Journals | Policy | Permission

This journal has moved to cii.elmerpub.com Please go to the new site to make submissions

Clinical Infection & Immunity

Editorial

Volume 6, Number 1, March 2021, pages 1-3

Metformin Prevents Severe COVID-19 and Death

Diabetes and obesity are both established risk factors for developing severe coronavirus disease-2019 (COVID-19) complications, including mortality [1, 2].

Excessive inflammation is a major phenomenon that contributes to the severity of COVID-19. Metformin (MTF) inhibits inflammatory responses, alleviating acute lung injuries [3].

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In the early stage of infection, virus particles and pathogen-associated molecular patterns (PAMPs) as well as molecules released from damaged cells activate innate immune cells such as macrophages, which then produce pro-inflammatory cytokines, such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α (TNF-α). The adaptive immune response subsequently leads to the secretion of pro-inflammatory cytokines and chemokines, which in turn promote further innate cell recruitment and activation. As a result, a cytokine storm induced by innate immune cells ultimately results in inflammation and injury (Fig. 1).

Click for large image

Figure 1. Metformin exerts an anti-inflammatory and regulatory effect on the inflammation phenomena elicited by SARS-CoV-2 infection. SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

TNF-α is found in high levels in the lungs of individuals with COVID-19, and contributes to insulin resistance [4]. Along with TNF-α, other pro-inflammatory mediators, such as IL-6, are also elevated in the acute phase of COVID-19 [5]. Individuals with type 2 diabetes mellitus (T2DM) tend to have low levels of anti-inflammatory cytokine IL-10 [6]. MTF decreases TNF-α and IL-6, while increasing IL-10, improving inflammation and cytokines associated with obesity in those with and without diabetes [3].

MTF is also proving to have beneficial effects in the context of Mycobacterium tuberculosis infection [7]. Furthermore, MTF has antiviral properties against SARS-CoV-2 targeting interactions between viral proteins and host factors, such as viral protein Nsp7 and human NDUFA2, and viral protein Orf9c and human NDUFAF1 or NDUFB9 [8]. As a matter of fact, MTF was originally introduced as an anti-influenza drug [9], and hypoglycemic properties were just only one of its side effects.

At a molecular level, MTF acts as a reversible inhibitor of nicotinamide dinucleotide (NADH) dehydrogenase activity of the respiratory chain, resulting in suppression of ATP production [10]. One of the key molecules by which MTF exerts its various effects is AMP-activated protein kinase (AMPK) [3, 11]. AMPK restricts the replication of another single-stranded RNA virus, the Zika virus in endothelial cells [12].

SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as its biding receptor [13]. AMPK has been shown to increase the expression of ACE2, and its stability by phosphorylating ACE2 in endothelial cells [14]. Since MTF works through AMPK activation via phosphorylation of ACE2 [14], this conformational change in the ACE2 receptor could lead to a decreased binding with SARS-CoV-2 by a steric hindrance as consequence of the addition of the phosphate group [15].

MTF also inhibits the mammalian target of rapamycin (mTOR) signalling pathway, which regulates many human proteins and plays an important role in influenza virus infection [15]. In the case of SARS-CoV-2, mTOR regulates proteins LARP1 and FKBP7, which interact with viral proteins, N and Orf8 [16]. MTF inhibits the mTOR pathway via AMPK activation [14], indirectly modulating the viral replication process.

A meta-analysis of the recent studies on MTF and COVID-19 mortality showed that mortality rates were lower in MTF users compared to non-users [17]. This information comes from four studies. The first one, a multicenter study from France, showed that MTF was associated with a reduced risk of early death [1]. Authors, nevertheless, state that it may reflect a less advanced stage of diabetes with fewer comorbidities such as severe chronic kidney disease that would otherwise contraindicate its use.

Two other retrospective studies from China showed that MTF users presented less IL-6 inflammation [18] and reduced mortality [19].

The fourth study from the USA found that the use of MTF was associated with a 21.5% lower risk of death of women with T2D with COVID-19 [20]. There was no significant reduction in mortality among men taking MTF. When data were analyzed using a propensity model matched on age, sex and comorbidities, it was shown that TNF-α inhibitors were significantly associated with decreased mortality. Although this may have been the result of a small sample size (n = 38), the findings are interesting supporting previous research on the role of TNF-α in the pathology of COVID-19, and underlining the role of anti-inflammatory drugs in a positive outcome of mortality.

