New review highlights growing evidence that diabetes drug metformin can prevent long COVID

Multiple randomized clinical trials and analyses of electronic health records (EHRs) suggest that metformin, a widely available diabetes drug, may reduce the risk of developing long COVID when taken during or shortly after acute COVID-19 infection, according to a literature review published last week in Clinical Infectious Diseases.

The review, written by University of Minnesota Medical School researchers Carolyn T. Bramante, MD, MPH, and David R. Boulware, MD, MPH, was commissioned to comment on a recent population-based cohort study by Ubonphan Chaichana, MSc, and colleagues and to situate the findings within a widening body of evidence that suggests metformin use during COVID infection can substantially reduce the risk of developing long COVID. 

The Chaichana study looked at overweight or obese people and found a strong protective association between metformin use and reduced risk of long COVID.

Possible 40% to 60% lower long-COVID risk in adults

The studies reviewed, including randomized controlled trials and EHR reviews, suggest that starting metformin during or shortly after acute SARS-CoV-2 infection lowers the risk of clinician-diagnosed long COVID by roughly 40% to 60%.

The authors emphasize that none of the studies examined metformin as a treatment for already-established long COVID. Rather, they focused on prevention and whether use of the drug during acute infection could reduce the likelihood of developing persistent post-COVID symptoms.

“That’s an important point,” Bramante told CIDRAP News. “None of the four studies that we wrote the editorial on were studying long COVID treatment. They address preventing long COVID.”

The earliest randomized trial included in the review, the 2021 COVID-OUT study, found a 41% lower risk of long COVID among participants who received metformin during acute infection. But defining and measuring long COVID posed challenges early in the pandemic, complicating interpretation and comparison across studies.

“The issue is that long COVID is a new disease, and the whole biomedical research community has grappled with how to define it,” says Bramante. “So for the first clinical trial, we asked participants, ‘Has a clinician diagnosed you?’”

Relying on clinician diagnosis rather than symptom surveys allowed the results to be replicated in EHR reviews and larger trials conducted later. “The big news now is that this has been replicated in these additional studies.”

Replication is a central theme of the commentary. Subsequent trials expanded participant eligibility, enrolling adults of any body mass index and those with prior COVID infection. The trials and EHR analyses confirmed similar risk reductions in real-world settings.

“This effect—that starting metformin during acute infection is safe and reduces the risk of developing long COVID by about half—has been replicated in multiple studies,” says Bramante. “And these results are relevant to most people getting infected today.” 

Potential reduced viral load during acute infection

The literature review also looked at some short-term outcomes of taking metformin, and the findings suggest that the drug may affect the course of acute COVID infection itself. In a small randomized trial, participants who received metformin had a larger reduction in viral load (93%) than those given placebo (78%). 

Participants receiving metformin also reached an undetectable viral load several days sooner than those who didn’t. Similar antiviral effects were observed in the COVID-OUT trial, in which metformin recipients had lower viral loads than those assigned to placebo.

A “longer follow-up could determine if the ability to decrease viral replication of MG would have an implication on subacute and/or chronic complications of the COVID-19 patients.”

An unexpected treatment for a viral infection

The review also addresses why the findings have been slow to translate into clinical practice. Metformin, a decades-old generic diabetes drug, is not an intuitive antiviral, Bramante notes, and its potential role in addressing viral infections has largely flown under the radar. 

“This idea of using a chronic diabetes med to treat viral infections is a foreign idea and seems nonsensical,” she says. 

Metformin is low-cost drug with a high safety profile, and it’s compatible with other antiviral therapies, such as nirmatrelvir-ritonavir (Paxlovid), notes Bramante, which makes a strong case for considering the drug as part of outpatient management aimed at preventing long COVID.