Can Cholesterol Drugs and Antihistamines Fight COVID-19?

John Whyte, MD, MPH; Yaakov (Koby) Nahmias, PhD


July 29, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

  • Studying primary human lung cells that were infected in the lab with SARS-CoV-2 showed how the cells began to accumulate large amounts of lipid droplets.

  • After infection, the lung proteins downregulate the ability of lung cells to burn carbohydrates and fatty acids. Lung cells are not designed to hold fat, which could explain some of the severe damage to the lungs of patients with COVID-19.

  • The virus is dependent on glucose uptake, cholesterol production, and fatty acid oxidation.

  • More research is needed on the cholesterol drug fenofibrate before clinical trials can begin.

  • The antihistamine cloperastine, which is mostly sold in Japan, blocks glucose uptake in lung cells and has shown a small effect in fighting COVID-19.

This transcript has been edited for clarity.

John Whyte, MD, MPH: Hi, everyone. I'm Dr John Whyte, chief medical officer at WebMD, and you're watching Coronavirus in Context.

In past episodes, we talked about potential drug treatments for COVID-19. Well, there's a very interesting study on lipid metabolism and a strategy for using cholesterol-lowering medicines in treating COVID-19.

To help share some insights, I've asked Dr Yaakov Nahmias, a professor of bioengineering at the Hebrew University of Jerusalem, to join me today. Thanks for joining us.

Yaakov (Koby) Nahmias, PhD: Hi, John.

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

Nahmias: We didn't start by thinking about lipid metabolism. My partner, Benjamin tenOever, and I were very interested in understanding what the virus does to lung cells. Viruses are parasites and can't replicate by themselves. They have to enter into cells and then change them to make more viruses.

Understanding what the virus does to the host — not in terms of immunology and immune response, but what actually happens on the cellular level — is fundamental to understanding the early pathogenesis of this virus and how we can modulate its replication and growth.

Whyte: We've seen that obesity seems to be a potential risk factor for COVID-19. Is hyperlipidemia related to that?

Nahmias: Early studies show there is a relationship between diabetes and COVID-19. In reviewing SARS-CoV-2 infection, the progression of the symptoms and respiratory failure data, dyslipidemia and hyperglycemia are clearly risk factors..

If controlled, diabetes appears to be disconnected from hyperglycemia. In some cases, obesity causes inflammatory physiology, and that seems to lead to worsening cases. There is a correlation between inflammatory state of the body and worse symptoms, and even earlier correlations between dyslipidemia, hyperglycemia, and worsening symptoms of COVID-19. I think part of our studies actually explain that.

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

Nahmias: We took primary human lung cells — cells from the patient that are not cancer cells. They don't have cancer metabolism; they don't grow all the time. They're more quiescent and mimic the normal response with the full span of the virus 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. We saw the virus proteins actually shut down respiration and downregulate the ability of the cells to burn carbohydrates and fatty acids.

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

Whyte: How does this relate to potential drug treatment? You've talked about a couple different drugs, including antihistamines and antitussives. Tell us where the research might be headed.

Nahmias: 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 and mutates fast, but human proteins don't.

There are a couple of places where we identified weak spots. Glucose uptake, cholesterol production, and fatty acid oxidation are three targets that the virus is really dependent on. The problem is that when you look at the glucose absorption and the cholesterol pathways, you need a very high concentration of [drugs]. In this case, it was a glucose uptake inhibitor like empagliflozin, or statins. Very high concentrations — they're about 10 times more than the maximum serum concentration (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. Then there are drugs of the fibrate family that activates PPAR-alpha specifically. 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.

Whyte: Are there clinical trials going on right now with the use of fenofibrate?

Nahmias: No, we're still going for ethical approvals. 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 has been protective or effective. And then we hope to go into a clinical study in a few weeks.

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

Nahmias: Cloperastine is an antihistamine, but it has another effect. It is actually an SGLT1 inhibitor. It blocks glucose uptake into lung cells. We are very interested in it because it's a cough suppressant; it's an antihistamine. It's already the right indication, like fenofibrate and dyslipidemia. It's readily available, even though it's mainly sold in Japan. It can actually block glucose absorption into the cells and it's effective. We see a 20% or 30% reduction in the virus, but it's nothing to write home about.

The biggest effect was around the fibrate family. A PPAR-alpha agonist, specifically fenofibrate, is the one that we tested.

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? You're looking at a totally different potential treatment strategy than some other folks are around the world.

Nahmias: I'm an engineer. Because of that, I have a slightly different perspective. I'm trying to understand the machine before I'm trying to figure out how to make it stop working in this case.

Whyte: And the cell is the machine here, right?

Nahmias: Right, the cell is the machine. I think that we are going to end up having an array of tools. There might be a drug that the general population is taking that is high-safety and low-risk that can suppress some of the symptoms of COVID-19. Then we have people who are infected and essentially have a common cold, right? Once these patients are on respirators, fenofibrate or fibrates are off the table. They are not IV drugs.

Dexamethasone is definitely on the table, and some of the new antivirals are definitely on the table. The problem is that these are higher-risk drugs. If you're trying to target a protease or a polymerase, you're going to have side effects. But they are useful if there is already respiratory failure.

The other tool is a vaccine. If we can vaccinate at least the older population that is most at risk, then we're going to have a multilayered approach to handle this pandemic for years to come.

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

Nahmias: It's anybody's guess. I hope we'll have information in about 2-3 months, right before the winter.

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

Nahmias: I'm not a clinician, and it's not my job to give clinical advice to patients. They 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 indications right now emerging in the literature about fasting and COVID-19. It makes sense; it's the same pathway. Fasting increases PPAR-alpha. Definitely controlling your glucose and lipid levels is very important.

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

Nahmias: Sounds great. Thank you very much, John.

Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.