#22 - Tom Dayspring, M.D., FACP, FNLA – Part III of V： HDL, reverse cholesterol transport, CETP inhibitors, and apolipoproteins
Episode Stats
Length
1 hour and 4 minutes
Words per Minute
173.28374
Summary
In this episode, we talk about reverse cholesterol transport, the role of lipoproteins in cholesterol production and transport, and the use of CTEP inhibitors to get rid of cholesterol in the body. We also talk about how cholesterol is transported from the body to the organs of the human body.
Transcript
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Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.
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The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,
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along with a few other obsessions along the way. I've spent the last several years working with
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some of the most successful top performing individuals in the world. And this podcast
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is my attempt to synthesize what I've learned along the way to help you live a higher quality,
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more fulfilling life. If you enjoy this podcast, you can find more information on today's episode
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Welcome everybody to episode three of the week of Dayspring. In this episode, we talk about reverse
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cholesterol transport, we talk about lipid transportation, we talk about apolipoproteins,
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and we talk about CTEP inhibitors and HDL. Of all the things we talk about here, the thing that I
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think is the most interesting is the discussion on HDL, which I think most people today would agree
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is far from being understood and is probably far more complicated than LDL biology. I would say that
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of all of the things that Tom and I discussed over this seven hours, I learned the most personally in
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our HDL discussion and our discussion of the CTEP inhibitors. I was very familiar with all of the
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trials here, but Tom brought a level of nuance to this that actually sharpened my understanding of
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this. And for that, I am, of course, eternally grateful. So welcome to episode three.
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All right. So if we're talking about the cholesterol, it's in lipoproteins. So at the
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end of the day, if you have perfect cholesterol homeostasis, if for some reason there's some
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cholesterol excess in your body, it's going to wind up in your artery wall, or if you're lucky, it's going
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to wind up in your stool. That would be the preferent way. So the body clearly knows beyond a certain point,
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we don't want cholesterol. We've talked about that at a bit of length so far. So now how can the body
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get rid of cholesterol that's already inside? It's made by cells, the most enjoy. And everybody
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thinks the liver makes most of the cholesterol. We're not talking about the brain now, that's
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separate. Of your rest of your cholesterol in your body, the liver makes 20% of it. The rest is
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made in your peripheral cells. So the bulk of your cholesterol is in your body. If your peripheral
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cells are making too much, it's got to get out or that cell will die. So the cells through even
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beyond ABCA1 efflux that we've talked about, it can free the fuse out of there. There's another ABC
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transporter that can pump cholesterol out and it gets in a lipoprotein or it binds to albumin or it
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binds to a red blood cell and it can be taken elsewhere. So classically, we were taught that,
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aha, the HDL particles are definitely a substrate that a cell can efflux cholesterol out into,
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especially in empty HDL. ApoA1, the protein itself, that's unlippidated or a real baby HDL
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particle, very small HDL particle, is a great cholesterol acceptor. And we have membrane
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transporters that can give them free cholesterol. All right. So now the HDL has cholesterol. And what
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were we taught? Well, of course, the HDL just brings it right back to the liver and the liver
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then will, if it has a need for cholesterol, it'll use it up and then it'll put it in your bile.
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It'll go down and go right out your rear end. Or your liver can actually change it to a bile
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soul, which it sends down the bile and your bile soul could be excreted in the stool. So in fact,
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that's a way, it's a major way of getting rid of cholesterol, but our ilium doesn't cooperate.
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Our ilium typically reabsorbs about 90 to 95% of the bile salts and reuses them. So it's not the best
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way, unless you can make sure that bile soul is being excreted. And we have a drug, the bile
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essence sequestrings that make sure that happens, then you would deplete internal cholesterol.
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So that's so simple. So our VLDLs and LDLs and column microns bring cholesterol to the tissues.
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And if for some reason there's too much cholesterol, the HDLs bring it back to the liver and it goes
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bye-bye. Well, if you're talking to a second grader or physician at one point in our careers,
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that made great sense. That's plausible. That's perfect. That's why HDLs are not delivering
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cholesterol to the artery wall. They're bringing it back to an organ that's going to get rid of it or
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use it properly. Perfect. And if the other, the VLDLs, chylos, and LDLs are bringing cholesterol to
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the tissues, they never called it that, but I would say, well, that's forward cholesterol transport.
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And if the HDLs are bringing it back, that's reverse. Perfect. And if we have a great balance
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between forward and reverse cholesterol transport, that's good cholesterol homeostasis. You're not
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going to get in trouble. And then we made the mistake of, aha, our metrics of these pathways are
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going to be LDL cholesterol, maybe total cholesterol or HDL cholesterol. And that's where the whole thing
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falls apart because those metrics have zero to do with describing the complex flux and trafficking of
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all these pools of cholesterol or so zero. There is no cholesterol measurement in the plasma that tells
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you anything about that movement and are your cells building up too much cholesterol or are they not,
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God, you have great reverse cholesterol transport. So it made such perfect sense. And we were all
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stupid in medical school. We're never going to contradict a professor or even give it two seconds
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worth of thought. If somebody told us something that the higher your HDL cholesterol, you got great
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reverse cholesterol transport because that HDL is going to take it to the liver. At a certain point in my
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studying of lipid understanding this stuff and I knew, God, what is it about, not everybody with
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high HDL cholesterol is protected. There are people with low HDL cholesterol who don't get disease.
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But if what HDLs do is reverse cholesterol transport and they're bringing cholesterol back to the liver,
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shouldn't your HDL cholesterol go down? Why would HDL cholesterol go up if it was bringing it back to the
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liver and being internalized or delipidated? That made no sense to me. So I knew there was more to
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the study. And of course, guys like Dan Rader, who I alluded to before, and Brian Brewer and John
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Chapman, our HDL experts in this world, have figured this out pretty much by now. So they know this lipid
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transportation system is way more complex than NHDL bringing it back. And in those, we give that a
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different name now. So HDLs indeed are capable of bringing cholesterol back to the liver itself.
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There is a receptor that will delipidate cholesterol ester from an HDL. That's called
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the scavenger receptor B1 and SRB1. There is a holoparticle receptor that can internalize
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large HDL particles and bring them into the liver. But free diffusion can also occur. A big HDL
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can abut against a hepatocyte and cholesterol just diffuses from the HDL membrane into the liver.
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So there are at least three pathways of cholesterol getting back to the liver. Hey, that same thing we
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now know happens at the intestine also. So HDLs don't even have to go anywhere near the liver. They
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can go get rid of some cholesterol at the intestine. Remember that TICE pathway, transintestinal cholesterol
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efflux. And now we are boggled our minds and there are great papers on this. Red blood cells carry way
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more cholesterol than do lipoproteins. They're so much bigger. Now, granted, the cholesterol is all in
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their surface, but they have a ton of cell membrane surface. So there's free cholesterol.
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Albumin, at least per albumin molecule, can attach to 17 molecules of cholesterol. So we now know to
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variable degrees, both red blood cells and albumin can just abut against any cell in your body and
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accept free cholesterol by free diffusion. An LDL particle can abut against the cell and accept
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cholesterol by free diffusion from a cell. So now LDLs have another way of acquiring cholesterol.
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It's interesting. This would be a great question for someone like Josh Knowles, who's such an expert
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on FH. But has anybody looked at red blood cell cholesterol membrane concentration or even size
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in FH patients? Because one hypothesis would be, especially the FH patients who have FH as a result
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of LDL receptor deficiencies in some sort, you'd think that there'd be more free diffusion of
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cholesterol from their LDL into their red blood cell. Yeah. And whether anybody's ever looked at that,
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I don't know. It might not be the case at all, but that would be a question.
