Metformin, which is commonly prescribed to treat type 2 diabetes, reduced knee arthritis pain over six months in a clinical trial published in JAMA.
The randomised clinical trial looked at whether metformin, compared to a placebo, reduced knee pain in patients with symptomatic knee osteoarthritis (knee OA) and overweight or obesity.
The research was performed entirely as a community-based study using telehealth. Some of the 107 participants with pain from knee osteoarthritis (73 women and 34 men), who had a mean age of 60, took up to 2000 mg of metformin daily for six months. Others took the placebo. None had diabetes.
Knee pain was measured on a 0-100 scale, with 100 being the worst. The metformin group reported a 31.3 point reduction in pain after six months, compared to 18.9 for the placebo group. This was considered a moderate effect on pain.
“These results support use of metformin for treatment of symptomatic knee osteoarthritis in people with overweight or obesity,” the researchers found. “Because of the modest sample size, confirmation in a larger clinical trial is warranted.”
Lead researcher Professor Flavia Cicuttini, who heads Monash University’s Musculoskeletal Unit and is The Alfred’s Head of Rheumatology, said the results showed that metformin was a potentially new and affordable way to improve knee pain in those with knee OA and overweight or obesity.
Knee OA treatments include lifestyle approaches such as exercise and weight loss, which patients often find difficult, and medications such as paracetamol, topical anti-inflammatory creams and oral anti-inflammatory medications which have small benefits and may be unsuitable for some patients for safety reasons.
No new OA drugs have been approved in Australia since Celebrex (celecoxib) and Vioxx (rofecoxib) in the late 1990s.
Professor Cicuttini said effective treatments that improved knee pain in osteoarthritis were limited. She said this led some patients and their doctors to seek alternative treatments including surgery.
This resulted in major problems managing knee OA in Australia and internationally, including an increase in the rate of knee replacements performed for earlier stages of OA. This was based on the idea that effective treatments for knee OA were limited and that knee replacements lasted a long time
“At first glance this may seem reasonable, but it is a major problem because patient dissatisfaction with knee replacements is already high at between 20-30 per cent, even when the operation is technically perfect*,” Professor Cicuttini said. “Dissatisfaction rates are highest when the operation is done for early knee OA.
“To go through the effort and cost of a big operation like a knee replacement, only to be unhappy with the results because of ongoing pain and symptoms, is definitely low-quality care. Doing a knee replacement earlier also increases the potential need for the procedure to be redone.
“This costs about 3.5 times as much, so about $70,000 compared to $20,000, and the results tend not to be as good as the first time. The best outcome for patients is to delay the knee replacements until it is absolutely needed.”
Professor Cicuttini said metformin now provided GPs an alternative they could offer patients in addition to managing weight and increasing activity. “Metformin works in a number of ways on the knee, including affecting low grade inflammation and other metabolic pathways that are important in knee OA,” she said. “It is a different way to treat knee OA pain.
“GPs are very familiar with metformin, which is a low-cost, safe medication. It could be provided to patients in addition to other treatments they use and has the potential to delay people having knee replacements before they are absolutely needed. If people on metformin have less knee pain and are able to do more physical activity, then knee replacements can wait.”
Professor Cicuttini and her colleagues are now working with consumers, GPs, orthopaedic surgeons and other healthcare professionals to introduce metformin into the knee OA management pathway in order to improve patient outcomes and potentially better target knee replacements. Metformin could be used ‘off label’ after discussions between patients and their doctor.
“Metformin is safe and well tolerated,” she said. “It is used safely in other non-diabetes conditions such as polycystic ovarian syndrome. Metformin could be provided simply and safely using a telehealth approach, as we did in our study, meaning that it could be provided across the community, including in regional and remote areas.”
About knee osteoarthritis (OA)
Effective therapy for knee OA is limited, with a growing international trend toward knee replacements on patients with even milder cases*, despite recommendations that surgery be reserved for symptomatic end-stage OA**. This trend has been partly explained by the lack of effective treatments for knee OA and improved longevity of knee replacements*. Other research has found pain is an ‘omni- present’ feature of knee osteoarthritis and perceived to interrupt and deter daily activities such as walking, making people less confident in their bodies***. Current guidelines leave the timing and patient appropriateness for surgery to the discretion of the treating clinicians****. However, a systematic review and meta-analysis provided consistent evidence that mild radiological OA was a major contributor to the 20-30% patient dissatisfaction with knee replacements, including persisting pain*****.
About metformin
Metformin is a safe, inexpensive, well-tolerated oral medication that has been first-line therapy for type 2 diabetes for more than 60 years. Metformin reduces the production of glucose produced and released by the liver, insulin resistance, and low blood-sugar levels. It causes modest weight loss and reduces inflammation in people with and without diabetes. Other effects of metformin, such as anti-inflammatory properties, and improved glucose and lipid metabolism, such as reduced insulin resistance, may reduce knee pain in osteoarthritis******.
This research was supported by the National Health and Medical Research Council (NHMRC).
*Shohat N, Heller S, Sudya D, Small I, Khawalde K, Khatib M, Yassin M. Mild radiographic osteoarthritis is associated with increased pain and dissatisfaction following total knee arthroplasty when compared with severe osteoarthritis: a systematic review and meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2022;30:965-81.
**Kloppenburg M, Namane M, Cicuttini F Osteoarthritis. Lancet. 405:71-85, 2025 Jan 04.59.
***Reference: Wallis JA, Taylor NF, Bunzli S, Shields N. Experience of living with knee osteoarthritis: a systematic review of qualitative studies. BMJ Open. 2019 Sep 24;9(9):e030060. doi: 10.1136/bmjopen-2019-030060. PMID: 31551381; PMCID: PMC6773287
****Usiskin I. Surgical Treatments for Osteoarthritis. Eur J Rheumatol. 2023;11:S41-7.
*****Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open. 2012;2:e000435.
******Lim YZ, Wang Y, Estee M, Abidi J, Udaya Kumar M, Hussain SM, Wluka AE, Little CB, Cicuttini FM. [Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies. Osteoarthritis Cartilage.2022 11];30(11):1434-1442
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