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

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.

Figure 1.

Effect of metformin versus placebo on viral load over time, detectable viral load, and rebound viral load. A, Adjusted mean change in log10 copies per milliliter (viral load) from baseline (day 1) to day 5 and day 10 for metformin (lower line) and placebo (upper line). Mean change estimates are based on the adjusted, multiply imputed Tobit analysis (the primary analytic approach) that corresponds to the overall metformin analysis presented in Figure 2. B, Adjusted percent of viral load samples that were detectable at day 1, day 5, and day 10. The percent viral load detected estimates were based on the adjusted, multiply imputed logistic generalized estimating equations (GEE) analysis corresponding to the overall metformin analysis depicted in Figure 3. Odds ratios correspond to adjusted effects on the odds ratio scale. C, Bar chart depicting the percent of participants whose day 10 viral load was greater than the day 5 viral load and the odds ratio for having viral load rebound using the multiply imputed logistic GEE. Abbreviation: CI, confidence interval.

Figure 2.

Overall results for metformin, ivermectin, and fluvoxamine on viral load; heterogeneity of treatment effect of metformin versus placebo. This is a forest plot that depicts the effect of active medication compared with control on log10 copies per milliliter (viral load), overall, and at day 5 and day 10. Viral Effect* denotes the adjusted mean change in viral load in log10 copies per milliliter with 95% confidence intervals for the adjusted mean change. Analyses were conducted using the primary analytic approach, a multiply imputed Tobit model. The vertical dashed line indicates the value for a null effect. The top 3 rows show ivermectin, the next 3 rows show fluvoxamine, and the following 3 rows show metformin. Below these, the effect of metformin compared with placebo is shown by a priori subgroups of baseline characteristics. Abbreviation: CI, confidence interval.

Figure 3.

Overall results for metformin, ivermectin, and fluvoxamine on detectability of viral load; heterogeneity of treatment effect of metformin versus placebo. This is a forest plot that depicts the effect of active medication compared with control on the proportion of participants with a detectable viral load, overall and at days 5 and 10. Estimate* denotes the adjusted mean risk difference in the percent of samples with detected viral load with 95% confidence intervals for the adjusted risk difference. The vertical dashed line indicates the value for a null effect. The estimated risk differences are derived from the adjusted, multiply imputed logistic generalized estimating equations (GEE) analytic approach. The top 3 rows show ivermectin, the next 3 rows show fluvoxamine, and the following 3 rows show metformin. Below these, the effect of metformin compared with placebo is shown by a priori subgroups of baseline characteristics. Abbreviation: CI, confidence interval.

Figure 4.

Overview of results from the COVID-OUT trial. This is a forest plot that combines the severe, acute coronavirus disease 2019 outcome as well as the long-term follow-up outcome from the COVID-OUT trial [1, 12]. Two a priori subgroups from the COVID-OUT trial are also presented: pregnant individuals and those who started the study drug within 4 days of symptom onset, to match the primary analytic sample of other antivirals. Abbreviations: COVID-19, coronavirus disease 2019; ITT, intention to treat; mITT, modified intention to treat; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.