A multi-institution team led by researchers at UC San Diego School of Medicine published a study Tuesday which found a common diabetes drug, when used in animal studies, prevents pulmonary or lung inflammation in animals infected with SARS-CoV-2, the virus that causes COVID- 19.
Metformin is a widely prescribed blood sugar-lowering drug. It is often used as an early therapy — in combination with diet and lifestyle changes — for type 2 diabetes, which afflicts more than 34 million Americans.
Metformin works by lowering glucose production in the liver, reducing blood sugar levels that, in turn, improve the body's response to insulin. But scientists have also noted that metformin possesses anti-inflammatory properties, though the basis for this activity was not known.
In a study published online Tuesday, the researchers identified the molecular mechanism for the anti-inflammatory activity of metformin in mouse studies.
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Over the past year, several retrospective clinical studies reported that metformin use by diabetic and obese patients prior to hospital admission for COVID-19 correlated to reduced severity and mortality. Both diabetes and obesity are recognized risk factors for COVID-19, and are linked to more severe outcomes. Notably, other drugs used to control blood sugar levels do not appear to produce a similar effect.
But while these clinical studies suggested metformin's anti- inflammatory activity could be responsible for reduced COVID-19 severity and mortality, none of the studies offered an explanation or prompted large, randomized clinical trials needed for obtaining conclusive answers.
"The clinical studies were plagued by confounders that made conclusions hard to reach," said corresponding study author Michael Karin, professor of pharmacology and pathology and chair for mitochondrial and metabolic diseases at UCSD School of Medicine. "There was some skepticism in their findings. And because metformin is an out-of-patent, low-cost drug, there is little impetus to conduct large-scale trials, which are quite expensive."
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Karin — with co-senior author Elsa Sanchez-Lopez, an assistant professor at the department of orthopedic surgery and postdoctoral fellow Hongxu Xian — turned their focus to a mouse model of acute respiratory distress syndrome, a life-threatening condition in which fluids leak into the lungs, making breathing difficult and restricting oxygen supply to essential organs.
ARDS is triggered by trauma and by bacterial or viral infections. It is a frequent cause of death in patients hospitalized with COVID-19. The researchers found that metformin administered to mice prior to or after exposure to bacterial endotoxin, a surrogate for bacterial pneumonia, resulted in the inhibition of ARDS onset and lessening of its symptoms.
Working with colleagues at The Scripps Research Institute, the UC San Diego researchers confirmed that metformin prevented SARS-CoV-2-induced pulmonary inflammation in mice.
