Metformin, a widely prescribed first-line therapy for type 2 diabetes, was found to reduce knee pain in overweight or obese patients with osteoarthritis, according to findings from a randomized clinical trial presented on April 24, 2025, at the World Congress on Osteoarthritis in Seoul and concurrently published in JAMA.
The community-based, double-blind, placebo-controlled trial enrolled 107 adults (mean age, 58.8 years; 68% female) with symptomatic knee OA and a BMI of 25 or greater. Individuals with diabetes or taking glucose-lowering therapy were excluded to isolate the drug’s effect in patients without diabetes.
"What I appreciate is that the authors excluded diabetic patients—so we now have a non-diabetic cohort with improved OA symptoms and function," said rheumatologist Elena Schiopu, MD, in an interview with Conexiant.
“Metformin is known to have anti-inflammatory and antioxidative stress properties, including decreased activation of NF-kB and increased AMPK activity, which may decrease cartilage breakdown. Its low cost and excellent safety profile make it a highly attractive candidate for drug repurposing in OA," added Dr. Schiopu, Professor of Medicine at Medical College of Georgia at Augusta University.
Participants were randomized to receive either 2,000 mg of metformin (n = 54) or placebo (n = 53) daily for 6 months.
Key Findings
At 6 months, participants in the metformin group had a mean reduction in knee pain of 31.3 mm on a 100-mm visual analog scale, compared with an 18.9-mm reduction in the placebo group. However, the between-group difference did not reach the minimum clinically important difference used to power the study (15 mm). Therefore, while statistically significant, the clinical meaningfulness of the primary outcome is uncertain.
Safety and Tolerability
No serious adverse events occurred. Gastrointestinal adverse effects were the most commonly reported, including diarrhea in 15% of the metformin group versus 8% in the placebo group. Abdominal discomfort was reported by 13% of the metformin group versus 9% in the placebo group.
These events were generally mild or moderate, and only two participants in the metformin group discontinued treatment due to adverse effects.
Mechanism of Action
Like Dr Schiopu, the study investigators also hypothesized that metformin’s effects on OA may result from its anti-inflammatory and metabolic actions, including inhibition of nuclear factor-kappa B and activation of AMP-activated protein kinase.
“Obesity-related knee OA is mediated by excess weight-bearing on joints, inflammation, and impaired glucose and lipid metabolism,” the authors wrote. “These mechanisms promote systemic inflammation, oxidative stress, and metabolic dysfunction in joint tissues, contributing to cartilage degradation and disease progression.”
Addressing a Therapeutic Gap in OA
Flavia Cicuttini, PhD, study author and Head of Rheumatology at Alfred Hospital in Melbourne, said the findings may help address a major gap in treatment options.
“Effective treatments that improve knee pain in osteoarthritis are limited. This is leading some patients and their doctors to seek alternative treatments, including surgery,” she noted in an interview with Conexiant. “No new OA drugs have been approved in Australia since celecoxib in 1998 and rofecoxib in 1999."
Rheumatologist Shailendra Singh, MD, added that the study "brings new hope for patients who are obese and suffer from OA. The findings support the use of metformin, a drug with a well-established safety profile, to potentially delay or reduce the need for joint replacement surgery.”
"Most therapies for OA are symptom-modifying and not disease-modifying. If metformin proves beneficial in halting progression, it could transform the treatment paradigm," said Dr. Singh, of Unity Health–Searcy Medical Center, Searcy, Ariz.
Implications for Practice and Research
Cicuttini noted that metformin could help delay total knee arthroplasty, especially in early-stage OA, and provide general practitioners with another nonsurgical option alongside lifestyle interventions. “Metformin can now provide GPs an alternative they could offer patients in addition to managing weight and increasing activity,” she said.
Next steps may include an off-label introduction of metformin into clinical care pathways for symptomatic OA, and a larger, multi-center trial with imaging endpoints to determine whether metformin alters disease progression.
“As pain improves, people get more active, and there is general improvement in surrounding structures that protect the knee such as the muscles,” Cicuttini added.
Limitations and Conclusions
Limitations of the trial include the small sample size, telemedicine-based assessments, reliance on self-reporting, and attrition. Adherence was measured remotely, which may have introduced bias.
Despite these limitations, the investigators noted that the "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.”
Author disclosures can be found in the published study in JAMA.
Source: JAMA