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Peter Attia MD#22 – Tom Dayspring Part III of V: reverse cholesterol transport, CETP inhibitors, & apolipoproteins
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60 min read · 11,624 words- 0:00 – 0:04
Intro
- PAPeter Attia
[upbeat music]
- 0:04 – 7:35
Direct vs. Indirect Reverse Cholesterol Transport: Where Cholesterol Goes
- PAPeter Attia
Hey everyone, welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. Welcome everybody to episode three of the week of Dayspring. In this episode, we talk about reverse cholesterol transport, we talk about lipid transportation, we talk about apolipoproteins, and we talk about CETP inhibitors and HDL. Of all the things we talk about here, the thing that I think is the most interesting is the discussion on HDL, which I think most people today would agree is far from being understood and is probably far more complicated than LDL biology. I would say that of all of the things that Tom and I discussed over this seven hours, I learned the most personally in our HDL discussion and our discussion of the CETP inhibitors. I was very familiar with all of the trials here, but Tom brought a level of nuance to this that actually sharpened my understanding of this, and for that I am, of course, eternally grateful. So welcome to episode three. Let's define now direct versus indirect RCT.
- TDTom Dayspring
All right. So if we're talking about the cholesterol that's in lipoproteins. So at the end of the day is if you, you have perfect cholesterol homeostasis, and for some reason there's some cholesterol excess in your body, it's going to wind up in your artery wall, or if you're lucky, it's going to wind up in your stool. That would be the preferred way. So the body clearly had-- knows beyond a certain point, we don't want cholesterol. We've talked about that at a bit of length so far. So now how can the body get rid of cholesterol that's already inside? It's made by cells, the most majority. And everybody thinks the liver makes most of the cholesterol. Liver ma-- We're not talking about the brain now, that's separate. Of your rest of your cholesterol in your body, the liver makes twenty percent of it. The rest is made in your peripheral cells. So the bulk of your cholesterol that's in your body, if your peripheral cells are making too much, it's got to get out or that cell will die. So the cells through even beyond ABCA1 efflux that we've talked about, they, it can free diffuse out of there as another ABC transporter that can pump cholesterol out, and it gets in a lipoprotein or it binds to albumin or it binds to a red blood cell, and it can be taken elsewhere. So classically, we were taught that, aha, the HDL particles are definitely a substrate that a cell can efflux cholesterol out into, especially an empty HDL, ApoA1, the protein itself that's unlipidated or a real baby HDL particle, very small HDL particle, is a great cholesterol acceptor, and we have membrane transporters that can give them free cholesterol. All right. So now the HDL has cholesterol, and what were we taught? Well, of course, the HDL just brings it right back to the liver, and the liver then will, if it has a need for cholesterol, it'll use it up, and then it'll put it in your bile. It'll go down. It'll go right out your rear end. Or your liver can actually change it to a bile salt, which it sends down the bile, and your bile salt could be excreted in a stool. So in effect, that's a way, it's a major way of getting rid of cholesterol. But our ileum doesn't cooperate. Our ileum u- typically reabsorbs about ninety to ninety-five percent of the bile salts and reuses them, so it's not the best way. Unless you can make sure that bile salt is being excreted, and we have a drug, the bile acid sequestrants, that make sure that happens, then you would deplete internal cholesterol. So, ah, that's so simple. So our VLDLs and LDLs and chylomicrons bring cholesterol to the tissues, and if for some reason there's too much cholesterol, the HDLs bring it back to the liver, and it goes bye-bye. Well, if you're talking to a second grader or physician at one point in our careers, that made great sense. That's plausible. That's perfect. That's why HDLs are not delivering cholesterol to the artery wall. They're bringing it back to an organ that's going to get rid of it or use it properly. Perfect. And if the other, the VLDLs, chylos, and LDLs are bringing cholesterol to the tissues, they never called it that, but I would say, well, that's forward cholesterol transport. And if the HDLs are bringing it back, that's reverse. Perfect. And if we have a great balance between forward and reverse cholesterol transport, that's good cholesterol homeostasis. You're not going to get in trouble. And then we made the mistake of, aha, our metrics of these pathways are going to be LDL cholesterol, maybe total cholesterol or HDL cholesterol, and that's where the whole thing falls apart because those metrics have zero to do with describing the complex flux and trafficking of all these pools of cholesterol or so. Zero. There is no cholesterol measurement in the plasma that tells you anything about-
- PAPeter Attia
About that movement
- TDTom Dayspring
... that movement and are your cells building up too much cholesterol or are they not, or God, you have great reverse cholesterol transport. So it made such perfect sense, and we were all stupid in medical school. We're never going to contradict a professor or even give it two seconds worth of thought if somebody told us something that the higher your HDL cholesterol, you got great reverse cholesterol transport because that HDL is going to take it to the liver. At a certain point in my studying of lipid understanding this stuff and I knew, God, what is it about... Not everybody with high HDL cholesterol is protected. There are people with low HDL cholesterol who don't get disease. But if what HDLs do is reverse cholesterol transport and they're bringing cholesterol back to the liver, shouldn't your HDL cholesterol go down? Eh, why would HDL cholesterol go up if it was bringing it back to the liver and being internalized or delipidated? That made no sense to me, so I knew there was more to the study. And of course, guys like Dan Rader, who I alluded to before, and Brian Brewer and, uh, John Chapman are HDL experts in this world, have figured this out pretty much by now, saying, "No, it's a w- this lipid transportation system is way more complex than an HDL bringing it back." And in those, we give that a different name now. So HDLs indeed are capable of bringing cholesterol back to the liver itself. There is a receptor that, that will delipidate cholesterol ester from an HDL that's called the scavenger receptor B1 and SR-B1. There is a holoparticle receptor that can internalize large HDL particles and bring them into the liver. But free diffusion can also occur. A big HDL can abut against a hepatocyte, and cholesterol just diffuses from the HDL membrane into the liver. So there are at least three pathways of cholesterol getting back to
- 7:35 – 10:59
Multiple Pathways Back: SR-B1, Intestine, Red Blood Cells and Albumin
- TDTom Dayspring
the liver. Hey, that same thing we now know happens at the intestine also. So HDLs don't even have to go anywhere near the liver. They can go get rid of some cholesterol at the intestine. Remember that TICE pathway, transintestinal cholesterol efflux? And now we are boggled our minds, and there are great papers on this, red blood cells carry way more cholesterol than do lipoproteins. They're so much bigger. Now, granted, the cholesterol is all in their surface, but they have a ton of cell membrane surface, so there's free cholesterol. Albumin, at least per albumin molecule, can attach to seventeen molecules of cholesterol. So we now know to variable degrees both red blood cells and albumin can just abut against any cell in your body and accept free cholesterol by free diffusion. An LDL particle can abut against a cell and accept cholesterol by free diffusion from a cell. So now LDLs have another way of acquiring cholesterol.
- PAPeter Attia
You know, it's interesting. Uh, this would be a great question for someone like Josh Knowles, who's such an expert in FH. But has anybody looked at red blood cell cholesterol membrane concentration or even size in FH patients? 'Cause one hypothesis would be they w- especially the FH patients who have FH as a result of LDL receptor deficiencies in some sort, you'd think that there'd be more free diffusion of cholesterol from their LDL into their red blood cell.
