Metformin Cuts Long COVID Risk by 50%, New Trial Confirms

A large, randomized, placebo-controlled clinical trial has found that metformin—a widely available diabetes medication—reduced the risk of clinician-diagnosed long COVID by approximately 50% when initiated during an acute SARS-CoV-2 infection. The findings, published in Clinical Infectious Diseases, add critical weight to a growing body of evidence supporting metformin's role as a preventive strategy against postacute sequelae of COVID-19.¹

About the ACTIV-6 Trial

The new evidence comes from the ACTIV-6 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) platform trial (NCT04885530), a nationwide, quadruple-blinded, randomized, placebo-controlled study evaluating repurposed medications for mild-to-moderate COVID-19. Researchers enrolled 2983 outpatient adults aged 30 years and older with confirmed SARS-CoV-2 infection and at least 2 COVID-19 symptoms, across 90 sites in the US between September 2023 and May 2024. Participants were randomly assigned to receive either metformin or placebo within 7 days of symptom onset and were followed for 6 months.¹

Notably, the trial enrolled a population that was largely immune-experienced, with more than 83% of participants reporting at least one prior COVID-19 infection or having received 2 or more SARS-CoV-2 vaccines. This makes the results particularly generalizable to the current phase of the pandemic, when most patients seeking care for acute COVID-19 have some degree of preexisting immunity.¹

Key Findings

While metformin did not meet the prespecified Bayesian efficacy threshold for the primary end point—the proportion of participants still experiencing COVID-19 symptoms attributed to the infection at day 180—investigators observed a high posterior probability of benefit across secondary outcomes.¹

The most striking result was in clinician-diagnosed long COVID. At 6 months, 0.56% of participants in the metformin arm received a formal long COVID diagnosis, compared with 1.17% in the placebo arm—a relative risk reduction of approximately 50% (risk ratio, 0.495 [95% CI, 0.155-0.995]; posterior probability of efficacy, 0.96). No safety signals emerged during the study.¹

Replication of Earlier Results

The ACTIV-6 findings closely mirror those from the COVID-OUT trial (NCT04510194), an earlier phase 3, randomized, quadruple-blind study also led by University of Minnesota researchers. Published in The Lancet Infectious Diseases, COVID-OUT found that adults with overweight or obesity who took metformin during an acute SARS-CoV-2 infection were approximately 41% less likely to develop long COVID compared with placebo recipients, and that benefit grew to 63% among those who initiated treatment within 4 days of symptom onset. Together, these two independent trials, bolstered by analyses of electronic health records, form a compelling multi-source evidence base.^2,3

Implications for Practice

For pharmacists, these findings raise an actionable question: should metformin be recommended to patients who did not have diabetes during acute COVID-19 to prevent long COVID?

The evidence does not yet support routine prescribing outside a clinical trial framework, and formal guideline updates have not been issued. However, health care professionals should be aware of this accumulating evidence when discussing COVID-19 management with patients, particularly those who are at higher risk for protracted illness. Given metformin's decades-long safety record, low cost, and global availability, researchers suggest it warrants serious consideration as an outpatient intervention during acute infection. Next steps include analyzing biospecimens collected during the ACTIV-6 trial to better understand the biological mechanisms underlying metformin's benefit.²

Expert Insights

In an interview with Pharmacy Times, 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, discussed cross-study consistency supporting metformin for long COVID prevention across most adults, with caution in those over 85, and barriers to formal guideline adoption.

Pharmacy Times: Given that metformin didn't meet the primary end point but showed a 50% reduction in clinician-diagnosed long COVID, how should pharmacists and prescribers interpret that distinction when counseling patients during an acute COVID-19 infection?

Carolyn Bramante, MD, MPH: Clinical guideline criteria [do not] typically specify that only primary outcomes will be used for making recommendations—they specify outcomes that can be assessed for consistency across multiple studies. Pharmacists and prescribers can interpret the consistency of outcomes across multiple sources, as well as the relevance of the populations studied.

Germany now requires insurance coverage of metformin for the new indication of preventing long COVID.

Pharmacy Times: Are there specific patient populations—beyond those already on metformin for diabetes—who you believe stand to benefit most from early metformin initiation during acute COVID-19, and are there any contraindications clinicians should be mindful of?

Bramante: All 4 studies in the table below were in patients without diabetes because metformin is the first-line medication for treating diabetes—so most individuals with diabetes are already taking metformin and are thus not eligible for an RCT of metformin.

The patient populations in those studies are low-, standard-, and high-risk adults (all adults). Including those with and without vaccination and those with and without prior infection.

The first RCT only included adults with overweight/obesity (a body mass index (BMI) > 25 kg/m²), but the ACTIV-6 RCT gave critical confirmation of the COVID-OUT results and expanded them to adults with a normal BMI or greater.

The clinical trials excluded adults over [85 years of age], so I would use caution when using metformin to treat acute SARS-CoV-2 in adults over age 85.

Observational studies in individuals with diabetes have shown similar benefits for protection with metformin in those who were taking metformin before their infection to treat their diabetes. In fact, several meta-analyses in individuals with diabetes have shown a high certainty of evidence for preventing mortality from COVID-19.

Pharmacy Times: With two independent randomized trials and electronic health record analyses now pointing in the same direction, what would it take for metformin to move from a research finding into formal clinical guidelines for long COVID prevention?

Bramante: Long COVID was not an outcome when clinical guideline committees were first created. It could be an outcome in future iterations of outpatient SARS-CoV-2 treatment guidelines.

REFERENCES

1. Bramante CT, Stewart TG, Boulware DR, et al. Metformin on the presence of COVID-19 symptoms 6 months after infection: the ACTIV-6 randomized clinical trial. Clin Infect Dis. 2026;ciag335. doi:10.1093/cid/ciag335

2. University of Minnesota Medical School. New study shows metformin given during acute COVID-19 infection reduced risk of clinician-diagnosed long COVID by 50%. EurekAlert! Published June 11, 2026. https://www.eurekalert.org/news-releases/1131805

3. Bramante CT, Buse JB, Liebovitz DM, et al; COVID-OUT Study Team. Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial. Lancet Infect Dis. 2023;23(10):1119-1129. doi:10.1016/S1473-3099(23)00299-2