Trial Report Metformin on the Presence of COVID-19 Symptoms Over 6 Months: The ACTIV-6 Randomized Clinical Trial, 2025, Bramante et al.

[SNT Gatchaman]

Now published - see post #3


Pre-print
Metformin on the Presence of COVID-19 Symptoms Over 6 Months: The ACTIV-6 Randomized Clinical Trial

Spoiler: Authors

Carolyn T Bramante; Thomas G Stewart; David R Boulware; Matthew W McCarthy; Yue Gao; Russell L Rothman; Ahmad Mourad; Florence Thicklin; Jonathan B Cohen; Idania T Garcia del Sol; Nirav S Shah; Manisha Mehta; Orlando Quintero Cardona; Jake Scott; Adit A Ginde; Mario Castro; Dushyantha Jayaweera; Mark Sulkowski; Nina Gentile; Kathleen McTigue; G Michael Felker; Sean Collins; Sarah E Dunsmore; Stacey J Adam; Christopher J Lindsell; Adrian F Hernandez; Susanna Naggie; the Accelerating Covid- Therapeutic Interventions and Vaccines (Activ)- Study Group and Investigators

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.

TRIAL REGISTRATION
ClinicalTrials.gov (NCT04885530).

Web | PDF | Preprint: MedRxiv | Open Access

 

[Yann04]

Overall, 96 (3.2%) reported COVID-19 symptoms on day 90, 101 (3.4%) on day 120, and 79 (2.6%) on day 180.

Interesting how much lower this is to many PCC prevalence estimates.

 

[SNT Gatchaman]

Published as —

Metformin on the Presence of COVID-19 Symptoms 6 Months after Infection: The ACTIV-6 Randomized Clinical Trial
357 authors

BACKGROUND
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.

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 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.

RESULTS
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).

CONCLUSIONS AND RELEVANCE
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.

Web | DOI | PDF | Clinical Infectious Diseases | Open Access

 

[Dolphin]

New study shows metformin given during acute COVID-19 infection reduced risk of clinician-diagnosed long COVID by 50%

New findings from the ACTIV-6 randomized clinical trial provide important confirmation of prior clinical trial results that metformin, a widely available and inexpensive medication with an established safety record, reduced the risk of clinician-diagnosed long COVID when started during acute...

www.eurekalert.org

News Release 11-Jun-2026

New study shows metformin given during acute COVID-19 infection reduced risk of clinician-diagnosed long COVID by 50%​

Peer-Reviewed Publication
University of Minnesota Medical School


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MINNEAPOLIS/ST. PAUL (6/11/2026) — New findings from the ACTIV-6 randomized clinical trial provide important confirmation of prior clinical trial results that metformin, a widely available and inexpensive medication with an established safety record, reduced the risk of clinician-diagnosed long COVID when started during acute COVID-19 infection.

The study, published in Clinical Infectious Diseases and co-led by a University of Minnesota Medical School research team, evaluated nearly 3,000 outpatient adults with mild-to-moderate COVID-19 across 90 sites in the United States. Participants were randomized to receive either metformin or placebo within seven days of symptom onset and were followed for six months.

At six months, participants who received metformin experienced a 50% relative reduction in the risk of clinician-diagnosed long COVID compared with those receiving placebo, indicating that metformin cut the risk of a medical diagnosis of long COVID by approximately half.

Among participants followed through 180 days, clinician-diagnosed long COVID occurred in 0.56% of those receiving metformin compared with 1.17% of those receiving placebo.

"This trial provides additional evidence that treating acute infection with this intervention that acts on metabolic health can reduce the likelihood of developing long COVID," said Carolyn Bramante, MD, MPH, assistant professor at the University of Minnesota Medical School, internist and pediatrician with M Health Fairview and lead author of the study. "The finding is particularly important because metformin is inexpensive, globally available and has decades of clinical use supporting its safety."

As a National Center for Advancing Translational Sciences (NCATS)-funded CTSI Scholar, Dr. Bramante developed a program to study metformin as an outpatient treatment for acute SARS-CoV-2 because of its history as an anti-viral in the early 1900s and because of its known anti-inflammatory actions.

The ACTIV-6 trial enrolled adults considered to be low, standard, or high risk between September 2023 and May 2024 during a period when most participants already had substantial immunity from prior vaccination, prior infection or both. More than 83% of participants had evidence of prior partial immunity, making the results highly relevant to the current phase of the pandemic.

While the trial's primary endpoint — responding yes to having any COVID-19 symptoms on Day 180 after starting the trial — did not meet the pre-specified threshold for efficacy, metformin consistently favored improved long-term outcomes. Investigators observed a high probability of benefit for reducing symptom burden and preventing clinician-diagnosed long COVID. Additionally, no safety concerns emerged during the study.

The findings replicate results from the earlier University of Minnesota-led COVID-OUT randomized trial, which reported a similar reduction in long COVID among participants treated with metformin during acute infection.

“Reproducing research is very important, and both trials have also been replicated in analyses of electronic health record data. Together, these independent studies support that in low- to high-risk adults, metformin is an effective strategy to reduce the risk of long COVID,” said David Boulware, MD, MPH, professor at the University of Minnesota Medical School, infectious disease physician with M Health Fairview and steering committee co-chair of the trial.

Next steps in this research include looking at biospecimens taken during acute infections and seeing if similar actions exist during other infections.

This research was funded by NCATS.

###

About the University of Minnesota Medical School
The University of Minnesota Medical School is at the forefront of learning and discovery, transforming medical care and educating the next generation of physicians. Our graduates and faculty produce high-impact biomedical research and advance the practice of medicine. We acknowledge that the U of M Medical School is located on traditional, ancestral and contemporary lands of the Dakota and the Ojibwe, and scores of other Indigenous people, and we affirm our commitment to tribal communities and their sovereignty as we seek to improve and strengthen our relations with tribal nations. Learn more at med.umn.edu.

