Latest therapeutics in CVD, APOE's role in Alzheimer's disease and CVD, familial hypercholesterolemia, and more | John Kastelein, M.D., Ph.D.

**Peter Attia, MD** (0:11)
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Now, without further delay, here's today's episode.
My guest this week is John Kastelein. John is a genetic researcher and clinician scientist known for his work in the field of familial hypercholesterolemia and the development of lipid modulating drugs. He is currently a professor of genetic medicine at the University of Amsterdam, where he leads the Department of Vascular Medicine. John has been the main driving force behind the development of a treatment for homozygous familial hypercholesterolemia, a severe form of FH. Now, some of you may be listening to this saying, what the heck are you talking about? Well, it's important to understand that FH or familial hypercholesterolemia is the second most common form of hereditary heart disease right after elevated LP little a. And you know from probably listening to previous versions of this podcast that elevated LP little a is staggeringly prevalent in the population and by extension, therefore so too is various forms of FH. And while we use FH as an important place to start this discussion, because it becomes an important way to understand therapeutic options, the subject matter that we cover here is of course applicable to anybody who's interested in minimizing their risk of cardiovascular disease. John has also led several clinical trials, including the pivotal Odyssey Long-Term and Odyssey Outcomes studies, which helped to establish the safety and efficacy of PCSK9 inhibitors in the treatment of FH and other forms of hypercholesterolemia.
As I said, we start the discussion by focusing on familial hypercholesterolemia. We talk about what it is, how you define it, how you can be aware if you have this, what the genetics are that underpin it, what we do with kids that have this, et cetera. We then talk about the history of CTEP inhibitors, which is indeed a sordid history. These have been a class of completely unsuccessful drugs that have resulted in much hype and fanfare without any tangible results. However, John makes a pretty compelling case for the most recent version of these drugs to be not only a potential game changer, a word that I hate, for cardiovascular disease, but perhaps even more interestingly for Alzheimer's disease and type 2 diabetes.
This dovetails very nicely into our final topic of discussion, which is that in the role of ApoE. Now, traditionally, when you hear me talk about ApoE, I'm talking about the gene ApoE, and its three isoforms, ApoE2, ApoE3, ApoE4. It's important to understand that, of course, those genes code for a protein that goes by the same name, ApoE, although it is not fully capitalized, and that's how, when you're reading it, you know the difference. What we talk about in this episode is what that actual protein does, and why is it that someone with the ApoE4 gene codes for a version of that protein, which, by the way, only differs in one amino acid from the one coded for by ApoE3, and we talk about why the protein that is coded by the ApoE4 isoform produces a much greater increase in the risk of Alzheimer's disease and cardiovascular disease. What's most interesting to me about all of this is that it ties back very nicely to the discussion of how this most recent CTEP inhibitor might work. And what I'm left with is a sense of profound optimism that sometime in the next five years, we may indeed have therapeutic molecules that we can use specifically for high risk patients such as those with ApoE4. So overall, I would say this discussion surprised and delighted me much more than I expected. And I know that even though it's a technical topic, it is something that is going to be of great interest to anybody who cares about heart health and brain health. So without further delay, please enjoy my conversation with John Kastelein.
John, thank you so much for staying up late into your evening in Amsterdam to make time to speak with me. This is a podcast that really came across my radar courtesy of one of my mentors, Tom Dayspring, who basically got me interested in the work you were doing and said, look, if you'd like to speak with John, we might be able to twist his arm to make time for this. And so I'm both gracious that Tom got me into your work and that he was able to convince you to sit down with us.