University of Minnesota Medical School researchers received funding from the Parsemus Foundation to initiate research on the widely-used diabetes medication, metformin, available globally as an inexpensive generic drug for prevention and treatment for COVID-19.
To prevent delay during the COVID-19 pandemic, the California-based Parsemus Foundation is funding the University of Minnesota's investigational new drug (IND) application to the Food and Drug Administration (FDA) to launch a multi-center randomized controlled clinical trial of the use of metformin as a COVID-19 treatment and prevention method. The U of M Medical School research team, led by co-principal investigators Carolyn Bramante, MD, MPH, in the Department of Medicine, and Christopher Tignanelli, MD in the Department of Surgery, submitted the IND application on August 12. The team has the next few weeks to secure additional funding.
The epidemiological data from multiple studies globally-- not just ours-- support a trend or effect of metformin in preventing hospitalization and death from COVID-19. And a mechanism of action is there-- metformin has a little-known past as an antiviral, in addition to its blood sugar reduction and inflammation-reducing effect. TNFα and mTOR are among the proposed pathways. But, a randomized clinical trial is needed to be sure the association is truly cause and effect."
Carolyn Bramante, MD, MPH, Department of Medicine, University of Minnesota
"Several observational studies in the U.S. and around the world have shown an association between outpatient metformin use and reduced mortality and hospitalizations for COVID-19," Bramante said. "The most recent papers (one not yet publicly available), were done in detailed databases that allowed accounting for body mass index and degree of glucose in the body (hemoglobin A1C). There are known mechanisms of metformin that would reduce severity of COVID-19, including its inflammation reducing effects, and potentially also its ability to inhibit mTOR, a protein that helps the virus grow."
Metformin, familiar to many by the brand names Fortamet or Glucophage, is used as a diabetes medication to lower glucose levels, with a common side benefit of reduced appetite and weight loss. Findings from previous studies provided Bramante's team with a reason to believe that metformin is a promising treatment and prevention method for COVID-19, including preliminary data from an observational study co-led by Bramante and Tignanelli.
The team examined de-identified data from UnitedHealthcare and found that women already taking metformin who were diagnosed with COVID-19 had about 25% reduced risk of mortality. Preliminary data from another observational study of patients with non-alcoholic fatty liver disease, co-led by Bramante and Tignanelli, showed that treatment for metabolic disease, including taking metformin, was associated with a lower likelihood of being hospitalized due to COVID-19. The findings align with results from observational studies in China and France and from the University of Alabama.
Upon approval of the IND application, the goal of the clinical trial will be two-fold: to definitively study whether or not metformin prevents SARS-CoV-2 infection and whether or not it can prevent severe COVID-19 disease and hospitalization in those who are infected. The unique study they have designed will also elucidate what duration of metformin is needed to achieve those benefits. Since metformin is already widely used and available, its use to fight COVID-19 could begin as soon as there are positive clinical results and would change the global standard of care for prevention and early-stage disease, similar to recent definitive results on dexamethasone for advanced disease.
The CDC forecasts predict 1,300 to 5,500 new COVID-19 hospitalizations per day by Oct. 12 in the U.S. alone. This means that a treatment that reduces hospitalization by about 50-60%, as evidenced by observational data, could potentially prevent thousands of hospitalizations each day in the U.S.. With generics available for less than $4 per month from manufacturers around the globe, metformin also has the advantage that it can be used immediately and inexpensively worldwide. Metformin is also safe in everyone (children, pregnant women, adults of any age), as long as they don't have significant kidney, liver or heart failure.
Though the Parsemus Foundation has provided the initial funding, it is too small to fund the full trial.
"We are proud to partner with the University of Minnesota Medical School by providing the seed funding to kick off the metformin trial. The team has a record of running fast, definitive trials and already has test sites from around the country ready to start," said Foundation Trustee, Elaine Lissner. "All the puzzle pieces are there, they just need to be put together with additional funders to launch the study."