Article
作者: Patel, Barkha ; Wu, Beiqing ; Erickson, Spencer M ; Stauffer, Maxwell T ; Fenno, Sarah L ; Christensen, Grace ; Belani, Hrishikesh K ; Dunn, Alex T ; Hartman, Katrina M ; Puskarich, Michael A ; Campora, Paula ; Tople, Tannon L ; Bramante, Carolyn T ; Anderson, Blake ; Watson, Ray HB ; Lindberg, Sarah ; Griffiths, Gwen ; Connelly, Bo ; Pullen, Matthew F ; Shahriar, Arman ; Daniel, Jerry J ; LaBar, Derek D ; Beckman, Kenneth B ; Broedlow, Courtney A ; Klatt, Nichole R ; Sinelli, Isabella ; Rose, Michael R ; Thompson, Jennifer ; Jeng, Arthur C ; Boulware, David R ; Hagen, Aubrey A ; Nicklas, Jacinda M ; Brea, Jannis ; Saveraid, Hanna G ; Charles, Jill ; Ingraham, Nicholas E ; Simmons, Lucas ; Hendrickson, Audrey F ; Tordsen, Walker J ; Deng, Nikita ; Zinkl, Lena ; Odde, David J ; Lee, Samuel ; Watson, Ray H B ; Griffiths, Gwendolyn ; Luke, Darlette G ; Karger, Amy B ; Snyder, Andrew ; Siegart, Jamie L ; Fraser, Daniel J ; Thompson, Jennifer L ; Avula, Nandini ; Cohen, Ken ; Fairbairn, Faith M ; Sherwood, Nancy E ; Atwater, Riannon C ; Reddy, Neha V ; Mehta, Tanvi ; Ngonyama, Rumbidzai ; Zolik, Madeline R ; Rao, Via ; Mohamud, Zeinab ; Zaman, Adnin ; Datta, Srijani ; Johnson, Darrell M ; Liebovitz, David M ; Parra, Daniela ; Christiansen, Theresa ; Buse, John B ; Kuehl, Erik A ; Proper, Jennifer L ; Singh, Palak ; Siegel, Lianne K ; Huling, Jared D ; Rypka, Katelyn J ; Tignanelli, Christopher J ; Sherwood, Nancy ; Seloadji, Paula ; Murray, Thomas A ; Machicado, Rosario ; Reddy, Naveen ; Beckman, Kenny B ; Parrens, Elliott ; Fricton, Regina D ; Challa, Anup
AbstractBackgroundMetformin 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%.MethodsCOVID-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.ResultsThe 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.ConclusionsIn 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 RegistrationNCT04510194.