Metformin on the Presence of COVID-19 Symptoms 6 Months after Infection: The ACTIV-6 Randomized Clinical Trial
et al., Clinical Infectious Diseases, doi:10.1093/cid/ciag335, NCT04885530, Jun 2026
Metformin for COVID-19
3rd treatment shown to reduce risk in
July 2020, now with p < 0.00000000001 from 111 studies.
Lower risk for mortality, ventilation, ICU, hospitalization, progression, recovery, and viral clearance.
No treatment is 100% effective. Protocols
combine treatments.
6,600+ studies for
220+ treatments. c19early.org
|
RCT 2,983 outpatients showing lower long COVID symptoms with metformin treatment, without statistical significance. Results are reported with the main paper1.
Bramante et al., 4 Jun 2026, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, median age 47.0, 27 authors, study period 19 September, 2023 - 1 May, 2024, trial NCT04885530 (history).
Contact: susanna.naggie@duke.edu.
Abstract: ## MAJOR ARTICLE
Metformin on the Presence of COVID-19 Symptoms 6 Months after Infection: The ACTIV-6 Randomized Clinical Trial Carolyn T. Bramante, MD, MPH, 1 Thomas G. Stewart, PhD, 2 David R. Boulware, MD, MPH, 1 Matthew W. McCarthy, MD, 3 Yue Gao, MS, Med, 4 Russell L. Rothman, MD, MPP, 4 Ahmad Mourad, MD, 5,6 Florence Thicklin, 7 Jonathan B. Cohen, MD, 8 Idania T. Garcia del Sol, MD, 9 Nirav S. Shah, MD, MPH, 10 Manisha Mehta, DPM, 11 Orlando Quintero Cardona, MD, 12 Jake Scott, MD, 12 Adit A. Ginde, MD, MPH, 13 Mario Castro, MD, MPH, 14 Dushyantha Jayaweera, MD, 15 Mark Sulkowski, MD, 16 Nina Gentile, MD, 17 Kathleen McTigue, MD, 18 G. Michael Felker, MD, 5,6 Sean Collins, MD, MSci, 4,19 Sarah E. Dunsmore, PhD, 20 Stacey J. Adam, PhD, 21 Christopher J. Lindsell, PhD, 6 Adrian F. Hernandez, MD, MHS, 6 Susanna Naggie, MD, MHS 6 for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators 1 Department of Medicine, University of Minnesota Medical School, Minneapolis, MN; 2 School of Data Science, University of Virginia, Charlottesville, VA; 3 Weill Cornell Medicine, New York, NY; 4 Vanderbilt University Medical Center, Nashville, TN; 5 Department of Medicine, Duke University School of Medicine, Durham, NC; 6 Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC; 7 Stakeholder Advisory Committee, Pittsburgh, PA; 8 Jadestone Clinical Research, LLC, Silver Spring, MD; 9 L&A Morales Healthcare, Inc., Miami, FL; 10 Endeavor Health, Evanston, IL; 11 GFC of Southeastern Michigan, PC, Detroit, MI; 12 Stanford University School of Medicine, Department of Medicine, Division of Infectious Diseases, ------------------------------------------Address for correspondence: Susanna Naggie, MD, MHS, Duke Clinical Research Institute, Duke University School of Medicine, 300 West Morgan St, Suite 800, Durham, NC 27701. Email: susanna.naggie@duke.edu ACCEPTED MANUSCRIPT
© The Author(s) 2026. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site -for further information please contact journals.permissions@oup.com.
Stanford, CA; 13 Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO; 14 Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, KS; 15 Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL; 16 Division of Infectious Diseases, Johns Hopkins University, Baltimore, MD; 17 Department of Emergency Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA; 18 Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; 19 Veterans Affairs Tennessee Valley Healthcare System, ..
DOI record:
{
"DOI": "10.1093/cid/ciag335",
"ISSN": [
"1058-4838",
"1537-6591"
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"URL": "http://dx.doi.org/10.1093/cid/ciag335",
"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>We conducted a quadruple-blinded, randomized, placebo-controlled trial of metformin for treating acute SARS-CoV-2 infection to prevent long COVID symptoms in low-risk adults.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023 and May 1, 2024, 2983 outpatient adults ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms were included within 7 days of symptom onset from 90 sites. Participants were randomized to metformin or placebo for 14 days. Post-acute sequelae of SARS-CoV-2 or death (PASCD) was ascertained by asking whether participants had symptoms they attributed to COVID-19 on day 180. Secondary outcomes included clinician-diagnosed long COVID.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>The median age was 47 years (interquartile range 38–57); 63% were female; 47% Hispanic/Latino; 83% reported ≥1 prior COVID-19 infections or ≥2 SARS-CoV-2 vaccines. There were no deaths. Overall, 96 (3.2%) reported COVID-19 symptoms on day 90, 101 (3.4%) on day 120, and 79 (2.6%) on day 180. The adjusted risk of symptoms on day 180 was 0.8 percentage points lower with metformin (95% credible interval [CrI] -2.2 to 0.6) with a posterior probability of efficacy [PPE] for preventing symptoms of 0.83, risk ratio 0.79 (95% CrI 0.474 to 1.230). Compared with placebo, the risk of clinician-diagnosed long COVID was 0.7 percentage points lower with metformin (95% CrI -1.5 to 0.1); PPE 0.96; risk ratio 0.495 (95% CrI 0.155 to 0.995).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions and Relevance</jats:title>\n <jats:p>In low-risk adults, most with prior immunity, metformin did not exceed the efficacy threshold of 0.975 for PASC. Metformin reduced the risk of clinician-diagnosed long COVID.</jats:p>\n </jats:sec>",
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