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

doi:10.1093/cid/ciae159

Randomized Controlled Trial

. 2024 Aug 16;79(2):354-363.

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

Carolyn T Bramante¹, Kenneth B Beckman², Tanvi Mehta³, Amy B Karger⁴, David J Odde⁵, Christopher J Tignanelli⁶, John B Buse⁷, Darrell M Johnson², Ray H B Watson², Jerry J Daniel², David M Liebovitz⁸, Jacinda M Nicklas⁹, Ken Cohen¹⁰, Michael A Puskarich¹¹, Hrishikesh K Belani¹², Lianne K Siegel³, Nichole R Klatt⁶, Blake Anderson^{13

14}, Katrina M Hartman¹, Via Rao¹, Aubrey A Hagen¹, Barkha Patel¹, Sarah L Fenno¹, Nandini Avula¹, Neha V Reddy¹, Spencer M Erickson¹, Regina D Fricton⁸, Samuel Lee⁸, Gwendolyn Griffiths¹, Matthew F Pullen¹⁵, Jennifer L Thompson¹⁶, Nancy E Sherwood¹⁷, Thomas A Murray³, Michael R Rose^{18

19}, David R Boulware¹⁵, Jared D Huling³; COVID-OUT Study Team

Collaborators, Affiliations

Collaborators

COVID-OUT Study Team:
Blake Anderson, Riannon C Atwater, Nandini Avula, Kenny B Beckman, Hrishikesh K Belani, David R Boulware, Carolyn T Bramante, Jannis Brea, Courtney A Broedlow, John B Buse, Paula Campora, Anup Challa, Jill Charles, Grace Christensen, Theresa Christiansen, Ken Cohen, Bo Connelly, Srijani Datta, Nikita Deng, Alex T Dunn, Spencer M Erickson, Faith M Fairbairn, Sarah L Fenno, Daniel J Fraser, Regina D Fricton, Gwen Griffiths, Aubrey A Hagen, Katrina M Hartman, Audrey F Hendrickson, Jared D Huling, Nicholas E Ingraham, Arthur C Jeng, Darrell M Johnson, Amy B Karger, Nichole R Klatt, Erik A Kuehl, Derek D LaBar, Samuel Lee, David M Liebovitz, Sarah Lindberg, Darlette G Luke, Rosario Machicado, Zeinab Mohamud, Thomas A Murray, Rumbidzai Ngonyama, Jacinda M Nicklas, David J Odde, Elliott Parrens, Daniela Parra, Barkha Patel, Jennifer L Proper, Matthew F Pullen, Michael A Puskarich, Via Rao, Neha V Reddy, Naveen Reddy, Katelyn J Rypka, Hanna G Saveraid, Paula Seloadji, Arman Shahriar, Nancy Sherwood, Jamie L Siegart, Lianne K Siegel, Lucas Simmons, Isabella Sinelli, Palak Singh, Andrew Snyder, Maxwell T Stauffer, Jennifer Thompson, Christopher J Tignanelli, Tannon L Tople, Walker J Tordsen, Ray H B Watson, Beiqing Wu, Adnin Zaman, Madeline R Zolik, Lena Zinkl

Affiliations

¹ General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
² Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA.
³ Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
⁴ Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
⁵ Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
⁶ Department of Surgery, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
⁷ Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
⁸ General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
⁹ General Internal Medicine, University of Colorado, School of Medicine, Aurora, Colorado, USA.
¹⁰ UnitedHealth Group, Optum Labs, Minnetonka, Minnesota, USA.
¹¹ Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA.
¹² Department of Medicine, Olive View-University of California, Los Angeles, California, USA.
¹³ Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA.
¹⁴ Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁵ Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁶ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁷ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁸ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁹ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 38690892
PMCID: PMC11327787 (available on 2025-05-01)
DOI: 10.1093/cid/ciae159

Randomized Controlled Trial

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

Carolyn T Bramante et al. Clin Infect Dis. 2024.

. 2024 Aug 16;79(2):354-363.

doi: 10.1093/cid/ciae159.

