Metformin on the Presence of COVID-19 Symptoms Over 6 Months: The ACTIV-6 Randomized Clinical Trial
MD, MPH Carolyn T Bramante, PhD Thomas G Stewart, MD, MPH David R Boulware, MD Matthew W Mccarthy, MS, Med Yue Gao, MD, MPP Russell L Rothman, MD Ahmad Mourad, Florence Thicklin, MD Jonathan B Cohen, Idania T Garcia Del Sol, MD, MPH Nirav S Shah, DPM Manisha Mehta, MD Orlando Quintero Cardona, MD Jake Scott, MD, MPH Adit A Ginde, MD, MPH Mario Castro, MD Dushyantha Jayaweera, MD Mark Sulkowski, MD Nina Gentile, MD Kathleen Mctigue, MD G Michael Felker, MD, MSci Sean Collins, PhD Sarah E Dunsmore, PhD Stacey J Adam, PhD Christopher J Lindsell, MD, MHS Adrian F Hernandez, MD, MHS Susanna Naggie
doi:10.1101/2025.08.08.25333305
Background: The effect of metformin on preventing long-term COVID-19 symptoms among low-risk adults has not been studied. The objective of this study was to Assess metformin compared with placebo during acute SARS-CoV-2 infection on the presence of COVID-19 symptoms 180 days later.
Methods: 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 for ≤7 days were included from 90 sites. Participants were randomized to metformin (titrated to 1500 mg daily) 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 diagnosis of long COVID. For the primary outcome, the single-sided threshold for efficacy was 0.975. Results: Among 2983 participants, the median age was 47 years (interquartile range [IQR] 38-57); 63% were female; 47% Hispanic/Latino; 83% reported ≥1 prior COVID-19 infections or 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 covariate-adjusted risk of PASCD on day 180 was lower in the metformin group (-0.008; 95% credible interval [CrI] -0.022 to 0.006; posterior probability of efficacy [PPE] 0.83), compared with the placebo group with an adjusted risk ratio of 0.79 (95% CrI 0.474 to 1.230). The risk of clinician diagnosis of long COVID (secondary outcome) on day 180 was lower in the metformin group (-0.007; 95% CrI -0.015 to 0.001; PPE 0.96), with a relative risk of 0.495 (95% CrI 0.155 to 0.995).
Conclusions: The posterior probability of efficacy for metformin preventing the primary endpoint did not exceed the prespecified threshold of 0.975 for declaring efficacy. Secondary outcomes were numerically better with metformin.
Author Contributions Drs Naggie, Hernandez, and Lindsell had full access to all the blinded data in the study. Dr Stewart was provided curated study data and takes responsibility for the integrity of the data analysis. All authors contributed to the drafting and review of the manuscript and agreed to submit for publication.
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doi:10.1038/s41575-022-00698-4DOI record:
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