Metformin and Time to Sustained Recovery in Adults With COVID-19: The ACTIV-6 Randomized Clinical Trial
Open accessPublished version of a preprint
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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- Authors
- Bramante, C. T., Stewart, T. G., Boulware, D. R., McCarthy, M. W., Gao, Y., Rothman, R. L., Mourad, A., Thicklin, F., Cohen, J. B., Garcia del Sol, I. T., Ruiz-Unger, J., Shah, N. S., Mehta, M., Cardona, O. Q., Scott, J., Ginde, A. A., Castro, M., Jayaweera, D., Sulkowski, M., Gentile, N., McTigue, K., Felker, G. M., Collins, S., Dunsmore, S. E., Adam, S. J., Lindsell, C. J., Hernandez, A. F., Naggie, S., Accelerating COVID-19 Therapeutic Interventions and Vaccines–6 Study Group and Investigators, DeLong, A., Wilder, R., Hanna, G., Fraser, R., Ward, M., Weaver, S., McAdams, M. P., Korzekwinski, K., Oyelakin, M., Dockery, S., Adkins, R., Crow, M., Light, S., Morris, R., Nowell, E., Wells, K., Herbert, A., Stone, A., Heavlin, H., Brown, L., Brunson, S., Harding, T., Harrington, A., Beauchaine, M., Lindblom, K., Burns, A., Mourad, A., Hamm, M. E., Phillips, K. T., Vasey, A., Edwards, T., Nelson, D., Merritt, G., Nguyen, J., Denson, J., Arnold, J., Aamodt, D., Clark, D., Collins, J., Collins, S., Dixon, S., Gao, Y., Graves, J., Grindstaff, J., Harrell, F., Lai, J., Liao, V., Lopez, I., Manis, E., Mankowski, K., Marlin, J., Merkel, A., Nwosu, S., Obregon, S., Orozco, D., Prato, N., Rohde, M., Shirey-Rice, J., Vermillion, K., Smith, J., Tan, H.-N., Vance, M., Weir, M., Bianchi, R., Premas, J., Gupta, M., Karawan, G., Lima, S., Ziomek, C., Arena, J., DeAlmeida, S., Malik, A., Bryce, J., Swint, S., Tiffany, B., Tanner, C., Sahelian, A., George-Adebayo, C., Adebayo, A., Ronan, T., Woods, A., Gallegos, C., Flys, T., Sloan, O., Olofintuyi, A., Samraj, J., Samraj, J., Averett, A., Slandzicki, A., Wallan, J., Vogel, C., Munoz, S., Kavtaradze, D., Watson, C., Singleton, D., Sevier, M., Rivon, M., Rao, S., Cantu, L., Krishna, A., Daugherty, H., Kerr, B., Evans, K., Spees, R., Marta, M., Amir, D., Collazo, J., Dolor, R., Vergara, L., Jordan, J., Burruss, V., Hurst, T., Rebolledo Esteinou, P. A., Ofotokun, I., Zhang, C., Traenkner, J., Atha, M. M., James, V., Rogers, M., Oragwu, C., Oguego, N., Pillai, R., Gabriel, A., Ghaly, E., Michal, M., Hassanien, G., Ismail, S., Samir, Y., Meltzer, A., Heidish, R. S., Loganathan, A., Brehaut, S., Roche, A., Koppinger, N., Baez, J., Pagan, I., Abdelsayed, D., Aziz, M., Robinson, P., Lozinski, G., Nguyen, J., Griffin, A., Morris, M., Love, N., Mattox, B., Martin, R., Pardue, V., Rowland, T., Reyes, L., Bacallao, N., Cienki, J., Yuan, Y., Li, J., Szeto, J., Stelmash, L., Mekhael, S., Morales Castillo, L., Gutierrez, A., Prieto, S., Amon, A., Barbera, A., Bugajski, A., Wills, W., Jacklin, K., Lamb, D., Harper, A., Stout, E., Griffin, M., Clark, N., Barsanti-Sekhar, M., Carbrera-Mendez, C., Evans, M. R., Maria, J., Raymond, O., Summers, J., Turner, T., Lenert, L., Panaccione, E., Miller, C., Wiley, H., Chan, A., Khizer, S., Adeyemi, O., Ning Chi, W., Chen, J., Morton-Jost, M., Castex, J., Quirch, A., Belani, H., Machicado, R., Bjornsson, B., Olivo, J., Maldonado, M., Vecchiarelli, A., Gaytan-Alvarez, D., Cherukuri, V., Alicic, R., Lambert, A. A., Urbat, C., Baxter, J., Cooper, A., Linn, D., Fisher, L., Patel, V., Patel, Y., Talati, R., Patel, P., Ellison, L., Roman, A., Harrison, J., Moy, J., Naquiallah, D., Shah, B., Jagannathan, P., Singh, U., O’Donnell, A., Jazayeri, Y., Gupta, A., Chandrasekar, N., Curtis, C., White, B., Dockery, M., Fortt, T., Fortt, A., Wilson, J., Marcelin, J., Farlow, B., Grady, C., Richwine, R., Pazier, P., Michelson, E., Watts, S., Kariyawasam, D., Rodriguez, L., Luis Garcia, J., Manresa, I., Achong, A. A., Garcia, M. C., Mahadevan, A., VandeWeerd, C., Lowenkron, J., Sappington, E., Roberts, M., Wang, J., Adams, M., Ding, X., Co, M., D'Andrea, M., Lim, S., Young, M., Wilson, M., Eastin, C., Cheathem, A., Nadeem, A., Walters, C., Powers-Fletcher, M., Brown, D., Miller, D., Mukunzi, S., Isache, C., Bowman, J., Martin, D., Duran, B., Schwasinger-Schmidt, T., Ast, A., Cornejo, A., Archer, A., Almanzar, M., Motel, V., Pullen, M., Bhat, N., Parra, D., Urbina, E., Arriaza, S., Sekikawa, A., Klawson, E., Weiland, N., Ostrosky-Zeichner, L., Patel, B., Umana, V., Nielsen, L., Grimes, C. Z., Patterson, T. F., Soileau, B. T., Jackson, P. E. H., Haughey, H. M., Vaidya-Tank, B., Gould, C., Goyal, P., Pangburn, H., Michalowski, L., Williamson, J., Wortham, B., Abbott, R., Umana, U., Alleyne, C., Witting, B., Armas, E., Perez Landaburo, R. O., De La Cruz, M., Ballmajo, M., & Alvarez, J.