Previous studies have shown that male sex is a risk factor for poor COVID-19 outcomes [21, 22]. The sex-specific response seen in this study suggests that a sex hormonal effect and epigenetic changes on the Y chromosome may contribute to the results.

We should be cautious about the retrospective nature of these studies [23]. Findings will need to be prospectively confirmed on large, randomized controlled trials. Side effects of MTF, such as lactic acidosis, also need to be evaluated in these patients. The low cost of MTF, nevertheless, could prove a very high cost-effectiveness measure in the context of the burden of disease caused by COVID-19.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Data Availability

The author declares that data supporting the findings of this study are available within the article.

1. Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, Allix I, Amadou C, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. 2020;63(8):1500-1515.
   doi pubmed
2. Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress. Diabetes Res Clin Pract. 2020;162:108142.
   doi pubmed
3. Chen X, Guo H, Qiu L, Zhang C, Deng Q, Leng Q. Immunomodulatory and antiviral activity of metformin and its potential implications in treating coronavirus disease 2019 and lung injury. Front Immunol. 2020;11:2056.
   doi pubmed
4. Tufan A, Avanoglu Guler A, Matucci-Cerinic M. COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turk J Med Sci. 2020;50(SI-1):620-632.
   doi pubmed
5. Sadanandam A, Bopp T, Dixit S, Knapp D, Emperumal CP, Vergidis P, Rajalingam K, et al. A blood transcriptome-based analysis of disease progression, immune regulation, and symptoms in coronavirus-infected patients. Cell Death Discov. 2020;6(1):141.
   doi pubmed
6. Bluher M, Fasshauer M, Tonjes A, Kratzsch J, Schon MR, Paschke R. Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism. Exp Clin Endocrinol Diabetes. 2005;113(9):534-537.
   doi pubmed
7. Oglesby W, Kara AM, Granados H, Cervantes JL. Metformin in tuberculosis: beyond control of hyperglycemia. Infection. 2019;47(5):697-702.
   doi pubmed
8. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O'Meara MJ, Guo JZ, et al. A SARS-CoV-2-human protein-protein interaction map reveals drug targets and potential drug-repurposing. bioRxiv. 2020.
9. Amin S, Lux A, O'Callaghan F. The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth. Br J Clin Pharmacol. 2019;85(1):37-46.
   doi pubmed
10. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(Pt 3):607-614.
    doi
11. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-1174.
    doi pubmed
12. Singh S, Singh PK, Suhail H, Arumugaswami V, Pellett PE, Giri S, Kumar A. AMP-Activated protein kinase restricts zika virus replication in endothelial cells by potentiating innate antiviral responses and inhibiting glycolysis. J Immunol. 2020;204(7):1810-1824.
    doi pubmed
13. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020;126(10):1456-1474.
    doi pubmed
14. Liu J, Li X, Lu Q, Ren D, Sun X, Rousselle T, Li J, et al. AMPK: a balancer of the renin-angiotensin system. Biosci Rep. 2019;39(9).
    doi pubmed
15. Sharma S, Ray A, Sadasivam B. Metformin in COVID-19: A possible role beyond diabetes. Diabetes Res Clin Pract. 2020;164:108183.
    doi pubmed
16. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):459-468.
    doi pubmed
17. Scheen AJ. Metformin and COVID-19: From cellular mechanisms to reduced mortality. Diabetes Metab. 2020;46(6):423-426.
    doi pubmed
18. Chen Y, Yang D, Cheng B, Chen J, Peng A, Yang C, Liu C, et al. Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication. Diabetes Care. 2020;43(7):1399-1407.
    doi pubmed
19. Luo P, Qiu L, Liu Y, Liu XL, Zheng JL, Xue HY, Liu WH, et al. Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis. Am J Trop Med Hyg. 2020;103(1):69-72.
    doi pubmed
20. Bramante CT, Ingraham NE, Murray TA, Marmor S, Hovertsen S, Gronski J, McNeil C, et al. Observational study of metformin and risk of mortality in patients hospitalized with COVID-19. medRxiv. 2020.
    doi
21. Palaiodimos L, Kokkinidis DG, Li W, Karamanis D, Ognibene J, Arora S, Southern WN, et al. Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York. Metabolism. 2020;108:154262.
    doi pubmed
22. Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G, Bonanomi E, et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern Med. 2020;180(10):1345-1355.
    doi pubmed
23. Dardano A, Del Prato S. Metformin: an inexpensive and effective treatment in people with diabetes and COVID-19? Lancet Healthy Longev. 2021;2(1):e6-e7.
    doi

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Clinical Infection and Immunity is published by Elmer Press Inc.