Metformin has an antiviral activity against RNA viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism of antiviral activity of metformin against RNA viruses appears to be the suppression of protein translation via targeting the host mechanistic target of the rapamycin pathway. However, the authors suggested that metformin has pleiotropic effects and has other actions, important for COVID-19 pathophysiology. Two randomized, placebo-controlled studies conducted by American authors, investigated the risk of long COVID syndrome and the reduction of viral load in outpatients infected with SARS-CoV-2 and treated with metformin, ivermectin, or fluvoxamine. The results show that metformin significantly reduces the viral load of SARS-CoV-2 and the incidence of long COVID syndrome.
SARS-CoV-2 infection can result in the post-COVID-19 or long COVID syndrome. The spectrum of long COVID is diverse, ranging from a single symptom to extensive multiorgan involvement, and from mild to chronically debilitating. The proportion of adults with SARS-CoV-2 infection who are diagnosed with long COVID by healthcare professionals is still poorly described.
The first study
The first randomized, placebo-controlled, quadruple-blind, phase 3 trial (COVID-OUT) had two objectives, to evaluate whether metformin, ivermectin, or fluvoxamine can prevent severe forms of COVID-19 within the first two weeks after infection with SARS-CoV-2, and to investigate whether outpatient treatment with metformin, ivermectin, or fluvoxamine shortly after infection can reduce the risk of long COVID syndrome over long-term follow-up.Â
The study was conducted at six locations in the United States. The SARS-CoV-2 infection was confirmed by a positive polymerase chain reaction (PCR) or antigen test within three days. All participants had COVID-19 symptoms for less than seven days before enrollment. On days 180, 210, 240, 270, and 300 participants were asked if they had been diagnosed with a long COVID. 1126 individuals completed at least one survey for long COVID on day 180. Of 1126 people, 56% were women and 44% were men.Â
Women who were pregnant or lactating were not excluded. They were randomly assigned to receive metformin or placebo and were not assigned to fluvoxamine or ivermectin. The authors noted that there is a substantial body of scientific literature supporting the safety of metformin during pregnancy and lactation, but, there is less safety data for fluvoxamine or ivermectin.
The vaccination against SARS-CoV-2 was not a criterion for exclusion. Before enrollment, 55% of 1126 participants had received a primary SARS-CoV-2 vaccine, including 5% who received an initial 2021 monovalent booster.
Metformin was administered to 564 participants and matched placebo to 562. Metformin dose was titrated over six days: 500 mg on day one, 500 mg twice daily on days two to five, then, 500 mg in the morning and 1000 mg in the evening until day 14.
Ivermectin was administered to 361 individuals and matched placebo to 378. The dose of ivermectin was 390 to 470 μg/kg per day for three days (median 430 μg/kg per day). Fluvoxamine was administered to 297 individuals and matched placebo to 298. The dose of fluvoxamine was 50 mg on day one, followed by 50 mg twice daily until day 14. The study drugs were all taken orally in tablet form.
Results
By day 300, 8.3% of 1126 participants were diagnosed with long COVID (11% of women and 5% of men). The mean incidence of long COVID was 7.9% during the alpha-dominant period, 8·3% during the delta-dominant period, and 8·4% during the omicron-dominant period.
By day 14, metformin reduced the risk of emergency department visits, hospitalizations, and death due to COVID-19 by 42.3% compared to placebo. Furthermore, by day 28, participants who received metformin were less likely to be hospitalized than those who received a placebo. Ivermectin and fluvoxamine had no significant effect on severe COVID-19 outcomes by day 14.
By day 300, the cumulative incidence of long COVID syndrome was 6.3% in the group who received metformin and 10.4% in those who received matched placebo. Early outpatient treatment with metformin decreased the incidence of long COVID syndrome by approximately 41%, with an absolute reduction of 4.1%, compared to placebo. When treatment with metformin was started less than four days after the onset of COVID-19 symptoms, the effect on reducing the risk of long COVID syndrome was potentially greater than when treatment with metformin was started four days or more after the onset of symptoms.
Ivermectin and fluvoxamine had no significant effect on the incidence of long COVID syndrome. By day 300, the cumulative incidence of long COVID was 7.7% in participants who received ivermectin, 8.1% in individuals who received a matched placebo, 10.1% in participants who received fluvoxamine, and 7.5% in those who received a matched placebo.
The authors stated that they would not recommend starting metformin therapy without a multiple-day dose titration. In this trial, the dose was titrated over six days. Safety concerns for metformin have been focused on the risk of lactic acidosis. Several large studies and Cochrane reviews have shown no increased risk of lactic acidosis in people receiving metformin compared to controls. Metformin prevents hepatic gluconeogenesis and does not decrease blood glucose concentration, therefore, the risk of hypoglycemia is low, even in people without diabetes. Metformin has also been shown to be safe for children and for women who are pregnant or lactating.
This article was published in the Lancet Infectious Disease.
Journal Reference
Bramante CT et al. Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomized, quadruple-blind, parallel-group, phase 3 trial. Lancet Infect Dis 2023, Published Online June 8, 2023. (Open Access)Â https://doi.org/10.1016/S1473-3099(23)00299-2
The second study
In this randomized, placebo-controlled double-blind trial, the authors evaluated the effect of outpatient treatment with metformin, fluvoxamine, and ivermectin on viral load in individuals infected with SARS-CoV-2. Viral load was quantified using rtPCR for SARS-CoV-2.
The trial included 999 participants who self-collected anterior nasal swabs on day one (n = 945), day five (n = 871), and day ten (n = 775).
Results
The mean viral load of SARS-CoV-2 was 3.6-fold lower in the group treated with metformin than in the placebo group. Viral rebound, defined as a higher viral load on day 10 than on day 5, was less frequent with metformin (3.28%) than with placebo. The effect of metformin was consistent across subgroups and increased over time.
In contrast, neither ivermectin nor fluvoxamine demonstrated any beneficial effect over placebo.
This article was published in Clinical Infectious Diseases.
Journal Reference
Bramante CT, Beckman KB, Mehta T, Karger AB, Odde DJ, Tignanelli CJ, et al. 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, Clinical Infectious Diseases, 2024; ciae159. https://doi.org/10.1093/cid/ciae159
Conclusion
Two randomized, placebo-controlled trials showed that metformin reduced SARS-CoV-2 viral load and decreased long COVID syndrome incidence. The authors of the first study emphasized that this trial did not prove whether metformin would be effective in preventing long COVID if treatment started during COVID-19 hospitalization, or as a treatment for people who were diagnosed with long COVID. They stated that prospective and interventional studies should assess the incidence of long COVID in vaccinated individuals or those previously infected with SARS-CoV-2 for all therapeutic approaches.