Authors

Collaborators

COVID-OUT Study Team:
Blake Anderson, Riannon C Atwater, Nandini Avula, Kenny B Beckman, Hrishikesh K Belani, David R Boulware, Carolyn T Bramante, Jannis Brea, Courtney A Broedlow, John B Buse, Paula Campora, Anup Challa, Jill Charles, Grace Christensen, Theresa Christiansen, Ken Cohen, Bo Connelly, Srijani Datta, Nikita Deng, Alex T Dunn, Spencer M Erickson, Faith M Fairbairn, Sarah L Fenno, Daniel J Fraser, Regina D Fricton, Gwen Griffiths, Aubrey A Hagen, Katrina M Hartman, Audrey F Hendrickson, Jared D Huling, Nicholas E Ingraham, Arthur C Jeng, Darrell M Johnson, Amy B Karger, Nichole R Klatt, Erik A Kuehl, Derek D LaBar, Samuel Lee, David M Liebovitz, Sarah Lindberg, Darlette G Luke, Rosario Machicado, Zeinab Mohamud, Thomas A Murray, Rumbidzai Ngonyama, Jacinda M Nicklas, David J Odde, Elliott Parrens, Daniela Parra, Barkha Patel, Jennifer L Proper, Matthew F Pullen, Michael A Puskarich, Via Rao, Neha V Reddy, Naveen Reddy, Katelyn J Rypka, Hanna G Saveraid, Paula Seloadji, Arman Shahriar, Nancy Sherwood, Jamie L Siegart, Lianne K Siegel, Lucas Simmons, Isabella Sinelli, Palak Singh, Andrew Snyder, Maxwell T Stauffer, Jennifer Thompson, Christopher J Tignanelli, Tannon L Tople, Walker J Tordsen, Ray H B Watson, Beiqing Wu, Adnin Zaman, Madeline R Zolik, Lena Zinkl

Affiliations

¹ General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
² Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA.
³ Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
⁴ Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
⁵ Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
⁶ Department of Surgery, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
⁷ Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
⁸ General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
⁹ General Internal Medicine, University of Colorado, School of Medicine, Aurora, Colorado, USA.
¹⁰ UnitedHealth Group, Optum Labs, Minnetonka, Minnesota, USA.
¹¹ Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA.
¹² Department of Medicine, Olive View-University of California, Los Angeles, California, USA.
¹³ Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA.
¹⁴ Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁵ Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁶ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁷ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁸ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁹ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 38690892
PMCID: PMC11327787 (available on 2025-05-01)
DOI: 10.1093/cid/ciae159

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.

© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Conflict of interest statement

Potential conflicts of interest. J. B. B. reports contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support by NIH, PCORI, Bayer, Boehringer-Ingelheim, Carmot, Corcept, Dexcom, Eli Lilly, Insulet, MannKind, Novo Nordisk, and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, Aqua Medical Inc, AstraZeneca, Boehringer-Ingelheim, CeQur, Corcept Therapeutics, Eli Lilly, embecta, GentiBio, Glyscend, Insulet, Mellitus Health, Metsera, Moderna, Novo Nordisk, Pendulum Therapeutics, Praetego, Stability Health, Tandem, Terns Inc, and Vertex.; personal compensation for expert testimony from Medtronic MiniMed; participation on advisory boards for Altimmune, AstraZeneca, and Insulet; a leadership role for the Association of Clinical and Translational Science; and stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, Praetego, and Stability Health. M. A. P. receives consulting fees from Opticyte and Cytovale. A. B. K. has served as an external consultant for Roche Diagnostics; received speaker honoraria from Siemens Healthcare Diagnostics, the American Kidney Fund, the National Kidney Foundation, the American Society of Nephrology, and Yale University Department of Laboratory Medicine; research support unrelated to this work from Siemens Healthcare Diagnostics, Kyowa Kirin Pharmaceutical Development, the Juvenile Diabetes Research Foundation, and the NIH; support for travel from College of American Pathologists Point-Of-Care Testing Committee; participation on an advisory board for the Minnesota Newborn Screening Advisory Committee; grants from NIH and JDRF for multiple unrelated clinical research projects and Kyowa Kirin Pharmaceutical Development and Siemens Healthcare Diagnostics for unrelated clinical research studies; and leadership roles for the American Board of Clinical Chemistry, Association for Diagnostics and Laboratory Medicine (ADLM) Evidence-Based Laboratory Medicine Subcommittee, and ADLM Academy Test Utilization Committee. M. R. R. reports consulting fees from 20/20 Gene Systems for coronavirus disease 2019 testing. D. B. R. reports grants from the NIH NCATS ACTIV-6 Steering Committee Chair. K. C. reports stock or stock options for United Health Group. C. T. B. reports consulting fees from NCATS/DCRI and the ACTIV-6 Executive Committee and support for travel from Academic Medical Education. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Comment in

Repurposing Revisited: Exploring the Role of Metformin for Treatment of COVID-19.
Siedner MJ, Sax PE. Siedner MJ, et al. Clin Infect Dis. 2024 Aug 16;79(2):292-294. doi: 10.1093/cid/ciae154. Clin Infect Dis. 2024. PMID: 38690870 No abstract available.

