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

Clin Infect Dis. 2024 Aug 16;79(2):354-363. doi: 10.1093/cid/ciae159.

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.

Keywords: long COVID; mTOR; metformin; outpatient COVID-19 treatment; viral load.

Publication types

  • Randomized Controlled Trial

MeSH terms

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

Substances

  • Metformin
  • Antiviral Agents
  • Ivermectin
  • Fluvoxamine

Associated data

  • ClinicalTrials.gov/NCT04510194