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

Episode Date: October 17, 2018

In this five-part series, Thomas Dayspring, M.D., FACP, FNLA, a world-renowned expert in lipidology, and one of Peter's most important clinical mentors, shares his wealth of knowledge on the subject of lipids. In Part III, Peter and Tom dig into HDL, why "reverse cholesterol transport" is a lot more nuanced than what most of us are taught, lipid transport, apolipoproteins, and more. In addition, this episode highlights the complexity of HDL and a discussion about the CETP inhibitor trials. We discuss: Reverse cholesterol transport [1:40]; Lipid transportation, apolipoproteins, VLDL, IDL, and LDL particles [11:00]; Remnant lipoproteins and apoC-III [16:45]; Particles having sex: lipid exchange [28:00]; Cholesteryl Ester Transfer Protein (CETP) and CETP inhibitors [40:45]; 2006 CETP inhibitor trial: torcetrapib (Pfizer) [54:45]; 2012 CETP inhibitor trial: dalcetrapib (Hoffmann–La Roche) [56:15]; 2017 CETP inhibitor trials: evacetrapib (Eli Lilly) and anacetrapib (Merck) [58:00]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. 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 peteratia-md.com.

Welcome everybody to episode three of the week of day spring. In this episode, we talk about reverse cholesterol transport, we talk about lipid transportation, we talk about apolipoproteins, and we talk about CTEP 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 CTEP 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. All right. So if we're talking about the cholesterol, it's in lipoproteins.

So at the end of the day, if you have perfect cholesterol homestasis, if there's 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 preferent way. So the body clearly had nose. Beyond the certain point we don't want cholesterol, we've talked about that a little 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 motion, and everybody thinks the liver makes most of the cholesterol. Liver may work not talking about the brain now, that's separate. Of your rest of your cholesterol in your body, the liver makes 20% of it. The rest is making your peripheral cells. So the bulk of your cholesterol is 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, E flux that we've talked about, they can free the fuse out of there. There's another ABC transporter that can pump cholesterol out.

It gets in a lipoprotein or binds to albumin or binds to a red blood cell and it can be taken elsewhere. So classically, we were taught that the HDL particles are definitely a substrate that a cell can efflux cholesterol out into, especially in MDHDL, APOA1, the protein itself, that's unlippidated 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 HL 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 and go right out your rear end. Or your liver can actually change it to a bile sore, which it sends down the bile. And your bile sore could be excreted in a stool. So in fact, that's a way it's a major way of getting rid of cholesterol. But our rillium doesn't cooperate. Our rillium, you typically

reabsorbs about 90 to 95% 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 acids, the question is that make sure that happens, then you would deplete internal cholesterol. So that's so simple. So our VLDLs and LDLs and column microns 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 by-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 It's going to get rid of it or use it properly perfect 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, Carlos 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 HLs 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 that movement that movement and Are yourselves building up too much cholesterol? 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 or somebody told us something to hire your HDL

cholesterol. You got great reverse cholesterol transport because that HL is going to take it to the liver. At a certain point in my studying of lipid understanding this stuff and and I knew, God, what is it about? Not everybody would 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? bringing cholesterol back to the liver. Shouldn't your HL cholesterol go down? Why would HL 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 Raider, who I

alluded to before, and Brian Brower, and John Chapman, our HDL experts in this world, have figured this out pretty much by now. So I know it's a, this lipid transportation system is way more complex than an HDL bringing it back. And it knows we give it a different name now. So HDLs indeed are capable of bringing cholesterol back to the liver itself. There is a receptor that will delipidate cholesterol ester from an HDL.

Let's call this scavenger receptor B1 and SRB1. 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 but 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 the liver. Hey, that same thing we now know happens at the

intestine also. So HDLs don't even have to go anywhere near delivered. They can go get rid of some cholesterol at the intestine. Remember that tice pathway, transintestinal cholesterol leaf flux. And now we are boggled our minds and there are great papers on this. Red blood cells carry way more cholesterol than dulypoprotines.

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 albumum molecule, can attach to 17 molecules of cholesterol. So we now know two variable degrees. Both red blood cells and albumin can just be bought against any cell in your body and accept free cholesterol by free diffusion.

And LDL particle can abut against the cell and accept cholesterol by free diffusion from a cell. So now LDLs have another way of acquiring cholesterol. It's interesting. 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,

because one hypothesis would be, they will, 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. Yeah, and whether anybody's ever looked at that, I don't know. I mean, it might not be the case at all, but that would be a question of being treated.

