Metformin Cuts Long COVID Risk by Half in New ACTIV-6 Trial Results

New evidence from the ACTIV-6 randomized clinical trial, recently published in Clinical Infectious Diseases, suggests that a common and inexpensive medication may significantly reduce the long-term burden of the pandemic. Metformin, a staple in diabetes management for decades, demonstrated a 50% relative reduction in the risk of clinician diagnosis.^1,2

Long COVID when administered during the acute phase of a COVID-19 infection. This finding provides a potential pharmaceutical tool for a condition that currently lacks any FDA-approved treatments specifically designed for its prevention or cure.^1,2

"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," Carolyn Bramante, MD, MPH, assistant professor at the University of Minnesota Medical School, said in the news release.² "The finding is particularly important because metformin is inexpensive, globally available, and has decades of clinical use supporting its safety."

About the Trial on Long COVID

Long COVID, formally known as post-acute sequelae of SARS-CoV-2 (PASC), is an infection-associated chronic condition that can result in profound, life-altering symptoms lasting months or even years. Patients navigating this illness often report a staggering array of over 200 symptoms, most commonly including extreme fatigue, cognitive impairment known as brain fog, shortness of breath, and cardiovascular issues like postural orthostatic tachycardia syndrome. The condition is a serious public health concern, with estimates suggesting that millions of adults and children in the United States have been affected, potentially leading to long-term disability.^3,4

The ACTIV-6 (NCT04885530) trial evaluated nearly 3000 outpatient adults 30 years and older with mild-to-moderate COVID-19 across 90 sites in the United States. This study is particularly relevant to current pharmacy practice because 83% of participants had some form of prior immunity through vaccination, previous infection, or both, reflecting the current state of the global population. Participants were randomized to receive either immediate-release metformin or a placebo within seven days of their initial symptom onset.¹

Although the trial’s primary end point—the total prevention of all self-reported symptoms on day 180—did not meet the strict statistical threshold for efficacy, the results for medical diagnoses were substantial. The study found a high probability of benefit in preventing clinician-diagnosed Long COVID, which occurred in only 0.56% of those receiving metformin compared to 1.17% of those in the placebo group by the 6-month mark. These results replicate findings from the earlier COVID-OUT (NCT04510194) trial, which also reported a similar reduction in long COVID incidence for those treated with metformin during acute infection.^1,2

The Pharmacist’s Role

For pharmacists, the specific 14-day titration regimen used in the trial highlights the practical application of this intervention. The dosing began with 500 mg once daily for 1 day, followed by 500 mg twice daily for 4 days, and concluded with 1500 mg daily—split into 500 mg in the morning and 1000 mg in the evening—for the remaining 9 days. The study reported no safety concerns regarding lactic acidosis and no significant differences in hypoglycemia between the metformin and placebo groups, even among those without a history of diabetes.¹

The biological mechanism behind metformin’s protective effect is believed to involve its host-directed anti-inflammatory actions and its ability to lower the SARS-CoV-2 viral load. Emerging research suggests that the virus may activate the mammalian target of rapamycin complex 1 in the gut, which can damage the epithelial barrier and allow harmful proteins to enter the system. Metformin may inhibit this mTOR signaling while simultaneously promoting the growth of beneficial bacteria that produce short-chain fatty acids, thereby protecting the integrity of the gut and preventing the systemic inflammation often linked to long COVID.¹

Despite these promising results, health officials emphasize that staying up to date with COVID-19 vaccinations remains the most effective primary strategy for preventing long COVID. However, for patients who do become infected, the ACTIV-6 findings offer a safe, globally available, and low-cost intervention that could halve the risk of a chronic, debilitating diagnosis. As frontline providers of medication management and patient education, pharmacists play a vital role in understanding these emerging therapeutic options for a complex condition that continues to evolve.^3-5

“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,” David Boulware, MD, MPH, professor at the University of Minnesota Medical School, said in the news release.²

READ MORE: COVID-19 Resource Center

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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. Published online June 4, 2026. doi:10.1093/cid/ciag335

2. New study shows metformin given during acute COVID-19 infection reduced risk of clinician-diagnosed long COVID by 50%. News release. University of Minnesota Medical School. June 11, 2026. Accessed June 12, 2026. https://www.eurekalert.org/news-releases/1131805

3. Recover COVID. What is Long COVID?. Accessed June 12, 2026. https://recovercovid.org/long-covid

4. CDC. Long COVID Basics. May 6, 2026. Accessed June 12, 2026. https://www.cdc.gov/long-covid/about/index.html

5. Mayo Clinic. Long COVID: Lasting effects of COVID-19. August 23, 2024. Accessed June 12, 2026. https://www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/coronavirus-long-term-effects/art-20490351