Metformin on Time to Sustained Recovery in Adults with COVID-19: The ACTIV-6 Randomized Clinical Trial
Open accessPreprint — published as 10.1001/jamainternmed.2025.2570 · Paper page
Abstract
Importance: The effect of metformin on reducing symptom duration among outpatient adults with coronavirus disease 2019 (COVID-19) has not been studied. Objective: Assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2. Design, Setting, and Participants: The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, 2991 participants age ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms for ≤7 days, 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 study drug. Secondary outcomes included time to hospitalization or death; time to healthcare utilization (clinic visit, emergency department visit, hospitalization, or death). Safety events of special interest were hypoglycemia and lactic acidosis. Results: Among 2991 participants who were randomized and received study drug, the median age was 47 years (IQR 38–58); 63.4% were female, 46.5% identified as Hispanic/Latino, and 68.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 1443 participants who received metformin and 1548 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [aHR] 0.96; 95% credible interval [CrI] 0.89–1.03; P(efficacy)=0.11). For participants enrolled during current variants, the aHR was 1.19 (95% CrI 1.05–1.34). The median time to sustained recovery was 9 days (95% confidence interval [CI] 9–10) for metformin and 10 days (95% CI 9–10) for placebo. No deaths were reported; 111 participants reported healthcare utilization: 58 in the metformin group and 53 in the placebo group (HR 1.24; 95% CrI 0.81–1.75; P(efficacy)=0.135). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. Five participants in each group reported having hypoglycemia. Conclusions and Relevance: In this randomized controlled trial, metformin was not shown to shorten the time to symptom resolution in adults with mild to moderate 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 ( 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., & the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators
- Affiliations
- University of Minnesota (US)
- University of Virginia (US)
- Weill Cornell Medicine (US)
- Vanderbilt University Medical Center (US)
- Endeavor Health (US)
- 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)
- 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
- Venue
- JAMA Internal Medicine
- Publisher
- openRxiv
- Published
- 2025-01-14
- Volume
- 185
- Issue
- 9
- Pages
- 1092-1092
- ISSN
- 2168-6106 (ISSN-L)
- OpenAlex
- W4412396478
- Cited by
- 8
- References
- 44
- Citations by year
- 2026: 3 · 2025: 5
- FWCI
- 6.15
- 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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