Well, theoretically, free diffusion can occur between any two membrane surfaces. So, do their red blood cells, I would imagine at a certain degree, it would cause red blood cell irregularity. It might be too much noise, but you'd look at the MCV or something like that, and you'd see, have you increased or decreased the mean corpuscular volume of these things, is there anything happening?

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 phytostarols into red blood cell membranes, you get hemolytic anemia and stuff, cytosolemia, phytostrolemia, that's part of their pathology because the red blood cells looking for cholesterol to stay healthy, not phytostarols. I didn't know that, so I didn't realize that that's one of the hallmarks. Part of the phenotypic picture of cytostrolemia's red blood cell hemolytic anemia's, you know,

or crazy red-bridge health structure, spira sites and things like that. So it's one way that the early investigators a well-usent person has an only five or so. What's this red blood cell problem going on this person too? So. So this is interesting. The HDL story is one where the more time goes on, the less I know.

I mean, there are a few things in lipidology that humble me more than my complete and utter buffoonery and ignorance when it comes to understanding high-density lipoproteins. True of all of us, and that's why I don't want you reading my 2002 lipid horrors. Oh, you're embarrassed. Yeah, yeah. Oh, God, I would criticize somebody with spout and that stuff today.

So, only if you read it with that in mind, and you would see how things change. Can we use a very specific example to explain this? Let's talk about the first failed CTEP inhibitor trial, which was Pfizer's back in the mid 2000. So let me give the background, and then I want you to explain why this may have failed. Before you even, maybe I just sort of explain a little more about the lipid transportation.

Yeah, that's the good idea. So you know what CETP is. 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 just such an absurd theory. Because when they intestine pumps out column microns, they 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 transport, triglycerides, energy to cells that either store or utilize energy and to transport phospholipids. All right, so that's what your VODLs and colomicrons do. So they're part of the forward cholesterol transportation system.

So the liver or the intestine excrete stem 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 do you left with when a chylamicron loses surface phospholipids and core triglycerides. You're left with a smaller VLDL or a smaller chylamicron. Any lipoprotein, it goes from a bigger size to a smaller size, but it's still within the density of a VLDL or chylamicron. It's called the remnant.

It's a smaller. Hey, if Peter just amputated my right arm now, I'd be a remnant of my former self because I'd have one less arm. So the VLDLs and Kylos have lost their core triglycerides and they've lost their core phospholipids, many of you proteins have broken off too. So now what happens to those remnant VLDLs and Kylos? They're virtually instantly cleared by receptors that exist in the liver primarily. And how do those receptors clear these VLDL particles and these chylamycrum particles that have accomplished their mission and delivered triglycerides. They bind to the APOB 100 that's on the VLDL, but LDL receptors won't bind APOB 48 in a chylomicron, but they bind to APOE. And chylose and VLDLs, typically, if you're lucky,

have multiple copies of VLDLs. So as soon as the Kylos are VLDLs, deliver your energy, deliver your phospholipids. They are cleared, which is why the Kylos Micron Half-Life is minutes, and the VLDL Half-Life is a couple of hours. Don't ever confuse Half-Life with plasma residents' 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 because ideals have a lot of apoi on it. But at the liver, as they're being cleared, there's another enzyme that transforms some of your ideals into a smaller, what's an ideal remnant cold? Well, you'd be entering a new specific, or a density boundary and it would be called the low density lipoprotein. So technically, you can say yes, some VLDLs do become IDLs, do become LDLs. And in the LDLs, we'll hang around forever until the LDL receptor clears an LDL by binding

to APOB. The reason Kylo's VLDLs and IDLs get cleared so much more quickly than LDLs is the APOE content, which is 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. Just interrupt you for a sec. ApoE greatly amplifies the efficacy of that ligand, the ApoB ligand. It just is a preferred ligand for the Aether and LDL receptor. This is all there. They're called LDL receptor-related receptors. So what percent, I'm sorry, I want to come right back with you, but just because I know

I'll forget to ask What percentage of LDL Particles also co-express APOE. Yeah, so if you are lucky enough to have that genetic gift and your LDL happens to contain in it It's half-life is pretty much the same as an ideal. They're gone. So if they're gone You have enhanced clearance your APO B your LDL particle level, we much lower. You don't get heart disease. In an average population, it's about three to four percent. But I guarantee you, there are, depending on a gene, you've heard some people have probably had a lot of APOB on the LDLs.

