A wealth of data published in the recent past has highlighted the pleiotropic actions of metformin, ranging from its role as an hypoglycemic agent to cardioprotective, nephroprotective, antifibrotic, antiproliferative, and antioxidant properties. Besides, studies in experimental models have shown its benefits in prolonging lifespan and as an antiaging molecule. Emerging in vivo and in vitro evidence suggests that metformin also displays immunomodulatory effects.¹

Although the pathogenesis of autoimmune diseases remains obscure, they are partially characterized by chronic inflammation due to production of inflammatory mediators, and disorders of redox processes. With regard to this, metformin possesses desirable properties for treating these diseases. These include anti-inflammatory and antioxidant effects, and the capability to regenerate endothelium.² The researchers have shown that this drug acts by interfering with main immunopathological mechanisms involved in systemic autoimmune diseases, like T-helper 17/regulatory T-cell balance, production of autoantibodies, formation of germinal centers, macrophage polarization, production of cytokine, neutrophil extracellular traps release, and bone or extracellular matrix remodeling. After entering the cell, metformin transiently blocksnicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) present in the inner mitochondrial membrane. This decreases the production of adenosine triphosphate (ATP) and increases adenosine monophosphate (AMP): ATP ratio. This metabolic shift activates the energy sensor 5-AMP-activated protein kinase.¹

Furthermore, various in vitro studies have shown that metformin can regulate the function of multiple cells implicated in the development and maintenance of autoimmunity. A study demonstrated that metformin can attenuate signs of autoimmunity including anti-ds deoxyribonucleic acid antibodies production and kidney and liver inflammation. This clinical improvement has been associated with a remarkable decrease in autoreactive marginal zone B-cells and reduced germinal center formation, the prime region for differentiation of B-cells in long-lived autoreactive plasma cells.¹

Several experimental studies have also shown its ability to restore immune homeostasis and improve disease severity in autoimmune disorders.¹ For instance, this anti-diabetic drug that regulates cellular and systemic metabolism, may exert disease-modifying action in systemic lupus erythematosus. It has been shown to have metabolic effects in many lineages of immune cells, such asneutrophils, T-helper and regulatory T-cells, and dendritic cells, which are key mediators of inflammation and autoimmunity, and characteristic features of systemic lupus erythematosus.³

Based on this preclinical data and a well-established safety profile of metformin, it is likely to be a powerful contributor to the management of autoimmune diseases.^1-3

References

1. Ursini F, Russo E, Pellino G, et al. Metformin and Autoimmunity: A "New Deal" of an Old Drug. Front Immunol. 2018;9:1236.
2. Tomczynska M, BijakM, Saluk J. Metformin - The Drug for the Treatment of Autoimmune Diseases; A New Use of a Known Anti-Diabetic Drug. Curr Top Med Chem. 2016;16(19):2223-30.
3. Nikpour M. Metformin in SLE: metabolism as a therapeutic target in autoimmune disease. 2020;2(4):E196-E197.