- TDTom Dayspring
Yeah, uh, and whether anybody's ever looked at that, I don't, I-
- PAPeter Attia
I mean, it might not be the case at all-
- TDTom Dayspring
No, but it-
- PAPeter Attia
... but that would be a question I'd be interested in.
- TDTom Dayspring
Look, theoretically, free diffusion can occur between any two membrane surfaces. So do their red blood cells... I, I would imagine at a certain degree it would cause-
- PAPeter Attia
It's gonna saturate
- TDTom Dayspring
... red blood cell irregularities-
- PAPeter Attia
Well, yeah, I mean, and it-
- TDTom Dayspring
... and there might be some-
- PAPeter Attia
There might be too much noise, but you'd look at the MCV or something like that and you'd see, have you increased-
- TDTom Dayspring
Yeah
- PAPeter Attia
... or decreased the mean corpuscular volume of these things? Is there anything happening?
- TDTom Dayspring
I don't know. You're changing certainly the membrane structure if that process is occurring in those people, whether that would affect red blood cell functionality. Remember, when you start putting phytosterols into red blood cell membranes, you get hemolytic anemias and stuff, sitosterolemia, phytosterolemia, that's part of their pathology 'cause the red blood cell is looking for cholesterol to stay healthy, not phytosterols. In other words-
- PAPeter Attia
I don't-- I didn't know that, so-
- TDTom Dayspring
Yeah
- PAPeter Attia
... I didn't realize that that's one of the hallmarks.
- TDTom Dayspring
It's part of a phenotypic picture of sitosterolemias, red blood cell hemolytic anemias, you know? So... Or crazy red blood cell structure, spherocytes and things like that, you know. So it's one way that the early investigators said, "Well, this person has non-phytosterol. What's this red blood cell problem going on in this person too?" So yeah.
- PAPeter Attia
So this is interesting. The HDL story is one where the more time goes on, the less I know.
- TDTom Dayspring
[laughs] Yes.
- PAPeter Attia
I mean, there are few things in lipidology that humble me more than my complete and utter buffoonery and ignorance when it comes to understanding high-density lipoproteins.
- TDTom Dayspring
It's true of all of us, and that's why I don't want you reading my two thousand and two lipid hallmarks and articles 'cause-
- PAPeter Attia
[laughs] You're embarrassed.
- TDTom Dayspring
Well, yeah, yeah. Oh, God, I would criticize somebody with spouting that stuff today. So only if you read it with that in mind and you would see how things change.
- PAPeter Attia
Can we use a very specific example to explain this? Let's, let's talk about the first failed CETP inhibitor trial, which was Pfizer's back in the mid-two thousands. So let me give the background, and then I want you to explain why this may have failed.
- 10:59 – 18:41
Chylomicrons, VLDL, IDL and LDL: Remnants and ApoE Clearance
- TDTom Dayspring
Well, be-before you even... Maybe I just want to explain a little more about the lipid transportation system-
- PAPeter Attia
Yeah, yeah, yeah. That's a good idea
- TDTom Dayspring
... so you know what CETP is.
- PAPeter Attia
Yeah, yeah, yeah.
- TDTom Dayspring
So remember I talked about the early on view was forward cholesterol transport, even though they didn't call it, and that's the ApoB family bringing cholesterol to tissues and the HDL family bringing it back. And here's why that's an, just such an absurd theory. 'Cause when the intestine pumps out chylomicrons that have a lot of your absorbed cholesterol in it, and your liver, certainly when it manufactures a VLDL particle, whose primary purpose, and everybody please listen to this, the VLDL has two purposes, one of which is not to deliver cholesterol anywhere. The liver is to develop, uh, transport triglycerides energy to cells that either store or utilize energy, fatty acids for energy, and to transport phospholipids. All right, so that's what your VLDLs and chylomicrons do. So they're part of the forward cholesterol transportation system. So the liver or the intestine excretes them, and then they're floating around. So what do they do? They go to adipocytes or they go to muscle cells, their triglycerides are extracted, and then their phospholipids break off and are utilized by cells. So what are you left with when a chylomicron loses surface phospholipids and core triglycerides? You're left with a smaller VLDL or a smaller chylomicron. Any lipoprotein that goes from a bigger size to a smaller size, but it's still within the density of a VLDL or chylomicron, it's called a remnant. It's a smaller. Hey, if Peter just amputated my right arm now, I'd be a remnant of my former self, 'cause I'd have [laughs] one less arm. So the f- uh, VLDLs and chylos have lost their core triglycerides, and they've lost their core phospholipids, and a few proteins have broken off, too. So now what happens to those remnant VLDLs and chylos? They're virtually instantly cleared by receptors that exist in the liver primarily. And what, how do those receptors clear these VLDL particles and these chylomicron particles that have accomplished their mission and delivered triglycerides? They bind to either the apoB 100 that's on the VLDL, but LDL receptors won't bind to apoB 48 in a chylomicron, but they bind to apoE. And chylos and VLDLs typically, if you're lucky, have multiple copies of VLDLs. So as soon as the chylos or VLDLs deliver your energy, deliver your phospholipids, they are cleared, which is why the chylomicron half-life is minutes, and the VLDL half-life is a couple of hours. Don't ever confuse half-life with plasma residence time. That's a little bit longer, but that's only a few particles that are persisting beyond those average half-life or so. So now any of the VLDLs that are not totally cleared by the liver keep getting smaller. They become smaller remnants, but then they change densities to a certain different degree density range. So you can't call it a VLDL anymore. You call it an intermediate density lipoprotein. The same thing, that's got a half-life of an hour. That's also clear 'cause IDLs have a lot of apoE on it. But at the liver, as they're being cleared, there's another enzyme that transforms some of your IDLs into a smaller... What's an IDL remnant called? Well, you'd be entering a new specific grav- uh, or a, a density boundary, and it would be called a low-density lipoprotein. So technically, you can say, yes, some VLDLs do become IDLs, do become LDLs, and then the LDLs will hang around forever until the LDL receptor clears an LDL by binding to apoB. The reason chylos, VLDLs, and IDLs get cleared so much more quickly than LDLs is the apoE content, which is [laughs] a mega ligand for the LDL receptor. The LDL receptor is really an apoB/apoE receptor, and there are other apoE receptors, too. So that's why those particles don't last long.
- PAPeter Attia
And just to interrupt you for a sec, apoE greatly amplifies the ef- efficacy of that ligand, the apoB ligand?
- TDTom Dayspring
It just is a, it's a preferred ligand for the, either an LDL receptor or-
- PAPeter Attia
This is, yeah, this is something-
- TDTom Dayspring
... other, uh, they're called LDL receptor related receptors.
- PAPeter Attia
So what percent... I'm sorry, I wanna come right back to what you're saying, but just be- I know I'll forget to ask. What percentage of LDL particles also co-express apoE?
- TDTom Dayspring
Yeah, so if you are lucky enough to have that genetic gift, and your LDL happens to contain an A, its half-life is pretty much the same as an IDL. They're gone. So if they're gone, guess what? They can't wind up-
- PAPeter Attia
You're just clearing those things out of circulation.