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Well, look, theoretically, free diffusion can occur between any two membrane surfaces. So
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do there are red blood cells? I would imagine at a certain degree, it would cause red blood cell
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irregularities. There might be too much noise, but you'd look at the MCV or something like that,
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and you'd say, have you increased or decreased the mean corpuscular volume of these things? Is
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there anything happening? I don't know. You're changing certainly the membrane structure,
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if that process is occurring in those people, whether that would affect red blood cell functionality.
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Remember, when you start putting phytosterols into red blood cell membranes, you get
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hemolytic anemias and stuff. Cytosterolemia, phytosterolemia, that's part of their pathology,
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because the red blood cell is looking for cholesterol to stay healthy, not phytosterols.
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I didn't know that, so I didn't realize that that's one of the hallmarks.
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It's part of the phenotypic picture of cytosterolemia is red blood cell hemolytic anemias,
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you know? So, or crazy red blood cell structure, spirocites and things like that, you know? So,
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it's one way that the early investigators say, well, this person has no phytosterol. So,
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what's this red blood cell problem going on in this person too? So, yeah.
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So, this is interesting. The HDL story is one where the more time goes on, the less I know. I mean,
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there are a few things in lipidology that humble me more than my complete and utter buffoonery and
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ignorance when it comes to understanding high-density lipoproteins.
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It's true of all of us, and that's why I don't want you reading my 2002 Lipid Hall. It's anonymous.
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Yeah, yeah. Oh, God. I would criticize somebody with spouting that stuff today. So,
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only if you read it with that in mind and you would see how things change.
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Can we use a very specific example to explain this? Let's talk about the first failed CTEP
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inhibitor trial, which was Pfizer's back in the mid-2000s. So, let me give the background,
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and then I want you to explain why this may have failed.
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Before you even, maybe I just want to explain a little more about the lipid transportation
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system so you know what CETP is. So, remember, I talked about the early on view was forward
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cholesterol transport, even though they didn't call it, and that's the APOB family bringing
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cholesterol to tissues and the HDL family bringing it back. And here's why that's just such an absurd
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theory. Because when the intestine pumps out chalomicrons that have a lot of your absorbed
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cholesterol in it and your liver, certainly when it manufactures a VLDL particle whose primary
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purpose, and everybody please listen to this, the VLDL has two purposes, one of which is not to
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deliver cholesterol anywhere. The liver is to develop, transport triglycerides energy to cells
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that either store or utilize fatty acids for energy, and to transport phospholipids.
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All right, so that's what your VLDLs and chalomicrons do. So, they're part of the forward
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cholesterol transportation system. So, the liver or the intestine excretes them, and then they're
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floating around. So, what do they do? They go to adipocytes, or they go to muscle cells,
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their triglycerides are extracted, and then their phospholipids break off and are utilized by cells.
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So, what are you left with when a chalomicron loses surface phospholipids and core triglycerides?
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You're left with a smaller VLDL or a smaller chalomicron. Any lipoprotein that goes from a bigger
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size to a smaller size, but it's still within the density of a VLDL or chalomicron. It's called the
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remnant. It's a smaller. Hey, if Peter just amputated my right arm now, I'd be a remnant of
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my former self because I'd have one less arm. So, the VLDLs and chalos have lost their core triglycerides,
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and they've lost their core phospholipids, and a few proteins have broken off too.
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So, now what happens to those remnant VLDLs and chalos? They're virtually instantly clear.
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by receptors that exist in the liver primarily. And how do those receptors clear these VLDL particles
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and these chalomicron particles that have accomplished their mission and delivered
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triglycerides? They bind to either the ApoB100 that's on the VLDL, but LDL receptors won't bind to
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ApoB48 and the chalomicron, but they bind to ApoE. And chylos and VLDLs typically, if you're lucky,
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have multiple copies of VLDLs. So, as soon as the chylos or VLDLs deliver your energy,
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deliver your phospholipids, they are cleared, which is why the chylomicron half-life is minutes,
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and the VLDL half-life is a couple of hours. Don't ever confuse half-life with plasma residence
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time. That's a little bit longer, but that's only a few particles that are persisting beyond those
00:14:02.420
average half-life or so. So, now any of the VLDLs that are not totally cleared by the liver keep
00:14:11.260
getting smaller. They become smaller remnants, but then they change densities to a certain
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different degree density range. So, you can't call it a VLDL anymore. You call it an intermediate
00:14:22.760
density lipoprotein. The same thing, that's got a half-life of an hour. That's also clear,
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because IDLs have a lot of ApoE on it. But at the liver, as they're being cleared,
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there's another enzyme that transforms some of your IDLs into a smaller. What's an IDL remnant
00:14:42.120
called? Well, you'd be entering a new specific density boundary, and it would be called the low
00:14:48.600
density lipoprotein. So, technically, you can say, yes, some VLDLs do become IDLs, do become LDLs,
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and then the LDLs will hang around forever until the LDL receptor clears an LDL by binding to ApoB.
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The reason Kylo's VLDLs and IDLs get cleared so much more quickly than LDLs is the ApoE content,
00:15:11.320
which is a megaligand for the LDL receptor. The LDL receptor is really an ApoB, ApoE receptor,
00:15:19.060
and there are other ApoE receptors too. So, that's why those particles don't last long.
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Just to interrupt you for a sec, ApoE greatly amplifies the efficacy of that ligand, the ApoB
00:15:29.120
ligand? It just is a preferred ligand for either an LDL receptor or other, they're called LDL
00:15:38.060
receptor-related receptors. So, what percent, I'm sorry, I want to come right back to what you're
00:15:42.400
saying, but just because I know I'll forget to ask, what percentage of LDL particles also
00:15:47.220
co-express ApoE? Yeah. So, if you are lucky enough to have that genetic gift and your LDL
00:15:54.160
happens to contain an A, its half-life is pretty much the same as an IDL, they're gone. So, if
00:15:59.100
they're gone, guess where they can't wind up? You have enhanced clearance, your ApoB, your LDL
00:16:04.480
particle level will be much lower, and you don't get heart disease. In an average population,
00:16:09.180
it's about three to four percent. But I guarantee you, there are, depending on the genes you've
00:16:14.640
heard, some people that probably have a lot of ApoE on their LDLs. And of course, I would
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bet if they were studied genetically, they don't get heart disease, you know, because it's being
00:16:22.320
cleared, all those particles. And we'll talk about it later. There are other Apo proteins that
00:16:27.000
can retard clearance of VLDLs, IDLs, and even LDLs. I'll just mention its name now. It's
00:16:33.920
apolipoprotein C3. You got that on your particles. You're going to have seriously increased
00:16:40.020
plasma residence time of all those things. And LDL with ApoC3 on it is intensely more
00:16:46.500
atherogenic than an LDL that only has ApoB100 on it.
00:16:50.780
You once told me, this was probably a couple of months ago, we were just shooting the breeze
00:16:54.360
one day by phone. And I remember you saying that if you could add one clinical assay to
00:17:00.000
the arsenal of lipidologists, it would be an ApoC3 assay. Is that still true?
00:17:06.160
It would be because I think that's going to be the way we really are going to smartly identify
00:17:11.040
remnant lipoproteins that are the VLDLs that are potentially causing trouble. Most VLDLs are not
00:17:17.540
troublemakers. They're cleared rapidly. Or the LDLs that are number one on the list as to what's going
00:17:24.460
in your arterial wall. ApoC3, as you know, Peter, is overexpressed in insulin-resistant situations.
00:17:32.080
So that is a—and I have no doubt that one day that would be a cool test unless maybe we can just
00:17:37.900
measure your genetic—you know, the genes that give you ApoC3.
