A 14-day course of metformin, a common drug used to manage type 2 diabetes, prevents long COVID, according to a new study in The Lancet Infectious Diseases.

The promising results come from the COVID-OUT study, which looked at three readily available drugs: ivermectin, fluvoxamine, and metformin, for both COVID treatment and long-COVID prevention. All three drugs had shown antiviral properties in vivo against SARS-CoV-2, and all had been promising medical treatments for the virus, as they are cheap and safe.

Now, more than 2 years after the outpatients trial began, metformin is the only medical intervention in the study shown to prevent long COVID.

The reduction in risk may warrant clinicians using the drug in patients sooner rather than later.

“Without an alternative treatment of SARS-CoV-2 infection to prevent subsequent long COVID, some providers may choose to prescribe metformin to patients presenting with COVID symptoms and a positive COVID test,” lead study author Carolyn Bramante, MD, MPH, an assistant professor of medicine at the University of Minnesota, told CIDRAP News.

“As the pandemic continues, all therapies should be confirmed in clinical trials that enroll individuals with prior infection.”

39% to 63% lower rate of long COVID

The phase 3 trial included 1,200 adult participants (30 to 85 years old) who had never had COVID-19 before. The trial ran from December 2020 through January 2022.

All volunteers were clinically overweight or obese, and were randomized to receive either metformin or placebo, and an additional subset received ivermectin, fluvoxamine, or placebos. Treatment or placebo started when patients had COVID-19 symptoms for less than 7 days and a documented SARS-CoV-2–positive polymerase chain reaction (PCR) or antigen test within 3 days of study enrollment.

Without an alternative treatment of SARS-CoV-2 infection to prevent subsequent long COVID, some providers may choose to prescribe metformin.

A total of 1,126 participants reported their symptoms during a 10-month follow-up. Fifty-six percent of participants were women, the median age was 45 years, and the median body mass index was 29.8.

By day 300 of follow-up, 93 (8.3%) of 1,126 participants said they had received a diagnosis of long COVID by a provider. The cumulative incidence of long COVID by day 300 in those who took a 14-day course of metformin was 6.3% (95% confidence interval [CI], 4.2 to 8.2) compared to 10.4% (7.8 to 12.9) in the placebo group, or 39.4% lower.

When metformin was started within 3 days of symptom onset, the hazard ratio was 0.37 for developing long COVID (95% CI, 0.15 to 0.95), or a 63% lower risk.

“There was no effect on cumulative incidence of long COVID with ivermectin (HR 0.99, 95% CI 0.59 to 1.64) or fluvoxamine (1.36, 0.78 to 2.34) compared with placebo,” the authors said. “Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4.1%, compared with placebo.”

Metformin reduces viral load

According to Bramante, the antiviral properties of metformin likely helped prevent long COVID in study participants, about half of whom were unvaccinated. Participants who received metformin were also less likely to be hospitalized by day 28 than those who received placebo (8 [1.3%] of 596, compared with 19 [3.2%] of 601; HR, 0.42; 95% CI, 0.18 to 0.9).

“The antiviral effect of metformin in unvaccinated participants was similar to Paxlovid when tested in unvaccinated persons,” Bramante said. “There may be additional mechanisms of action, as metformin has been shown to reduce inflammation and neuroinflammation.”

Eric Topol, MD, director of the Scripps Research Translational Institute, said that metformin’s benefit is at least partly mediated by a near fourfold reduction in viral load.

We need to see it replicated, especially among vaccinated individuals, and to determine the additive benefit with Paxlovid.

“If that is indeed the driver,” Topol told CIDRAP News, “then we would expect it to be beneficial in a wider group of people than tested. We need to see it replicated, especially among vaccinated individuals, and to determine the additive benefit with Paxlovid.”

Results confirm long COVID exists

In a commentary on the study, Jeremy Faust, MD, MS, from Harvard University said the study is a landmark for two reasons: First, metformin could become the first medical prevention for long COVID, and second, the difference in outcomes in and of itself confirms the existence of long COVID.

“Treatment can only be effective if there is something to treat,” Faust wrote. “Even with definitions as amorphous and heterogenous as those currently in use for diagnosing long COVID, there was to be found within this study population an ample cohort of individuals with syndromes similar enough that disease incidence could be modified, and metformin appeared to achieve that.”

“The results of this study are important because long COVID can have a significant impact on people’s lives,” Bramante said in a University of Minnesota news release. “Metformin is an inexpensive, safe and widely available drug, and its use as a preventive measure could have significant public health implications.

“This long-term outcome from a randomized trial is high-quality evidence that metformin prevents harm from the SARS-CoV-2 virus.”

Read More