And of course, I would bet if they were studied genetically, they don't get heart disease, you know, because it's being cleared all those particles. And we'll talk about it later, or other apoproteins that we can retard clearance of VLDL's IDL's and even LDL's, I'll just mention its name now, it's apolipoprotein C3. You got that on your particles.

You're gonna have seriously increased plasma residents time of all those things. And LDL with APOC3 on it is intensely more atherogenic than an LDL that only has APOB 100 on it. You once told me this was probably a couple of months ago we were just shooting the breeze one day. And 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? It would be, because I think that's going to be the way we really are going to smartly identify remnant lipoproteins that are the VLDLs that are potentially causing trouble. Most VLDLs are not trouble makers. They're cleared rapidly or the LDLs that are number one in a list as to what's going in your arterial war. APOC3, as you know, Peter, is overexpressing 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 genetics. You know, the genes that give you APOC3... Except that insulin sensitivity and insulin resistance impact that 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.

And I think we got enough data now, shows that, and to show you, pharma believes that, there's a major ongoing now with an ApoC3 inhibitor that's coming because it'll be the way to get rid of these. Is this ISIS doing this? Yeah, I believe so. Oh, sorry, just for the listener.

ISIS, I'm not referring to. Yeah, yeah, yeah. This is ISIS. There's a pharma company in San Diego. They're actually based out of San Diego because that's where San Tamiqa says, but it is IS. Yeah, it's one of these new... Yeah, and they're looking at all of these things.

Yeah, I think that's a good sense. Keep your fingers crossed. So we should come back and talk about that because the anti-C3 and the anti-sense oligonucleotide against apolipoprotein little A, those are hugely interesting. Yeah, they're going to 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 payers ever going to pay some lab for doing that. It's going to need a little more proof than 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 are not insulin resistant and you don't have a, however you define a triglyceride issue, which I might define as a trig above one third 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

because they're not carrying extra triglycerides because 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 because that VLDL would come out, and I guarantee it's probably got ApoC3 on it, it doesn't have a half life of a few hours. Its plasma resonance 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 will 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, and I'm pretty sure it's in Peter's package here.

Even when you take these type two diabetics with severe insulin resistance or insulin resistance, just prove by an insulin clamp study, their APOB level, their particle levels are going up. But it's all through the APOB. But it's all through the APOB. Let the APOB particles go up astronomically in the VLDL, maybe doubles or triples,

it goes from 30 to 90, whereas the VLDL particles go from 1,000 to 3,000. The LDL, yeah. So. That's an important distinction. So a lot of people will say, when you're insulin resistant, all of that net difference is,

that we see, because there's no disputing, the more insulin resistant you get, the more discordant you get between your LDLP and your LDLC. And all things equal, the LDLP is just going up and up and up as you become more insulin resistance. 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 point it out, if you're referring to the Garvey paper, I think. Yeah. So in that paper, you might see VLDL particle number, I'm making this up, so someone will see the numbers and decide for themselves. But it might go from 30 to 60. Yeah, or 150, you know.

And they're all per liter. And you think, well, God, that's a much bigger relative increase. And it is. But if anybody's read our lengthy treaties on relative versus absolute risk, you cannot evaluate a relative change for that understanding its absolute change. And so, even though the relative change on the LDLP is smaller, it's starting from such a high base that it might add three to 400 Nm 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 an animal per liter you might get on the VLDL. This is a really important point if you want to be a lipid geek. It is. And this is one reason why non-HDL cholesterol is becoming vague. Because remember non-HDL cholesterol, we told you you calculated by subtracting HDL cholesterol from total cholesterol, but

you could really add directly measured LDL cholesterol to a VLDL cholesterol. That's your cholesterol is not in your HDL particles, theoretically, potentially, after a genoclystral. 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 heart. Yeah, it's funny. I used to always sit a patient down and 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 LDLP. I'd like to know how many of those are small

because it's a proxy for some other stuff. And I wanna know your VLDL remnant. Well, I can't measure that, so I'm gonna approximate it with VLDLC. Well, I don't say that anymore because I've come to realize that's a very crude, crude estimation that's almost useless.

I wouldn't call it useless because I use the word almost different. Okay, yeah, and I'll get all my lipid colleagues real mad at me if I start saying that because they, and I get into this in a lot of the papers. I mean, I still say to patients, I want your VLD cholesterol less than 15 milligrams per vessel. And the odds are good in an insulin-resistant patient. You have other ways of knowing who's insulin-resistant, who's not. If that marker is up, remnant lipoproteins are part of their pathology. But the exact same therapy I'm going to give you to get rid of the real trouble make your

LDL part of, who's going to get rid of the remnant's too. So at the end of the day, it's, got a normalized APO B or LDL particle number. And there is significant discordance. Allen Snyderman has published it many times. It's good as non-HL cholesterol, meaning better than LDL cholesterol is a metric of APO B. There's a lot of discordance between APO B or LDL particle number and non-HL cholesterol.

