Metformin has an antiviral activity against RNA viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the first randomized, placebo-controlled, phase 3 trial, conducted by American authors, metformin showed a beneficial effect in individuals with COVID-19 and reduced the incidence of long COVID syndrome. The most recent randomized, placebo-controlled trial, also conducted by the American authors, showed that outpatient treatment with metformin significantly reduced the viral load of SARS-CoV-2.
The mechanism of antiviral activity of metformin against RNA viruses, including SARS-CoV-2, 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.
SARS-CoV-2 infection can result in the post-COVID-19 condition, commonly referred to as 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. In follow-up surveys on days 180, 210, 240, 270, and 300, participants were questioned if they had been diagnosed with a long COVID.
The study was conducted at six locations in the United States and included 1126 individuals who completed at least one survey for long COVID on day 180. The SARS-CoV-2 infection was confirmed by a positive polymerase chain reaction or antigen test within three days, and participants had COVID-19 symptoms for less than seven days before enrollment. Out of 1126 people, 56% were women and 44% were men. The trial included adults aged 30–85 years, and the median BMI was 29,8 kg/m2.
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.
Participants were randomly assigned to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Metformin was administered to 564 participants and matched placebo to 562. The dose of metformin 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.
Metformin showed a beneficial effect in COVID-19. By day 14, metformin reduced the risk of emergency department visits, hospitalizations, and death due to COVID-19 by 42.3% in comparison to placebo. Furthermore, by day 28, participants who received metformin were also less likely to be hospitalized than those who received a placebo. However, ivermectin and fluvoxamine did not reduce 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 reduced 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 said, based on the TogetherTrial, 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 those not receiving metformin. The authors noted that metformin prevents hepatic gluconeogenesis, and does not decrease blood glucose concentration. Therefore, the risk of hypoglycemia is very low, even in people without diabetes. Metformin has also been shown to be safe for children and for women who are pregnant or lactating.
The researchers emphasized that this COVID-OUT trial does not prove whether metformin would be effective in preventing long COVID if treatment started at time of COVID-19 hospitalization, or as a treatment for people who already have long COVID. As the COVID-19 pandemic continues to evolve, prospective and interventional studies are needed for all therapeutic approaches to assess the incidence of long COVID and to include individuals who have received vaccination and booster vaccination or were previously infected with SARS-CoV-2.
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) https://doi.org/10.1016/S1473-3099(23)00299-2
The second study
In this randomized, placebo-controlled double-blind trial (COVID-OUT), 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 reverse-transcription quantitative polymerase chain reaction.
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 results showed that the mean viral load of SARS-CoV-2 was reduced by 3.6-fold in the group treated with metformin in comparison to the placebo group. On day 5 or day 10, those who received metformin were less likely to have a detectable viral load than those who received a placebo. 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
