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.
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About the University of Minnesota Medical School
The University of Minnesota Medical School is at the forefront of learning and discovery, transforming medical care and educating the next generation of physicians. Our graduates and faculty produce high-impact biomedical research and advance the practice of medicine. We acknowledge that the U of M Medical School is located on traditional, ancestral and contemporary lands of the Dakota and the Ojibwe, and scores of other Indigenous people, and we affirm our commitment to tribal communities and their sovereignty as we seek to improve and strengthen our relations with tribal nations. Learn more at med.umn.edu .
About ACTIV-6
ACTIV-6 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) is a nationwide, randomized, placebo-controlled platform trial designed to evaluate repurposed medications for the treatment of COVID-19. The study was supported by the National Center for Advancing Translational Sciences (NCATS).
Clinical Infectious Diseases
Randomized controlled/clinical trial
People
Metformin on the Presence of COVID-19 Symptoms 6 Months after Infection: The ACTIV-6 Randomized Clinical Trial
4-Jun-2026
Bramante: Reports grants from the NIH outside the current work during the conduct of the study. Stewart: Reports grants from NIH NCATS during the conduct of the study; Grants from NIH outside the submitted work. Boulware: Reports grants from NIH during the conduct of the study. McCarthy: Nothing to report. Gao: Nothing to report. Rothman: Reports grants from NIH, PCORI, AHRQ, CDC, CardioHealth Alliance during the conduct of the study. Spouse owns stock in Moderna unrelated to the current work. Mourad: Nothing to report. Thicklin: Nothing to report. Cohen: Nothing to report. Garcia del Sol: Nothing to report. Shah: Nothing to report. Mehta: Nothing to report. Cardona: Nothing to report. Scott: Nothing to report. Ginde: Reports grants from NIH during the conduct of the study; Grants from NIH, CDC, DoD, AbbVie (investigator-initiated), and Faron Pharmaceuticals (investigator-initiated) outside the submitted work. Castro: Reports institutional grant funding from NIH, ALA, PCORI, AstraZeneca, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi; Speaker/Consultant fees from Grant Funding, Genentech, Teva, Sanofi-Aventis; Consultant fees from Merck, Novartis, Arrowhead, OM Pharma, Allakos; Speaker honorarium from Amgen, AstraZeneca, GSK, Regeneron; Royalties from Elsevier all outside the submitted work. Jayaweera: Reports grants from NCATS during the study; Grants from Gilead, Pfizer, Janssen, and ViiV. advisory board fees from ViiV and Theratechnologies outside the submitted work. Sulkowski: Reports advisory board fees from AbbVie, Gilead, GSK, Atea, Antios, Precision Bio, Viiv, and Virion; Institutional grants from Janssen outside the submitted work. Gentile: Reports personal fees from Duke University for protocol development and oversight during the conduct of the study; grants from NIH outside the submitted work. McTigue: Reports grants from NIH to the University of Pittsburgh during the conduct of the study; Research contracts to the University of Pittsburgh from Pfizer, Eli Lilly, and Janssen outside the submitted work. Felker: Reports institutional research grants from NIH during the conduct of the study and from Novartis outside the submitted work. Collins: Reports grant funding from NHLBI and personal fees from Vir Biotechnology during the conduct of the study. Dunsmore: Nothing to report. Adam: Reports other from US Government Funding through Operation Warp Speed during the conduct of the study. Lindsell: Reports institutional grants from NCATS during the conduct of the study; Institutional grants from NIH, CDC, and DoD; Contract with institution for research services from Endpoint Health, bioMerieux, Entegrion Inc, Abbvie, and Astra Zeneca, Biomeme, and Novartis outside the submitted work; Dr Lindsell has a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center. Hernandez: Reports grants from American Regent, Amgen, Boehringer Ingelheim, Merck, Verily, Somologic, and Pfizer; Personal fees from AstraZeneca, Boston Scientific, Cytokinetics, Bristol Myers Squibb, and Merck outside the submitted work. Naggie: Reports grants from NIH, the sponsor for this study, during the conduct of the study; Institutional research grants from Gilead Sciences, AbbVie; Consulting fees from Pardes Biosciences; Scientific advisor/Stock options from Vir Biotechnology; Consulting with no financial payment from Silverback Therapeutics; DSMB fees from Personal Health Insights, Inc; Event adjudication committee fees from BMS/PRA outside the submitted work