- TDTom Dayspring
Yeah, you, you have enhanced clearance. Your apoB, your LDL particle level will be much lower, and you don't get heart disease. In an average population, it's about 3 to 4%, but I, I guarantee you there are, depending on genes you inherit, some people that probably have a lot of apoE [laughs] on their LDLs, and of course, I would bet if they were studied genetically, they don't get heart disease, you know, 'cause it's being cleared, all those particles. And we'll talk about it later. There are other apolipoproteins that re- can retard clearance of VLDLs, IDLs, and even LDLs. I'll just mention its name now. It's apolipoprotein C3. You got that on your particles, you're gonna have seriously increased plasma residence time of all those things. An LDL with apoC3 on it is intensely more atherogenic than an LDL that only has apoB 100 on it.
- PAPeter Attia
Y- you once told me... This was probably a f- couple months ago. We were just shooting the breeze one day and y- by phone, and I remember you saying that if you could add one clinical assay to the arsenal of lipidologists, it would be an apoC3 assay. Is that still true?
- TDTom Dayspring
It would be, 'cause I think that's gonna be the way we really are gonna smartly identify remnant lipoproteins that are the VLDLs that are potentially causing trouble. Most VLDLs are not troublemakers. They're cleared rapidly. Or the LDLs that are number one on the list as to what's going in your arterial wall. ApoC3, as you know, Peter, is overexpressed in insulin-resistant situations, so that is a... And I have no doubt that one day that would be a cool test, unless maybe we can just measure your genetic ex- you know, the genes that give you apoC3.
- PAPeter Attia
Except that insulin sensitivity and insulin resistance impact it, which would suggest that if you took two people with the same lipid profile at the lipoprotein level, but one had higher apoC3 than the other, that person's at higher risk.
- TDTom Dayspring
A- a- and I think we got enough data now that shows that, and to show you pharma believes that, there's a major trial ongoing now with an apoC3 inhibitor that's coming, uh, because it'll be the way to get rid of these-
- PAPeter Attia
Is this also-
- TDTom Dayspring
... extremely atherogenic-
- PAPeter Attia
Is this, is this, uh, is this Isis doing this?
- TDTom Dayspring
Yeah, believe so, yeah.
- PAPeter Attia
Oh, sorry, just for the listener. Isis, I'm not referring to-
- TDTom Dayspring
[laughs]
- PAPeter Attia
Yeah, yeah, yeah. So this is Isis. There's a pharma company in San... It's in San Diego. They're actually based out of San Diego-
- TDTom Dayspring
Interesting
- PAPeter Attia
... 'cause that's where Sam T- Tomecki is. But it is I-S-I-S.
- TDTom Dayspring
Yeah, it's one of these new, uh-
- PAPeter Attia
Yeah, and they're looking at oligonucleotides
- TDTom Dayspring
... oligonucleotide anti-
- PAPeter Attia
Yeah, they're looking at oligonucleotides
- 18:41 – 25:15
Insulin Resistance, LDL-P vs. VLDL, and Non-HDL Cholesterol
- TDTom Dayspring
Yeah, and yeah, they're gonna probably be great therapeutic avenues for us if we need it. So yeah, I think there will be utility for measuring this right now before a third-party payer's ever gonna pay some lab for doing that. It's gonna need a little more proof than the, what we have so far and everything. But back to our lipid transportation system. So please understand, and there are just too many people out there who think every VLDL becomes an LDL. It's not even close. And in fact, if you're not insulin resistant and you don't have a, however you define a triglyceride issue, which I might define as a trig above 130 or so anyway, 40% of the apoB particles coming out of your liver are, they're not VLDLs, they're LDLs. And the VLDLs that are coming out are not big 'cause they're not carrying extra triglycerides 'cause you don't have them. They're just carrying some degree of cholesterol and a little bit of triglycerides to supply the energy you really need. And that's why if you are measuring some VLDL metric, big VLDLs occur only in triglyceride-rich lipoprotein pathologies, by far the most common of which is insulin resistance. And clearly 'cause that VLDL would come out, and I guarantee it's probably got apoC-III on it, it doesn't have a half-life of a few hours. Its plasma residence time is much longer. There is more conversion of that VLDL particle into LDL particles, which would be triglyceride-rich. Through some transformation, they become the small LDLs, which are even less rapidly cleared. So your apoB particle number, your LDL particle number goes through the roof. Now yes, part of those apoB are the remnants, but I've posted enough slides on Twitter lately, and I'm pretty sure it's in Peter's package here. Even when you m- take these v- type 2 diabetics with severe insulin resistance or insulin resistance just proved by an insulin clamp study, their apoB level, their particle levels are going up-
- PAPeter Attia
But it's all through the LDL
- TDTom Dayspring
... but the LDL particles go up astronomically, and the VLDL maybe doubles or triples. It goes from 30 to 90, whereas the VLDL particles go from 1,000 to 3,000.
- PAPeter Attia
The LDL.
- TDTom Dayspring
The LDL.
- PAPeter Attia
Yeah.
- TDTom Dayspring
Yeah.
- PAPeter Attia
Yeah.
- TDTom Dayspring
So-
- PAPeter Attia
And that's an important distinction. So a lot of people will say when you're insulin resistant, all of that net difference is, it, it, that we see, 'cause there's no disputing the more insulin resistant you get, the more discordant you get between your LDL-P and your LDL-C. And all things equal, the LDL-P is just going up and up and up as you become more insulin resistant. So people will say it's all the VLDL. Furthermore, they'll confuse a percentage increase that's relative with an absolute increase. So as you pointed out, the, if you're, you're referring to the Garvey paper, I think.
- TDTom Dayspring
Yes, I am.
- PAPeter Attia
Yeah. So in that paper, you might see VLDL particle number... I, I'm making this up, but it, let's, so someone will see the numbers and decide for themselves, but it might go from 30 to 60.
- TDTom Dayspring
Yeah, or 150 even. So-
- PAPeter Attia
Yeah, nanomole per liter.
- TDTom Dayspring
Yeah.
- PAPeter Attia
And you think, "Well, God, that's a much bigger relative increase."
- TDTom Dayspring
Yeah.
- PAPeter Attia
And it is, but if anybody's read our lengthy treatise on relative versus absolute risk, you, you cannot evaluate a relative change without understanding its absolute change. And so even though the relative change on the LDL-P is smaller, it's starting from such a high base that it might add 300 to 400 nanomole per liter, which might only be a 30 or 40% increase, but that absolutely dominates the lion's share of the increase, not the extra 30 to 50 nanomole per liter you might get on the VLDL. This is a really important point if you want to be a lipid geek.
- TDTom Dayspring
It is, and this is one reason why non-HDL cholesterol has be- come in vogue, because remember, non-HDL cholesterol, we told you, you calculate it by subtracting HDL cholesterol from total cholesterol, but you could really add directly measured LDL cholesterol to a VLDL cholesterol, and that's your cholesterol is not in your HDL particles, theoretically potentially atherogenic cholesterol, and hey, that's a free calculation too. So they use non-HDL cholesterol as a marker of remnants. Okay, and there's no doubt some of those VLDL particles would be remnants, but we'll get into this later, I hope. I'll make the case that a lot of those VLDL particles are not remnants and they're not going into your arteriole.
- PAPeter Attia
Yeah, it's funny.
- TDTom Dayspring
Yeah.
