The Peter Attia Drive - #22 - Tom Dayspring, M.D., FACP, FNLA – Part III of V： HDL, reverse cholesterol transport, CETP inhibitors, and apolipoproteins

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions along the way. I've spent the last several years working with

00:00:19.840 some of the most successful top performing individuals in the world. And this podcast

00:00:23.600 is my attempt to synthesize what I've learned along the way to help you live a higher quality,

00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

00:00:33.000 and other topics at peteratiyahmd.com.

00:00:41.260 Welcome everybody to episode three of the week of Dayspring. In this episode, we talk about reverse

00:00:48.220 cholesterol transport, we talk about lipid transportation, we talk about apolipoproteins,

00:00:54.280 and we talk about CTEP inhibitors and HDL. Of all the things we talk about here, the thing that I

00:01:00.960 think is the most interesting is the discussion on HDL, which I think most people today would agree

00:01:07.560 is far from being understood and is probably far more complicated than LDL biology. I would say that

00:01:15.560 of all of the things that Tom and I discussed over this seven hours, I learned the most personally in

00:01:21.520 our HDL discussion and our discussion of the CTEP inhibitors. I was very familiar with all of the

00:01:26.920 trials here, but Tom brought a level of nuance to this that actually sharpened my understanding of

00:01:33.780 this. And for that, I am, of course, eternally grateful. So welcome to episode three.

00:01:41.420 Let's define now direct versus indirect RCT.

00:01:44.400 All right. So if we're talking about the cholesterol, it's in lipoproteins. So at the

00:01:49.860 end of the day, if you have perfect cholesterol homeostasis, if for some reason there's some

00:01:54.860 cholesterol excess in your body, it's going to wind up in your artery wall, or if you're lucky, it's going

00:02:02.380 to wind up in your stool. That would be the preferent way. So the body clearly knows beyond a certain point,

00:02:10.260 we don't want cholesterol. We've talked about that at a bit of length so far. So now how can the body

00:02:15.900 get rid of cholesterol that's already inside? It's made by cells, the most enjoy. And everybody

00:02:21.380 thinks the liver makes most of the cholesterol. We're not talking about the brain now, that's

00:02:25.820 separate. Of your rest of your cholesterol in your body, the liver makes 20% of it. The rest is

00:02:31.380 made in your peripheral cells. So the bulk of your cholesterol is in your body. If your peripheral

00:02:36.560 cells are making too much, it's got to get out or that cell will die. So the cells through even

00:02:42.160 beyond ABCA1 efflux that we've talked about, it can free the fuse out of there. There's another ABC

00:02:47.980 transporter that can pump cholesterol out and it gets in a lipoprotein or it binds to albumin or it

00:02:54.540 binds to a red blood cell and it can be taken elsewhere. So classically, we were taught that,

00:02:59.980 aha, the HDL particles are definitely a substrate that a cell can efflux cholesterol out into,

00:03:09.760 especially in empty HDL. ApoA1, the protein itself, that's unlippidated or a real baby HDL

00:03:16.860 particle, very small HDL particle, is a great cholesterol acceptor. And we have membrane

00:03:22.420 transporters that can give them free cholesterol. All right. So now the HDL has cholesterol. And what

00:03:29.760 were we taught? Well, of course, the HDL just brings it right back to the liver and the liver

00:03:34.300 then will, if it has a need for cholesterol, it'll use it up and then it'll put it in your bile. 0.93

00:03:39.620 It'll go down and go right out your rear end. Or your liver can actually change it to a bile 0.99

00:03:45.980 soul, which it sends down the bile and your bile soul could be excreted in the stool. So in fact,

00:03:51.900 that's a way, it's a major way of getting rid of cholesterol, but our ilium doesn't cooperate.

00:03:55.960 Our ilium typically reabsorbs about 90 to 95% of the bile salts and reuses them. So it's not the best

00:04:02.560 way, unless you can make sure that bile soul is being excreted. And we have a drug, the bile

00:04:07.340 essence sequestrings that make sure that happens, then you would deplete internal cholesterol.

00:04:13.060 So that's so simple. So our VLDLs and LDLs and column microns bring cholesterol to the tissues.

00:04:20.160 And if for some reason there's too much cholesterol, the HDLs bring it back to the liver and it goes

00:04:26.200 bye-bye. Well, if you're talking to a second grader or physician at one point in our careers,

00:04:34.400 that made great sense. That's plausible. That's perfect. That's why HDLs are not delivering

00:04:38.960 cholesterol to the artery wall. They're bringing it back to an organ that's going to get rid of it or

00:04:43.060 use it properly. Perfect. And if the other, the VLDLs, chylos, and LDLs are bringing cholesterol to

00:04:50.440 the tissues, they never called it that, but I would say, well, that's forward cholesterol transport.

