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

Publisher: Oxford University Press Country of Publication: United States NLM ID: 9203213 Publication Model: Print Cited Medium: Internet ISSN: 1537-6591 (Electronic) Linking ISSN: 10584838 NLM ISO Abbreviation: Clin Infect Dis Subsets: MEDLINE

Publication: Jan. 2011- : Oxford : Oxford University Press
Original Publication: Chicago, IL : The University of Chicago Press, c1992-

Metformin*/therapeutic use ; Metformin*/pharmacology ; Viral Load*/drug effects ; SARS-CoV-2*/drug effects ; COVID-19 Drug Treatment* ; Antiviral Agents*/therapeutic use ; Antiviral Agents*/pharmacology ; COVID-19*/virology; Humans ; Male ; Female ; Middle Aged ; Double-Blind Method ; Adult ; Ivermectin/therapeutic use ; Ivermectin/pharmacology ; Fluvoxamine/therapeutic use ; Fluvoxamine/pharmacology ; Aged

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.
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K23 DK124654-01-A1 United States NH NIH HHS; OT2HL156812 National Heart, Lung, and Blood Institute of the NIH; UL1 TR002494 United States TR NCATS NIH HHS; Institute for Engineering in Medicine; Minnesota's Rainwater Foundation Grant; OT2 HL161847 United States HL NHLBI NIH HHS; Fast Grants; K23 HL133604 United States HL NHLBI NIH HHS; Olive View-; Edenbridge Pharmacy; Education and Research Institute; OT2 HL156812 United States HL NHLBI NIH HHS; INV-017069 United States GATES Bill & Melinda Gates Foundation; K23 DK124654 United States DK NIDDK NIH HHS; KL2 TR002492 United States TR NCATS NIH HHS; P01 CA254849 United States CA NCI NIH HHS; OT2HL161847 NIH RECOVER; National Cancer Institute of the NIH; Subaward of the University; Rainwater Charitable Foundation; T32HL129956 National Heart, Lung, and Blood Institute of the NIH; Leidos Biomedical; Apotex Pharmacy; 00086722 Minnesota Partnership for Biotechnology and Medical Genomics; KL2TR002492 UnitedHealth Group Foundation; Parsemus Foundation; R21 LM012744 United States LM NLM NIH HHS; U54 CA210190 United States CA NCI NIH HHS

Investigator: B Anderson; RC Atwater; N Avula; KB Beckman; HK Belani; DR Boulware; CT Bramante; J Brea; CA Broedlow; JB Buse; P Campora; A Challa; J Charles; G Christensen; T Christiansen; K Cohen; B Connelly; S Datta; N Deng; AT Dunn; SM Erickson; FM Fairbairn; SL Fenno; DJ Fraser; RD Fricton; G Griffiths; AA Hagen; KM Hartman; AF Hendrickson; JD Huling; NE Ingraham; AC Jeng; DM Johnson; AB Karger; NR Klatt; EA Kuehl; DD LaBar; S Lee; DM Liebovitz; S Lindberg; DG Luke; R Machicado; Z Mohamud; TA Murray; R Ngonyama; JM Nicklas; DJ Odde; E Parrens; D Parra; B Patel; JL Proper; MF Pullen; MA Puskarich; V Rao; NV Reddy; N Reddy; KJ Rypka; HG Saveraid; P Seloadji; A Shahriar; N Sherwood; JL Siegart; LK Siegel; L Simmons; I Sinelli; P Singh; A Snyder; MT Stauffer; J Thompson; CJ Tignanelli; TL Tople; WJ Tordsen; RHB Watson; B Wu; A Zaman; MR Zolik; L Zinkl
Keywords: long COVID; mTOR; metformin; outpatient COVID-19 treatment; viral load

ClinicalTrials.gov NCT04510194

9100L32L2N (Metformin)
0 (Antiviral Agents)
70288-86-7 (Ivermectin)
O4L1XPO44W (Fluvoxamine)

Date Created: 20240501 Date Completed: 20240816 Latest Revision: 20240818

20240818

PMC11327787

10.1093/cid/ciae159

38690892