- PAPeter Attia
I used to always sit a patient down and, uh, the very first time we reviewed a blood test, I would say, "Look, there's four things we're gonna talk about from a lipid standpoint. We gotta know your LP little A, we have to know your LDL-P. I'd like to know how many of those are small because it's a proxy for some other stuff, and I want to know your VLDL remnant. Well, I can't measure that, so I'm going to approximate it with VLDL-C." Well, I don't say that anymore because I've come to realize-
- TDTom Dayspring
Really shouldn't
- PAPeter Attia
... that's a very crude, crude estimation that's almost useless.
- TDTom Dayspring
Uh, I wouldn't call it useless because-
- PAPeter Attia
Well, yeah, I used the word almost in front of it.
- TDTom Dayspring
Yeah. Okay, yeah.
- PAPeter Attia
[laughs]
- TDTom Dayspring
And I'll get all my lipid colleagues real mad at me if I start saying that 'cause they... And I get into this in a lot of the papers I review.
- PAPeter Attia
And we still target. I mean, I still say to patients-
- 25:15 – 32:45
Why Particles Exchange Lipids: ApoD/CETP and "Good Cholesterol"
- TDTom Dayspring
But let's get back to our lipid transportation system now. So we have our theoretical forward, uh, delivering particles, the ApoB particles, and I tell you how they transform into one another, how they deliver their cholesterol. By the way, no VLDL or IDL or chylomicrons delivering cholesterol to your peripheral cells. They don't need it. They're making all they need. So-
- PAPeter Attia
Just restate that please for the court's transcript.
- TDTom Dayspring
Yeah. Yeah.
- PAPeter Attia
So te- tell me again.
- TDTom Dayspring
When-
- PAPeter Attia
What chylomicrons are doing... Are not doing what?
- TDTom Dayspring
You walked out of the room to do something when I was explaining what chylomicrons and VLDLs do.
- PAPeter Attia
Yeah, everybody... To- Tom, Tom just outed me. I, I went to go take a leak a minute ago.
- TDTom Dayspring
[laughs]
- PAPeter Attia
But all right.
- TDTom Dayspring
So I explicitly went over that the purpose, the functional purpose of chylomicrons and VLDLs is to deliver energy in the form of triglycerides to adipocytes and myocytes, and phospholipids, not to deliver cholesterol to any darn cell in your body. So spend your time reading on it. That's what they do. You could even make the case that if they're not delivering cholesterol, why is cholesterol even in their particles? And it goes back to something what Peter said. These particles have to be spherical. So when a VLDL or an enterocyte is starting to lipidate ApoB 48 or especially liver ApoB 100, i- if you put cholesterol in that, and we have proteins that do that, microsomal triglyceride transfer and other cellular lipid transport proteins, by putting cholesterol on the ApoB, it becomes a spherical particle. So all primordial VLDLs and chylomicrons are first just very cholesterol-rich spherical particles. They don't have the triglycerides yet. Then when they're spherical particle, they can really fill up with their triglycerides. So the cholesterol is in there for a structural property to make them spherical particles so that they can carry more triglycerides. And that's why when they go out, they become smaller spherical particles that are triglyceride depleted, and they just bring their cholesterol back to the liver or the intestine, and they do what it, whatever they do with it. So that's why cholesterol's in there. They're not bringing cholesterol to my nose or your kidney or anyplace else 'cause those cells need cholesterol. Those cells will make it, or they'll get it by some free diffusion if they really need it. Or absolutely virtually any cell, if it absolutely needed cholesterol, 'cause for some reason the synthesis was broken, any cell could ultimately upregulate an LDL receptor. But most of them don't, so 'cause they have no need for the cholesterol that's in an LDL.
- PAPeter Attia
Yeah.
- TDTom Dayspring
The liver upregulates most of your LDL receptors 'cause that's involved with clearance of these particles. That's where your LDL receptors are heavily expressed. But now you do have these particles that have certain half-lives or plasma residence times, VLDLs even for a few hours or A- LDLs for at least a day, in some instances more, HDLs for a few days. So are they stagnant particles that never change? No. Guess what? They're living, breathing particles. So I used to have nice animated diagrams of this. Every second of every minute of every day, your particles are having sex with one another. They're transferring bodily fluids. They exchange from their core. Every lipoprotein in your body has some degree in its core of triglycerides and cholesterol ester, every particle from an HDL to a chylomicron to a VLDL, IDL, and LDL. And we actually have a protein that's pretty much carried on HDLs. It was originally called apoprotein or apolipoprotein D, as in dog, capital D. And in my dirty New Jersey mind, think of an HDL particle which carries most of the apoD. You... Men carry something between their legs that if it got erect, it's sticking up and it can penetrate something else. So if, uh, HDLs are carrying this apoD and it suddenly sticks up, it can penetrate a, another particle, be it another HDL or an ApoB particle. And that's a phospholipid sort of tunnel. It's a, it's like a little tunnel that can connect two circulating lipoproteins, and therefore the core lipids can exchange.
- PAPeter Attia
And this is HDL to HDL or can it be HDL to LDL?
- TDTom Dayspring
It can be HDL to HDL, in which case it's called a homotypic transfer 'cause it's two like particles exchanging their bodily fluids.
- PAPeter Attia
Or hetero-
- TDTom Dayspring
Or a heterotypic where apoA particles exchange their core lipids with ApoB particles. What is hardly known out there is two ApoB particles can exchange their lipids. A VLDL can exchange li- its core lipids with an LDL, and I'm gonna tell you, that's where remnants get a lot of their cholesterol. So that would be homotypic exchange of cholesterol and triglycerides between two different v- ApoB-containing particles. So a lot of it is between HDLs and ApoB particles. And why? Why would we even be given that lipid transfer protein? Because HDL's job is to be a great cholesterol acceptor. It is very important in delipidation, helping cells efflux the cholesterol they don't want. So when an HDL acquires that free cholesterol from a cell, what does it do? Well, HDL carries that ACAT enzyme, I talk about it, except it's called LCAT 'cause it's in a lipoprotein. It esterifies the cholesterol to cholesterol ester, goes to the core of the particle, the HDL becomes bigger. Then the HDL transfers its cholesterol ester to, let's say, an ApoB particle, 95% of which are LDL particles. So here's where the joke comes in. So I know you're all calling the cholesterol in an HDL, "That's good cholesterol." But what do you call that cholesterol molecule the second an HDL transfers it to an LDL? Does it instantly become, "Oh, it's bad now"? If I looked at it, it's still the same exact cholesterol molecule. So what deter- if you want to use those darn adjectives with a patient, I guess what's gonna determine what's good or bad cholesterol is, what is that lipoprotein gonna do with its cholesterol molecule? If it's an HDL and it's an LDL and it's bringing it back to the liver or the intestine or... Oh, that's not bad, I don't think, 'cause those organs know how to get rid of cholesterol, so I don't know, maybe that's a good cholesterol pathway, but I don't kn- think you can apply that to the cholesterol molecule itself. But follow me here. What if that HDL pulled cholesterol out of your cell 'cause it was overproducing too much and he gave it to an LDL and said, "Buddy, take off. The liver's got that LDL receptor. It's gonna clear you," and that LDL particle ra- race back to the liver and for some reason there was no LDL receptors or there weren't enough of them there. Where's that LDL going?