So I understand so free calculation, please and people who you really are worried about or you think, I risk you got to use particle numbers to make the proper clinical decisions. This reminds me, I need an excuse to go to Montreal so I can interview Allen. Ah, if you can get him on a hot gas, I'll be your first listener. That is nothing comes out of his mouth that you don't want to write down. Yeah. And you don't make anything up. Alan is.

Alan's a special guy. He is just and Alan is not afraid to call the spade a spade so to speak. He will just tell you and that's why I love him. You know, I don't mind Alan telling me I'm an idiot. No time you're wrong. I know here's where it is. You know, you learn from guys like that or not afraid to put you in place., no time you're wrong. I know here's where it is. I can, you know, elanson, guys like that or not afraid to put you in the place.

Alan, if you're listening to this, why don't you come up with an excuse to come to New York or San Diego? And if I do have an excuse to come to Montreal, I will. But let's get back to our lipid transportation system now. So we have our theoretical forward 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 Kilo's delivering cholesterol to your peripheral cells. They don't need it, they're making all they need. So just restate that, please, for the courts transcript. So tell me again, what Kilo's are doing, are not doing what? You walked out of the room to do so, and when I was explaining what Kyle was in the

field, the... Tom Tom just added me. I went to go take a leak a minute ago. But... So I explicitly went over that the purpose, the functional purpose of Kyle on microns in VLD, else is to deliver energy in a former triglycerides, that, opusides 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 enthreside is starting to lipidate, APOB 48, or especially liver APOB 100, if you put cholesterol in that, and we have proteins that do that,

microtomol, triglyceride transorant, other cellular lipid transport proteins, by putting cholesterol on the APOB, it becomes a spherical particle. So all premortial VLDs and column icons are first just very cholesterol-rich spherical particles. They don't have the triglyceride 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 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 deliver or the intestine and they do whatever they do with it. So that's why cholesterol is in there. They're not bringing cholesterol to my nose or your kidney or any play cells because 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 of it absolutely needed cholesterol because for some reason, a synthesis was broken, any cell could ultimately upregulate an LDL receptor, but most of them don't. So, because they have no need for the cholesterol that's in an LDL. The liver upregulates most of your LDL receptors, because 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-lifes or plasma residents times VLDLs, even for a few hours, 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 that is 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

and your body has some degree in its core of triglycerides and cholesterol ester. Every particle from an HDL to a column-micron 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 though a 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, HDLs are carrying this apod, and it suddenly sticks up, it can penetrate another particle, be it

another HDL or an APOD particle. And that's a phospholipid sort of tunnel. It's like a little tunnel that can connect two circulating lipoproteins. And therefore, the core lipids can exchange. And this is HDL to HDL or can it be HDL to LDL? It can be HDL to HDL in which case it's called a homotypic transfer because it's too like particles exchange in their bodily fluids or a hetero tip where APOA particles exchange or core lipids with APOB particles. What is hardly known out there

is two APOB particles can exchange their lipids. Aial, the alken exchange, it's core lipids with an LDL. And I'm going to 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 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, HL carries that 8-cat enzyme I talk about it, except it's called LCAT, because it's in a lipoprotein. It starifies the cholesterol to cholesterol ester goes to the cordoparticle, the HL becomes bigger. Then the HDL transfers its cholesterol ester to, let's say, an apobapB 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 HL. That's good cholesterol. But what do you call that cholesterol molecule, the second in HL, transfers it to an LDL? Does it instantly become bad? Oh, it's bad now. If I looked at it, it's still the same exact cholesterol molecule. So what do you, if you want to use those darn adjectives with a patient,

I guess what's going to determine what's good or bad cholesterol is, what is that lipoprotein going to do with its cholesterol molecule? If it's an HDL, and it's an LDL, and it's bringing it back to the liver already in test in there. Well, that's not bad. I don't think because 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 think you can apply that to the cholesterol molecule itself. But follow me here. What if that HDL pulled cholesterol out of your cell because it was overproducing too much and it gave it to an LDL and said, buddy, take off, the liver's got that LDL receptor,

it's going to clear you. And an LDL particle race back to the liver. And for some reason there was no LDL receptors that are wearing enough of them there. Where's that LDL going? He might wind his way back into circulation. He will, because he's not going to be clear. And he might wind his way back to the end of the deal, and all of a sudden, your good cholesterol is in the macrophage in your arterial wall.

