Efficacy and Safety of Metformin Use in Rheumatoid Arthritis: A Randomized Controlled Study

Abstract

Objective: To evaluate the efficacy and safety of metformin use in rheumatoid arthritis (RA) patients receiving conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs).Methods: A prospective, randomized, controlled, single blinded, study was carried on 66 RA patients with moderate and high disease activity state, receiving csDMARDs. Patients were simply randomized to receive either metformin 850 mg twice daily (Metformin group, n = 33), or placebo twice daily (Control group, n = 33) in addition to their stable anti-rheumatic regimen and followed up for 6 months. Serum C-reactive protein (CRP), disease activity of 28 joints based on CRP (DAS-28-CRP), and quality of life (QOL) were evaluated at baseline and then every 3 months. Moreover, serum adiponectin was assessed at baseline and after 6 months.Results: Sixty patients completed the study. Drop out was due to intolerance to metformin side effects (n = 3) and non-compliance (n = 3). Metformin significantly decreased CRP levels and DAS-28-CRP after 6 months compared to the control group (p-value <0.001). A significant improvement in QOL of metformin group was observed as early as after 3 months (p-value = 0.006) with a continued improvement observed at 6 months (p-value <0.001) compared to the control group. Despite the significantly higher serum adiponectin in the metformin group at baseline, it was significantly reduced after 6 months in the metformin group with median percent change of −63.49% compared to the significant increase in the control group with median percent change of 92.40%.Conclusion: Metformin significantly improved inflammation, disease severity, and QOL in RA patients with high safety profile.Clinical Trial Registration: Clinical-Trials.gov, identifier [NCT08363405].

Metformin Treatment Reduces the Incidence of Rheumatoid Arthritis: A Two-Sample Mendelian Randomized Study

“…Although a large number of studies have shown that metformin treatment can reduce inflammation, delay disease progression, protect bone tissue, and improve metabolic dysfunction and immune system function in the progression of RA [ 24 , 50 , 51 , 52 , 53 , 54 ], few studies focus on the relationship between metformin treatment and the risk of RA. In an 18-year retrospective cohort study, Naffaa found that adherence to metformin therapy reduced the risk of RA, but this conclusion was limited to women alone [ 26 ].…”

“…Metformin modulates immune response, autophagy, mitophagy, endoplasmic reticulum (ER) stress, and apoptosis and exerts epigenetic effects [ 21 ]. Many studies have shown that metformin treatment can reduce the severity of RA [ 22 , 23 , 24 ]. Chen [ 25 ] demonstrated metformin can effectively inhibit RA-FLS (fibroblast-like cells) proliferation through inducing the cell cycle and up-regulating and down-regulating p70s6k and 4E-BP1 phosphorylation, thus reducing the severity of RA in his study.…”

Increased susceptibility to pneumonia due to tumour necrosis factor inhibition and prospective immune system rescue via immunotherapy

“…Marcucci et al., theorize that high concentrations of metformin may have an immunostimulatory effect (such as in tumour cells, where it is allowed to accumulate) and low concentrations have an immunosuppressive effect ( Marcucci et al., 2020 ). Evidence exists for metformin use in treatment of both tuberculosis and rheumatological diseases, suggesting that metformin may even be a safer alternative to TNF inhibitors ( Gharib et al., 2021 ; Kim et al., 2022 ). In addition, metformin also facilitates phagolysosome fusion in macrophages indicating that there is further potential for metformin to aid infections caused by intracellular pathogens, such as M. tuberculosis ( Singhal et al., 2014 ; Wallis and Hafner, 2015 ; Rana et al., 2021 ; Bone et al., 2021 ).…”

Rheumatoid arthritis and the risk of end-stage renal disease: A nationwide, population-based study

“…Due to the complexity of the disease, the current understanding of the pathophysiology and therapeutics for RA is still limited. For instance, although a large number of studies have shown that metformin treatment can reduce inflammation, delay disease progression and protect bone tissue in the RA progression, few studies focus on the relationship between metformin treatment and the risk of RA (5). Epidemiologic studies suggested that RA contributes to the other comorbidities, such as cardiovascular diseases (6)(7)(8).…”