00:04:55.760 And if the HDLs are bringing it back, that's reverse. Perfect. And if we have a great balance

00:04:59.720 between forward and reverse cholesterol transport, that's good cholesterol homeostasis. You're not

00:05:05.260 going to get in trouble. And then we made the mistake of, aha, our metrics of these pathways are

00:05:12.040 going to be LDL cholesterol, maybe total cholesterol or HDL cholesterol. And that's where the whole thing

00:05:17.840 falls apart because those metrics have zero to do with describing the complex flux and trafficking of

00:05:24.100 all these pools of cholesterol or so zero. There is no cholesterol measurement in the plasma that tells

00:05:31.800 you anything about that movement and are your cells building up too much cholesterol or are they not,

00:05:38.060 God, you have great reverse cholesterol transport. So it made such perfect sense. And we were all

00:05:45.140 stupid in medical school. We're never going to contradict a professor or even give it two seconds 1.00

00:05:49.720 worth of thought. If somebody told us something that the higher your HDL cholesterol, you got great

00:05:56.540 reverse cholesterol transport because that HDL is going to take it to the liver. At a certain point in my

00:06:02.840 studying of lipid understanding this stuff and I knew, God, what is it about, not everybody with

00:06:08.820 high HDL cholesterol is protected. There are people with low HDL cholesterol who don't get disease.

00:06:14.760 But if what HDLs do is reverse cholesterol transport and they're bringing cholesterol back to the liver,

00:06:22.720 shouldn't your HDL cholesterol go down? Why would HDL cholesterol go up if it was bringing it back to the

00:06:28.980 liver and being internalized or delipidated? That made no sense to me. So I knew there was more to

00:06:35.300 the study. And of course, guys like Dan Rader, who I alluded to before, and Brian Brewer and John

00:06:41.900 Chapman, our HDL experts in this world, have figured this out pretty much by now. So they know this lipid

00:06:49.420 transportation system is way more complex than NHDL bringing it back. And in those, we give that a

00:06:57.600 different name now. So HDLs indeed are capable of bringing cholesterol back to the liver itself.

00:07:04.620 There is a receptor that will delipidate cholesterol ester from an HDL. That's called

00:07:09.660 the scavenger receptor B1 and SRB1. There is a holoparticle receptor that can internalize

00:07:16.780 large HDL particles and bring them into the liver. But free diffusion can also occur. A big HDL

00:07:24.940 can abut against a hepatocyte and cholesterol just diffuses from the HDL membrane into the liver.

00:07:31.460 So there are at least three pathways of cholesterol getting back to the liver. Hey, that same thing we

00:07:37.000 now know happens at the intestine also. So HDLs don't even have to go anywhere near the liver. They

00:07:42.340 can go get rid of some cholesterol at the intestine. Remember that TICE pathway, transintestinal cholesterol

00:07:48.720 efflux. And now we are boggled our minds and there are great papers on this. Red blood cells carry way

00:07:57.960 more cholesterol than do lipoproteins. They're so much bigger. Now, granted, the cholesterol is all in

00:08:03.460 their surface, but they have a ton of cell membrane surface. So there's free cholesterol.

00:08:08.720 Albumin, at least per albumin molecule, can attach to 17 molecules of cholesterol. So we now know to

00:08:15.960 variable degrees, both red blood cells and albumin can just abut against any cell in your body and

00:08:22.640 accept free cholesterol by free diffusion. An LDL particle can abut against the cell and accept

00:08:29.240 cholesterol by free diffusion from a cell. So now LDLs have another way of acquiring cholesterol.

00:08:36.120 It's interesting. This would be a great question for someone like Josh Knowles, who's such an expert

00:08:39.780 on FH. But has anybody looked at red blood cell cholesterol membrane concentration or even size

00:08:45.960 in FH patients? Because one hypothesis would be, especially the FH patients who have FH as a result

00:08:52.300 of LDL receptor deficiencies in some sort, you'd think that there'd be more free diffusion of

00:08:58.420 cholesterol from their LDL into their red blood cell. Yeah. And whether anybody's ever looked at that,

00:09:04.060 I don't know. It might not be the case at all, but that would be a question.

