MINNEAPOLIS/ST. PAUL (6/11/2026) — New findings from the ACTIV-6 randomized clinical trial provide important confirmation of prior clinical trial results that metformin, a widely available and inexpensive medication with an established safety record, reduced the risk of clinician-diagnosed long COVID when started during acute COVID-19 infection.
The study, published in Clinical Infectious Diseases and co-led by a University of Minnesota Medical School research team, evaluated nearly 3,000 outpatient adults with mild-to-moderate COVID-19 across 90 sites in the United States. Participants were randomized to receive either metformin or placebo within seven days of symptom onset and were followed for six months.
At six months, participants who received metformin experienced a 50% relative reduction in the risk of clinician-diagnosed long COVID compared with those receiving placebo, indicating that metformin cut the risk of a medical diagnosis of long COVID by approximately half.
Among participants followed through 180 days, clinician-diagnosed long COVID occurred in 0.56% of those receiving metformin compared with 1.17% of those receiving placebo.
"This trial provides additional evidence that treating acute infection with this intervention that acts on metabolic health can reduce the likelihood of developing long COVID," said Carolyn Bramante, MD, MPH , assistant professor at the University of Minnesota Medical School, internist and pediatrician with M Health Fairview and lead author of the study. "The finding is particularly important because metformin is inexpensive, globally available and has decades of clinical use supporting its safety."
As a National Center for Advancing Translational Sciences (NCATS)-funded CTSI Scholar , Dr. Bramante developed a program to study metformin as an outpatient treatment for acute SARS-CoV-2 because of its history as an anti-viral in the early 1900s and because of its known anti-inflammatory actions.
The ACTIV-6 trial enrolled adults considered to be low, standard, or high risk between September 2023 and May 2024 during a period when most participants already had substantial immunity from prior vaccination, prior infection or both. More than 83% of participants had evidence of prior partial immunity, making the results highly relevant to the current phase of the pandemic.
While the trial's primary endpoint — responding yes to having any COVID-19 symptoms on Day 180 after starting the trial — did not meet the pre-specified threshold for efficacy, metformin consistently favored improved long-term outcomes. Investigators observed a high probability of benefit for reducing symptom burden and preventing clinician-diagnosed long COVID. Additionally, no safety concerns emerged during the study.
The findings replicate results from the earlier University of Minnesota-led COVID-OUT randomized trial, which reported a similar reduction in long COVID among participants treated with metformin during acute infection.
"Reproducing research is very important, and both trials have also been replicated in analyses of electronic health record data. Together, these independent studies support that in low- to high-risk adults, metformin is an effective strategy to reduce the risk of long COVID," said David Boulware, MD, MPH , professor at the University of Minnesota Medical School, infectious disease physician with M Health Fairview and steering committee co-chair of the trial.
Next steps in this research include looking at biospecimens taken during acute infections and seeing if similar actions exist during other infections.
This research was funded by NCATS.
