Could metformin improve knee osteoarthritis pain?

Pain due to osteoarthritis can be debilitating, and my patients often tell me how this pain impairs their quality of life. Osteoarthritis related to elevated weight is caused not only by increased weight stress on the joints, but also by the chronic inflammatory state that is seen in obesity. Metformin is a medication used to treat type 2 diabetes which reduces insulin resistance and also inflammation, so it is interesting to consider whether it could reduce pain in osteoarthritis.

A recent Australian study, published as as preliminary communication in the Journal of the American Medical Association (JAMA), investigated whether metformin could be of benefit to reduce knee pain in people with elevated weight and knee osteoarthritis. The study enrolled 107 people with BMI of at least 25 and a pain score on a visual analog scale (VAS) of at least 40 (score range 0-100), and randomized them to receive metformin 2000mg/day or placebo.

At 6 months, they found that the VAS pain score had decreased by 31.3 in the metformin group vs 18.9 in the placebo group (difference, 11.4). While this was a statistically significant difference, this did not make the cuts for a clinically significant difference in this score of at least 15. For the WOMAC pain score (which they scored on a scale of 0-500), the improvement was 113.9 with metformin vs 68.2 with placebo.

As blogged previously, a recent trial of GLP1 weight management medication semaglutide 2.4mg (Wegovy) showed clinically significant improvements in knee pain in people with osteoarthritis and obesity, alongside an average weight loss of 13.7%. Accordingly, in our new 2025 Obesity Canada Pharmacotherapy Clinical Practice Guidelines, we recommend semaglutide for weight loss and improvement in knee pain in people with obesity and knee osteoarthritis (disclosure: I am the lead author of this Guideline). The reasons for improvement in pain in that study were likely some combination of reduction in weight and reduction in inflammation (the available analyses of this study do not parse this out for us).

BOTTOM LINE: Metformin did not result in a clinically meaningful improvement in knee pain in people with osteoarthritis. I suspect that weight loss in people with elevated weight, in addition to reduction in inflammation, is what is needed to see more clinically meaningful benefits. Metformin has lots going for it: it’s cheap, it’s been around for decades, it reduces insulin resistance, and has other health benefits including reducing risk of developing type 2 diabetes in people with prediabetes, improvement in polycystic ovary syndrome, and may have benefits re malignancy. But I’m not convinced that reduction in osteoarthritis knee pain makes the list for benefits of metformin.

Disclaimer: I am an investigator in clinical trials of semaglutide. I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide (Novo Nordisk).

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