BMC Rheumatology meta-analysis of 4 trials: metformin plus csDMARDs lowered CRP in rheumatoid arthritis
Pooled data from four randomised trials with 350 patients link add-on metformin to lower CRP, DAS28 and HAQ-DI; the authors call for larger, longer trials.
A systematic review and meta-analysis published in BMC Rheumatology pooled four randomised controlled trials with 350 participants who had rheumatoid arthritis (RA) and were receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The authors searched PubMed, Embase, Cochrane Central and Scopus up to 31 December 2025 and compared add-on metformin with placebo biomedcentral.com
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Pooled results for CRP, DAS28 and HAQ-DI
After three months, metformin was associated with lower C-reactive protein (CRP): mean difference (MD) −5.55, 95% CI −7.46 to −4.52. The Disease Activity Score in 28 joints (DAS28) changed by an MD of −0.8 (p < 0.001), and the Health Assessment Questionnaire Disability Index (HAQ-DI) by −0.12, 95% CI −0.19 to −0.05 (p < 0.001). After six months, CRP was still lower than in the placebo group: MD −6.96, 95% CI −7.79 to −6.13, p < 0.001.
According to the publication's summary, metformin was given alongside stable csDMARD regimens, such as methotrexate alone or in combination, for periods from twelve weeks to six months. The authors describe the evidence as moderate-to-high certainty. They state that larger, longer randomised trials are needed to confirm the findings and improve generalisability.
Methods and background
The review followed PRISMA guidelines, and its protocol was registered in PROSPERO (CRD420251271612). Risk of bias was assessed with the RoB 2 tool. Pooled mean differences with 95% confidence intervals were estimated with random-effects models in StataNow 19.5 biomedcentral.com
BMC Rheumatologybiomedcentral.comOpen source ↗.
The authors cite a mechanistic rationale: metformin activates AMP-activated protein kinase (AMPK), which is involved in regulating immune cell activation and inflammatory responses. In cell and rodent models, including collagen-induced arthritis, metformin reduced synovitis, cytokine expression, and cartilage and bone damage.
They also refer to observational and genetic data. A 2020 population cohort study by Naffaa and colleagues reported that metformin adherence was associated with a 38% lower incidence of RA (adjusted hazard ratio 0.62). A 2025 two-sample Mendelian randomization study by Liang and colleagues reported an odds ratio of 0.023 (p = 0.006) for genetic variants linked to metformin exposure.