- Affiliations
- University of Minnesota (US)
- University of Virginia (US)
- Weill Cornell Medicine (US)
- Vanderbilt University Medical Center (US)
- Stakeholder Advisory Committee, Pittsburgh, Pennsylvania
- Jadestone Clinical Research LLC, Silver Spring, Maryland
- L&A Morales Healthcare Inc, Miami, Florida
- Innovation Clinical Trials Inc, Miami, Florida
- Endeavor Health (US)
- GCF of Southeastern Michigan, PC, Detroit
- Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Stanford Medicine (US)
- University of Colorado Anschutz (US)
- University of Kansas Medical Center (US)
- University of Miami (US)
- Johns Hopkins University (US)
- Temple University (US)
- University of Pittsburgh Medical Center (US)
- Duke University (US)
- National Institutes of Health (US)
- Foundation for the National Institutes of Health (US)
- for the Accelerating COVID-19 Therapeutic Interventions and Vaccines–6 Study Group and Investigators
- ORCID
- Bramante, Carolyn T.
- Stewart, Thomas G.
- Boulware, David R.
- McCarthy, Matthew W.
- Rothman, Russell L.
- Cohen, Jonathan B.
- Shah, Nirav S.
- Scott, Jake
- Ginde, Adit A.
- Castro, Mario
- Jayaweera, Dushyantha
- Gentile, Nina
- McTigue, Kathleen
- Felker, G. Michael
- Adam, Stacey J.
- Lindsell, Christopher J.
- Hernandez, Adrian F.
- Naggie, Susanna
- Weaver, Sarah
- Hamm, Megan E.
- Vasey, Andrew
- Nguyen, Jeannie
- Harrell, Frank
- Smith, Jacob
- Tiffany, Brian
- Dolor, Rowena
- Ofotokun, Igho
- Heidish, Ryan S.
- Loganathan, Aditya
- Nguyen, Julie
- Morris, Michael
- Yuan, Ying
- Li, Jenny
- Bugajski, Andrew
- Wills, Walter
- Lenert, Leslie
- Adeyemi, Oluwadamilola
- Morton-Jost, Melissa
- Belani, Hrishikesh
- Maldonado, Maria
- Alicic, Radica
- Lambert, Allison A.
- Cooper, Ann
- Jagannathan, Prasanna
- Singh, Upinder
- Gupta, Anita
- Michelson, Edward
- Kariyawasam, Diluma
- Wang, Jennifer
- Adams, Melissa
- Ding, Xinyi
- Lim, Stephen
- Eastin, Carly
- Miller, Delia
- Isache, Carmen
- Schwasinger-Schmidt, Tiffany
- Parra, Daniela
- Sekikawa, Akira
- Grimes, Carolyn Z.
- Patterson, Thomas F.
- Jackson, Patrick E.H.
- Goyal, Parul
- Williamson, John
- Venue
- JAMA Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2025-09-01
- Volume
- 185
- Issue
- 9
- Pages
- 1092
- ISSN
- 2168-6106 (ISSN-L)
- OpenAlex
- W4412396478
- Cited by
- 8
- References
- 5
- Citations by year
- 2026: 3 · 2025: 5
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- JAMA Internal Medicine (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Massachusetts General Hospital
- Vanderbilt University
- University of Pennsylvania
- Northwestern University
- University of Pittsburgh
- Children's Mercy Hospital
- Vanderbilt University Medical Center (UL1 TR002243)
- National Institutes of Health (U24TR001608, UL1TR002243)
- School of Medicine, Duke University
- University of North Carolina at Chapel Hill
- Feinberg School of Medicine
- Biomedical Advanced Research and Development Authority
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK124654)
- National Center for Advancing Translational Sciences
- Duke Clinical Research Institute
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- metformin, COVID-19 pandemic, SARS-CoV-2, drug repurposing, symptom resolution, mild to moderate COVID-19, hypoglycemia, lactic acidosis, adverse events, emergency department visits, hospitalization, mortality, drug efficacy
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Adult, Aged, Female, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Treatment Outcome
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