Metformin use associated with 70% mortality reduction in covid-19 patients with diabetes

Since March, I have been hoping someone would study whether covid-19 patients with type 2 diabetes (T2D) on metformin fare better than those on other types of anti-diabetes medications. Many of the risk factors associated with severe covid-19 (e.g., obesity, diabetes, hypertension, older age) relate to AMPK signalling and metformin, a drug that improves AMPK signalling, has been found to benefit these conditions. 

My question has finally been answered  - T2D patients on metformin have a 70% reduced  risk of death as compared with those on other anti-diabetic medications [1,2]. Unfortunately the study did not control for other important factors such as age, degree of blood sugar control, BMI, and time since diagnosis; a future study designed specifically to examine metformin in covid-19 should be conducted that controls for these factors.

The study authors discuss the potential role of AMPK signalling in covid-19, delineating a number of possible mechanisms by which it could impact the disease process. One aspect that was not mentioned was AMPK activation's role in interferon production in response to TLR-7 activation [3].

mTOR signalling is also discussed in the article.  Just from eyeballing the data on worldometer, per capita death rates seem to be lower in less developed nations where protein/meat consumption is typically much lower as compared with more industrialized, wealthier nations. It is possible these populations have lower baseline mTOR activation due to lower consumption of methionine and leucine. An alternative explanation is high rates of seroprevalence for  hepatitis A in less developed countries [4]. 

Quote from [4]: 

"Many confounding factors can affect these results, including age distribution of the country, the accessibility of health services, the diagnostic facilities, the living environment, and cultural responses toward isolation precautions; however, the major gaps in disease burden between these 2 groups of countries cannot be explained by any of these factors. Of note, gathering epidemiologic data to understand what causes these differences among countries is not easy."

Update:

Brief commentary/review on mTOR inhibition in COVID-19 [5] published in December 2020:

https://onlinelibrary.wiley.com/doi/10.1002/jmv.26728

1 -

Medscape. “Trending Clinical Topic: Metformin.” Accessed August 29, 2020. http://reference.medscape.com/viewarticle/935386.

 

2 -

Hariyanto, Timotius Ivan, and Andree Kurniawan. “Metformin Use Is Associated with Reduced Mortality Rate from Coronavirus Disease 2019 (COVID-19) Infection.” Obesity Medicine 19 (September 2020): 100290. https://doi.org/10.1016/j.obmed.2020.100290. 

 

3 -

Hurley, Harry J., Hannah Dewald, Zachary S. Rothkopf, Sukhwinder Singh, Frank Jenkins, Pratik Deb, Saurav De, Betsy J. Barnes, and Patricia Fitzgerald-Bocarsly. “Frontline Science: AMPK Regulates Metabolic Reprogramming Necessary for Interferon Production in Human Plasmacytoid Dendritic Cells.” Journal of Leukocyte Biology, July 8, 2020. https://doi.org/10.1002/JLB.3HI0220-130.

 

4 -

Sarialioglu, Faik, Fatma Burcu Belen Apak, and Mehmet Haberal. “Can Hepatitis A Vaccine Provide Protection Against COVID-19?” Experimental and Clinical Transplantation: Official Journal of the Middle East Society for Organ Transplantation 18, no. 2 (2020): 141–43. https://doi.org/10.6002/ect.2020.0109.

 

5 -

Karam, Basil S., Rachel S. Morris, Carolyn T. Bramante, Michael Puskarich, Emily J. Zolfaghari, Sahar Lotfi‐Emran, Nicholas E. Ingraham, Anthony Charles, David J. Odde, and Christopher J. Tignanelli. “MTOR Inhibition in COVID-19: A Commentary and Review of Efficacy in RNA Viruses.” Journal of Medical Virology 93, no. 4 (2021): 1843–46. https://doi.org/10.1002/jmv.26728.