So spare me the nonsense. Stop using it. Subserve term has no meaning. You're in this educating patients if you tell him it's good cholesterol, because they use that because they're measuring HL cholesterol and blood is a market that I'm in good shape or not. And trust me, virtually all of the early trials that showed low H.L. cholesterol was bad news were never, ever adjusted for APOB or LDL particle counts because I'm going to tell you right now. And that includes framing him, which I alluded to earlier because a lot of people like to hang their hat on the fact that framing him, because most people forget what framing him is, they

throw the term around. So let me just spend one minute explaining this. Framing him started out as a five geography, a five city or five region observational study, purely observational of which framing him was one. And I used to know them all, but it was all framing him as only framing him as Massachusetts. No, no, no, but the original cohort of that study from NIH was framing him, Puerto Rico, San Francisco, Hollywood, and that framing him evolved from because that's right. Then the pro city group here.

And that's where they gathered the information. That's where they made the observation. So there was a purely retrospective assessment of five cities and I'm blanking on the fit but I know I think one was Puerto Rico I don't really understand. Fred might have been one. But anyway the point but the prospective work was then concentrated in framing him 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 calculated, not measured directly,

so you've introduced a new ability. And you're a later, not in the first 20 years of the show. Correct. It turned out to be less predictive than the ratio, not the ratio, I'm sorry, the absolute level of HDLC 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. That's all they are. And virtually all of your insulin resistant patients are getting atherosclerotic disease at APOB. It's LDL particle mediated because everybody who's not on a drug or a serious diet who had a triglyceride HDL cholesterol, acys abnormality has astronomical APOB. So if you go back for all this sighted forever epidemiologic data, that low HL cholesterol

is such an important risk factor. Do me a favor, pal, adjust it for APOB or LDLP, which is never done and can't be done in those studies now. It would disappear as an independent risk factor, low HL cholesterol. 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 framing him offspring? It does. Mesa has certainly shown in the discordant people where there's the discordant with apob and LDL cholesterol or and people have low H a cholesterol, apob, LDL particle is your

most important metric. So Mesa has shown it. And Mesa, when we're saying this by the way, folks, we're not talking Mesa, Arizona, we're talking about the multiethnic study of atherosclerosis, which is abbreviated Mesa. So we'll often, you'll often hear people refer to Mesa and framing him, 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.

Yeah, and Mace is much more contemporary and multiethnic. So it's... Yeah, because I've got another criticism of framing him is, you've taught me a lot about middle-class white people in North East, but what have you told me about, African-American, Hispanic, et cetera. All information is always good. There's always weaknesses with all information or shortcomings or so, in Northeast, but what have you told me about, you know, African-American, Hispanic, et cetera? All information is always good.

There's always weaknesses with all information or shortcomings or so, but, you know, we built stepwise on it. So before you declare, make any statements based on an HDL metric. Please make sure you have an LDL particle or APobymetric in front of you also and pretty much base what you're going to advise the patient on risk and assessment based on that. 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, was a case study of a woman who had an HDL cholesterol of about 130 to 140 milligrams per

desolate or 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 because 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 desolate or so this woman is showing up at two and a half times normal. And interestingly, I don't even know you remember this case study time, 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 desiol or 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?

Not per se, but I have. What is your blood cancer? That's been well explained. And this is a rare genetic thing where this cholesterol trafficking pattern is disrupted in certain ways, something's wrong with that pathway, because that HDL should be getting rid of its cholesterol and should be bringing both 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. It turns out, and they're not being cleared as much as this issue.

This is going to turn out to be cholesterol rich HDL particles that don't have a protein that's very integral with clearing HDGLs and sapoe again. So if you don't have apoe on your HDLs, they might become very cholesterol-rich or HL cholesterol 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 because when you have a surface area that's big, the proteins that should be binding to it no longer bind because 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 a circumstance of very dysfunction. And I remember the context, which was a really good friend of mine from med school sent me some, a friend of a from med school sent me some 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?

You just have to chase. It's sort of like what do we do for LP Little A? Now, as you chase every other identifiable cardiovascular risk factor, interesting, nobody would do it to her, but there is a product that induces a receptor in a liver that pulls cholesterol out of HDL particles. It's a cold probucal. I don't know if it's even still available by prescription. It induces the scavenger receptor.