- PAPeter Attia
He might wind his way back into circulation.
- TDTom Dayspring
Uh, he will, because he's not gonna be cleared.
- PAPeter Attia
Yeah, and he might wind his way back to the endothelium, yeah.
- TDTom Dayspring
And right through that endothelium, and all of a sudden your good cholesterol is in the macrophage in your arterial wall. So spare me the nonsense. Stop using it. It's absurd term. It has no meaning. You're miseducating patients if you tell them it's good cholesterol, 'cause they use that because they're measuring HDL cholesterol in the blood as a marker that I'm in good shape or not.
- 32:45 – 36:30
Low HDL-C in Framingham Is a Proxy for ApoB
- TDTom Dayspring
And trust me, virtually all of the early trials that showed low HDL cholesterol was bad news were never, ever adjusted for ApoB or LDL particle counts. 'Cause I'm gonna tell you right now-
- PAPeter Attia
And that includes Framingham, which-
- TDTom Dayspring
Yes
- PAPeter Attia
... I alluded to earlier.
- TDTom Dayspring
Yep.
- PAPeter Attia
'Cause a lot of people like to hang their hat on the fact that Framingham... 'Cause most people forget what Framingham is. They throw the term around, so let me just spend one minute explaining this. Framingham started out as a five geography, a five city or five region observational study, purely observational, of which Framingham was one, and I used to know them all, but-
- TDTom Dayspring
No, it was all F- on- Framingham is only Framingham, Massachusetts.
- PAPeter Attia
No, no, no, but, but the original cohort of, of that study from NIH was Framingham, Puerto Rico, San Francisco, Honolulu.
- TDTom Dayspring
Oh, yeah, that, that Framingham evolved from, because-
- PAPeter Attia
That's right
- TDTom Dayspring
... yeah.
- PAPeter Attia
Then the f- then the pr- the pros-
- TDTom Dayspring
There was a five city, uh, group, you're right, yeah.
- PAPeter Attia
And, and that's where they gathered the information. That's where they made the observation. So there was a retr- a purely retrospective assessment of five cities, and I'm blanking on the f- but I know, I, I think one was Puerto Rico, Honolulu.
- TDTom Dayspring
I'm pretty sure Stanford might've been one, uh.
- PAPeter Attia
But anyway, the point... But the prospective work was then concentrated in Framingham, Massachusetts. But the point is, a lot of people like to point out that LDL is irrelevant because the LDL cholesterol, which by the way, was calculated, not measured directly, so you've introduced a variability.
- TDTom Dayspring
And years later, not in the first 20 years of the study.
- PAPeter Attia
Correct. It turned out to be less predictive than the ratio, not the ratio, I'm sorry, the absolute level of HDL-C and triglyceride. And a lot of people like to stop at that and say, "Well look, that means LDL doesn't matter." What they don't realize is those are two enormous proxies for ApoB.
- TDTom Dayspring
That's all they are. And y- virtually all of your insulin-resistant patients are getting atherosclerotic disease. It's ApoB, it's LDL particle mediated, because everybody who's not on a drug or a serious diet who had a triglyceride HDL cholesterol axis abnormality has astronomical ApoB. So if you go back for all this cited forever epidemiologic data that low HDL cholesterol is such an important risk factor, uh, do me a favor, pal, adjust it for ApoB or LDLP, which was never done and can't be done in those studies now. It would disappear as an independent risk factor, low HDL cholesterol.
- PAPeter Attia
Well, that's certainly the hypothesis. I mean, I guess the question is, does MESA still have enough blood kicking around to measure that, or Framingham offspring might?
- TDTom Dayspring
It, it does. MESA has certainly shown in the discordant people where there's a discordance with ApoB and LDL cholesterol, or in people who have low HDL cholesterol, ApoB, LDL particle is your most important metric. So MESA has shown-
- PAPeter Attia
And MESA, when we're saying this, by the way, folks, we're not talking Mesa, Arizona. We're talking about the Multi-Ethnic Study of Atherosclerosis, which is abbreviated MESA. So we'll often, you'll often hear people refer to MESA and Framingham, and what they're referring to are enormous studies of atherosclerosis that still have biobanks that are available to do these retrospective analyses on prospectively collected samples.
- TDTom Dayspring
Yeah, and MESA's much more contemporary and multi-ethnic, so it's, uh-
- PAPeter Attia
Yeah, because of, another criticism of Framingham is you've taught me a lot about, you know, middle class white people in, you know-
- TDTom Dayspring
Mostly, right
- PAPeter Attia
... the Northeast.
- TDTom Dayspring
Yeah.
- PAPeter Attia
But what have you told me about, you know, African American-
- TDTom Dayspring
Right
- PAPeter Attia
... Hispanic, et cetera?
- 36:30 – 40:45
Very High HDL-C and Dysfunctional HDL: The Case Study
- PAPeter Attia
So one of the most amazing papers you've ever sent me, and this was actually kind of recent. I feel like this was a year ago, maybe a year and a half ago. It was a case study of a woman who had a An HDL cholesterol of about 130 to 140 milligrams per deciliter. So for the listener, you just never see levels of HDL like that unless you work in the lipid community or you're a lipidologist, which means I don't see them 'cause I'm not a lipidologist. I just pretend to be one. But, you know, the average person, the average female might walk around with an HDL cholesterol of 60 milligrams per deciliter. So this woman is showing up at two and a half times normal, and interestingly, I don't even know if you remember this case study, Tom, but if not, I think I remember enough of the details. She had very accelerated atherosclerosis. She did not, by the way, to my recollection, have particularly elevated LDL cholesterol. Her LDL cholesterol was probably about 110 milligrams per deciliter, slightly below her HDL cholesterol. And of course, the question was: Why did this woman have elevated atherosclerosis when she had normal amounts of, quote-unquote, "the bad cholesterol" and two and a half to three times normal good cholesterol? Do you remember this case?
- TDTom Dayspring
Not per se, but, uh, if-
- PAPeter Attia
What do you, what would be your ex-
- TDTom Dayspring
... cases like that has been well explained.
- PAPeter Attia
Yeah, yeah, yeah. Yeah.
- TDTom Dayspring
And, and this is a rare genetic thing where this cholesterol trafficking pattern is disrupted in certain ways. Something's wrong with that pathway 'cause that HDL should be getting rid of its cholesterol, and it should be bringing more back someplace. So this person would have to have incredibly massive HDL particles that are carrying way more cholesterol particles per HDL particle than it should be. And it turns out, and they're not being cleared as much as they should, so this is gonna turn out to be cholesterol-rich HDL particles that don't have a protein that's very integral with clearing HDLs and ApoE again. So if you don't have ApoE on your HDLs, they might become very cholesterol rich, your HDL cholesterol's through the roof. Those are incredibly dysfunctional HDLs, and part of their dysfunction is they're probably carrying the wrong type of phospholipids and are not carrying the type of protective proteins that an HDL should be carrying. 'Cause when you have a, a surface area that's, that's big, the proteins that should be binding to it no longer bind 'cause it's not-- They're looking for the molecules they're supposed to covalently bind to, and they can't find it or so. So that's the circumstance of a very dysfunctional HDL.