00:17:41.580
Except that insulin sensitivity and insulin resistance impact it, which would suggest that
00:17:46.580
if you took two people with the same lipid profile at the lipoprotein level, but one had higher
00:17:52.520
ApoC3 than the other, that person's at higher risk.
00:17:55.520
And I think we got enough data now that shows that. And to show you, pharma believes that there's a
00:18:00.720
major trial ongoing now with an ApoC3 inhibitor that's coming because it'll be the way to get
00:18:11.880
Oh, sorry. Just for the listener. ISIS, I'm not referring to. Yeah, yeah, yeah. This is ISIS.
00:18:17.500
There's a pharma company in—it's in San Diego. They're actually based out of San Diego because
00:18:26.080
Yeah, and they're looking at oligonucleotide, anti-sense things. So keep your fingers crossed.
00:18:32.040
So we should come back and talk about that because the anti-C3 and the anti-sense oligonucleotide
00:18:37.180
against apolipoprotein little a, those are hugely interesting.
00:18:41.080
Yeah, they're going to probably be great therapeutic avenues for us if we need it. So yeah, I think there
00:18:46.260
will be utility for measuring this right now before a third-party payer is ever going to
00:18:50.820
pay some lab for doing that. It's going to need a little more proof than what we have so far and
00:18:56.660
everything. But back to our lipid transportation system. So please understand, and there are just
00:19:03.340
too many people out there who think every VLDL becomes an LDL. It's not even close. And in fact,
00:19:09.340
if you are not insulin resistant and you don't have a, however you define a triglyceride issue,
00:19:15.000
which I might define as a trig above 130 or so anyway, 40% of the ApoB particles coming out of
00:19:22.460
your liver, they're not VLDLs, they're LDLs. And the VLDLs that are coming out are not big because
00:19:28.420
they're not carrying extra triglycerides because you don't have them. They're just carrying some
00:19:32.380
degree of cholesterol and a little bit of triglycerides to supply the energy you really
00:19:36.340
need. And that's why if you are measuring some VLDL metric, big VLDLs occur only in triglyceride
00:19:44.240
rich lipoprotein pathologies, by far the most common of which is insulin resistance. And clearly
00:19:50.300
because that VLDL would come out, and I guarantee it's probably got ApoC3 on it, it doesn't have a
00:19:56.440
half-life of a few hours. Its plasma residence time is much longer. There is more conversion of that
00:20:02.620
VLDL particle into LDL particles, which would be triglyceride rich. Through some transformation,
00:20:08.780
they become the small LDLs, which are even less rapidly cleared. So your ApoB particle will number,
00:20:16.840
your LDL particle number goes through the roof. Now, yes, part of those ApoB are the remnants,
00:20:22.520
but I've posted enough slides on Twitter, and I'm pretty sure it's in Peter's package here.
00:20:26.600
Even when you take these type 2 diabetics with severe insulin resistance, or insulin resistance
00:20:32.920
just proved by an insulin clamp study, their ApoB level, their particle levels are going up,
00:20:39.960
but the LDL particles go up astronomically, and the VLDL maybe doubles or triples. It goes from 30 to 90,
00:20:47.220
whereas the VLDL particles go from 1,000 to 3,000.
00:20:52.300
That's an important distinction. So a lot of people will say,
00:20:54.660
when you're insulin resistant, all of that net difference is that we see, because there's no
00:21:00.700
disputing. The more insulin resistant you get, the more discordant you get between your LDL-P and
00:21:05.140
your LDL-C. And all things equal, the LDL-P is just going up and up and up as you become
00:21:09.440
more insulin resistant. So people will say, it's all the VLDL. Furthermore, they'll confuse a
00:21:15.060
percentage increase that's relative with an absolute increase. So as you pointed out, if you're referring
00:21:20.340
to the Garvey paper, I think, yeah. So in that paper, you might see VLDL particle number,
00:21:26.320
I'm making this up, but so someone will see the numbers and decide for themselves, but it might
00:21:32.940
Yeah, an animal per liter. And you think, well, God, that's a much bigger relative increase.
00:21:37.540
And it is. But if anybody's read our lengthy treaties on relative versus absolute risk,
00:21:43.800
you cannot evaluate a relative change without understanding it's absolute change. And so even
00:21:49.060
though the relative change on the LDL-P is smaller, it's starting from such a high base that it might
00:21:54.600
add 300 to 400 nanomole per liter, which might only be a 30 or 40% increase, but that absolutely
00:22:01.860
dominates the lion's share of the increase, not the extra 30 to 50 nanomole per liter you might
00:22:07.380
get on the VLDL. This is a really important point if you want to be a lipid geek.
00:22:11.120
It is. And this is one reason why non-HDL cholesterols become in vogue, because remember,
00:22:18.560
non-HDL cholesterol, we told you, you calculate it by subtracting HDL cholesterol from total cholesterol,
00:22:25.200
but you could really add directly measured LDL cholesterol to a VLDL cholesterol. And that's,
00:22:32.420
your cholesterol is not in your HDL particles, theoretically, potentially atherogenic cholesterol.
00:22:38.720
And hey, that's a free calculation too. So they use non-HDL cholesterol as a marker of remnants.
00:22:47.880
Okay. And there's no doubt some of those VLDL particles would be remnants, but we'll get into
00:22:53.800
this later. I hope I'll make the case that a lot of those VLDL particles are not remnants and they're
00:22:58.380
not going into your heart. Yeah, it's funny. I used to always sit a patient down and the very first
00:23:03.380
time we reviewed a blood test, I would say, look, there's four things we're going to talk about from
00:23:07.100
a lipid standpoint. We got to know your LP little a, we have to know your LDLP. I'd like to know how
00:23:12.480
many of those are small because it's a proxy for some other stuff. And I want to know your VLDL
00:23:16.660
remnant. Well, I can't measure that. So I'm going to approximate it with VLDLC. Well, I don't say that
00:23:20.960
anymore because I've come to realize that's a very crude, crude estimation. That's almost
00:23:27.420
useless. I wouldn't call it useless because I use the word almost in front of it. And I'll get all
00:23:33.280
my lipid colleagues real mad at me if I start saying that because they, and I get into this
00:23:39.160
in a lot of the papers. And we still target. I mean, I still say to patients, I want your VLDL
00:23:43.280
cholesterol less than 15 milligrams per deciliter. And the odds are good in an insulin resistant
00:23:47.200
patient. And you have other ways of knowing whose insulin is, is who's not. If that marker is up,
00:23:52.100
remnant lipoproteins are part of their pathology. But the exact same therapy I'm going to give you to
00:23:57.880
get rid of the real troublemaker, your LDL part is going to get rid of the remnants too.
00:24:02.200
So at the end of the day, it's, I got to normalize APOB or LDL particle number. And there is
00:24:08.540
significant discordance. Alan Snyderman has published it many times. As good as non-HGL cholesterol,
00:24:15.120
meaning better than LDL cholesterol is a metric of APOB. There's a lot of discordance between APOB
00:24:21.540
or LDL particle number and non-HDL cholesterol. So I understand it's a free calculation. Please,
00:24:28.160
and people who you really are worried about, or you think, Iris, you got to use particle numbers
00:24:33.220
to make the proper clinical decisions. This reminds me, I need an excuse to go to Montreal
00:24:38.660
so I can interview Alan. If you can get him on a podcast, I'll be your first listener.
00:24:43.560
Nothing comes out of his mouth that you don't want to write down. And he don't make anything up.
00:24:51.740
He's just, and Alan's not afraid to call a spade a spade, so to speak. He will
00:24:56.700
just tell you. And that's why I love him. You know, I don't mind Alan telling me I'm an idiot.
