A growing body of randomized clinical trial and real-world evidence suggests that metformin, a widely prescribed biguanide for type 2 diabetes mellitus, may reduce the risk of developing post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as long COVID, when administered early during acute COVID-19.
In an editorial commentary published in Clinical Infectious Diseases, investigators argue that metformin should be considered as an early outpatient intervention in adults with SARS-CoV-2 infection to mitigate long-term morbidity. The commentary synthesizes data from large randomized trials and observational cohorts demonstrating both the safety and potential efficacy of metformin in reducing the incidence of persistent symptoms following COVID-19.
PASC is characterized by prolonged, heterogeneous symptoms, including fatigue, cognitive dysfunction (often described as “brain fog”), dyspnea, and exercise intolerance, that persist for months after acute infection. Despite its clinical burden, no widely accepted preventive pharmacotherapy currently exists.
Although primarily indicated for glycemic control, metformin has well-described pleiotropic effects on cellular metabolism, immune modulation, and inflammation. Biguanides were historically investigated for antimicrobial and antiviral properties, and laboratory studies dating back to the early 2000s demonstrated that metformin can influence host-cell pathways involved in viral replication. Early in the COVID-19 pandemic, in silico modeling, in vitro studies, and observational data suggested potential activity against SARS-CoV-2.
The pivotal COVID-OUT trial, initiated in July 2021, evaluated early outpatient treatment strategies for COVID-19. Because formal definitions of long COVID were still evolving, the primary long-term outcome was clinician-diagnosed PASC, verified through medical records. Over a 10-month follow-up period, metformin was associated with a 41 percent relative reduction in the risk of developing long COVID compared with placebo. Among participants who initiated therapy within three days of symptom onset, the risk reduction reached 63 percent, highlighting the importance of early administration.
Mechanistic support comes from smaller randomized studies demonstrating substantial reductions in SARS-CoV-2 viral load with metformin treatment. One trial reported more than a 93 percent reduction in viral load compared with 78 percent in the placebo group, with faster viral clearance observed in the metformin arm. These findings are consistent with viral kinetics seen in COVID-OUT.
These results were further explored in the ACTIV-6 trial, which included a broader population across BMI categories and allowed prior SARS-CoV-2 infection. Using a similar dosing regimen, ACTIV-6 found no significant safety concerns and estimated approximately a 50 percent lower risk of clinician-diagnosed PASC, although with wider confidence intervals due to statistical uncertainty.
Although long COVID was a secondary outcome in both trials, the consistency across randomized designs, populations, and real-world analyses strengthens the biological and clinical plausibility of benefit. Given metformin’s long-established safety profile, low cost, global availability, and compatibility with other COVID-19 therapies, early use during acute SARS-CoV-2 infection may represent a practical strategy to reduce the burden of long COVID on individuals and health systems.
Reference
- Bramante CT, Boulware DR. Preventing Long COVID With Metformin. Clin Infect Dis. 2026 Jan29;ciaf700.