Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19
Carolyn T. Bramante, Kenneth B. Beckman, Tanvi Mehta, Amy B. Karger, David J. Odde, Christopher J. Tignanelli, John B. Buse, Darrell M. Johnson, Ray Watson, Jerry J Daniel, David Liebovitz, Jacinda M. Nicklas, Ken Cohen, Michael A. Puskarich, Hrishikesh Belani, Lianne Siegel, Nichole R. Klatt, Blake Anderson, Katrina M Hartman, Via Rao, Aubrey A Hagen, Barkha Patel, Sarah L. Fenno, Nandini Avula, Neha V Reddy, Spencer M Erickson, Regina Fricton, Samuel Lee, Gwendolyn Griffiths, Matthew F Pullen, Jennifer L. Thompson, Nancy E. Sherwood, Thomas A. Murray, Michael R. Rose, David R. Boulware, Jared D. Huling, COVID-OUT Study Team, Blake Anderson, Riannon C Atwater, Nandini Avula, Kenny Beckman, Hrishikesh Belani, David R. Boulware, Carolyn T. Bramante, Jannis Brea, Courtney A. Broedlow, John B. Buse, Paula Campora, Anup P. Challa, Jill Charles, Grace M. Christensen, Theresa Christiansen, Ken Cohen, Bo Connelly, Srijani Datta, Nikita Deng, Alex T Dunn, Spencer M Erickson, Faith M Fairbairn, Sarah L. Fenno, D Fraser, Regina Fricton, Gwen Griffiths, Aubrey A Hagen, Katrina M Hartman, Audrey Hendrickson, Jared D. Huling, Nicholas E. Ingraham, Arthur Jeng, Darrell M Johnson, Amy B. Karger, Nichole R Klatt, Erik A Kuehl, Derek LaBar, Samuel Lee, David Liebovitz, Sarah Lindberg, Darlette Luke, Rosario Machicado, Zeinab Mohamud, Thomas A. Murray, Rumbidzai Ngonyama, Jacinda M Nicklas, David J. Odde, Elliott Parrens, Daniela Parra, Barkha Patel, Jennifer Proper, Matthew F Pullen, Michael A. Puskarich, Via Rao, Neha V Reddy, Naveen Reddy, Katelyn Rypka, Hanna G Saveraid, Paula Seloadji, Arman A. Shahriar, Nancy E. Sherwood, Jamie L Siegart, Lianne Siegel
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.