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It has been found that hospitalized COVID-19 patients have a greater risk of dying if they are men or are obese or have complications from diabetes or hypertension (University of Maryland School of Medicine, 2020).

Yet, use of the diabetes drug metformin — before a diagnosis of COVID-19 — is associated with a threefold decrease in mortality in COVID-19 patients with Type 2 diabetes (Crouse, et al. 2021).

Interestingly:

[N]either BMI nor HbA1C were lower in metformin users who survived as compared to those who died (Table 4). While surprising, this is consistent with the notion that long-term glycemic control does not affect COVID-19 outcome.

While I understand at the moment that more investigation is needed to determine how Metformin helps, if BMI or HbA1C is not a contributing factor in the protective nature of Metformin, what other effects of Metformin on the body could be helping type 2 diabetics and how?

References

Crouse, A. B.; Grimes, T.; Li, P.; Might, M. Ovalle, F.; Shalev. A. (2021). Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes. Frontiers in Endocrinology 11(600439) https://doi.org/10.3389/fendo.2020.600439

University of Maryland School of Medicine. (2020). New study identifies greatest risk factors of mortality from COVID-19: Findings could help guide healthcare clinicians with managing hospitalized patients in the weeks ahead. ScienceDaily https://www.sciencedaily.com/releases/2020/12/201218152733.htm

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The latter paper (Crouse, et al.) discusses this:

Interestingly, metformin has previously been shown to also have anti-inflammatory (16, 17) and anti-thrombotic effects (18, 19) and excessive inflammatory responses, e.g., cytokine storm as well as disseminated thromboembolic events have been recognized as deadly complications of COVID-19 infection (20–22). It is therefore tempting to speculate that by exerting some of its anti-fibrinolytic activities (18) and inhibiting inflammatory cytokines such as tumor necrosis factor alpha or interleukin-6 (16, 17), suspected to play a role in the immune response to COVID-19 (12), metformin might improve outcome.

It wouldn't be surprising given that dexamethasone is basically used for that anti-thrombotic effect in treating Covid-19. I'm not sure how much of an anti-thrombotic effect metformin has in comparison; you may wan to check the refs cited in Crouse, et al.

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The following information obtained by searching PUBMED is NOT a systematic review.

The search yields interesting information in support of the speculation by the previous answer (and by Crouse) that an effect of metformin in reducing the risk of mortality in patients with COVID-19 might be explained by an anti-thrombotic effect of metformin. One of the three identified studies (Xin) involving rats is cited by Crouse et al. The two epidemiologic studies provide direct evidence of a possible anti-thrombotic effect of metformin in humans.

THREE PERTINENT STUDIES

Metformin in Experimental Study in Diabetic and Non-Diabetic Rats

In a study that involved rats with and without diabetes published in 2016, metformin treatment:

“significantly decreased the incidence of pulmonary embolism (Fig. 4G), reduced the weight and length of arterial and venous thrombus (Fig. 4A–F), prolonged the average time to occlusive thrombosis in FeCl3-induced inferior vena cava and carotid arteries injury (Supplementary Fig. 3C,D), and improved blood viscosity (Supplementary Table 1).”

Xin G, Wei Z, Ji C, et al. Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release. Sci Rep. 2016;6:36222. Published 2016 Nov 2. doi:10.1038/srep36222

https://pubmed.ncbi.nlm.nih.gov/27805009/

Epidemiologic Studies in Humans

In a record linkage study based on data about 14,945 people with Type 2 diabetes published in 2014, the adjusted hazard ratio for deep vein thrombosis comparing 7,167 people who had a prescription for metformin with 7,778 people who had no prescription for metformin (matched by age, sex, and co-morbidity) was 0.43 (95% confidence interval 0.24-0.76).

Lu DY, Huang CC, Huang PH, et al. Metformin use in patients with type 2 diabetes mellitus is associated with reduced risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. BMC Cardiovasc Disord. 2014;14:187. Published 2014 Dec 15. doi:10.1186/1471-2261-14-187

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274716/

In an epidemiologic cohort study based on data from 277 patients age 65+ years with a venous thromboembolism that was published in 2020, the adjusted hazard ratio for recurrent venous thromboembolism was 0.16 (95% confidence interval 0.08-0.33) in patients who took metformin.

Aleidan FAS. The Cumulative Incidence and Risk Factors of Recurrent Venous Thromboembolism in the Elderly. Vasc Health Risk Manag. 2020;16:437-443. Published 2020 Oct 19. doi:10.2147/VHRM.S264814

https://pubmed.ncbi.nlm.nih.gov/33116554/

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