- PAPeter Attia
And, and, and, and now I remember the context, which was a really good friend of mine from med school sent me some, a friend of a friend's blood, and the numbers were like that, and I remember reaching out to you saying, "This is odd, Tom. What do you make of this?" You sent me the case study. There's really nothing to do to treat these people except lower ApoB, right?
- TDTom Dayspring
You just have to chase... It's sort of like what do we do for Lp (a) nowadays. You chase every other identifiable cardiovascular risk factor. Interesting, no- nobody would do it to her, but there is a product [chuckles] that induces a receptor in the liver that pulls cholesterol out of HDL particles. It's a, uh... Was, uh, uh, called Probucol. I don't know if it's even still available by prescription. It induces the scavenger receptor. It drastically lowers HDL, but it's a powerful antioxidant, and there were some early arteriographic studies that suggested this is good. Arteries, at least on an arterial imaging, look better. So Cesar Milano-
- PAPeter Attia
And sorry, just to be clear, the reason why... I mean, again, there's, uh, 217 ways to be fooled by an angiogram. It's about as crude a way to assess this process as anything. That said, if you believe that this is improving, you believe it's basically increasing the throughput of HDL to delipivate?
- TDTom Dayspring
Y- yeah. So the theory would be, aha, there's... This is the case where, hey, remember I espoused the theory before that if HDLs are really delivering cholesterol back to the liver, shouldn't HDL cholesterol be going down? Well, here's a drug that depletes HDL cholesterol, and at least arteriographically, people look better. We now have identified a gene that regulates the functioning of the scavenger receptor, so if you have an inactivity of that scavenger receptor, you have very big HDL particles, high HDL cholesterol, and coronary atherosclerosis.
- 40:45 – 48:13
Defining Direct and Indirect RCT and the Limits of HDL Measurement
- PAPeter Attia
So, so this is, this is, this is a nice transition, so let's summarize that. This is, again, overly simplistic. This is a zeroth order analysis, so we're just gonna put our fourth grade hats on, which is acceptable for limited periods of time. If you have low HDL-C, you cannot infer if it's low because you're failing to, quote-unquote, "pick up cholesterol" or because you're delivering it quickly.
- TDTom Dayspring
You don't know. You don't know.
- PAPeter Attia
Conversely, or similarly I should say, if you have high HDL-C, it is not clear if it is high because you pick up a lot, which in theory would be, quote-unquote, "good," or because you're deficient at dropping it off-
- TDTom Dayspring
Right
- PAPeter Attia
... which would be, quote-unquote, "bad." And therein lies perhaps one of the most interesting or certainly top five interesting drug stories, which are these CETP inhibitors.
- TDTom Dayspring
Right. And again, I'm just gonna do like... 'cause I just wanna finish this whole... So I told you HDL has this erect-
- PAPeter Attia
ApoD
- TDTom Dayspring
... ApoD. But A- ApoD is better known as cholesterol ester transfer protein. It really ought to be called cholesterol ester triglyceride transfer protein, CETP. So we're gonna talk about a CETP inhibitor in a moment because it's gonna stop that process. The lipoproteins can't exchange the particles anymore. Now, wait a minute. If you're following me so far, an HDL which is pulling cholesterol out of cells, it's really good at that, is then transferring a lot of that cholesterol to LDLs. Here's something that's gonna shock you. In an average person, anywhere from 30 to 60% of the cholesterol in that LDL particle arrived via an HDL particle. So if that LDL particle will accept that cholesterol from an HDL and race it back to the liver, thank you, LDL. It's like the HDL was a quarterback, it passed it to the tight end who ran it across the goal line. Who gets the credit, the quarterback or the tight end or both of them? So in the lipid transportation system, they work harmoniously together if everything works, including the lipid transfer proteins. We're not gonna talk about it today, but God also gave us lipid inhibitory transfer proteins, apolipoprotein F, apoC1. So everything is tightly regulated in our homeostatic system, but we'll leave that for another day.
- PAPeter Attia
Yeah, so if this is the master's class on lipid-
- TDTom Dayspring
[laughs]
- PAPeter Attia
... that will be the, uh, whatever, whatever falls above-
- TDTom Dayspring
Yeah
- PAPeter Attia
... a master. Yeah.
- TDTom Dayspring
So it's always more complicated. So now just to finish up the definitions of a reverse cholesterol transport, old days, HDL back to the liver. Nowadays, it's HDL g- gets cholesterol from wherever. If things go right, it could bring it back to either the liver or the small intestine or an adrenal gland or an ovary or a testis. So that's gonna be called direct because the HDL is doing it, and we're saying he's the primary factor here 'cause he does pull cholesterol out of the cells. But we now also know that HDL can give its cholesterol to an LDL, to a VLDL, to a chylomicron, to an IDL. Since most of them are LDLs, it's giving most of it to an LDL, and they can bring that cholesterol. They're gonna be cleared at the liver if you have the proper number of LDL receptors. Hey, so if an HDL give its cholesterol to an ApoB particle that brings it back to the liver, that is called indirect reverse cholesterol transport. We're still debating can an LDL bring it back to the small intestine also. For a while, that was yes, then it was probably not. Now it's back to a probably yes again. But if an LDL brings it back to the liver for sure and the intestine, then that's indirect cholesterol or reverse cholesterol transport if you still need the reverse adjective put in there or so. But part of that pathway is the in... It's not the liver, it's the intestine, the transintestinal cholesterol efflux. So if you wanna talk about total reverse cholesterol transport, I would rather just talk about lipid transport. It's every particle is part of the system. So but if you wanna stick with reverse cholesterol transport, total RCT is the sum of indirect plus direct, and both direct and indirect involve the liver and the intestine. And a serum HDL cholesterol tells you nada about that process.
- PAPeter Attia
Yeah, we may or may not have time to get into this, but yesterday over dinner we talked about the futility or the challenges maybe is a better way of saying it to be a little more optimistic, but the challenges in coming up with HDL functional assays because that's, you know, once you get deep enough into this topic as, as we're getting now, you very quickly start to realize that to measure HDL cholesterol or even HDL particle number is so crude in terms of providing an insight into its functional status that, you know, the best we can do today is we measure HDL cholesterol, HDL particle number, and HDL particle size, and we try to triangulate just as we used to when we could look at LP little a mass and LP little a cholesterol. We could sort of triangulate if we were in the zone, but that's still not the answer. I mean, that just-
- TDTom Dayspring
No
- PAPeter Attia
... doesn't tell us how well these things function.
- TDTom Dayspring
We, we, we just need more specific biomarkers nowadays to take it to the next level and the types of therapies that are coming along, and I, I think that's even important knowledge to know when you're gonna prescribe a specific nutritional, uh, therapy also that all these things come into play, you know? So, uh, very important to understand this stuff, but I hope you can see how this world has changed, and we ought to stop using even the term reverse cholesterol transport. It's idiotic. It's so immensely complex. You don't know what you're talking about, and you have no biomarker that you can evaluate that on a given patient. And the functionality of these particles, like do they really participate in these pathways or not, are determined in large part by their phospholipid content and the proteins that are on these surfaces apart from just the ApoD we talked about. And, uh, with HDLs, just briefly, I think there is a probably hundreds of HDL subpopulations. HDL's carrying immense number of proteins, way more than LDLs or VLDLs ever can. But they all can carry one or two proteins. They can't carry 200 proteins that have been identified as coming from HDLs. So it's probably the protein signature of an HDL or even the phospholipid makeup, the lipidome of an HDL. We have just like, uh, you know, I love fire departments. Fire departments have hook and ladder trucks. They have pumper trucks. They have hazmat trucks. They got a variety of rescue vehicles nowadays. They got ambulances, rescue trucks, and they don't all show up at every fire. The dispatch sends the trucks that are needed to specific types of fires. Well, your HDL subpopulations show up where they're needed, and they know where they're needed because the cells that need them recognize the proteins or the phospholipids that are on their surface and pull them in. So I don't know when it's gonna come down to lipidomic or proteomic analysis of these particles. I think that maybe will take us to the next level and wouldn't hold your breath on that anytime soon.