Cited by

Mechanisms of long COVID and the path toward therapeutics.
Peluso MJ, Deeks SG. Peluso MJ, et al. Cell. 2024 Oct 3;187(20):5500-5529. doi: 10.1016/j.cell.2024.07.054. Epub 2024 Sep 25. Cell. 2024. PMID: 39326415 Review.
Prevalent Metformin Use in Adults With Diabetes and the Incidence of Long COVID: An EHR-Based Cohort Study From the RECOVER Program.
Johnson SG, Abedian S, Stürmer T, Huling JD, Lewis V C, Buse JB, Brosnahan SB, Mudumbi PC, Erlandson KM, McComsey GA, Arnold J, Wiggen TD, Wong R, Murphy S, Rosen C, Kaushal R, Weiner MG, Bramante C; RECOVER PCORnet EHR Cohort and the N3C Consortium. Johnson SG, et al. Diabetes Care. 2024 Nov 1;47(11):1930-1940. doi: 10.2337/DCa24-0032. Diabetes Care. 2024. PMID: 39287394
Repurposing existing drugs for the treatment ofCOVID-19/SARS-CoV-2: A review of pharmacological effects and mechanism of action.
Liang Y, Quan X, Gu R, Meng Z, Gan H, Wu Z, Sun Y, Pan H, Han P, Liu S, Dou G. Liang Y, et al. Heliyon. 2024 Aug 11;10(16):e35988. doi: 10.1016/j.heliyon.2024.e35988. eCollection 2024 Aug 30. Heliyon. 2024. PMID: 39247343 Free PMC article. Review.

References

1. Bramante CT, Huling JD, Tignanelli CJ, et al. . Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. New Engl J Med 2022; 387:599–610. - PMC - PubMed
1. Castle BT, Dock C, Hemmat M, et al. Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets. bioRxiv 111237 [Preprint]. June 16, 2020. Available from: 10.1101/2020.05.22.111237. - DOI
1. Gordon DE, Jang GM, Bouhaddou M, et al. . A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020; 583:459–68. - PMC - PubMed
1. Schaller MA, Sharma Y, Dupee Z, et al. . Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses. JCI Insight 2021; 6:e148003. - PMC - PubMed
1. Howell JJ, Hellberg K, Turner M, et al. . Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab 2017; 25:463–71. - PMC - PubMed

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[1] Bramante CT, Huling JD, Tignanelli CJ, et al. . Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. New Engl J Med 2022; 387:599–610. - PMC - PubMed

[2] Bramante CT, Huling JD, Tignanelli CJ, et al. . Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. New Engl J Med 2022; 387:599–610. - PMC - PubMed

[3] Castle BT, Dock C, Hemmat M, et al. Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets. bioRxiv 111237 [Preprint]. June 16, 2020. Available from: 10.1101/2020.05.22.111237. - DOI

[4] Castle BT, Dock C, Hemmat M, et al. Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets. bioRxiv 111237 [Preprint]. June 16, 2020. Available from: 10.1101/2020.05.22.111237. - DOI

[5] Gordon DE, Jang GM, Bouhaddou M, et al. . A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020; 583:459–68. - PMC - PubMed

[6] Gordon DE, Jang GM, Bouhaddou M, et al. . A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020; 583:459–68. - PMC - PubMed

[7] Schaller MA, Sharma Y, Dupee Z, et al. . Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses. JCI Insight 2021; 6:e148003. - PMC - PubMed

[8] Schaller MA, Sharma Y, Dupee Z, et al. . Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses. JCI Insight 2021; 6:e148003. - PMC - PubMed

[9] Howell JJ, Hellberg K, Turner M, et al. . Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab 2017; 25:463–71. - PMC - PubMed

[10] Howell JJ, Hellberg K, Turner M, et al. . Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab 2017; 25:463–71. - PMC - PubMed

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

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

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