Statins Reduce COVID-19 Severity by Removing Cholesterol Used by SARS-CoV-2 to Infect Cells

Researchers analyzing anonymized patient medical records have discovered that cholesterol-lowering statins reduced risk of severe COVID-19 infection, while lab experiments have uncovered a cellular mechanism that helps explain why.

Researchers from the UC San Diego Health (San Diego, CA, USA) have reported that statins - widely used cholesterol-lowering medications - are associated with reduced risk of developing severe COVID-19 disease, as well as faster recovery times. A second research team at UC San Diego School of Medicine (San Diego, CA, USA) has uncovered evidence that helps explains why: In short, removing cholesterol from cell membranes prevents the coronavirus from getting in.

The team retrospectively analyzed the electronic medical records of 170 patients with COVID-19 and 5,281 COVID-negative control patients hospitalized at UC San Diego Health between February and June 2020. They collected anonymized data that included the patients’ disease severity, length of hospital stay, outcome, and use of statins, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) within 30 days prior to hospital admission. Among the patients with COVID-19, 27% were actively taking statins on admission, while 21% were on an ACE inhibitor and 12% on an ARB. The median length of hospital stay was 9.7 days for patients with COVID-19. The researchers found that statin use prior to hospital admission for COVID-19 was associated with a more than 50% reduction in the risk of developing severe COVID-19, as compared to those with COVID-19 but not taking statins. Patients with COVID-19 who were taking statins prior to hospitalization also recovered faster than those not taking the cholesterol-lowering medication.

Another team from the UC San Diego School of Medicine was studying which genes are switched “on” in human lung cells in response to SARS-CoV-2 infection. They found a gene called CH25H which encodes an enzyme that modifies cholesterol. CH25H’s enzymatic activity produces a modified form of cholesterol called 25-hydroxycholesterol (25HC). In turn, 25HC activates another enzyme called ACAT, found inside cells in the endoplasmic reticulum. ACAT then depletes accessible cholesterol on the cell’s membrane. This normally occurring process gets kicked into high gear during some viral infections. The team quickly got to work examining 25HC in the context of SARS-CoV-2 from several angles. They explored what happens to human lung cells in the lab with and without 25HC treatment when they are exposed to first a noninfectious virus that carries the SARS-CoV-2 spike protein (its key to cell entry) or to live SARS-CoV-2 virus itself. No matter which way they came at it, added 25HC inhibited the ability of the virus to enter cells, blocking infection almost completely.

While SARS-CoV-2 uses the ACE2 receptor to initially dock on a cell, the study by the UC San Diego School of Medicine suggests that the virus also needs cholesterol (normally found in cell membranes) in order to fuse with and enter the cell. 25HC takes away a lot of that membrane cholesterol, preventing viral entry. In a similar way, statins are likely beneficial in preventing or reducing the severity of SARS-CoV-2 infection because, while intended to remove cholesterol from blood vessels, they are also removing cholesterol from cell membranes. As a result, the coronavirus cannot get in. The researchers believe that if 25HC can be developed into a therapeutic, then it might work even better as an antiviral than statins as it works specifically on cholesterol in cell membranes, rather than cholesterol throughout the body.

“We found that statins are not only safe but potentially protective against a severe COVID-19 infection,” said Lori Daniels, MD, professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health. “Statins specifically may inhibit SARS-CoV-2 infection through its known anti-inflammatory effects and binding capabilities as that could potentially stop progression of the virus.”

“I tell my patients who are on statins, ACE inhibitors or other ARBs to keep taking them,” added Daniels. “Fears of COVID-19 should not be a reason to stop, if anything our research findings should be incentive to continue with their medication.”

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UC San Diego Health
UC San Diego School of Medicine