The University of Minnesota led the COVID-OUT clinical trial that finished enrolling participants in 2022. It was a large rigorous study to understand if common, inexpensive medicines (metformin, fluvoxamine or ivermectin) prevented severe COVID-19 infection and Long Covid symptoms. The initial results on the impact of the treatments on COVID-19 were published in the New England Journal of Medicine.  The results of the analysis of Long COVID was published in The Lancet Infectious Diseases and viral load results are available as a preprint.

The main findings were that metformin reduced emergency room visits, hospitalization, or death from COVID-19 infection by 42%. When taken immediately after symptoms, metformin reduced serious outcomes by over 50%.

There was also a 41% decrease in the incidence of Long Covid when metformin was taken shortly after COVID-19 infection. When taken within four days of symptoms, metformin reduced Long COVID by 63%. Ivermectin and low-dose fluvoxamine did not improve outcomes of COVID-19 or Long Covid.

Further analyses indicated that metformin (but not ivermectin or fluvoxamine) had anti-viral effects. Metformin decreased the amount of COVID-19 virus (SARS-CoV-2) 3.6 fold.

From the university’s press release: “We are pleased to contribute to the body of knowledge around COVID-19 therapies in general, with treatments that are widely available,” said Carolyn Bramante, MD, principal investigator of the study and an assistant professor of internal medicine and pediatrics at the University of Minnesota Medical School.

Metformin is the first COVID treatment proven to reduce serious outcomes of COVID-19 infection, reduce Long COVID  incidence, and lower the level of the COVID-19 virus. It is safe, accessible and low-cost. Metformin is also one of the most commonly prescribed medications in the United States and globally, taken by more than 150 million people each year. This medication should be considered as the first globally-available treatment for COVID-19.

Additional facts about the study:

• 1323 individuals participated in the study.
• Only adults with a BMI (body mass index) greater than or equal to 25kg/m² were enrolled.
• Pregnant women were included in the metformin group.
• The majority of participants were vaccinated, and metformin was effective for both vaccinated and unvaccinated individuals.
• Fluvoxamine doses were a third to half as much as used in previous studies in an attempt to avoid side effects.

The results of the COVID-OUT clinical trial were preceded by several studies that supported the concept that metformin might be used to effectively treat COVID-19. Metformin lowers blood sugar and inflammation by activating an enzyme called AMPK. This activity also appears to reduce angiotensin-converting enzyme 2 (or ACE2), which serves as a gateway for COVID-19 to enter and infect cells.

Metformin has been used for years off-label to treat other metabolic conditions like obesity, cardiovascular disease, and high blood pressure — the same risk factors for poor outcomes after COVID-19 infection. Metformin is also inexpensive and safe to use during pregnancy.

Early observational studies

A publication by an Italian team provided evidence that COVID-19 patients with hyperglycemia who were treated with insulin infusion had a lower risk of severe disease than patients without insulin infusion. And scientists in China, France, and the U.S. reported that patients with the virus and pre-existing Type 2 diabetes had better outcomes if they had improved glycemic control or were on diabetes medication (metformin), and worse outcomes with uncontrolled hyperglycemia.

Controlled clinical trials

The Together Trial was a randomized, controlled clinical trial conducted in Brazil that reported on the use of metformin and other medications to treat COVID-19. Of 1497 participants, 327 individuals were provided metformin. The study did not find that metformin reduced hospitalizations or emergency room visits. However, there were several methodological differences from the COVID-OUT trial. The Together Trial reported that high-dose fluvoxamine reduced the chance of COVID-19-related hospitalization.

The COVID-OUT double-blind, controlled, randomized clinical trial evaluated the impact of metformin, fluvoxamine, ivermectin, and combinations as a treatment for 1323 newly diagnosed COVID-19 participants. Metformin lowered the odds of emergency department visits, hospitalizations, or death. It also reduced the occurrence of Long Covid. However, fluvoxamine and ivermectin did not have a significant effect.

A drug derived from metformin (called metformin glycinate) has recently been shown to reduce the COVID viral load in cell cultures by 98%. Metformin glycinate also reduced the amount of virus and the need for supplemental oxygen in a small clinical trial of COVID-19-infected individuals. The COVID-OUT trial also found that the viral load in participants taking metformin shortly after COVID-19 infection had a significantly reduced level of SARS-CoV-2 virus.

Last updated on December 9, 2024