We read with interest the recommendations on the management of diabetes in patients with COVID-19 by Stefan Bornstein and colleagues.1 However, their suggestion of discontinuing metformin in patients with severe symptoms of COVID-19 (to reduce the risk of lactic acidosis) raises a number of issues. We believe that it is important to maintain a thoughtful approach to metformin therapy in patients with diabetes and COVID-19.
After the synthesis of the first glucose-lowering biguanides in the 1920s, metformin was rediscovered in the 1940s for the treatment of malaria. In 1949, a dimethylbiguanide preparation (flumamine) was used to treat influenza virus infections. Since then, metformin has shown adjuvant efficacy in malaria, tuberculosis, hepatitis C virus infection, and Zika virus infection, indicating that it has considerable potential as an antimicrobial. Of note, metformin is reportedly one of the drugs that targets human host factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the mTOR pathway.2
Metformin has direct and indirect immunosuppressive effects. In particular, metformin reduces the secretion of pro-inflammatory cytokines (IL-6, IL-1β, CXCL1, and CXCL2) by macrophages. These cytokines are involved in the development of acute respiratory distress syndrome in COVID-19. Moreover, lung inflammation in COVID-19 can lead to fibrosis. Metformin is known to reverse established fibrosis in various lung models by facilitating the deactivation and apoptosis of myofibroblasts.3
Generally, metformin is considered to act as a cell protector; it modulates energy metabolism (thus attenuating the harmful effects of stress on mitochondrial function), activates AMP-activated protein kinase (potentiating the autophagic process), scavenges reactive oxygen species, and modulates dysbiosis. These characteristics might explain why metformin has been shown to be associated with a relative reduction in mortality among patients with diabetes in the intensive care unit.4
Finally, severe infections are associated with insulin resistance and hyperglycaemia (even in patients without diabetes), whereas tight blood glucose control is essential for reducing mortality among patients who are critically ill. Hence, we suggest that investigators in ongoing cohort studies should check whether metformin is associated with a favourable outcome in patients with diabetes. Pending these analyses, we recommend that metformin treatment should be maintained in patients with diabetes who are hospitalised for COVID-19, as long as they have not developed concomitant kidney and liver failure. Kidney failure leads to metformin accumulation and liver failure reduces lactate elimination, increasing the risk of lactic acidosis.5
Acknowledgments
We declare no competing interests.
References
- 1.Bornstein SR, Rubino F, Khunti K. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol. 2020;8:546–550. doi: 10.1016/S2213-8587(20)30152-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gordon DE, Jang GM, Bouhaddou M. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020 doi: 10.1038/s41586-020-2286-9. published online April 30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Rangarajan S, Bone NB, Zmijewska AA. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24:1121–1127. doi: 10.1038/s41591-018-0087-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Christiansen C, Johansen M, Christensen S, O'Brien JM, Tønnesen E, Sørensen H. Preadmission metformin use and mortality among intensive care patients with diabetes: a cohort study. Crit Care. 2013;17:R192. doi: 10.1186/cc12886. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lalau J-D, Kajbaf F, Protti A, Christensen MM, De Broe ME, Wiernsperger N. Metformin-associated lactic acidosis (MALA): moving towards a new paradigm. Diabetes Obes Metab. 2017;19:1502–1512. doi: 10.1111/dom.12974. [DOI] [PubMed] [Google Scholar]