About ACTIV-6

ACTIV-6 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) is a nationwide, randomized, placebo-controlled platform trial designed to evaluate repurposed medications for the treatment of COVID-19. The study was supported by the National Center for Advancing Translational Sciences (NCATS).

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Journal​

Clinical Infectious Diseases

DOI​

10.1093/cid/ciag335

Method of Research​

Randomized controlled/clinical trial

Subject of Research​

People

Article Title​

Metformin on the Presence of COVID-19 Symptoms 6 Months after Infection: The ACTIV-6 Randomized Clinical Trial

Article Publication Date​

4-Jun-2026

COI Statement​

Bramante: Reports grants from the NIH outside the current work during the conduct of the study. Stewart: Reports grants from NIH NCATS during the conduct of the study; Grants from NIH outside the submitted work. Boulware: Reports grants from NIH during the conduct of the study. McCarthy: Nothing to report. Gao: Nothing to report. Rothman: Reports grants from NIH, PCORI, AHRQ, CDC, CardioHealth Alliance during the conduct of the study. Spouse owns stock in Moderna unrelated to the current work. Mourad: Nothing to report. Thicklin: Nothing to report. Cohen: Nothing to report. Garcia del Sol: Nothing to report. Shah: Nothing to report. Mehta: Nothing to report. Cardona: Nothing to report. Scott: Nothing to report. Ginde: Reports grants from NIH during the conduct of the study; Grants from NIH, CDC, DoD, AbbVie (investigator-initiated), and Faron Pharmaceuticals (investigator-initiated) outside the submitted work. Castro: Reports institutional grant funding from NIH, ALA, PCORI, AstraZeneca, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi; Speaker/Consultant fees from Grant Funding, Genentech, Teva, Sanofi-Aventis; Consultant fees from Merck, Novartis, Arrowhead, OM Pharma, Allakos; Speaker honorarium from Amgen, AstraZeneca, GSK, Regeneron; Royalties from Elsevier all outside the submitted work. Jayaweera: Reports grants from NCATS during the study; Grants from Gilead, Pfizer, Janssen, and ViiV. advisory board fees from ViiV and Theratechnologies outside the submitted work. Sulkowski: Reports advisory board fees from AbbVie, Gilead, GSK, Atea, Antios, Precision Bio, Viiv, and Virion; Institutional grants from Janssen outside the submitted work. Gentile: Reports personal fees from Duke University for protocol development and oversight during the conduct of the study; grants from NIH outside the submitted work. McTigue: Reports grants from NIH to the University of Pittsburgh during the conduct of the study; Research contracts to the University of Pittsburgh from Pfizer, Eli Lilly, and Janssen outside the submitted work. Felker: Reports institutional research grants from NIH during the conduct of the study and from Novartis outside the submitted work. Collins: Reports grant funding from NHLBI and personal fees from Vir Biotechnology during the conduct of the study. Dunsmore: Nothing to report. Adam: Reports other from US Government Funding through Operation Warp Speed during the conduct of the study. Lindsell: Reports institutional grants from NCATS during the conduct of the study; Institutional grants from NIH, CDC, and DoD; Contract with institution for research services from Endpoint Health, bioMerieux, Entegrion Inc, Abbvie, and Astra Zeneca, Biomeme, and Novartis outside the submitted work; Dr Lindsell has a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center. Hernandez: Reports grants from American Regent, Amgen, Boehringer Ingelheim, Merck, Verily, Somologic, and Pfizer; Personal fees from AstraZeneca, Boston Scientific, Cytokinetics, Bristol Myers Squibb, and Merck outside the submitted work. Naggie: Reports grants from NIH, the sponsor for this study, during the conduct of the study; Institutional research grants from Gilead Sciences, AbbVie; Consulting fees from Pardes Biosciences; Scientific advisor/Stock options from Vir Biotechnology; Consulting with no financial payment from Silverback Therapeutics; DSMB fees from Personal Health Insights, Inc; Event adjudication committee fees from BMS/PRA outside the submitted work

 

[Yann04]

It’s surreal that they had a sample size of over 3’000 and the number in that sample diagnosed with long COVID was ~50% lower in the metformin subgroup. Yet due to Long COVID diagnosis being a rare event in the data, that 50% reduction in the secondary outcome was not significant, even without adjusting for multiple comparisons (though it was very close to significance).

The primary outcome also points in the right direction. 2.3% with metformin vs 3% with placebo reported Post-COVID symptoms on day 180. Though it’s actually far from statistically significant difference.

This trial kind of annoys me, not to blame the authors. Just that such a massive sample size doesn’t seem to answer the question. What sample size do we need to get a high chance of differentiating a theoretical effect from noise at this point haha.

 

[Hutan]

We've seen some trials making it pretty clear that metformin doesn't effectively treat Long Covid eg here and here

But, preventing Long Covid is a different question, so this is interesting.

I haven't read the paper yet. I'm interested to know if they provided any detail on what symptoms people were reporting as post-Covid-19 symptoms. Perhaps metformin has some impact on lung damage healing for example, something not relevant to post-Covid-19 ME/CFS.

 

[hotblack]

Weren’t people who were overweight more likely to suffer worse outcomes from a covid infection itself? Maybe there’s something there rather than then results being linked to LC itself? Not so much weight itself but the changes to glucose production or insulin resistance subtly changing how the initial infection progresses in some at risk people?

Over a 6 month period I also wonder if it’s possible many were exposed to covid multiple times rather than this being linked to the initial infection?