LONG COVID is a condition in which individuals continue to experience symptoms such as fatigue, shortness of breath, and cognitive difficulties weeks or months after the acute SARS-CoV-2 infection has resolved. While vaccines reduce severe disease, effective strategies to prevent long COVID remain limited. Recent research highlights that the common diabetes medication metformin, when taken during acute infection, may offer protection against this debilitating condition.
Repurposing Metformin for Viral Infection
Metformin has been widely used for type 2 diabetes since the mid-20th century due to its safety, tolerability, and low cost. Early research also indicated antiviral and anti-inflammatory properties, prompting investigators to explore whether metformin could prevent long-term COVID-19 sequelae. Two large randomised clinical trials, COVID-OUT and ACTIV-6, tested metformin in non-hospitalised adults with acute SARS-CoV-2 infection. Both trials enrolled participants across a range of risk levels, including vaccinated individuals and those infected with the Omicron variant.
Reduced Risk of Long COVID
In the COVID-OUT trial, participants who started metformin at the onset of COVID-19 symptoms had a 41% lower risk of developing long COVID over 10 months. Starting metformin within three days of symptom onset further reduced risk by 63%. These findings were corroborated by the ACTIV-6 trial, which included adults with normal body mass index and prior infections, reporting a 50% reduction in long COVID diagnoses compared to placebo. Target trial emulations using electronic health records confirmed these protective effects across diverse populations.
Safety and Tolerability
Both trials found metformin to be highly tolerable in the short-term, with minimal side effects. Gastrointestinal symptoms were mild, and episodes of hypoglycaemia were rare and comparable to placebo. No serious adverse events were reported, and the drug was compatible with standard COVID-19 therapies, including nirmatrelvir-ritonavir.
Clinical Implications
These results support the early administration of metformin in outpatient adults with acute SARS-CoV-2 infection as a practical strategy to prevent long COVID. Clinicians can consider prescribing metformin safely without extensive monitoring, particularly for patients at high risk of prolonged post-COVID symptoms. Adding metformin to clinical guidelines could improve long COVID prevention and disseminate evidence-based care to wider populations.
Reference
Bramante CT, Boulware DR. Preventing long COVID with metformin. Clin Infect Dis. 2026; doi:10.1093/cid/ciaf700.