00:25:01.240
No time you're wrong on it. Here's the way it is. You learn from guys like that who are not afraid
00:25:07.240
Alan, if you're listening to this, why don't you come up with an excuse to come to New York or San Diego?
00:25:12.520
And if I do have an excuse to come to Montreal, I will.
00:25:15.540
But let's get back to our lipid transportation system now. So we have our theoretical forward
00:25:20.340
delivering particles, the ApoB particles. And I tell you how they transform into one another,
00:25:25.260
how they deliver their cholesterol. By the way, no VLDL or IDL or Kylo is delivering cholesterol to
00:25:32.480
your peripheral cells. They don't need it. They're making all they need.
00:25:36.340
Just restate that, please, for the court's transcript. So tell me again, what Kylos are
00:25:44.640
You walked out of the room to do something when I was explaining what Kylos and VLDLs do.
00:25:49.440
Tom just outed me. I went to go take a leak a minute ago.
00:25:52.940
So I explicitly went over that the purpose, the functional purpose of chylomicrons and VLDLs is
00:26:00.480
to deliver energy in a form of triglycerides, the adipocytes and myocytes and phospholipids,
00:26:06.360
not to deliver cholesterol to any darn cell in your body. So spend your time reading on it. That's what
00:26:14.640
they do. You could even make the case that if they're not delivering cholesterol, why is cholesterol
00:26:18.840
even in their particles? And it goes back to something, what Peter said. These particles
00:26:23.000
have to be spherical. So when a VLDL or an anthracite is starting to lipidate ApoB 48 or
00:26:31.340
especially the liver, ApoB 100, if you put cholesterol in that and we have proteins that do that,
00:26:38.840
microsomal triglyceride transfer and other cellular lipid transport proteins, by putting cholesterol
00:26:45.300
on the ApoB, it becomes a spherical particle. So all primordial VLDs and chylomicrons are first
00:26:52.360
just very cholesterol rich spherical particles. They don't have the triglycerides yet. Then when
00:26:58.960
they're spherical particle, they can really fill up with their triglycerides. So the cholesterol is
00:27:05.040
in there for a structural property to make them spherical particles so that they can carry more
00:27:12.240
triglycerides. And that's why when they go out, they become smaller spherical particles that are
00:27:17.420
triglyceride depleted and they just bring their cholesterol back to the liver or the intestine and
00:27:21.740
they do whatever they do with it. So that's why cholesterol is in there. They're not bringing
00:27:26.920
cholesterol to my nose or your kidney or any place else because those cells need cholesterol.
00:27:33.300
Those cells will make it or they'll get it by some free diffusion if they really need it or
00:27:39.040
absolutely virtually any cell of it absolutely needed cholesterol because for some reason a
00:27:44.940
synthesis was broken. Any cell could ultimately upregulate an LDL receptor, but most of them
00:27:50.780
don't because they have no need for the cholesterol that's in an LDL. The liver upregulates most of your
00:27:56.900
LDL receptors because that's involved with clearance of these particles. That's where your LDL receptors
00:28:02.160
are heavily expressed. But now you do have these particles that have certain half-lives or
00:28:08.420
plasma residence times, VLDLs even for a few hours or LDLs for at least a day, in some instances more,
00:28:16.960
HDLs for a few days. So are they stagnant particles that never change? No, guess what? They're living,
00:28:25.160
breathing particles. So I used to have nice animated diagrams of this every second of every minute of
00:28:30.800
every day. Your particles are having sex with one another. They're transferring bodily fluids.
00:28:38.340
They exchange from their core. Every lipoprotein in your body has some degree in its core of triglycerides
00:28:46.700
and cholesterol ester. Every particle from an HDL to a chylomicron to a VLDL, IDL, and LDL.
00:28:54.040
And we actually have a protein that's pretty much carried on HDLs. It was originally called
00:29:00.520
apoprotein or apolipoprotein D, as in dog, capital D. And in my dirty New Jersey mind,
00:29:08.980
think of an HDL particle which carries most of the apod. Men carry something between their legs that if it
00:29:15.520
got erect, it's sticking up and it can penetrate something else. So if HDLs are carrying this apod and
00:29:22.580
it suddenly sticks up, it can penetrate another particle, be it another HDL or an ApoB particle.
00:29:29.880
And that's a phospholipid sort of tunnel. It's like a little tunnel that can connect
00:29:34.840
two circulating lipoproteins. And therefore, the core lipids can exchange.
00:29:41.060
And this is HDL to HDL or can it be HDL to LDL?
00:29:43.740
HDL to HDL, in which case it's called a homotypic transfer because it's two
00:29:49.420
like particles exchanging their bodily fluids or a heterotypic where ApoA particles exchange
00:29:57.180
their core lipids with ApoB particles. What is hardly known out there is two ApoB particles can
00:30:03.260
exchange their lipids. A VLDL can exchange its core lipids with an LDL. And I'm going to tell you
00:30:08.800
that's where remnants get a lot of their cholesterol. So that would be homotypic exchange of cholesterol
00:30:15.160
and triglycerides between two different ApoB containing particles. So a lot of it is between
00:30:21.720
HDLs and ApoB particles. And why? Why would we even be given that lipid transfer protein?
00:30:29.200
Because HDL's job is to be a great cholesterol acceptor. It is very important in delipidation,
00:30:36.920
helping cells efflux the cholesterol they don't want. So when an HDL acquires that free cholesterol
00:30:42.880
from a cell, what does it do? Well, HDL carries that ACAT enzyme. I talk about it,
00:30:48.640
except it's called LCAT because it's in a lipoprotein. It starifies the cholesterol to
00:30:54.160
cholesterol ester, goes to the core of the particle. The HDL becomes bigger. Then the HDL transfers
00:30:59.640
its cholesterol ester to, let's say, an ApoB particle, 95% of which are LDL particles.
00:31:06.880
So here's where the joke comes in. So I know you're all calling the cholesterol in an HDL,
00:31:11.400
oh, that's good cholesterol. But what do you call that cholesterol molecule the second an HDL
00:31:16.760
transfers it to an LDL? Does it instantly become, oh, it's bad now? If I looked at it,
00:31:24.120
it's still the same exact cholesterol molecule. So if you want to use those darn adjectives with a
00:31:31.080
patient, I guess what's going to determine what's good or bad cholesterol is what is that
00:31:36.480
lipoprotein going to do with its cholesterol molecule? If it's an HDL and it's an LDL and
00:31:42.980
it's bringing it back to the liver or the intestine, well, that's not bad, I don't think,
00:31:48.560
because those organs know how to get rid of cholesterol. So I don't know, maybe that's a
00:31:51.980
good cholesterol pathway. But I don't think you can apply that to the cholesterol molecule itself.
00:31:58.420
But follow me here. What if that HDL pulled cholesterol out of your cell because it was
00:32:02.880
overproducing too much? And he gave it to an LDL and said, buddy, take off. The liver's got that LDL
00:32:08.180
receptor. It's going to clear you. And that LDL particle raced back to the liver. And for some
00:32:12.720
reason, there was no LDL receptors or there weren't enough of them there. Where's that LDL going?
00:32:24.780
And right to that endothelium. And all of a sudden, your good cholesterol is in the
00:32:28.540
macrophage in your arterial wall. So spare me the nonsense. Stop using its absurd term. It has no
00:32:34.600
meaning. You're miseducating patients if you tell them it's good cholesterol, because they use that
00:32:40.380
because they're measuring HDL cholesterol in the blood as a marker that I'm in good shape or not.
00:32:44.760
And trust me, virtually all of the early trials that showed low HDL cholesterol was bad news were
00:32:53.760
never, ever adjusted for APOB or LDL particle counts, because I'm going to tell you right now.
