Metformin Decreases Risk Of COVID-19 Severity

Study findings from yet another research led by scientists from the University of Minnesota Medical School has added to the growing evidence that metformin, a common and cheap generic diabetic drug is able to decrease the risk of COVID-19 severity.

The study findings were published in the peer reviewed journal: PLOS One.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271574

This analysis of adults with T2DM and +SARS-CoV-2 infection was the first analysis of prevalent users of diabetes monotherapy and was possible because of the size of this database. We found that compared to SU use, metformin use was significantly associated with less severe outcomes from COVID-19 compared to SU users, but associations were not significant compared to DPP4i use.

The size of this database allowed us to conduct this analysis with prevalent user comparator groups of diabetes medications that are therapeutically similar, as SU and DPP4i are less common than metformin.

We feel this approach has advantages over a non-user comparison, as it explicitly compares to patients receiving an alternative treatment for the same indication, which is a significant consideration when assessing diabetes medications and outcomes from COVID-19 in persons with T2DM.

A recent paper by Wang et al, [45] conducted a similar analysis in adults with T2DM comparing metformin to other diabetes medications. They found favorable hazard ratios for metformin compared to the other diabetes medications, but none of the matched analyses reached the 5% level of statistical significance [44].

We conducted a prespecified subgroup analysis by sex based on earlier work showing that metformin lowers CRP more in women than men, improved cancer mortality in women but not men, and conveyed greater protection against severe outcomes from COVID-19 in women compared to men [46].

The association with lower risk of ventilation and mortality with metformin versus SU was significant for females but not for males in this analysis. This potential influence of sex as a biologic variable should be further assessed. Much of the mechanistic research on metformin and DPP4i’s was done before 2014, when the NIH started to promote the study of sex as a biologic variable [47].

However metformin has been found to reduce TNF-alpha, IL-6, and possibly boost IL-10 in females more than males, which is relevant to the pathophysiology of COVID-19 [48–50].

Subgroup analysis was conducted comparing those with a BMI>25kg/m2 (the definition of overweight, and the BMI at which visceral adiposity starts to accumulate more rapidly) to those with a BMI<25kg/m2 [51]. If metformin were effective only in individuals with an elevated BMI, the antiviral actions of metformin might be less significant than anti-inflammatory and anti-thrombotic effects of metformin.

However, we saw no obvious difference between these BMI groups. It is possible that this BMI threshold is too low, or that potential benefit from metformin is not dependent on baseline amount of adipokines (many of which are associated with poor outcomes from COVID-19).

These results may contribute to the growing body of evidence suggesting that metformin use may be associated with less severe COVID-19 disease. There is also in-silico, in-vitro, and in-tissue data suggesting that metformin associated with less severe outcomes from COVID-19 [10, 11, 16–18].

Metformin is safe in nearly all individuals, including individuals with heart, liver, and kidney disease, but should be used with caution in persons with advanced heart, liver, or kidney disease [9, 52–56]. Metformin has very few interactions with other medications and requires no follow-up until after 1 year of use, making it an ideal option for persons on other chronic medications or persons with lack of access to follow-up care.

Given the significant global impact of SARS-CoV-2 and the COVID-19 pandemic, patients should have several options for safe, available, inexpensive early outpatient treatment of SARS-CoV-2 infection to prevent severe COVID-19 disease. There is also evidence that early outpatient treatment with may possibly prevent long COVID symptoms (post-acute sequelae of COVID, PASC) [57].

While in-vitro and in-silico data supports its use in active infection, observational analyses such as this only add information about metformin use before infection with SARS-CoV-2. Few papers describe metformin continued or initiated during hospitalizations for COVID [58].

Randomized trials are needed to understand whether metformin has any efficacy in the setting of SARS-CoV-2 infection, exposure to infection, or treatment and prevention of PASC. Metformin’s safety and cost make it a medication that is low-risk enough to reasonably consider using in a PEP fashion. While viral variants may evade vaccine-induced immunity because of their cell-entry abilities, they will still depend on host proteins for transcription and translation. Metformin’s inhibition of proteins that are critical to viral replication may mean it is still relevant for most viral variants.