COVID-19 Treatments: Studies By University Of California Show That Statin Usage Reduces COVID-19 Severity And Indirectly Affects Virus Cell Entry
: Two new studies by researchers from the University of California-San Diego show that statin usage is linked to a lower risk of developing COVID-19 severity and that removing cholesterol from cell membranes prevents the virus from getting into these cells.
Furthermore there is some biologic plausibility for a protective role of statins in COVID-19 through known anti-inflammatory and immunomodulator effects.
The research findings on statin usage and reduced COVID-19 severity are published in the American Journal of Cardiology. The clinical study was led by Dr Lori Daniels, MD, Professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health, and Dr Karen Messer, Ph.D., Professor and chief of the Division of Biostatics and Bioinformatics in the Department of Family Medicine and Public Health. https://www.ajconline.org/article/S0002-9149(20)30947-4/fulltext
While the research papers on the mechanistic study led by by Dr Tariq Rana, Ph.D., Professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center are published in the EMBO Journal. https://www.embopress.org/doi/abs/10.15252/embj.2020106057
The University of California-San Diego Health researchers recently reported that statins which are widely used cholesterol-lowering medications are associated with reduced risk of developing severe COVID-19 disease, as well as faster recovery times.
Another study team at UC San Diego School of Medicine has uncovered evidence that helps explains why: In short, removing cholesterol from cell membranes prevents the coronavirus from getting in.
The ACE2 enzyme which resides on the outer surfaces of many human cells, helps regulate and lower blood pressure but at the same time can be affected by prescription statins and other medications used for cardiovascular disease.
In mid-January 2020, scientist discovered that the SARS-CoV-2, the coronavirus that causes COVID-19 primarily uses the receptor to enter lung cells and establish respiratory infections.
Lead researcher for the first study, Dr Daniels told Thailand Medical News, "When faced with this new coronavirus at the beginning of the pandemic, there was a lot of speculation surrounding certain medications that affect ACE2, including statins, and if they may influence COVID-19 risk. We needed to confirm whether or not the use of statins has an impact on a person's severity of SARS-CoV-2 infection and determine if it was safe for our patients to continue with their medications."
In order to do this the study 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.&l
It was found that among the patients with COVID-19, 27 percent were actively taking statins on admission, while 21 percent were on an ACE inhibitor and 12 percent on an ARB. The median length of hospital stay was 9.7 days for patients with COVID-19.
The study team discovered that statin use prior to hospital admission for COVID-19 was associated with a more than 50 percent reduction in risk of developing severe COVID-19, compared to those with COVID-19 but not taking statins.
Significantly, it was also found that patients with COVID-19 who were taking statins prior to hospitalization also recovered faster than those not taking the cholesterol-lowering medication.
Dr Daniels added "We found that statins are not only safe but potentially protective against a severe COVID-19 infection. 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."
However this initial study was relatively small and focused on a single health system. Dr Daniels is now partnering with the American Heart Association to analyze thousands of patients all over the country to corroborate the data she's developed locally.
She further added, "I tell my patients who are on statins, ACE inhibitors or other ARBs to keep taking them. Fears of COVID-19 should not be a reason to stop, if anything our research findings should be incentive to continue with their medication."
In the second study led by Dr Rana, it was found that draining cholesterol from cell membranes blocks SARS-CoV-2 entry.
Initially statins were not yet on Dr Rana's radar when his team began their study approximately six months ago.
Initially, his study team was simply curious to see which genes are switched "on" in human lung cells in response to SARS-CoV-2 infection.
Their focus was initially on a gene called CH25H which encodes an enzyme that modifies cholesterol.
Dr Rana said, "We were excited because with HIV, Zika, and a few others, it was found that CH25H blocks the virus' ability to enter human cells."
Inside human cells, 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. It's a normally occurring process that gets kicked into high gear during some viral infections.
The study 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.
It was found that no matter which way they came at it, added 25HC inhibited the ability of the virus to enter cells blocking infection almost completely.
Dr Rana added, "The difference between untreated cells and those treated with 25HC was like day and night.”
Although the SARS-CoV-2coronavirus uses the ACE2 receptor to initially dock on a cell, Dr Rana's study suggests that the virus also needs cholesterol (normally found in cell membranes) in order to fuse with and enter the cell.
However 25HC takes away a lot of that membrane cholesterol, preventing viral entry.
Hence 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 SARS-Cov-2 coronavirus cannot get in.
Dr Rana said, "This is already happening in our bodies on a regular basis, so perhaps we just need to give it a boost, with statins or by other means, to better resist some viruses. “
Dr Rana suggested that 25HC might work even better as an antiviral than statins if it can be developed into a therapeutic as it works specifically on cholesterol in cell membranes, rather than cholesterol throughout the body.
However like all medications, statins can cause negative side effects, including digestive problems and muscle pains, and may not be an option for many individuals with COVID-19.
Also some previous studies suggested statins may also elevate ACE2 levels, which could allow more viral entry. Dr Rana's team however did not see an increase in the receptor in response to 25HC but further studies are warranted on this.
While statins are FDA-approved for human use, 25HC is a natural product currently available only for laboratory work. Dr Rana and his team plan to continue optimizing 25HC as a potential antiviral agent.
Since 25HC is a natural product with no known toxicity at effective concentrations, it provides a potential therapeutic candidate for COVID‐19 and emerging viral diseases in the future
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