Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19
Authors: Bramante Carolyn T , Beckman Kenneth B , Mehta Tanvi , Karger Amy B , Odde David J , Tignanelli Christopher J , Buse John B , Johnson Darrell M , Watson Ray H B , Daniel Jerry J , Liebovitz David M , Nicklas Jacinda M , Cohen Ken , Puskarich Michael A , Belani Hrishikesh K , Siegel Lianne K , Klatt Nichole R , Anderson Blake , Hartman Katrina M , Rao Via , Hagen Aubrey A , Patel Barkha , Fenno Sarah L , Avula Nandini , Reddy Neha V , Erickson Spencer M , Fricton Regina D , Lee Samuel , Griffiths Gwendolyn , Pullen Matthew F , Thompson Jennifer L , Sherwood Nancy E , Murray Thomas A , Rose Michael R , Boulware David R , Huling Jared D ,   COVID-OUT Study Team, Anderson Blake , Atwater Riannon C , Avula Nandini , Beckman Kenny B , Belani Hrishikesh K , Boulware David R , Bramante Carolyn T , Brea Jannis , Broedlow Courtney A , Buse John B , Campora Paula , Challa Anup , Charles Jill , Christensen Grace , Christiansen Theresa , Cohen Ken , Connelly Bo , Datta Srijani , Deng Nikita , Dunn Alex T , Erickson Spencer M , Fairbairn Faith M , Fenno Sarah L , Fraser Daniel J , Fricton Regina D , Griffiths Gwen , Hagen Aubrey A , Hartman Katrina M , Hendrickson Audrey F , Huling Jared D , Ingraham Nicholas E , Jeng Arthur C , Johnson Darrell M , Karger Amy B , Klatt Nichole R , Kuehl Erik A , LaBar Derek D , Lee Samuel , Liebovitz David M , Lindberg Sarah , Luke Darlette G , Machicado Rosario , Mohamud Zeinab , Murray Thomas A , Ngonyama Rumbidzai , Nicklas Jacinda M , Odde David J , Parrens Elliott , Parra Daniela , Patel Barkha , Proper Jennifer L , Pullen Matthew F , Puskarich Michael A , Rao Via , Reddy Neha V , Reddy Naveen , Rypka Katelyn J , Saveraid Hanna G , Seloadji Paula , Shahriar Arman , Sherwood Nancy , Siegart Jamie L , Siegel Lianne K , Simmons Lucas , Sinelli Isabella , Singh Palak , Snyder Andrew , Stauffer Maxwell T , Thompson Jennifer , Tignanelli Christopher J , Tople Tannon L , Tordsen Walker J , Watson Ray H B , Wu Beiqing , Zaman Adnin , Zolik Madeline R , Zinkl Lena 
Published: May 2024

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.