tetano
Editor, Senior Moderator
Clin Infect Dis
. 2024 May 1:ciae159.
doi: 10.1093/cid/ciae159. Online ahead of print. Favorable Antiviral Effect of Metformin on Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of Coronavirus Disease 2019
Carolyn T Bramante[SUP] 1 [/SUP], Kenneth B Beckman[SUP] 2 [/SUP], Tanvi Mehta[SUP] 3 [/SUP], Amy B Karger[SUP] 4 [/SUP], David J Odde[SUP] 5 [/SUP], Christopher J Tignanelli[SUP] 6 [/SUP], John B Buse[SUP] 7 [/SUP], Darrell M Johnson[SUP] 2 [/SUP], Ray H B Watson[SUP] 2 [/SUP], Jerry J Daniel[SUP] 2 [/SUP], David M Liebovitz[SUP] 8 [/SUP], Jacinda M Nicklas[SUP] 9 [/SUP], Ken Cohen[SUP] 10 [/SUP], Michael A Puskarich[SUP] 11 [/SUP], Hrishikesh K Belani[SUP] 12 [/SUP], Lianne K Siegel[SUP] 3 [/SUP], Nichole R Klatt[SUP] 6 [/SUP], Blake Anderson[SUP] 13 14 [/SUP], Katrina M Hartman[SUP] 1 [/SUP], Via Rao[SUP] 1 [/SUP], Aubrey A Hagen[SUP] 1 [/SUP], Barkha Patel[SUP] 1 [/SUP], Sarah L Fenno[SUP] 1 [/SUP], Nandini Avula[SUP] 1 [/SUP], Neha V Reddy[SUP] 1 [/SUP], Spencer M Erickson[SUP] 1 [/SUP], Regina D Fricton[SUP] 8 [/SUP], Samuel Lee[SUP] 8 [/SUP], Gwendolyn Griffiths[SUP] 1 [/SUP], Matthew F Pullen[SUP] 15 [/SUP], Jennifer L Thompson[SUP] 16 [/SUP], Nancy E Sherwood[SUP] 17 [/SUP], Thomas A Murray[SUP] 3 [/SUP], Michael R Rose[SUP] 18 19 [/SUP], David R Boulware[SUP] 15 [/SUP], Jared D Huling[SUP] 3 [/SUP]; COVID-OUT Study Team
Collaborators, Affiliations
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.
. 2024 May 1:ciae159.
doi: 10.1093/cid/ciae159. Online ahead of print. Favorable Antiviral Effect of Metformin on Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of Coronavirus Disease 2019
Carolyn T Bramante[SUP] 1 [/SUP], Kenneth B Beckman[SUP] 2 [/SUP], Tanvi Mehta[SUP] 3 [/SUP], Amy B Karger[SUP] 4 [/SUP], David J Odde[SUP] 5 [/SUP], Christopher J Tignanelli[SUP] 6 [/SUP], John B Buse[SUP] 7 [/SUP], Darrell M Johnson[SUP] 2 [/SUP], Ray H B Watson[SUP] 2 [/SUP], Jerry J Daniel[SUP] 2 [/SUP], David M Liebovitz[SUP] 8 [/SUP], Jacinda M Nicklas[SUP] 9 [/SUP], Ken Cohen[SUP] 10 [/SUP], Michael A Puskarich[SUP] 11 [/SUP], Hrishikesh K Belani[SUP] 12 [/SUP], Lianne K Siegel[SUP] 3 [/SUP], Nichole R Klatt[SUP] 6 [/SUP], Blake Anderson[SUP] 13 14 [/SUP], Katrina M Hartman[SUP] 1 [/SUP], Via Rao[SUP] 1 [/SUP], Aubrey A Hagen[SUP] 1 [/SUP], Barkha Patel[SUP] 1 [/SUP], Sarah L Fenno[SUP] 1 [/SUP], Nandini Avula[SUP] 1 [/SUP], Neha V Reddy[SUP] 1 [/SUP], Spencer M Erickson[SUP] 1 [/SUP], Regina D Fricton[SUP] 8 [/SUP], Samuel Lee[SUP] 8 [/SUP], Gwendolyn Griffiths[SUP] 1 [/SUP], Matthew F Pullen[SUP] 15 [/SUP], Jennifer L Thompson[SUP] 16 [/SUP], Nancy E Sherwood[SUP] 17 [/SUP], Thomas A Murray[SUP] 3 [/SUP], Michael R Rose[SUP] 18 19 [/SUP], David R Boulware[SUP] 15 [/SUP], Jared D Huling[SUP] 3 [/SUP]; COVID-OUT Study Team
Collaborators, Affiliations
- PMID: 38690892
- DOI: 10.1093/cid/ciae159
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.