Effectiveness of metformin as an adjunctive therapy in rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease that impacts patients' quality of life. Evidence regarding the effectiveness of metformin use as an adjunct therapy in RA is limited and fragmented. This systematic review and meta-analysis aimed to evaluate the effectiveness of metformin as an adjunct therapy in RA and to quantitatively synthesize available evidence. METHODS: This systematic review and meta-analysis were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, focusing on randomised controlled trials (RCTs) that assessed the effect of metformin as an adjunct therapy for patients with RA receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). C-reactive protein (CRP), Disease Activity Score in 28 joints (DAS-2)8, and Health Assessment Questionnaire Disability Index (HAQ-DI) were included as an outcome. A search was conducted across four databases up to 31 December 2025, including PubMed, Embase, Cochrane Central, and Scopus. The methodological quality of the included RCTs was evaluated using risk of bias 2 (RoB 2) tool. Statistical analysis was conducted with StataNow version 19.5. For each outcome, pooled mean differences (MDs) with 95% confidence intervals (CIs) were estimated using random-effects models. RESULTS: A total of four RCTs with 350 participants were included in this review. The use of metformin was associated with significant decreases in several indicators after three months, including a reduction in the CRP level (MD = -5.55, 95% CI = -7.46 to -4.52, p-value = 0.00), DAS-28 (MD = -0.8, %CI = -0.87 to 0.73, p-value < 0.001), and HAQ-DI (MD =-0.12, %CI = -0.19 to -0.05, p-value < 0.001). Additionally, a significant reduction in CRP after six months (MD = -6.96, %95 CI = -7.79 to -6.13, p-value < 0.001) compared to the placebo group. CONCLUSION: This systematic review provides moderate-to-high certainty evidence supporting the use of metformin as an adjunctive therapy in RA. However, larger, longer-duration randomized trials are required to confirm these findings and improve generalizability.