• Early studies show a link between high cholesterol and blood fats (dyslipidemia) and worsening symptoms of COVID-19.
  • The link between cholesterol and COVID has prompted researchers to look at how cholesterol-lowering drugs might fight the virus.
  • When scientists mixed samples of healthy lung cells with the virus in a lab, they discovered a massive build up of bad cholesterol and blood fats in the infected cells. 

Video Transcript

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JOHN WHYTE: Hi, everyone. I'm Dr. John Whyte, chief medical officer at WebMD, and you're watching Coronavirus in Context. We spent a lot of episodes talking about, potentially, different drug treatments for COVID-19. Well, there's a very interesting study going on about the role of lipid metabolism, and is there a strategy for some cholesterol-lowering medicines in the treatment of COVID-19? To help share some insights, I've asked Dr. Yaakov Nahmias, who is professor of bioengineering at the Hebrew University of Jerusalem. Thanks for joining me today.

YAAKOV NAHMIAS: Hi, John.

JOHN WHYTE: Let's start off by talking about what made you think about lipid metabolism as a potential strategy in addressing COVID-19.

YAAKOV NAHMIAS: So, honestly, we didn't start by thinking about lipid metabolism. My partner, Benjamin [INAUDIBLE], and I, were very interested in trying to understand, what does the virus do to lung cells? Viruses are parasites. They can't replicate by themselves. They have to enter into cells and then change them to make more viruses.

So understanding what the virus does to the host-- not in terms of immunology and immune response and everything else, but actually what happens on the cellular level-- what I think is fundamental to understanding some of the early pathogenesis of this virus, and then, you know, how we can modulate its replication, its growth.

JOHN WHYTE: Now, we've seen that obesity seems to be a potential risk factor for COVID-19. Is hyperlipidemia related to that?

YAAKOV NAHMIAS: So there are-- early studies show there is a relationship between diabetes and COVID-19-- essentially, the disease-- not the infection-- not SARS-CoV-2 infection-- but actually the progression of the symptoms and respiratory failure. So dyslipidemia and hyperglycemia are clearly risk factors from all of the studies.

Diabetes, per se, if it's controlled, appears to be disconnected from hyperglycemia. Obesity causes, in some cases, you know, inflammatory physiology. And that seems to lead to worsening cases. So there is a correlation between inflammatory state of the body and worse symptoms. But [INAUDIBLE] even in earlier correlations between dyslipidemia and hyperglycemia and worsening symptoms of COVID-19. And I think part of our studies actually explain that.

JOHN WHYTE: Tell us a little more about your study and where it is.

YAAKOV NAHMIAS: So what we did is we took primary human lung cells-- so cells from the patient, cells that are not cancer cells. They don't have cancer metabolism. They don't grow all the time. They're more quiescent, and they really mimic the normal respons-- with the full span of the virus from-- that was isolated from patients in New York.

When you infect the lung cells, one of the things that you see is that the cells start accumulating massive amounts of lipids. You see lipid droplets, and you see a lot of membranes. The membranes are the areas where the virus production factory is created. And it seems like the vi-- we saw the virus proteins actually shut down respiration and down-regulate the ability of the cells to burn carbohydrates and burn fatty acids.

So the cells-- the lung cells-- by themselves, take more carbohydrates from the blood and start synthesizing this massive amount of fat inside the lung cells. And obviously, lung cells are these thin epithelial cells. They are there to transport oxygen and transport CO2. They can't hold fat. It's not the liver. It's not the fat issue. So that might explain some of the horrible damage we see in lung-- in patient lungs. And indeed, we saw the same transcriptomic signature in biopsies from COVID-19 patients.

JOHN WHYTE: And then how does this relate to potential drug treatment? You've talked about a couple different drugs, including some that are antihistamine, antitussives. Tell us where the research might be headed.

YAAKOV NAHMIAS: So If you know what the virus is doing inside the cells, you can try to block these pathways. And there is less chance of escape mutations. The virus replicates very, very fast-- mutates fast. But human proteins don't. And there are a couple of places that we identified-- weak spots. You know, glucose uptake, cholesterol production, and fatty acid oxidation--

JOHN WHYTE: Right.

YAAKOV NAHMIAS: --are these three targets that are-- the virus is really dependent on. The problem is that when you look at the glucose absorption in the cholesterol pathways, you need a very high concentration of-- in this case, it was a glucose uptake inhibitor--

JOHN WHYTE: Mm-hmm.

