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

Autor:	Bramante CT; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Beckman KB; Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA., Mehta T; Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Karger AB; Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA., Odde DJ; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA., Tignanelli CJ; Department of Surgery, Medical School, University of Minnesota, Minneapolis, Minnesota, USA., Buse JB; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA., Johnson DM; Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA., Watson RHB; Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA., Daniel JJ; Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA., Liebovitz DM; General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Nicklas JM; General Internal Medicine, University of Colorado, School of Medicine, Aurora, Colorado, USA., Cohen K; UnitedHealth Group, Optum Labs, Minnetonka, Minnesota, USA., Puskarich MA; Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA., Belani HK; Department of Medicine, Olive View-University of California, Los Angeles, California, USA., Siegel LK; Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Klatt NR; Department of Surgery, Medical School, University of Minnesota, Minneapolis, Minnesota, USA., Anderson B; Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA.; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA., Hartman KM; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Rao V; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Hagen AA; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Patel B; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Fenno SL; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Avula N; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Reddy NV; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Erickson SM; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Fricton RD; General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Lee S; General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Griffiths G; General Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Pullen MF; Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Thompson JL; Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Sherwood NE; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Murray TA; Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Rose MR; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Boulware DR; Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Huling JD; Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Jazyk:	angličtina
Zdroj:	Clinical infectious diseases : an official publication of the Infectious Diseases Society of America [Clin Infect Dis] 2024 Aug 16; Vol. 79 (2), pp. 354-363.
DOI:	10.1093/cid/ciae159
Abstrakt:	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. Competing Interests: 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. (© 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. 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Databáze:	MEDLINE
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