Metformin shows promising antiviral activity against SARS-CoV-2

In a recent article posted on medRxiv* On a preprint server, researchers present 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 a Phase 3 randomized placebo-controlled clinical trial.Image credit: LeviMax / Shutterstock.com

*Important Notices: medRxiv Publishes preliminary scientific reports that have not been peer-reviewed and should therefore not be considered definitive, to guide clinical practice or health-related actions, or to be treated as established information. not.

Background

in silico modeling showed that protein translation is a key process in the replication of SARS-CoV-2, the ribonucleic acid (RNA) virus that causes coronavirus 2019 disease (COVID-19).

in vitro Experiments consistent with model predictions showed that metformin, a widely available and inexpensive oral diabetes drug, exhibited antiviral activity against RNA viruses, including SARS-CoV-2. In addition, metformin is thought to suppress the growth of SARS-CoV-2 and improve host cell viability, making it an ideal drug for drug repurposing and the fight against her COVID-19. emerged as a candidate.

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

Previous studies on metformin have described it. in vitro Antiviral activity against Zika virus, hepatitis C virus, influenza virus, and parainfluenza virus. These findings prompted researchers to initiate COVID-OUT, a Phase III, placebo-controlled, randomized clinical trial (RCT) to test different treatments for COVID-19. gave me the motivation to

About the COVID-OUT Clinical Trial

Researchers conducted a remote COVID-OUT trial at multiple sites from December 30, 2020 to January 28, 2022. All study participants received concurrent treatment with three oral and generic drugs, including immediate-release metformin, ivermectin, and fluvoxamine.

As a quadruple-blind study, study participants, investigators, and laboratory personnel handling study samples were blinded to study drug assignment. The novel coronavirus disease (COVID-19) was also decentralized to prevent human-to-human transmission of SARS-CoV-2.

About research

In this study, the researchers used viral load Samples were self-collected from the anterior nares on days 1, 5, and 10 by study participants.

The endpoint of the study was the development of severe novel coronavirus disease (COVID-19) by day 14. Finally, the team used a Tobit regression model to assess different effects of metformin use on days 5 and 10.

research result

Of the 1,323 COVID-OUT study participants, 999 who were randomized volunteered to participate in this optional substudy and provided self-administered nasal swab samples. A total of 945, 871 and 775 participants provided nasal swab samples on days 1, 5 and 10 with mean viral loads of 4.88, 1.90 and 0 log10 copies/ml, respectively, and zero represents the limit of quantification.

Ivermectin or fluvoxamine showed no antiviral activity by day 5 or 10. In comparison, metformin reduced the mean SARS-CoV-2 viral load by -0.56 log10 copies/ml more than placebo at all follow-up assessments in day 1 samples.

The antiviral effects of metformin compared to placebo on days 5 and 10 were -0.47 and -0.67 log10 copies/mL, respectively. These results did not change after adjusting the covariates one at a time.

The likelihood of detecting a SARS-CoV-2 viral load in the metformin group compared to placebo was expressed as an odds ratio (OR) of 0.73, 0.65 and 0.79 on days 1, 5 and 10, respectively. bottom. Viral rebound, reflecting higher viral load on day 10 compared to day 5, was 3.28% in the metformin group and 5.95% in the placebo group.

Conclusion

In this COVID-OUT sub-study, researchers demonstrate that metformin’s antiviral activity against SARS-CoV-2 is more effective when drug treatment is initiated within 5–10 days of symptom onset. increase. With metformin use, he had an undetectable SARS-CoV-2 viral load 2.3 days earlier than placebo and had an improved clinical outcome.

Although 5′ adenosine monophosphate-activated protein kinase-independent inhibition of the mammalian target rapamycin (mTOR) by metformin may be more efficient, the current study demonstrated that metformin inhibited interleukins 1–6 and It has been demonstrated to induce dose-dependent inhibition of other pro-inflammatory mediators. Similar to tumor necrosis factor alpha, it correlates with the severity of COVID-19.

Furthermore, the magnitude of metformin’s antiviral activity was much more pronounced on day 10 compared to day 5, indicating that escalating the dose to 1,500 mg over 6 days had a faster effect. was suggested. Most importantly, the effects of metformin were consistent across subgroups.

According to the authors, therapeutics that target host factors rather than viral factors are less likely to cause drug-resistant viral variants through mutation selection. Moreover, metformin induces clinically relevant anti-inflammatory effects.

Future studies should explore the synergistic effects of metformin and SARS-CoV-2-directed antiviral drugs to improve clinical outcomes in patients with COVID-19 and reduce resistance pressure caused by direct antiviral drugs. There is More data are also needed to determine whether metformin use can reduce transmission of SARS-CoV-2.

*Important Notices: medRxiv Publishes preliminary scientific reports that have not been peer-reviewed and should therefore not be considered definitive, to guide clinical practice or health-related actions, or to be treated as established information. not.