How Nonstatin Drugs Lower Cholesterol

Let's go on to another question that actually has to do with changing lipids. Alex asked the question about considering my APOE4 status, whether or not I've looked at PCSK9 inhibitors as an alternative to statins to prevent atherosclerosis and cardiovascular disease later in life. Is there enough long-term data on PCSK9 inhibitors to rule out things like other potential adverse events, like, for example, Alzheimer's disease risk, which is something you get with statins, particularly if you have an APOE4 allele?

I'm going to talk a little bit about the PCSK9 inhibitors, but not as much as a couple of others because it is a very expensive drug. It's highly effective and it's pretty expensive, and there's really no side effects. Most of the time it's not covered by insurance unless there's an adverse reaction to statins. Perhaps that is one case where insurance companies will cover PCSK9 inhibitors, but it's like $500 a month. A lot of people can't afford it.

Its mechanism of action: it removes apoB particles in plasma via LDL receptors, which the liver internalizes upon binding to the LDL particle. Basically, when you're having these PCSK9 inhibitors, you're decreasing the LDL receptor degradation. There's essentially more LDL receptors that are pulling in these apoB particles, clearing them from your circulation. It's a pretty clean effect with respect to the mechanism of action.

There's a variety of clinical trials that have been done looking at follow-up. It's been around—I mean, some of the longest follow-up I'm seeing is 26 months, and the only adverse events that are noted, they're due to adverse reactions to the injection site. Really, it doesn't seem to have adverse effects in the majority of using them.

I do want to discuss a couple of other options that Peter also brought up on the podcast that I thought were very interesting. Bempedoic acid was one. It's what Peter calls a prodrug. This is something that after you take it, then it's metabolized to something that's more of an active drug in the body, but initially it's inactive. Once you ingest it, it goes to the liver where it's then metabolized into an active drug form.

What happens is in the active form, bempedoic acid inhibits cholesterol synthesis only in liver cells. It's only doing it in your liver cells, which are hepatocytes. It's not like statins where it's affecting other cells as well. It has a very targeted effect, and that really distinguishes it from statins with respect to it only affecting the liver. It's reducing the liver's ability to produce cholesterol. In response to that, the liver then also increases the number of LDL receptors on its cell surface to capture more LDL from blood, which in turn lowers cholesterol levels. It's essentially doing something similar to the PCSK9 inhibitors with respect to increasing the number of LDL receptors, which are essentially then lowering the number of apoB LDL particles in circulation.

It's acting specifically in the liver, not in other parts of the body. It really has fewer side effects because of that reason, particularly when you're comparing it to something like statins, which can affect every cell in your body, and there are a variety of side effects, and it's targeting mitochondria, which is not good. The bempedoic acid is only affecting the liver cells, and it really does seem to have an impact on apoB. That is, I think, another potential option for people wanting to discuss a variety of lipid-lowering drugs with their healthcare provider to see if they could do something that perhaps has less side effects and even long-term effects than statins.

I'm not going to go into all the randomized controlled trials with bempedoic acid, but there are quite a few. There's not as many long-term studies as, for example, statins, but it does look very promising in my opinion, looking at it. It certainly isn't going to lower apoB as much as statins, but it seems like it does a pretty good job, especially for people that are looking for just that little push, the little extra lowering of apoB without negative side effects.

There's been some long-term safety and efficacy data with bempedoic acid, and it seems like really it's pretty well tolerated for up to at least what has been studied, which is 130 weeks. The most frequent adverse effect during the study was related to muscle spasms, but it was mostly people that were taking other drugs at the same time.

The other thing to consider with bempedoic acid is it can raise the amount of uric acid. People that are prone to gout—high levels of uric acid can lead to gout. That is something to keep in mind, particularly in people that are already predisposed to gout. Obviously, measuring, monitoring uric acid levels is important for anyone that is going to be using bempedoic acid to make sure that your uric acid levels aren't going too out of range. I think that's probably the biggest consideration with bempedoic acid is the uric acid.

The last lipid-lowering drug I wanted to talk about was ezetimibe. Ezetimibe works by blocking the absorption of cholesterol that comes from food, and also the cholesterol produced in the liver. It's doing both, and it also does affect some absorption of plant sterols, which are kind of similar to cholesterol. It works in the small intestine, on a certain protein that's in the small intestine that's crucial for cholesterol absorption. That's basically what it's doing is kind of blocking the levels of this protein called NPC1L1. In turn, when it inhibits that protein, that then blocks the absorption of cholesterol as well as plant sterols in your enterocytes. That overall then leads to a decrease in cholesterol levels that are delivered to the liver and therefore reduced liver cholesterol stores in general.

The efficacy of ezetimibe has been shown to be about 54%. There's been some additional health benefits as well to ezetimibe, including reducing inflammatory biomarkers and improving insulin resistance and also fatty liver. Now, this is in contrast to statins, which increase insulin resistance. If you look at the data out there, it seems like ezetimibe is a pretty safe, well-tolerated drug. It's less potent than statins in terms of lipid-lowering effects, but it also seems to have a really good safety profile.

Most of the time people are prescribed ezetimibe along with something else, but it can be used as a monotherapy, again for people that are just looking to get a little bit more of that lipid-lowering effect, getting their apoBs just a little bit lower. I'm not going to go through all the clinical studies on that as well, but again, it seems to be pretty well tolerated, pretty safe, and again, it does have an effect on lowering apoB as well.

Squashy is asking in the chat if there's any effect of bempedoic acid on increasing HbA1c, which I haven't seen. I haven't seen any increases in HbA1c. It's really just the uric acid with the bempedoic acid. And then with the ezetimibe, it seems to improve glucose regulation, which is kind of an added benefit as well.

There's really no—Bobby's asking about all-cause mortality. There's no all-cause mortality that I've seen yet on PCSK9 inhibitors and some of these newer drugs, but that's not to say that there won't be. Certainly, if you're lowering apoB, you would imagine that would have a beneficial effect on all-cause mortality, certainly on cardiovascular-related mortality, which is a major contributor to all-cause mortality.