Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19

for the COVID-OUT study team

doi:10.1093/cid/ciae159

Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19

for the COVID-OUT study team

Medicine, General Medicine Division

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Background. Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. Methods. COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. Results. The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log₁₀ copies/mL; 95% confidence interval [CI], −1.05 to −.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. Conclusions. In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. Clinical Trials Registration. NCT04510194.

Original language	English (US)
Pages (from-to)	354-363
Number of pages	10
Journal	Clinical Infectious Diseases
Volume	79
Issue number	2
DOIs	https://doi.org/10.1093/cid/ciae159
State	Published - Aug 15 2024

Funding

Financial support. The fluvoxamine placebo tablets were donated by the Apotex Pharmacy. The ivermectin placebo and active tablets were donated by the Edenbridge Pharmacy. The trial was funded by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and the UnitedHealth Group Foundation. C. T. B. was supported by grants (KL2TR002492 and UL1TR002494) from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) and by a grant (K23 DK124654) from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. J. B. B. was supported by a grant (UL1TR002489) from NCATS. J. M. N. was supported by a grant (K23HL133604) from the National Heart, Lung, and Blood Institute (NHLBI) of the NIH. D. J. O. was supported by the Institute for Engineering in Medicine, University of Minnesota Office of Academic and Clinical Affairs COVID-19 Rapid Response Grant, the Earl E. Bakken Professorship for Engineering in Medicine, and by grants (U54 CA210190 and P01 CA254849) from the National Cancer Institute of the NIH. D. M. L. receives funding from NIH RECOVER (OT2HL161847). L. K. S. was supported by NIH grants (18X107CF6 and 18X107CF5) through a contract with Leidos Biomedical and by grants from the HLBI of the NIH (T32HL129956) and the NIH (R01LM012982 and R21LM012744). M. A. P. receives grants from the Bill and Melinda Gates Foundation (INV-017069), Minnesota Partnership for Biotechnology and Medical Genomics (00086722) and NHLBI (OT2HL156812).

Keywords

long COVID
mTOR
metformin
outpatient COVID-19 treatment
viral load

ASJC Scopus subject areas

Microbiology (medical)
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/cid/ciae159

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@article{0035e1a75eff4af39ab7c5d182c26332,

title = "Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19",

abstract = "Background. Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. Methods. COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. Results. The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log10 copies/mL; 95% confidence interval [CI], −1.05 to −.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. Conclusions. In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. Clinical Trials Registration. NCT04510194.",

keywords = "long COVID, mTOR, metformin, outpatient COVID-19 treatment, viral load",

author = "{for the COVID-OUT study team} and Bramante, {Carolyn T.} and Beckman, {Kenneth B.} and Tanvi Mehta and Karger, {Amy B.} and Odde, {David J.} and Tignanelli, {Christopher J.} and Buse, {John B.} and Johnson, {Darrell M.} and Watson, {Ray H.B.} and Daniel, {Jerry J.} and Liebovitz, {David M.} and Nicklas, {Jacinda M.} and Ken Cohen and Puskarich, {Michael A.} and Belani, {Hrishikesh K.} and Siegel, {Lianne K.} and Klatt, {Nichole R.} and Blake Anderson and Hartman, {Katrina M.} and Via Rao and Hagen, {Aubrey A.} and Barkha Patel and Fenno, {Sarah L.} and Nandini Avula and Reddy, {Neha V.} and Erickson, {Spencer M.} and Fricton, {Regina D.} and Samuel Lee and Gwendolyn Griffiths and Pullen, {Matthew F.} and Thompson, {Jennifer L.} and Sherwood, {Nancy E.} and Murray, {Thomas A.} and Rose, {Michael R.} and Boulware, {David R.} and Huling, {Jared D.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.",

year = "2024",

month = aug,

day = "15",

doi = "10.1093/cid/ciae159",

language = "English (US)",

volume = "79",

pages = "354--363",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "2",

}

TY - JOUR

T1 - Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19

AU - for the COVID-OUT study team

AU - Bramante, Carolyn T.

AU - Beckman, Kenneth B.

AU - Mehta, Tanvi

AU - Karger, Amy B.

AU - Odde, David J.

AU - Tignanelli, Christopher J.

AU - Buse, John B.

AU - Johnson, Darrell M.

AU - Watson, Ray H.B.

AU - Daniel, Jerry J.

AU - Liebovitz, David M.

AU - Nicklas, Jacinda M.

AU - Cohen, Ken

AU - Puskarich, Michael A.

AU - Belani, Hrishikesh K.

AU - Siegel, Lianne K.

AU - Klatt, Nichole R.

AU - Anderson, Blake

AU - Hartman, Katrina M.

AU - Rao, Via

AU - Hagen, Aubrey A.

AU - Patel, Barkha

AU - Fenno, Sarah L.

AU - Avula, Nandini

AU - Reddy, Neha V.

AU - Erickson, Spencer M.

AU - Fricton, Regina D.

AU - Lee, Samuel

AU - Griffiths, Gwendolyn

AU - Pullen, Matthew F.

AU - Thompson, Jennifer L.

AU - Sherwood, Nancy E.

AU - Murray, Thomas A.

AU - Rose, Michael R.

AU - Boulware, David R.

AU - Huling, Jared D.

PY - 2024/8/15

Y1 - 2024/8/15

N2 - Background. Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. Methods. COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. Results. The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log10 copies/mL; 95% confidence interval [CI], −1.05 to −.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. Conclusions. In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. Clinical Trials Registration. NCT04510194.

AB - Background. Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. Methods. COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. Results. The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log10 copies/mL; 95% confidence interval [CI], −1.05 to −.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. Conclusions. In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. Clinical Trials Registration. NCT04510194.

KW - long COVID

KW - mTOR

KW - metformin

KW - outpatient COVID-19 treatment

KW - viral load

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UR - http://www.scopus.com/inward/citedby.url?scp=85201113790&partnerID=8YFLogxK

U2 - 10.1093/cid/ciae159

DO - 10.1093/cid/ciae159

M3 - Article

C2 - 38690892

AN - SCOPUS:85201113790

SN - 1058-4838

VL - 79

SP - 354

EP - 363

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 2

ER -

Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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