- 48:13 – 52:40
ApoA-1 Milano and the Rationale for CETP Inhibition
- PAPeter Attia
All right, so let's go back to this idea of... 'Cause I wanna start talking a little bit about some drugs. But rather than start chronologically, which I wanna do after we get to the, to this question, but just because while we're on HDL, there are really two drugs that have been discussed as ways to, quote unquote, "raise HDL," one being niacin, which we'll come to later on, but the other being these CETP inhibitors, which are relatively recent. It was 2006 when the first CETP trial, or at least when the first data became available, and they weren't promising. So first of all, why would inhibition of CETP been thought to be an optimal strategy? And two, why do you think it didn't turn out that way?
- TDTom Dayspring
Because we don't know what [laughs] we're doing with HTLs and especially using metrics to analyze them. And the story starts a lot longer than that in Italy, that little section up on northeastern Italy where, uh, ApoA-1 Milano was discovered, and these were people who had HDL cholesterol levels of five and 10, and yet had longevity. And how could that possibly be? 'Cause Framingham has taught us low HDL cholesterol, you're out of here. And yet here's where people with longevity. And it turns out they had a very functional ApoA-1 that really did the flux system very quickly or had other properties that it didn't matter how much cholesterol was in the HDL. The HDL was unbelievably functional.
- PAPeter Attia
Do you know anything about their ApoBs?
- TDTom Dayspring
I think even if they have high ApoB, [laughs] they don't get, uh... I don't know that-
- PAPeter Attia
Yeah, yeah. So they're-
- TDTom Dayspring
That's probably out there. I can't answer that off the-
- PAPeter Attia
Yeah, yeah. So they're... Maybe we'll look that up if, if we can.
- TDTom Dayspring
Uh, but, but I-
- PAPeter Attia
But, but their high-functioning ApoA seems to-
- TDTom Dayspring
Yeah
- PAPeter Attia
... protected them.
- TDTom Dayspring
And they just... So I doubt if ApoB matters, 'cause some of them probably would, y- you know, 'cause... Although they're all on that Mediterranean diet and stuff, so may- maybe they don't have atherogenic parts, so I can't answer that. So that led pharma to, "Hey, let's just invent, either synthesize ApoA-1 or a truncated ApoA-1 and, uh, commercialize that. We'll, at least for people who had acute coronary syndromes, we'll infuse that into them. It'll delipivate their plaque and home free." Every single trial failed, including a very recent trial. So there's one where they got a especially protective type of HDL, but they couldn't reproduce it, whatever it is. So that failed. So but, you know, there were people in the past that Peter talked about. He gave a case where a woman had very high HDL cholesterol but had coronary atherosclerosis. But there is a bunch of people out there with very high HDL cholesterol who don't have coronary. I'm gonna theorize in retrospect maybe ApoE's got something to do with that, but I don't know that, 'cause that would enhance their clearing. But what is one of the genetic conditions that would give you high HDL cholesterol? Remember I just taught you what ApoD is, C-E-T-P, CETP. It takes the cholesterol out of your HDL and gives it to an ApoB particle, so theoretically that would lower your HDL cholesterol. But if I inhibited CETP, your HDL would get to keep all its cholesterol. What would go through the roof? Your HDL cholesterol. And the genetic model was at least some people with certain CETP variants had very high HDL cholesterol and they didn't seem to get much heart disease.
- PAPeter Attia
Although what I'm confused by, Tom, is that in 2000... I want to say '11-ish, didn't a Mendelian randomization look at this and conclude... Now, this was long after these drugs were in the pipeline, but didn't the MR suggest that those people were not better off?
- TDTom Dayspring
I think that-
- PAPeter Attia
It, it's a Nature paper-
- TDTom Dayspring
I think it-
- PAPeter Attia
... and we'll pull it, but-
- TDTom Dayspring
CETP and the investigative drugs were long before the Mendelian randomization.
- PAPeter Attia
A- absolutely. Yeah, yeah, yeah.
- TDTom Dayspring
So they didn't have that data that Mendelian randomization shows not necessarily so that with high HDL cholesterol you're protected, whereas nowadays most of that data would show it's not.
- PAPeter Attia
Yeah, yeah. My recollection is that the MR came out in 2010, 2011, and it basically validated what had n- at the time been seen in two trials, which was, "Wow, inhibit CETP, things don't get better."
- TDTom Dayspring
Well, well, yeah, so I think Mendelian randomization, had they had that data first, they would have never-
- PAPeter Attia
They might never have made the drugs
- TDTom Dayspring
... investigated these drugs.
- PAPeter Attia
Yeah.
- TDTom Dayspring
And which is why they did chase PCSK9 inhibitors, 'cause the genetic model told them this can't fail unless there's a downside to the drug-
- PAPeter Attia
That's right
- TDTom Dayspring
... that we don't know about. And that's always a problem with a drug that's gonna change a gene. It may do good to a marker and do bad to some other marker you're not smart enough to know about yet.
- PAPeter Attia
Oh, I can't wait till we're gonna talk about-
- TDTom Dayspring
Yeah
- 52:40 – 1:00:34
The CETP Inhibitor Trials: Torcetrapib, Dalcetrapib, Evacetrapib, Anacetrapib
- TDTom Dayspring
So let's inhibit CETP. The HTLs get to keep all their cholesterol. HDL cholesterol goes through the roof. That's good epidemiologically, right? And it turn-
- PAPeter Attia
Except on first principles, it doesn't even make sense in light of what you just told us.
- TDTom Dayspring
No, but they didn't know that then either. Remember, this whole HDL story has evolved, too, about-
- PAPeter Attia
Oh, wait. So that, so that's interesting. I don't think I understood that, and so I should give them more credit. Are you saying that it absolutely was not known?
- TDTom Dayspring
No, there was theories on it. Guys like Dan Rader was always talking about it, but you don't know how much you're interrupting the system with that and everything.
- PAPeter Attia
Yeah.
- TDTom Dayspring
And, you know, they're so heavily focused on basic lipid biomarkers like LDL cholesterol and HDL cholesterol.
- PAPeter Attia
LDL bad, HDL good.
- TDTom Dayspring
And it's the same, the niacin story. How could it not work? It raises HDL cholesterol and turns out niacin doesn't work if you want to take legitimate trials to show it works. And is there a price for using niacin, even if you don't believe the legitimate trials? So that's another story which we'll probably get into.
- PAPeter Attia
We will definitely get into that-
- TDTom Dayspring
Yeah
- PAPeter Attia
... 'cause this is one area where your peers will argue with you.
