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Randomized Controlled Trial
. 2025 Sep 1;185(9):1092-1101.
doi: 10.1001/jamainternmed.2025.2570.

Metformin and Time to Sustained Recovery in Adults With COVID-19: The ACTIV-6 Randomized Clinical Trial

Carolyn T Bramante  1 , Thomas G Stewart  2 , David R Boulware  1 , Matthew W McCarthy  3 , Yue Gao  4 , Russell L Rothman  4 , Ahmad Mourad  5   6 , Florence Thicklin  7 , Jonathan B Cohen  8 , Idania T Garcia Del Sol  9 , Juan Ruiz-Unger  10 , Nirav S Shah  11 , Manisha Mehta  12 , Orlando Quintero Cardona  13 , Jake Scott  13 , Adit A Ginde  14 , Mario Castro  15 , Dushyantha Jayaweera  16 , Mark Sulkowski  17 , Nina Gentile  18 , Kathleen McTigue  19 , G Michael Felker  5   6 , Sean Collins  4   20 , Sarah E Dunsmore  21 , Stacey J Adam  22 , Christopher J Lindsell  6 , Adrian F Hernandez  6 , Susanna Naggie  6 ; Accelerating COVID-19 Therapeutic Interventions and Vaccines–6 Study Group and Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Metformin and Time to Sustained Recovery in Adults With COVID-19: The ACTIV-6 Randomized Clinical Trial

Carolyn T Bramante et al. JAMA Intern Med. .

Abstract

Importance: The effect of metformin on reducing symptom duration among outpatient adults with COVID-19 has not been studied.

Objective: To assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2.

Design, setting, and participants: The Accelerating COVID-19 Therapeutic Interventions and Vaccines platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, participants 30 years or older with confirmed SARS-CoV-2 infection and 2 or more COVID-19 symptoms for 7 days or less were included at 90 US sites.

Interventions: Participants were randomized to receive metformin (titrated to 1500 mg, daily) or placebo for 14 days.

Main outcomes and measures: The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving the study drug. Secondary outcomes included time to clinic visit, emergency department (ED) visit, hospitalization, or death. Safety events of interest were hypoglycemia and lactic acidosis.

Results: Among 2991 participants who were randomized and received study drug, the median age was 47 (IQR, 38-58) years; 1895 (63.4%) were female, 25 (0.8%) were American Indian of Alaska Native, 77 (2.6%) were Asian, 350 (11.7%) were Black, African American, or African, 1392 (46.5%) identified as Hispanic or Latino, 8 (0.3%) were Native Hawaiian or other Pacific Islander, 2395 (80.1%) were White, and 2044 (68.3%) reported 2 or more doses of a SARS-CoV-2 vaccine. Among 1443 (48.2%) participants who received metformin and 1548 (51.8%) who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio, 0.96; 95% credible interval [CrI], 0.89-1.03; P for efficacy = .11). The median time to sustained recovery was 9 days (95% CI, 9-10) for metformin and 10 days (95% CI, 9-10) for placebo. No deaths were reported; 103 participants reported clinic visits, ED visits, or hospitalization: 54 in the metformin group and 49 in the placebo group (hazard ratio, 1.25; 95% CrI, 0.82-1.78; P for efficacy = .13). Overall, 35 (1.2%) reported ED visits or hospitalization (1.1% in the metformin and 1.3% in the placebo group). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. There were 4 episodes of participant-reported hypoglycemia in the placebo group and 2 in the metformin group.

Conclusions and relevance: In this randomized clinical trial, metformin was not shown to shorten the time to symptom resolution in low-risk adults with COVID-19. The median days to symptom resolution was numerically but not significantly lower for metformin. Safety was not a limitation in the study population.

Trial registration: ClinicalTrials.gov Identifier: NCT04885530.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Stewart reported grants from the National Institutes of Health (NIH) via Duke University during the conduct of the study. Dr Rothman reported grants from the NIH during the conduct of the study, and his spouse previously owned stock in Moderna. Dr Shah reported grants from NIH during the conduct of the study and outside the submitted work. Dr Ginde reported personal fees from the NIH during the conduct of the study as well as grants from the NIH, US Centers for Disease Control and Prevention, US Department of Defense, and Patient-Centered Outcomes Research Institute and personal fees from Seastar and Biomeme outside the submitted work. Dr Castro reported grants from NIH during the conduct of the study as well as grants from the ALA, AstraZeneca, Genentech, GSK, Nocion, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi, Theravanace, and Gala Therapeutics, stocks in Aer Therapeutics, and personal fees from Amgen, Allakos, Apogee Therapeutics, Apreo Health, Arrowhead Pharmaceuticals, AstraZeneca, Blueprint Medicines, Connect BioPharma, Evommune, Genentech, GSK, Jasper Therapeutics, Kinaset, MedLearningGroup, Merck, Novartis, OM Pharma, Pfizer, Pioneering, Regeneron, Sanofi-Aventis, Teva, Third Rock, Upstream, Verona Pharmaceuticals, Enveda, Polarean, Generate Biomedicines, and Uniquity Bio outside the submitted work. Dr Jayaweera reported grants from Gilead and ViiV and personal fees from ViiV and Clinical Care Options outside the submitted work. Dr Sulkowski reported grants from Vir Research and personal fees from Gilead, ImmunoCore, Aligos, Precision Biosciences, GSK, Virion Scientific, AbbVie, and the Journal of Viral Hepatitis outside the submitted work. Dr McTigue reported research support from Pfizer and Eli Lilly and grants from Amgen outside the submitted work. Drs Felker and Collins reported grants from the NIH during the conduct of the study. Dr Lindsell reported grants from the National Center for Advancing Translational Sciences (NCATS) during the conduct of the study as well as research support from Novartis, Biomerieux, Entegrion Inc, Persistence Bio, Regeneron, Rocket Pharmaceuticals, Nyxoah, Cytokinetics, Novo Nordisk, and Novartis, a patent for risk prediction in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center, and stock options in Bioscape Digital outside the submitted work. Dr Hernandez reported grants from Pfizer outside the submitted work. Dr Naggie reported grants from the NIH during the conduct of the study as well as grants from Gilead and AbbVie; nonfinancial support from Pardes Biosciences, Silverback Therapeutics, and Personal Health Insights; stock options and stocks owned in Vir Biotechnology; and personal fees from BMS/PRA Health Sciences outside the submitted work. No other disclosures were reported.

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