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

Abstract

Several studies have shown that rheumatologic patients can benefit from metformin, but it remains unclear whether metformin treatment is causally associated with the risk of rheumatoid arthritis (RA). A two-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between metformin treatment and the incidence of rheumatoid arthritis. The genome-wide significant (p < 5 × 10−8) single-nucleotide polymorphisms (SNPs) associated with metformin use were selected as instrumental variables (IVs). Summary statistics on RA were extracted from a large genome-wide association study (GWAS) meta-analysis. The inverse variance-weighted (IVW) method was used as the determinant of the causal effects of metformin treatment on RA. Cochran’s Q was used to detect heterogeneity. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression were used to detect horizontal pleiotropy. A total of 34 SNPs significantly associated with metformin treatment were obtained. Thirty-two SNPs were selected as IVs after removing two SNPs for being palindromic with intermediate allele frequencies (rs11658063 and rs4930011). The IVW results showed a negative causal association between metformin treatment and RA (OR = 0.0232, 95% CI 1.6046 × 10−3 − 0.3368; p = 0.006). Meanwhile, no heterogeneity or pleiotropy was detected, indicating that the results were reliable. This study indicated a negative causality between metformin treatment and RA, indicating that the treatment of metformin can prevent the pathogenesis of RA.

Causal association of metformin treatment with diverse cardiovascular diseases: a Mendelian randomization analysis

“…In practice, even though metformin can cause side effects such as acidosis, nausea, abdominal discomfort, and diarrhea, it is still worthwhile to study its mechanism of action in depth, as opposed to the “beneficial” effects of metformin [ 19 ]. In a series of studies such as the prevention of rheumatoid arthritis, metformin has been shown to not only lower blood glucose, but also reduce body weight and indirectly inhibit inflammation by altering the intestinal flora, thus reducing the risk of developing a number of diseases [ 20 – 24 ]. Available studies have demonstrated that metformin acts not only through AMP-activated protein kinase, but also through mitochondrial complex 1, growth differentiation factor 15, and glucagon-like peptide 1/glucagon [ 25 – 28 ].…”

Advances of the small molecule drugs regulating fibroblast-like synovial proliferation for rheumatoid arthritis

“…Table 4 is a summary of the synthetic small molecules and natural drugs that have been developed recently that target PI3k/Akt. Metformin, a drug used to treat type 2 diabetes, has been shown to have a protective effect against the development of RA (Liang et al, 2023), and RA-FLS proliferation is inhibited by metformin in a doseand time-dependent manner (Chen et al, 2019). The natural products targeted at PI3k/Akt regulating FLS came from a variety of sources.…”