00:09:06.500 Well, look, theoretically, free diffusion can occur between any two membrane surfaces. So

00:09:11.380 do there are red blood cells? I would imagine at a certain degree, it would cause red blood cell

00:09:17.220 irregularities. There might be too much noise, but you'd look at the MCV or something like that,

00:09:23.180 and you'd say, have you increased or decreased the mean corpuscular volume of these things? Is

00:09:27.380 there anything happening? I don't know. You're changing certainly the membrane structure,

00:09:30.860 if that process is occurring in those people, whether that would affect red blood cell functionality.

00:09:35.660 Remember, when you start putting phytosterols into red blood cell membranes, you get

00:09:40.540 hemolytic anemias and stuff. Cytosterolemia, phytosterolemia, that's part of their pathology,

00:09:46.300 because the red blood cell is looking for cholesterol to stay healthy, not phytosterols.

00:09:51.500 I didn't know that, so I didn't realize that that's one of the hallmarks.

00:09:54.540 It's part of the phenotypic picture of cytosterolemia is red blood cell hemolytic anemias,

00:09:58.740 you know? So, or crazy red blood cell structure, spirocites and things like that, you know? So,

00:10:04.740 it's one way that the early investigators say, well, this person has no phytosterol. So,

00:10:09.940 what's this red blood cell problem going on in this person too? So, yeah.

00:10:13.620 So, this is interesting. The HDL story is one where the more time goes on, the less I know. I mean,

00:10:20.580 there are a few things in lipidology that humble me more than my complete and utter buffoonery and

00:10:26.420 ignorance when it comes to understanding high-density lipoproteins.

00:10:29.380 It's true of all of us, and that's why I don't want you reading my 2002 Lipid Hall. It's anonymous.

00:10:35.380 You're embarrassed.

00:10:36.260 Yeah, yeah. Oh, God. I would criticize somebody with spouting that stuff today. So,

00:10:41.140 only if you read it with that in mind and you would see how things change.

00:10:44.500 Can we use a very specific example to explain this? Let's talk about the first failed CTEP

00:10:51.460 inhibitor trial, which was Pfizer's back in the mid-2000s. So, let me give the background,

00:10:56.660 and then I want you to explain why this may have failed.

00:10:58.900 Before you even, maybe I just want to explain a little more about the lipid transportation

00:11:02.660 system so you know what CETP is. So, remember, I talked about the early on view was forward

00:11:10.180 cholesterol transport, even though they didn't call it, and that's the APOB family bringing 1.00

00:11:13.620 cholesterol to tissues and the HDL family bringing it back. And here's why that's just such an absurd

00:11:19.700 theory. Because when the intestine pumps out chalomicrons that have a lot of your absorbed

00:11:25.380 cholesterol in it and your liver, certainly when it manufactures a VLDL particle whose primary

00:11:31.540 purpose, and everybody please listen to this, the VLDL has two purposes, one of which is not to

00:11:37.460 deliver cholesterol anywhere. The liver is to develop, transport triglycerides energy to cells

00:11:44.580 that either store or utilize fatty acids for energy, and to transport phospholipids.

00:11:52.900 All right, so that's what your VLDLs and chalomicrons do. So, they're part of the forward

00:11:58.020 cholesterol transportation system. So, the liver or the intestine excretes them, and then they're 0.64

00:12:03.700 floating around. So, what do they do? They go to adipocytes, or they go to muscle cells,

00:12:11.060 their triglycerides are extracted, and then their phospholipids break off and are utilized by cells.

00:12:18.500 So, what are you left with when a chalomicron loses surface phospholipids and core triglycerides?

00:12:25.940 You're left with a smaller VLDL or a smaller chalomicron. Any lipoprotein that goes from a bigger

00:12:33.860 size to a smaller size, but it's still within the density of a VLDL or chalomicron. It's called the

00:12:39.380 remnant. It's a smaller. Hey, if Peter just amputated my right arm now, I'd be a remnant of

00:12:45.220 my former self because I'd have one less arm. So, the VLDLs and chalos have lost their core triglycerides, 0.99

00:12:53.700 and they've lost their core phospholipids, and a few proteins have broken off too.