- TDTom Dayspring
Some. M- many will not, other than, "All right. I've tried everything else. Nothing else has worked. Let me, uh, give it a..." And look, I'm a guy who took niacin myself for a bunch of years, so, um, before I knew what I knew now, and it didn't unfortunately work for me anyway. So the CETP, it's gonna raise HDL cholesterol, but how much it raises it really depends on the potency of the CETP inhibitor. And there are different degrees of CETP inhibition. We have weak inhibitors and we have super strong inhibitors. The first one that came out, Pfizer had developed a drug that inhibited, uh, thought it was gonna be a multi-billion dollar drug 'cause it lowe- raised HDL cholesterol. Pfizer and many other companies already proved lowering ApoB, LDL cholesterol works and really works well. Imagine if we can take those people with residual risk 'cause their H- low, HDL cholesterol is still low and we could raise their HDL cholesterol. That niacin angiographic trial would really support doing that. Okay. So they said, "Let's inhibit CETP and raise HDL cholesterol." So Pfizer went to market. Many people were buying that stock in its infancy, thought they'd make a zillion dollars.
- PAPeter Attia
I remember where I was standing the da- the moment those results were announced, and it's interesting because I was not at all a lipid guy, but at the time I was working at McKinsey. I was in San Francisco. It was on a September day, a beautiful September day in San Francisco, 2006, and I took it as a fait accompli that this drug would work and Pfizer stock was going to skyrocket.
- TDTom Dayspring
Oh, look, we all knew the company, Esperion, who developed that, and we knew their guys. We had heard them lecture many time, many to top... Everybody was banking on that. Boy, this is real. I mean, you never know in a clinical trial, but-
- PAPeter Attia
It looked like a slam dunk
- TDTom Dayspring
... uh, it really did. And I remember whenever I found out, I forget the weather that day, but it was late at night and, uh, I think the internet was even... And I saw a little thing, and it was like 11:30 at night, I don't even know why I saw it, that Pfizer terminates torcetrapib trial.
- PAPeter Attia
Yeah. Well, in fairness, you were actually seeing it in real time.
- TDTom Dayspring
[laughs]
- PAPeter Attia
I saw it the next morning.
- TDTom Dayspring
Oh, right.
- PAPeter Attia
Yeah.
- TDTom Dayspring
So, ah, and look, I, there was no Twitter then. I couldn't call up every lipidologist I know. I emailed a few close buddies, "Look at what I just saw." And then so they stopped the trial, not because it was harming people, and as it turns out, it looks like that drug had some other properties that screwed up certain electrolytes and other hormonal levels that, okay, no wonder. So we, raising HDL cholesterol, if it's gonna bring a downside to the table, goodbye. So Pfizer lost a lot of money in that. But that didn't stop research on the drug. They, as they developed these other toxicities that maybe were specifically related to that C- CETP inhibitor, let's develop better CETPs inhibitors and go with them. So they did, and they came up with a very weak one called dalcetrapib, and it-
- PAPeter Attia
Who made that? It wasn't Merck-
- TDTom Dayspring
No, it wasn't Merck
- PAPeter Attia
... because Merck did the third one. So there's someone in between I keep forgetting.
- TDTom Dayspring
Yeah.
- PAPeter Attia
Anyway, okay. So we can figure that out.
- TDTom Dayspring
I confuse all these, you know. [laughs] I was certainly a bit consulting with them, uh, back too. And then two other companies, again, it was Merck and Lilly, had super potent CETP inhibitors, but they did all the tests and it didn't have this other toxicity with electrolytes and, uh, renin-angiotensin levels and things like that, so maybe this would work. And of course, the stronger your CETP inhibition, the more you would raise HDL cholesterol. So dalcetrapib, uh, raised it 20% to 30%, whereas the stronger ones raised it 80%, 100% HDL cholesterol. So the dalcetrapib, they enrolled in acute coronary syndrome, a humongous population, and were doing a randomized trial. And after f- a few years, they didn't see any downside.
- PAPeter Attia
They just... Yeah.
- 1:00:34 – 1:04:18
Merck, Vioxx and Pharma Risk Aversion
- PAPeter Attia
Well, kudos to Merck, 'cause I don't... I think the FDA would've approved it, don't you?
- TDTom Dayspring
Not with the, uh, tissue residual time.
- PAPeter Attia
Oh, so you think the FDA would've denied it based on that?
- TDTom Dayspring
I, I think they, they had that fear, and even if they thought they could get it by, their lawyers probably told them, "You know-"
- PAPeter Attia
Well, Merck, you know, it's funny. A lot of people don't remember what happened to Merck with, uh, Vioxx.
- TDTom Dayspring
Sure.
- PAPeter Attia
The failure of the black box warning, and I actually, I gotta tell you, that, that to me is one example of an overreaction too late. Versus an appropriate reaction sooner. So, uh, you know, not that I'm a pharma guy and know much about pharma, but Vioxx was an amazing drug. I mean, 10 times better than Celebrex ever was. For the listener who's wondering what we're talking about, uh, Celebrex and Vioxx were the first two versions of these things called selective COX-2 inhibitors, which were potent and much more selective anti-inflammatory drugs. So for people with, you know, or- orthopedic issues, joint pain, things like that. But they don't have some of the drawbacks you have with using just non-selective inhibitors of cyclooxygenase, where, uh, such as Advil or Aleve or things like that. Anyway, to make a long story short, it was about 2001 when they saw a small subset of patients, and it turned out those, I think, that were hypertensive were having a higher risk of MI taking Vioxx. The drug got immediately yanked. I think it was the best anti-inflammatory COX inhibitor ever out there. And in reality, I think what emerged after the fact was, hey, the guys at Merck sort of knew this earlier on. There, they, there was data that suggested there was something going on, and instead they should have partitioned it and said, "Hey, maybe there's a subset of patients in whom we don't let this drug be taken." Because I think a lot of patients got deprived of an amazing drug on the basis of a few. So anyway, my guess is Merck's highly sensitive to, uh-
- TDTom Dayspring
Sure
- PAPeter Attia
... to that stuff.
- TDTom Dayspring
In, in today's medical legal world, that stuff comes back to-
- PAPeter Attia
Yeah
- TDTom Dayspring
... uh, haunt those companies. Uh, one person goes south, and it's a, a zillion dollar lawsuit, so it is very, very tough. And look, it goes back to my young days where we couldn't do anything for MI but suppress ventricular arrhythmias with any number of [laughs] great vent-- And all we did was kill people with them.
- PAPeter Attia
Some of the... Yeah, those things were the most toxic drugs imaginable.
- TDTom Dayspring
Yeah. Right. But the VPCs disappeared.
- PAPeter Attia
Yeah.
- TDTom Dayspring
You know, and so did they.
- PAPeter Attia
Yeah.
- TDTom Dayspring
[laughs] You know, so you gotta be careful.
- PAPeter Attia
So, so well... [upbeat music] You can find all of this information and more at peterattiamd.com/podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at peterattiamd.com. What's a Nerd Safari, you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once-a-week email, where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer, this podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and/or advise, please visit peterattiamd.com/about. [upbeat music]
Episode duration: 1:04:18
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Transcript of episode 3ZWLxElxIBg