YAAKOV NAHMIAS: --like [INAUDIBLE] or, you know, statins-- very high concentrations. They're about 10 times more than Cmax. So 10 times more than you see in patients that actually take these drugs. However, if you look at fatty acid oxidation, it's like the virus is shutting down PPAR-alpha. And then there are drugs of the fibrate family that activates PPAR-alpha specifically. And it seems like they are working at a concentration that is essentially Cmax-- essentially what patients already see when they take a high dose of fenofibrate. JOHN WHYTE: Now, are there clinical trials going on right now-- the use of fenofibrate?

YAAKOV NAHMIAS: Now, we're still going for ethical approvals. So there are-- you know, we are writing down the protocols and trying to come to an understanding with a couple of medical centers, both in Israel and the United States. We are gathering retrospective data right now, because even though bezafibrate and fenofibrate are taken by a very small percentage of the population-- in Israel, it's about 1.6%-- it's still there. So we're trying to see, retrospectively, whether it is-- it has been protected or effective. And then we hope to go into a clinical study in a few weeks.

JOHN WHYTE: Did you have anything, also, about antitussants and antihistamines as well? What's the role of cloperastine in this?

YAAKOV NAHMIAS: Right. So cloperastine is an antihistamine, but it has another effect. It is actually an SGLT1 inhibitor.

JOHN WHYTE: OK. Mm-hmm.

YAAKOV NAHMIAS: It blocks glucose uptake into lung cells. So we are very interested in it, because, well, it's a cough suppressant. It's an antihistamine. So it's already the right indication, like fenofibrate and dyslipidemia. it's readily available, even though it's mainly sold in Japan.

And-- but it's-- but it can actually block glucose absorption into the cells. It's there. It's effective. We see, like, a 20%, 30% reduction in the virus. But it's nothing to write home about. So the biggest effect was around the fibrate family. So PPAR-alpha agonist, specifically fenofibrate is the one that we tested [INAUDIBLE].

JOHN WHYTE: Do you think COVID-19 is a disease that's going to end up needing to be treated like we do HIV, where there's going to be multiple drug therapy? 'Cause you're looking at a totally different potential treatment strategy than some other folks are around the world.

YAAKOV NAHMIAS: Right. So I'm an engineer. And because of that, I have a slightly different perspective. You know, I'm trying to understand the machine before I'm trying to figure out how to make it stop working, in this case.

JOHN WHYTE: And the cell is the machine here, right?

YAAKOV NAHMIAS: Right, the cell is the machine. And I think that we need-- we are going to end up having an array of tools. There might be a drug that, you know, the general population is taking that is very low-- that is very high-safety, low-risk, that can suppress some of the symptoms of COVID-19. And then we just have-- you know, people that are infected and essentially have a co-- you know, like, a common cold, right? And then once these patients are on respirators, you know, fenofibrate, or fibrates, are off the table. You know, they are not IV drugs, right?

JOHN WHYTE: [INAUDIBLE]

YAAKOV NAHMIAS: So dexamethasone is definitely on the table, and some of the, you know, antivirals-- the new antivirals-- are definitely on the table. The problem is that these are higher-risk drugs. Probably going to have-- if you're trying to target [INAUDIBLE], you're going to have side effects. But you know, that's useful if it's already respiratory failure.

And then the other tool is, obviously, a vaccine. So if we can vaccinate at least the older population, the risk-- the population that is at-risk-- then we're going to have, you know, a multi-layered approach to handle this pandemic for years to come.

JOHN WHYTE: So you're just starting to seek approval for trials. When do you think you'll have more information?

YAAKOV NAHMIAS: Ah, anybody's guess. I'd hope to do it in about-- I hope we'll have information in about two to three months.

JOHN WHYTE: OK.

YAAKOV NAHMIAS: And then that means right before the next winter.

JOHN WHYTE: For those patients that have high cholesterol, high lipids, should they be doing anything differently right now?

YAAKOV NAHMIAS: Well, I'm not a clinician, and it's not my job to give clinical advice to patients. They sh-- always should consult their primary care physicians. That has to be said. High cholesterol and hyperglycemia are risk factors for many diseases. SARS-CoV-2 infection-- COVID-19-- is only one of them. So yes, they should definitely do something about that. I think that's not under debate.

There are, you know, indications right now emerging in the literature about fasting and COVID-19. And it makes sense. It's the same pathway. Fasting increases PPAR-alpha. And then-- but definitely, you know, controlling your glucose level, controlling your lipid levels, is very, very important for [INAUDIBLE].

JOHN WHYTE: Well, Dr. Nahmias, I want to thank you for taking the time today to share your insights. And hopefully, we can check in with you in a couple of months to see how your research is progressing.

YAAKOV NAHMIAS: Sounds great. Thank you very much, John.

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