Metformin

Last review completed on
April 10th, 2020
Therapy Description

It is a lesser-known fact that metformin was originally introduced as an anti-influenza drug and that glucose-lowering was only one of its side effects [1]. The many pleiotropic effects of metformin and its widespread utility in medicine today have led scientists to call it the aspirin of the 21st century [2].

In the current scenario, when there is no specific agent against COVID-19, and when re-purposing of drugs is the primary weapon, we suggest that metformin be used as one of the drugs to combat the virus.

Recommendation

Information related to metformin and its impact on the novel coronavirus, COVID-19 is theoretical at best. No in vitro studies have been performed specific to SARS-CoV-2.

Clinical Circumstances
List of Evidence/ Discussion

Sources

  1. Gordon, David E., et al. "A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing." BioRxiv (2020).
    • Theoretical virus interactions with human proteins regulated by the mTORC1 pathway, such as LARP1, have led researchers to believe that inhibitors of mTORC1 may provide some benefit in reducing severity of COVID-19, even though the kinase itself is not found to directly interact with a viral protein. Metformin in as indirect modulator of this protein complex (see Figure).
    • The mTOR inhibitor rapamycin has been shown to disrupt the binding of LARP1 to mTORC1 and reduce MERS infection by ~60% in vitro. The SARS-CoV-2 nucleocapsid (N) intertactome includes many host mRNA binding proteins such as the mTOR translational repressors LARP1. Therefore, researchers believe it would be reasonable to consider medications that inhibitor mTORC1 directly or indirectly, such as the antidiabetic medication metformin, as adjunctive therapies.
  2. Zumla, Alimuddin, et al. "Reducing mortality from 2019-nCoV: host-directed therapies should be an option." The Lancet 395.10224 (2020): e35-e36.
    • Article in The Lancet indicating that metformin, amongst many other medications, may be able to be repurposed to treated COVID-19 infection. This claim includes a citation that links to another article in The Lancet, which contains another claim that metformin may be beneficial based on a study that demonstrated metformin’s ability to increase mitochondrial ROS production and enhance macrophage autophagy in mice (though not specific to COVID-19).
    • Inhibition of complex I with metformin was associated with increased intracellular levels of both superoxide and hydrogen peroxide, as well as inhibition of LPS-induced IκB-α degradation, NF-κB nuclear accumulation, and proinflammatory cytokine production.
    • Treatment of LPS-exposed mice with metformin resulted in inhibition of complex I in the lungs, as well as diminished severity of lung injury. These results demonstrate that mitochondrial complex I plays an important role in modulating Toll-like receptor 4–mediated neutrophil activation and suggest that metformin may be useful in the prevention or treatment of acute inflammatory processes in which activated neutrophils play a major role, such as acute lung injury.