00:32:59.860
And that includes Framingham, which I alluded to earlier, because a lot of people like to hang
00:33:03.960
their hat on the fact that Framingham, because most people forget what Framingham is. They throw the
00:33:08.160
term around. So let me just spend one minute explaining this. Framingham started out as a five
00:33:13.100
geography, a five city or five region observational study, purely observational,
00:33:19.480
of which Framingham was one. And I used to know them all.
00:33:21.780
No, it was all Framingham is only Framingham, Massachusetts.
00:33:24.860
No, no, no. But the original cohort of that study from NIH was Framingham, Puerto Rico,
00:33:37.020
And that's where they gathered the information. That's where they made the observation. So there
00:33:40.800
was a purely retrospective assessment of five cities. And I'm blanking on the-
00:33:51.260
But the prospective work was then concentrated in Framingham, Massachusetts.
00:33:55.200
But the point is, a lot of people like to point out that LDL is irrelevant because
00:33:59.640
the LDL cholesterol, which by the way, was calculated, not measured directly. So you've
00:34:08.120
That's correct. It turned out to be less predictive than the ratio, not the ratio,
00:34:12.740
I'm sorry, the absolute level of HDLC and triglyceride. And a lot of people like to stop
00:34:18.540
at that and say, well, look, that means LDL doesn't matter. What they don't realize is those
00:34:24.540
That's all they are. And virtually all of your insulin-resistant patients are getting
00:34:29.700
atherosclerotic disease. It's ApoB. It's LDL particle-mediated because everybody who's not
00:34:34.800
on a drug or a serious diet who had a triglyceride HDL cholesterol axis abnormality has astronomical
00:34:41.700
ApoB. So if you go back for all this cited forever epidemiologic data that low-weight
00:34:48.180
shell cholesterol is such an important risk factor, do me a favor, pal, adjust it for ApoB
00:34:53.140
or LDL-P, which was never done and can't be done in those studies now. It would disappear
00:34:57.540
as an independent risk factor, low-weight shell cholesterol.
00:35:00.480
Well, that's certainly the hypothesis. I mean, I guess the question is, does Mesa still have
00:35:04.640
enough blood kicking around to measure that or Framingham offspring light?
00:35:08.640
It does. Mesa has certainly shown in the discordant people where there's the discordance
00:35:14.480
with ApoB and LDL cholesterol or in people who have low HDL cholesterol, ApoB. LDL particle
00:35:22.620
is your most important metric. So Mesa has shown that.
00:35:25.880
And Mesa, when we're saying this, by the way, folks, we're not talking Mesa, Arizona. We're
00:35:29.280
talking about the multi-ethnic study of atherosclerosis, which is abbreviated Mesa. So
00:35:33.680
we'll often, you'll often hear people refer to Mesa and Framingham and what they're referring
00:35:38.260
to are enormous studies of atherosclerosis that still have biobanks that are available
00:35:43.820
to do these retrospective analyses on prospectively collected samples.
00:35:48.940
Yeah. And Mesa is much more contemporary and multi-ethnic. So it's...
00:35:53.140
Yeah. Because I've got another criticism of Framingham is you've taught me a lot about,
00:35:57.560
you know, middle-class white people in, you know, the Northeast. But what have you told
00:36:01.860
me about, you know, African-American, Hispanic, et cetera?
00:36:04.760
All information is always good. There's always weaknesses with all information or shortcomings
00:36:09.060
or so, but, you know, we built stepwise on it. So before you declare, make any statements
00:36:15.920
on, based on an HDL metric, please make sure you have an LDL particle ApoB metric in front of you
00:36:24.340
also and pretty much base what you're going to advise the patient on risk and assessment based
00:36:30.200
So one of the most amazing papers you ever sent me, and this was actually kind of recent,
00:36:34.220
I feel like this was a year ago, maybe a year and a half ago, was a case study of a woman who had
00:36:39.720
an HDL cholesterol of about 130 to 140 milligrams per deciliter. So for the listener, you just never
00:36:48.840
see levels of HDL like that unless you work in the lipid community or you're a lipidologist,
00:36:53.340
which means I don't see them because I'm not a lipidologist. I just pretend to be one.
00:36:57.380
But, you know, the average person, the average female might walk around with an HDL cholesterol
00:37:01.400
of 60 milligrams per deciliter. So this woman is showing up at two and a half times normal.
00:37:06.460
And interestingly, I don't even know if you remember this case study, Tom, but if not,
00:37:09.920
I think I remember enough of the details. She had very accelerated atherosclerosis.
00:37:13.920
She did not, by the way, to my recollection, have particularly elevated LDL cholesterol.
00:37:19.900
Her LDL cholesterol was probably about 110 milligrams per deciliter, slightly below her
00:37:25.980
HDL cholesterol. And of course, the question was, why did this woman have elevated atherosclerosis
00:37:31.180
when she had normal amounts of quote unquote, the bad cholesterol and two and a half to three times
00:37:38.940
normal good cholesterol? Do you remember this case?
00:37:41.520
Not per se, but that has been well explained. And this is a rare genetic thing where this
00:37:49.860
cholesterol trafficking pattern is disrupted in certain ways. Something's wrong with that pathway
00:37:55.180
because that HDL should be getting rid of its cholesterol and it should be bringing blood back
00:37:59.040
someplace. So this person would have to have incredibly massive HDL particles that are carrying
00:38:06.300
way more cholesterol particles per HDL particle than it should be. And it turns out, and they're not
00:38:13.420
being cleared as much as they should. So this is going to turn out to be cholesterol-rich HDL
00:38:18.780
particles that don't have a protein that's very integral with clearing HDLs and SAPOE again.
00:38:25.960
So if you don't have APOE on your HDLs, they might become very cholesterol-rich. Your HDL
00:38:31.300
cholesterol is through the roof. Those are incredibly dysfunctional HDLs. And part of
00:38:35.880
their dysfunction is they're probably carrying the wrong type of phospholipids and are not carrying
00:38:40.360
the type of protective proteins that an HDL should be carrying. Because when you have a surface area
00:38:46.040
that's big, the proteins that should be binding to it no longer bind because it's not. They're
00:38:51.300
looking for the molecules they're supposed to covalently bind to and they can't find it or so.
00:38:55.580
So that's the circumstance of very dysfunctional HDL. And now I remember the context, which was a
00:39:01.560
really good friend of mine from med school sent me a friend of a friend's blood and the numbers were
00:39:08.080
like that. And I remember reaching out to you saying, this is odd, Tom. What do you make of this?
00:39:12.260
You sent me the case study. There's really nothing to do to treat these people except lower APOB,
00:39:16.480
right? You just have to chase. It's sort of like, what do we do for LP little a nowadays? You chase
00:39:21.060
every other identifiable cardiovascular risk factor. Interesting. Nobody would do it to her,
00:39:27.240
but there is a product that induces a receptor in the liver that pulls cholesterol out of HDL
00:39:34.220
particles. It's a, was that called ProBucol? I don't know if it's even still available by
00:39:39.700
prescription. It induces the scavenger receptor. It drastically lowers HDL, but it's a powerful
00:39:44.640
antioxidant. And there were some early arteriographic studies that suggested this is good.