00:12:59.700 So, now what happens to those remnant VLDLs and chalos? They're virtually instantly clear. 1.00

00:13:09.940 by receptors that exist in the liver primarily. And how do those receptors clear these VLDL particles

00:13:20.100 and these chalomicron particles that have accomplished their mission and delivered

00:13:23.860 triglycerides? They bind to either the ApoB100 that's on the VLDL, but LDL receptors won't bind to

00:13:32.500 ApoB48 and the chalomicron, but they bind to ApoE. And chylos and VLDLs typically, if you're lucky,

00:13:40.100 have multiple copies of VLDLs. So, as soon as the chylos or VLDLs deliver your energy,

00:13:46.020 deliver your phospholipids, they are cleared, which is why the chylomicron half-life is minutes,

00:13:51.300 and the VLDL half-life is a couple of hours. Don't ever confuse half-life with plasma residence

00:13:57.060 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

00:14:16.660 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,

00:14:29.500 because IDLs have a lot of ApoE on it. But at the liver, as they're being cleared,

00:14:34.600 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,

00:14:55.660 and then the LDLs will hang around forever until the LDL receptor clears an LDL by binding to ApoB.

00:15:03.520 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.

00:15:23.220 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

00:16:18.080 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 0.99

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

00:18:07.180 rid of these extremely athergenic—

00:18:08.940 Is this ISIS doing this?

00:18:10.500 Yeah, I believe so. Yeah.

00:18:11.880 Oh, sorry. Just for the listener. ISIS, I'm not referring to. Yeah, yeah, yeah. This is ISIS. 0.66

00:18:17.500 There's a pharma company in—it's in San Diego. They're actually based out of San Diego because

00:18:21.080 that's where Sam Tamekis is. But it is ISIS. 0.59

00:18:24.280 Yeah, it's one of these new—

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.

00:20:50.260 VLDL.

00:20:50.880 VLDL, yeah.

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

00:21:30.140 go from 30 to 60.

00:21:31.320 Yeah, or 150 even.

00:21:32.940 Yeah, an animal per liter. And you think, well, God, that's a much bigger relative increase.

00:21:37.380 Yeah.

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.

00:24:49.820 Alan is, Alan's a special guy.

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 0.99

00:25:06.020 to put you in your place.

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

00:25:43.040 doing, are not doing what?

00:25:44.640 You walked out of the room to do something when I was explaining what Kylos and VLDLs do. 1.00

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, 0.91

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 0.96

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 0.97

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. 0.97

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 0.99

00:31:31.080 patient, I guess what's going to determine what's good or bad cholesterol is what is that 0.97

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?

00:32:18.660 He might wind his way back into circulation.

00:32:21.260 He will, because he's not going to be clear.

00:32:23.280 And he might wind his way back to endothelium.

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,

00:33:29.580 San Francisco, Haluulu.

00:33:31.180 Did Framingham evolve from?

00:33:33.360 That's right. Then the-

00:33:34.700 There was a five city group here.

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-

00:33:46.180 But I think one was Puerto Rico, Honolulu.

00:33:48.620 I'm pretty sure Stanford might have been one.

00:33:50.480 But anyway, the point-

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

00:34:05.360 introduced a variability-

00:34:06.540 And years later, not in the first 20 years-

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

00:34:21.940 are two enormous proxies for ApoB.

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

00:36:29.860 on that.

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 1.00

00:37:01.400 of 60 milligrams per deciliter. So this woman is showing up at two and a half times normal. 0.97

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, 0.80

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

00:40:10.840 to delipidate?

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.

00:41:10.260 You don't know.

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.

00:41:37.640 So, I told you HDL has this.

00:41:39.780 APOD.

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% 0.71

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,

00:43:07.560 but we'll leave that for another day.

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. 0.59

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

00:46:12.360 these things function.

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.

00:51:49.420 Absolutely. Yeah, yeah, yeah.

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

00:52:00.960 it's not.

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

00:52:19.500 never investigated these drugs.

00:52:21.340 Yeah.

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

00:52:35.620 marker you're not smart enough to know about.

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.

00:53:21.680 LDL bad. HDL good.

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

00:53:37.900 probably get into.

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,

00:56:47.140 I keep forgetting. Yeah.

00:56:48.440 Anyway. Okay. So we can figure that out.

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.

00:57:41.660 They weren't killing anybody or-

00:57:43.760 There was no superiority, no inferiority.

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

00:57:57.940 this, this approach to lipid modulation.

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

01:00:11.340 becomes the problem.

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

01:00:37.760 you?

01:00:38.640 Not with the tissue residual time.

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

01:00:48.240 told them.

01:00:48.900 Well, Merck, you know, it's funny. A lot of people don't remember what happened in Merck

01:00:51.940 with the Vioxx. Sure.

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. 0.85

01:02:37.920 But the VPCs disappeared. Yeah. You know, and so did they. Yeah. You got to be careful.

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The Peter Attia Drive - October 17, 2018

#22 - Tom Dayspring, M.D., FACP, FNLA – Part III of V： HDL, reverse cholesterol transport, CETP inhibitors, and apolipoproteins

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