Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial

Abstract

Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.^1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.⁴ Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.⁵ In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.^6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.^8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log₁₀ copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.^10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,¹² well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.

Figure 1.. Effect of metformin versus placebo on viral load over time, detectable viral load, and rebound viral load.

Panel A: adjusted mean change in log10 copies per ml (viral load) from baseline (Day 1) to Day 5 and Day 10 for metformin (blue) and placebo (red). Mean change estimates are based on the adjusted, multiply imputed Tobit analysis (the primary analytic approach) corresponding to the overall metformin analysis presented in Figure 2. Panel B: adjusted percent of viral load samples that were detectable at Day 1, 5, and 10. The percent viral load detected estimates were based on the adjusted, multiply imputed logistic GEE analysis corresponding to the overall metformin analysis depicted in Figure 3. Odds ratios correspond to adjusted effects on the odds ratio scale. Panel C: stacked bar chart depicting the adjusted 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.

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 to control on log10 copies per ml (viral load), overall and at Days 5 and 10. “Viral Effect*” denotes the adjusted mean change in viral load in log10 copies per ml 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 three rows show ivermectin, the next three rows show fluvoxamine, and the following three show metformin. Below these, the effect of metformin compared to placebo is shown by a priori subgroups of baseline characteristics.

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 to 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 GEE analytic approach. The top three rows show ivermectin, the next three rows show fluvoxamine, and the following three show metformin. Below these, the effect of metformin compared to placebo is shown by a priori subgroups of baseline characteristics.