00:39:49.480
But arteries, at least on an arterial imaging, look better. So, Cesar Milano-
00:39:55.680
I'm sorry, just to be clear, the reason why, I mean, again, there's a 217 ways to be fooled by
00:40:00.680
an angiogram. It's about as crude a way to assess this process as anything. That said,
00:40:05.680
if you believe that this is improving, you believe it's basically increasing the throughput of HDL
00:40:11.900
Yeah. So, the theory would be, aha, there's, this is the case where, hey, remember I espoused
00:40:19.000
a theory before that if HDLs are really delivering cholesterol back to the liver, shouldn't HDL
00:40:23.220
cholesterol be going down? Well, here's a drug that depletes HDL cholesterol, and at least
00:40:29.280
arteriographically, people look better. We now have identified a gene that regulates the functioning of
00:40:35.800
the scavenger receptor. So, if you have an inactivity of that scavenger receptor, you have
00:40:41.800
very big HDL particles, high HDL cholesterol, and coronary atherosclerosis.
00:40:45.720
So, this is a nice transition. So, let's summarize that. This is, again, overly simplistic. This is a
00:40:52.160
zeroth order analysis. So, we're just going to put our fourth grade hats on, which is acceptable for
00:40:57.280
limited periods of time. If you have low HDL-C, you cannot infer if it's low because you're failing
00:41:05.720
to, quote-unquote, pick up cholesterol or because you're delivering it quickly.
00:41:11.200
Conversely, or similarly, I should say, if you have high HDL-C, it is not clear if it is high
00:41:17.460
because you pick up a lot, which in theory would be, quote-unquote, good, or because you're deficient
00:41:23.500
at dropping it off, which would be, quote-unquote, bad. And therein lies, perhaps, one of the most
00:41:30.040
interesting or certainly top five interesting drug stories, which are the CTEP inhibitors.
00:41:34.420
Right. And again, I'm just going to delay because I just want to finish this whole.
00:41:40.560
APOD. But APOD is better known as cholesterol ester transfer protein. It really ought to be called
00:41:48.000
cholesterol ester triglyceride transfer protein, CETP. So, we're going to talk about a CTEP inhibitor
00:41:56.680
in a moment because it's going to stop that process. The lipoproteins can't exchange the
00:42:02.260
particles anymore. Now, wait a minute. If you're following me so far, an HDL, which is pulling
00:42:08.160
cholesterol out of cells, it's really good at that, is then transferring a lot of that cholesterol to
00:42:13.440
LDLs. Here's something that's going to shock you. In an average person, anywhere from 30 to 60%
00:42:21.000
of the cholesterol in that LDL particle arrive via an HDL particle. So, if that LDL particle will
00:42:30.660
accept that cholesterol from an HDL and race it back to the liver, thank you, LDL. It's like the HDL was
00:42:38.900
a quarterback. It passed it to the tight end who ran it across the goal line. Who gets the credit?
00:42:43.120
The quarterback or the tight end or both of them. So, in the lipid transportation system,
00:42:48.120
they work harmoniously together if everything works, including the lipid transfer proteins.
00:42:54.700
We're not going to talk about it today, but God also gave us lipid inhibitory transfer proteins,
00:43:00.880
apolipoprotein F, APOC1. So, everything is tightly regulated in our homeostatic system,
00:43:08.680
Yeah. So, if this is the master's class on lipid, that will be whatever falls above a master.
00:43:14.340
So, it's always more complicated. So, now, just to finish up the definitions of a reverse
00:43:19.040
cholesterol transport, old days, HDL back to the liver. Nowadays, it's HDL gets cholesterol from
00:43:28.740
wherever. If things go right, it could bring it back to either the liver or the small intestine,
00:43:33.880
or an adrenal gland, or an ovary, or a testis. So, that's going to be called direct because the HDL is
00:43:43.460
doing it. And we're saying he's the primary factor here because he does pull cholesterol out of the
00:43:49.040
cells. But we now also know that HDL can give its cholesterol to an LDL, to a VLDL, to a chylomicron,
00:43:57.880
to an IDL. Since most of them are LDLs, it's giving most of it to an LDL. And they can bring
00:44:04.040
that cholesterol. They're going to be cleared at the liver if you have the proper number of LDL
00:44:08.260
receptors. Hey. So, if an HDL give its cholesterol to an APOB particle, it brings it back to the liver.
00:44:17.540
That is called indirect reverse cholesterol transport. We're still debating, can an LDL
00:44:24.440
bring it back to the small intestine also? For a while, that was yes. Then it was probably not.
00:44:29.880
Now it's back to a probably yes again. But if an LDL brings it back to the liver for sure and the
00:44:36.800
intestine, then that's indirect cholesterol or reverse cholesterol transport if you still need
00:44:43.180
the reverse adjective put in there or so. But part of that pathway is it's not the liver. It's the
00:44:50.040
intestine, the transintestinal cholesterol efflux. So, if you want to talk about total reverse
00:44:55.720
cholesterol transport, I would rather just talk about lipid transport. It's every particle is part
00:45:00.960
of the system. But if you want to stick with reverse cholesterol transport, total RCT is the sum of
00:45:08.000
indirect plus direct. And both direct and indirect involve the liver and the intestine.
00:45:14.880
And a serum HGL cholesterol tells you nada about that process.
00:45:21.180
Yeah. We may or may not have time to get into this. But yesterday over dinner, we talked about
00:45:25.280
the futility or the challenges maybe is a better way of saying it to be a little more optimistic.
00:45:31.160
But the challenges in coming up with HDL functional assays. Because that's, you know,
00:45:35.540
once you get deep enough into this topic as we're getting now, you very quickly start to realize
00:45:41.040
that to measure HDL cholesterol or even HDL particle number is so crude in terms of providing
00:45:50.000
an insight into its functional status that, you know, the best we can do today is we measure HDL
00:45:55.040
cholesterol, HDL particle number, and HDL particle size. And we try to triangulate just as we used to
00:46:02.800
when we could look at LP little a mass and LP little a cholesterol, we could sort of triangulate
00:46:07.240
if we were in the zone. But that's still not the answer. I mean, that just doesn't tell us how well
00:46:13.300
We just need more specific biomarkers nowadays to take it to the next level and the types of
00:46:18.620
therapies that are coming along. And I think that's even important knowledge to know when you're
00:46:23.080
going to prescribe a specific nutritional therapy also, that all these things come into play,
00:46:28.820
you know. So very important to understand this stuff. But I hope you can see how this world has
00:46:34.300
changed. And we ought to stop using even the term reverse cholesterol transport. It's idiotic. It's
00:46:39.200
so immensely complex. You don't know what you're talking about. And you have no biomarker that you
00:46:44.060
can evaluate that on the given patient. And the functionality of these particles, like do they
00:46:50.500
really participate in these pathways or not, are determined in large part by their phospholipid content
00:46:56.240
in the proteins that are on these surfaces, apart from just the APOD we talked about.
00:47:01.720
And with HDLs, just briefly, I think there is probably hundreds of HDL subpopulations. HDLs
00:47:08.920
carrying an immense number of proteins, way more than LDLs or VLDLs ever can. But they all can carry
00:47:15.000
one or two proteins. They can't carry 200 proteins that have been identified as coming from HDLs.
