Metformin shows promising antiviral activity against SARS-CoV-2

By Neha MathurJun 12 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent article posted to the medRxiv* preprint server, researchers present the results of severe acute respiratory coronavirus 2 (SARS-CoV-2) load quantification obtained during the COVID-OUT clinical trial.

Study: Metformin reduces SARS-CoV-2 in Phase 3 Randomized Placebo-Controlled Clinical Trial.Image Credit: LeviMax / Shutterstock.com

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

In silico modeling has shown that protein translation is a critical process in SARS-CoV-2 replication, a ribonucleic acid (RNA) virus that causes coronavirus 2019 disease (COVID-19).

In vitro experiments, consistent with model predictions, have shown that metformin, a widely available and inexpensive oral medication for diabetes, exhibits antiviral activity of RNA viruses, including SARS-CoV-2. Moreover, metformin appears to reduce the growth of SARS-CoV-2 and improve host cell viability, thus emerging as an ideal drug candidate for drug repurposing and combating COVID-19.

Specifically, metformin mechanistically targets the rapamycin (mTOR) pathway), which regulates protein translation.

Previous studies on metformin have described its in vitro antiviral actions against Zika and hepatitis C viruses, as well as influenza and parainfluenza viruses. Together, these findings motivated researchers to initiate COVID-OUT, a phase III placebo-controlled randomized clinical trial (RCT) that tested various treatments for COVID-19.

About the COVID-OUT clinical trial

Researchers remotely delivered the COVID-OUT trial across multiple sites between December 30, 2020, and January 28, 2022. All study participants parallelly received treatments with three oral and generic drugs, including immediate-release metformin, ivermectin, and fluvoxamine.

As a quadruple-blinded trial, study participants, investigators, and laboratory personnel processing the trial samples were blinded to study drug(s) allocation. COVID-19 was also decentralized to prevent the person-to-person spread of SARS-CoV-2.

About the study

In the present study, researchers used viral load samples self-collected by study participants from their anterior nares on days one, five, and 10.

The trial endpoint was the development of severe COVID-19 by Day 14. Finally, the team used a Tobit regression model to assess the varying effects of metformin use on Days 5 and 10.

Study findings

Of the 1,323 COVID-OUT trial participants, 999 randomized individuals voluntarily participated in this optional sub-study and provided self-administered nasal swab samples. In total, 945, 871, and 775 participants provided nasal swab samples on days one, five, and 10 with respective mean viral loads of 4.88, 1.90, and 0 log10 copies/ml, respectively, in which zero represented the quantification limit.

Ivermectin or fluvoxamine exhibited no antiviral activity by days five or 10. Comparatively, metformin reduced the average SARS-CoV-2 viral load by -0.56 log10 copies/ml more than the placebo across all follow-up evaluations of day one samples.

The antiviral effect of metformin as compared to placebos on days five and ten were -0.47 and -0.67 log10 copies/mL, respectively. These results did not vary after adjusting for covariates one at a time.

The likelihood of detecting SARS-CoV-2 viral load in the metformin group as compared to placebo, expressed as odds ratio (OR), was 0.73, 0.65, and 0.79 on days one, five, and 10, respectively. Viral rebound, which reflects a higher viral load on day ten compared to day five, was 3.28% and 5.95% in the metformin and placebo groups, respectively.

Conclusions

In this COVID-OUT substudy, researchers demonstrate that the antiviral activity of metformin against SARS-CoV-2 was more effective when the drug treatment started within five to 10 days of disease onset. The use of metformin also improved clinical outcomes, as the SARS-CoV-2 viral load became undetectable 2.3 days faster than the placebo.

Although a 5' adenosine monophosphate-activated protein kinase-independent inhibition of the mammalian target of rapamycin (mTOR) by metformin might be more efficient, the current study demonstrates that metformin elicits a dose-dependent inhibition of interleukins one through six and other proinflammatory mediators like tumor necrosis factor-alpha, correlated to COVID-19 severity.

In addition, the scale of metformin's antiviral activity was much more significant on day ten as compared to day five, thereby suggesting that dose titration to 1,500 mg over six days worked faster. Most importantly, the metformin effect was consistent across subgroups.

According to the authors, therapeutics targeting host factors rather than viral factors are less likely to trigger drug-resistant viral variants through mutation selection. In addition, metformin-induced clinically relevant anti-inflammatory actions.

Future research should explore the synergy between metformin and SARS-CoV-2-directed antivirals to improve clinical outcomes in COVID-19 patients and reduce resistance pressure induced by direct antivirals. More data is also needed to determine whether metformin use could decrease onward transmission of SARS-CoV-2.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.