in Melbourne, Australia, and researcher on the study, described the metformin’s effect size of 0.43 as moderate.

The study also found significant differences in favor of metformin in the secondary outcomes of improvements in the Western Ontario and McMaster Universities Arthritis Index scores for pain (−113.9 with metformin vs −68.2 with placebo), stiffness (−56.9 vs −26.7), and function (−426.1 vs −221.7). These analyses used imputed data to address missing primary and secondary outcomes for the 18% of patients in the trial who were lost to follow-up and did not provide data at 6 months.

“I think this provides a different approach that has the potential to slow this rapid move towards knee replacements for early OA,” Cicuttini said.

An earlier systematic review, which Cicuttini co-authored, found consistent preclinical and clinical evidence suggesting metformin had chondroprotective, immunomodulatory, and pain-reducing effects in knee OA.

“Metformin has a whole lot of different actions or benefits on joint cartilage, on low-grade inflammation, on the metabolism,” Cicuttini commented to Medscape Medical News. “What’s also attractive about metformin is it doesn’t cause hypoglycemia; you can use it in normal healthy people, you don’t have to monitor their blood sugar.”

There was some weight loss in both groups (mean change, −1.8 kg in the metformin group and −1.2 kg in the placebo group), but Cicuttini said the impact on OA symptoms was independent of weight loss.

Some patients experienced adverse events, with 15% of the metformin group reporting diarrhea compared with 8% of the placebo group, but there were high levels of adherence to the medication.

Rheumatologist Anita Wluka, MBBS, PhD, of the Alfred Hospital and Monash University — who was also a co-author on the study — said to Medscape Medical News that “metformin ticks all the metabolic boxes, and it’s cheap as chips.”

Commenting on the findings, physiotherapist Brooke Patterson, PhD, of La Trobe University in Melbourne, Australia, said there are numerous trials looking for medications to help with OA, but it is challenging to find effects because of the nature of the disease.

“You’ve got all these different subgroups within the 50 participants that are getting the intervention, but only a small proportion of those might respond to one treatment,” she said. “I would just recommend that people with OA talk to not only their doctor but a range of health professionals or get their doctor to try and understand potentially what are some of their risk factors” and their OA disease phenotype.

The study was funded by the National Health and Medical Research Council (NHMRC) of Australia. Cicuttini reported receiving funding from the NHMRC Investigator Grant and being on the advisory board of Magellan Stem Cells. Patterson and Wluka had no relevant conflicts of interest.