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