00:47:20.280
So it's probably the protein signature of an HDL or even the phospholipid makeup,
00:47:25.860
the lipid dome of an HDL. We have, just like, you know, I love fire departments. Fire departments
00:47:32.480
have hook and ladder trucks. They have pumper trucks. They have hazmat trucks. They got a variety
00:47:38.060
of rescue vehicles nowadays. They got ambulances, rescue trucks, and they don't all show up at every
00:47:44.960
fire. The dispatch sends the trucks that are needed to specific types of fires. Well, your HDL
00:47:51.980
subpopulations show up where they're needed, and they know where they're needed because the cells
00:47:56.880
that need them recognize the proteins or the phospholipids that are on their surface and pull
00:48:01.620
them in. So I don't know when it's going to come down to lipidomic or proteomic analysis of these
00:48:07.400
particles. I think that maybe will take us to the next level and wouldn't hold your breath on that
00:48:12.420
anytime soon. All right. So let's go back to this idea of, because I want to start talking a little
00:48:17.440
bit about some drugs, but rather than start chronologically, which I want to do after we
00:48:21.980
get to this question, but just because while we're on HDL, there are really two drugs that have
00:48:28.760
been discussed as ways to quote unquote raise HDL, one being niacin, which we'll come to later on,
00:48:34.800
but the other being these CTEP inhibitors, which are relatively recent. It was 2006 when the first
00:48:42.260
CTEP trial, or at least when the first data became available and they weren't promising. So first of
00:48:48.920
all, why would inhibition of CTEP been thought to be an optimal strategy? And two, why do you think
00:48:54.340
it didn't turn out that way? Because we don't know what we're doing with HTLs and especially using
00:49:00.460
metrics to analyze them. And the story starts a lot longer than that in Italy, that little section up
00:49:06.240
on Northeastern Italy, where APOA1 Milano was discovered. And these were people who had HDL
00:49:13.080
cholesterol levels of five and 10, and yet had longevity. And how could that possibly be? Because
00:49:19.900
Framingham has taught us low HDL cholesterol, you're out of here. And yet here's where people
00:49:24.480
with longevity. And it turns out they had a very functional APOA1 that really did the flux system
00:49:31.540
very quickly or had other properties that didn't matter how much cholesterol was in the HDL. The
00:49:36.340
HDL was unbelievably functional. Do you know anything about their APOBs?
00:49:40.760
I think even if they have high APOB, they don't get that. I don't know that. That's probably out
00:49:45.380
there. I can't answer that. Maybe we'll look that up if we can, but their high functioning APOA seems to
00:49:51.060
protect them. I doubt if APOB matters because some of them probably would, you know, although they're
00:49:56.960
on that Mediterranean diet and stuff. So maybe they don't have atherogenic parts. So I can't answer
00:50:01.920
that. So that led pharma to, hey, let's just invent either synthesize APOA1 or a truncated APOA1
00:50:10.680
and commercialize that. At least for people who've had acute carnage syndromes, we'll infuse that into
00:50:16.200
them. It'll delipidate their plaque and home free. Every single trial failed, including a very recent
00:50:21.900
trial. So there's one where they got a specially protective type of HDL, but they couldn't reproduce
00:50:28.500
it, whatever it is. So that failed. So, but, you know, there were people in the past that Peter
00:50:34.660
talked about. He gave a case where a woman had very high HDL cholesterol, but had coronary atherosclerosis.
00:50:40.620
But there is a bunch of people out there with very high HDL cholesterol who don't have coronary.
00:50:45.320
I'm going to theorize in retrospect, maybe APOE's got something to do with that, but I don't know that
00:50:49.540
because that would enhance their clearing. But what is one of the genetic conditions that would
00:50:55.640
give you high HDL cholesterol? Remember, I just taught you what APOD is, CETP, CTEP. It takes the
00:51:02.560
cholesterol out of your HDL and gives it to an APOB particle. So theoretically, that would lower your
00:51:07.560
HDL cholesterol. But if I inhibited CTEP, your HDL would get to keep all its cholesterol. What would
00:51:13.840
go through the roof? Your HDL cholesterol. And the genetic model was at least some people with
00:51:18.740
certain CETP variants had very high HDL cholesterol and they didn't seem to get much heart disease.
00:51:25.180
Although what I'm confused by, Tom, is that in 2000, I want to say 11-ish, didn't a Mendelian
00:51:32.500
randomization look at this and conclude, now this was long after these drugs were in the pipeline,
00:51:37.800
but didn't the MR suggest that those people were not better off? It's a nature paper and we'll pull it.
00:51:44.800
Well, CETP and the investigation of these drugs were long before the Mendelian randomization.
00:51:50.580
So they didn't have that data that Mendelian randomization shows not necessarily so that
00:51:56.860
with high HDL cholesterol, you're protected. Whereas nowadays, most of that data would show
00:52:01.580
Yeah, yeah. My recollection is that the MR came out in 2010, 2011, and it basically validated what
00:52:09.060
had at the time been seen in two trials, which was, wow, inhibit CETEP, things don't get better.
00:52:15.220
Well, yeah. So I think Mendelian randomization, had they had that data first, they would have
00:52:21.520
And which is why they did chase PCSK9 inhibitors because the genetic model told them this can't
00:52:26.100
fail unless there's a downside to the drug that we don't know about. And that's always a problem
00:52:30.640
with a drug that's going to change a gene. It may do good to a marker and do bad to some other
00:52:37.500
Oh, I can't wait till we're going to talk about PCSK9.
00:52:40.380
So let's inhibit CETP. The HDLs get to keep all their cholesterol. HDL cholesterol goes through
00:52:46.440
the roof. That's good epidemiologically, right?
00:52:49.460
Except on first principles, it doesn't even make sense in light of what you just told us.
00:52:53.760
No, but they didn't know that then either. Remember, this whole HDL story has evolved too.
00:52:58.120
Oh, wait. So that's interesting. I don't think I understood that. And so I should give them more
00:53:01.920
credit. Are you saying that it absolutely was not known?
00:53:05.260
No, there was theories on it. Guys like Dan Rader was always talking about it, but you don't know
00:53:09.980
how much you're interrupting the system with that and everything. And they're so heavenly focused on
00:53:16.140
basic lipid biomarkers like LDL cholesterol and HDL cholesterol.
00:53:22.280
And it's the same, the niacin story. How could it not work? It raises HDL cholesterol and turns out
00:53:26.360
niacin doesn't work if you want to take legitimate trials to show it works. And is there a price for using
00:53:32.900
niacin, even if you don't believe the legitimate trials? So that's another story, which we'll
00:53:38.540
We'll definitely get into that because this is one area where your peers will argue with you.
00:53:42.360
Some, many will not. Other than, all right, I've tried everything else. Nothing else has worked.
00:53:47.560
Let me, uh, and look, I'm a guy who took niacin myself for a bunch of years. So that was before I
00:53:52.200
knew what I knew now. And it didn't unfortunately work for me anyway. So this CETP, it's going to raise
00:53:59.780
HDL cholesterol, but how much it raises, it really depends on the potency of the CETP inhibitor.
00:54:05.860
And there are different degrees of CETP inhibition. We have weak inhibitors and we have super strong
00:54:10.140
inhibitors. The first one that came out, Pfizer had developed a drug that inhibited it and thought
00:54:16.160
it was going to be a multi-billion dollar drug because it raised HDL cholesterol. Pfizer and many
00:54:22.180
other companies already proved lowering ApoB, LDL cholesterol works, really works well. Imagine if we
00:54:28.320
can take those people with residual risk because they're low, HDL cholesterol is still low and we
00:54:33.260
could raise their HDL cholesterol. That niacin angiographic trial would really support doing
00:54:38.700
that. Okay. So they said, let's inhibit CETP and raise HDL cholesterol. So Pfizer went to market.
00:54:47.000
Many people were buying that stock in its infancy, thought they'd make a zillion dollars.
00:54:51.340
I remember where I was standing the moment those results were announced. And it's interesting
00:54:57.780
because I was not at all a lipid guy, but at the time I was working at McKinsey, I was in San
00:55:02.440
Francisco. It was on a September day, a beautiful September day in San Francisco, 2006. And I took it
00:55:10.000
as a fait accompli that this drug would work and Pfizer stock was going to skyrocket.
00:55:15.140
Oh, look, we all knew the company Asperion who developed that. And we knew their guys,
00:55:21.020
we'd heard them lecture many times, many to top. Everybody was banking on that. Boy, this is real.
00:55:26.120
I mean, you never know in a clinical trial, but it looked like a slam dunk. It really did.
00:55:30.860
And I remember whenever I found out, I forget the weather that day, but it was late at night. And
00:55:35.580
I think the internet was even, and I saw a little thing and it was like 1130 at night. I don't even
00:55:41.820
know why I saw it, that Pfizer terminates torcetripib trial.
00:55:45.880
Yeah. Well, in fairness, you were actually seeing it in real time. I saw it the next morning.
00:55:49.980
Right. So, and look, there was no Twitter then. I couldn't call up every lipidologist. I know I
00:55:56.120
emailed a few close buddies. Look at what I just saw. And so they stopped the trial, not because it
00:56:04.180
was harming people. And as it turns out, it looks like that drug had some other properties that
00:56:09.560
screwed up certain electrolytes and other hormonal levels that, okay, no wonder. So we raising
00:56:18.760
HL cholesterol, if it's going to bring a downside to the table, goodbye. So Pfizer lost a lot of money
00:56:24.460
in that, but that didn't stop research on the drug. As they develop these other toxicities that
00:56:30.580
maybe were specifically related to that CTEP inhibitor, let's develop better CTEP inhibitors
00:56:37.300
and go with them. So they did. And they came up with a very weak one called dalsetripib.
00:56:42.900
Who made that? It wasn't Merck because Merck did the third one. So there's someone in between,
00:56:50.520
I was certainly a bit consulting with them back too. And then two other companies, again,
00:56:57.620
it was Merck and Lilly had super potent CTEP inhibitors, but they did all the tests and it
00:57:03.440
didn't have this other toxicity with electrolytes and ran and angiotensin levels and things like
00:57:10.060
that. So maybe this would work. And of course, the stronger your CTEP inhibition, the more you would
00:57:16.660
raise HDL cholesterol. So dalsetripib raised it 20 to 30%, whereas the stronger ones raised it 80,
00:57:26.720
100% HDL cholesterol. So the dalsetripib, they enrolled in acute carnage syndrome, a humongous
00:57:33.300
population, and we're doing a randomized trial. And after a few years, they didn't see any downside.
00:57:45.660
But it was futility. And those are very expensive trials. So the bean counter said,
00:57:49.820
it's it, it's you to trial, forget about it. So dalsetripib-
00:57:53.720
I think that, I think that those trials combined with the MR have put an end to
00:58:01.880
They did. And the two other companies though said, well, it's a weak CTEP inhibitor. We're
00:58:06.980
potent. So we're going to continue. Our trials are well underway too. So with anacetripib and
00:58:12.860
evacetripib, the remaining things, they did them. And sooner or later, Lilly just bailed on their trial.
00:58:20.000
More futility. They weren't going to take it out. But Merck continued their trial.
00:58:23.620
So Lilly, with a potent evacetripib, was seeing not only drastic raisings in HDL cholesterol,
00:58:31.100
but LDL cholesterol. But, you know, PCSK9 inhibitors are starting to appear. But then
00:58:36.780
nobody's going to ever prescribe this drug based on what it does to LDL cholesterol. And we're not
00:58:42.720
so convinced that raising HDL cholesterol matters anymore. So they, and their early thing was some
00:58:48.760
futility. So they bailed on their trial too. People think they should have, some people wish
00:58:53.300
they would have continued that trial, but Merck did continue. And Merck did hit its endpoint that it
00:58:58.320
did reduce coronary events. It did drastically raise HDL cholesterol, but it dramatically lowered
00:59:04.340
APOB also. So the theory came to be what a CTEP inhibitor does to the metric HDL cholesterol has
00:59:10.840
nothing to do with anything. But if it can lower APOB, it works. But, and they, the trial was,
00:59:17.300
it worked, but they're not going to bring it to market because it stays in the human body for
00:59:23.560
years. And they just are afraid of that. They have no idea what might show up.
00:59:28.560
Well, especially when there's no upside relative to what you can do anyway.
00:59:31.760
There are other things that will give you that type of APOB lowering that seem to be safe and
00:59:35.420
been around. And so Merck is not going to commercialize that product, even though it
00:59:39.980
has a successful trial. So if you want to definitively say CTEP inhibition doesn't reduce
00:59:45.300
atheroscopy, well, it did, but at what price and at what benefit? And we just can do it with
00:59:51.200
some, and there are other LDL lowering things coming to the market.
00:59:54.540
It still seems too crude is the point. Like it's not entirely clear why one of those drugs
01:00:00.140
is working and why one is not because the inhibition of CTEP is, it's interrupting a
01:00:07.240
transfer, but it doesn't actually tell you what happens after the transfer. And that
01:00:12.240
No, it doesn't tell you. Even though some of the primitive HCL function studies they did
01:00:16.480
on, it didn't look like they were screwing up the HCL, but there's immense numbers of
01:00:20.240
HCL function. You don't know what you're doing. And if that protein is going to stay in your
01:00:24.380
body forever, what other consequences might there be long-term screwing up of other
01:00:30.040
biological systems or something. So it couldn't risk that.
01:00:33.800
Yeah. Well, kudos to Merck. Cause I don't, I think the FDA would have approved it. Don't
01:00:40.640
Oh, so you think the FDA would have denied it based on that?
01:00:43.100
They had that fear. And even if they thought they could get it by their lawyers probably
01:00:48.900
Well, Merck, you know, it's funny. A lot of people don't remember what happened in Merck
01:00:53.480
The failure of the black box warning. And I actually, I got to tell you that that to
01:00:56.580
me is one example of an overreaction too late versus an appropriate reaction sooner. So I,
01:01:02.540
you know, not that I'm a pharma guy and know much about pharma, but Vioxx was an amazing
01:01:06.120
drug. I mean, 10 times better than Celebrex ever was for the listener. Who's wondering what
01:01:10.280
we're talking about. Celebrex and Vioxx were the first two versions of these things called
01:01:14.460
selective Cox two inhibitors, which were potent and much more selective anti-inflammatory drugs.
01:01:20.160
So for people with, you know, orthopedic issues, joint pain, things like that, but they don't
01:01:25.440
have some of the drawbacks you have with using just non-selective inhibitors of cycle oxygenase
01:01:30.440
where such as Advil or Aleve or things like that. Anyway, to make a long story short, it
01:01:35.080
was about 2001 when they saw a small subset of patients and turned out those I think that
01:01:40.620
were hypertensive were having a higher risk of MI taking Vioxx. The drug got immediately
01:01:45.140
yanked. I think it was the best anti-inflammatory Cox inhibitor ever out there.
01:01:49.980
And in reality, I think what emerged after the fact was, Hey, the guys at Merck sort of
01:01:55.200
knew this earlier on there, there was data that suggested there was something going on
01:01:59.260
and instead they should have partitioned it and said, Hey, maybe there's a subset of patients
01:02:03.720
in whom we don't let this drug be taken because I think a lot of patients got deprived of an
01:02:07.660
amazing drug on the basis of a few. So anyway, my guess is Merck's highly sensitive to, uh,
01:02:12.900
sure. Today's medical legal world, that stuff comes back to haunt those companies. One person
01:02:20.440
goes south and it's a zillion dollar lawsuit. So it is very, very tough. And look, it goes back to my
01:02:27.700
young days where we couldn't do anything for MI, but suppress ventricular arrhythmies with any number
01:02:33.300
of grave. And all we did was kill people. Yeah. Those things were the most toxic drugs.
01:02:37.920
But the VPCs disappeared. Yeah. You know, and so did they. Yeah. You got to be careful.
01:02:44.220
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