Dressically lowers HDL, but it's a powerfully antioxidant. In there were some early arteriographic studies that suggested this is good, arteries at least on an arterial imaging look better. So say sarmalano. I'm sorry, just to be clear, the reason why, I mean, again, there's 217 ways to be fooled by an angiogram.

It's about as crude a way to assess this process, anything. That said, if you believe that this is improving, you believe it's basically increasing the throughput of HDL to delipidate. Yeah, so the theory would be, ah-huh. There is this is the case where, hey, remember I espoused the theory before that, if HDL is a really delivering cholesterol back to the liver,

shouldn't HDL cholesterol be going down? Well, here's a drug that depletes HL cholesterol, and at least archaeographically 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 HL particles, high HL cholesterol, and carinary aspects of the process. So this is a nice transition.

So let's summarize that. This is, again, overly simplistic. This is a zero-thorder analysis. So we're just going to put our fourth grade hats on, which is acceptable for limited periods of time. If you have low HDLC, you cannot infer if it's low because you're failing to, quote, unquote, pick up cholesterol, or because you're delivering it quickly. Conversely, or similarly, I should say, if you have high HDLC, 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, which would be quote unquote bad. And therein lies perhaps one of the most interesting or certainly top five interesting drug stories, which are the C-tap inhibitors. Right. And again, I'm just going to do like, I just want to finish this whole, so I told you HL has this, ApoD. ApoD. But ApoD is better known as cholesterol estertransfer protein.

It really ought to be called cholesterol estertraglyceride transfer protein, C-E-T-P. We're going to talk about a C-Tep inhibitor in a moment because it's going to 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. We ran it across the goal line. Who gets the credit to quarterback or to 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 going to talk about it today, but God also gave us lipid inhibitory transfer proteins, apolipoprotein,

f, apoc1. So everything is tightly regulated in our home esthetic system, but we'll leave that for another day. So this is the master's class on lipid, that will be the whatever falls about the master. So it's always more complicated. So now just to finish up the definitions of our reverse cholesterol, transport all days HDL back to the liver. Nowadays, it's HDL 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 going to be called direct because

the HDL is doing it. And we're saying he's the primary factor here because 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 cholamacron, 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 APO, be particle, it brings it back to the liver.

That is called indirect or versed 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 how it's back to a probably yes again. But if an LDL brings it back to the liver for sure, any intestine, then that's indirect cholesterol, reverse cholesterol transport, if you still need the reverse adjective put in there or so. But part of that pathway is the it's not deliverance, the intestine, the trans intestinal cholesterol leaf looks. So if you want to talk about TORROR, reverse cholesterol transport, I would rather just talk about lipid transport.

It's every particle is part of the system. So, but if you want to 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 CRMHL cholesterol tells you not about that process. 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 as 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 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 the best we can do today is we measure HDL particle number and HDL particle size, and we try to triangulate just as we used to when we could look at LP- 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 doesn't tell us how well these things

function. We just need more specific biomarkers nowadays, take it to the next level and the types of therapies that are coming along. And I think that's even important knowledge to know when you're going to prescribe a specific nutritional therapy also that all these things come into play, you know. So 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 the given patient. And the functionalities, 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 APO-D we talked about. And with HDOs, just briefly, I think there is probably hundreds of HDL subpopulations. HDLs carrying a immense number of proteins, way more than LDLs or VLDLs ever can. But they all can carry one or two proteins. They can 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, you know, I love fire departments. Fire departments have hook and ladder trucks. They have bumper 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 subpopulation show up where they need it, 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 proteomechanalysis at these particles, I think that maybe we'll take us to the next level and wouldn't hold your breath on at any time soon. All right, so let's go back to this idea of, because I wanna start talking a little bit about some drugs, but rather than start chronologically,

which I wanna do after we get 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 Niesin, which we'll come to later on. But the other being these CTEP inhibitors, which are relatively recent, it was 2006 when the first CTEP trial, or at least when the first data became available and they weren't promising So first of all, why would inhibition of CTEP been thought to be an optimal strategy and two, why do you think it didn't turn out that way? Because we don't know what we're doing with HTLs and especially using metrics to analyze them in the story starts a lot longer than it and Italy, that little section up on Northeastern Italy

where APOA1 Milano was discovered. And these were people who had HL cholesterol levels of 5 and 10 and yet had longevity. And how could that possibly be? Because Framingham is taught as low HL cholesterol. You're out of here. And yet here's where people with longevity. And it turns out they had a very functional APOA one that really did the flux system very quickly or had other properties that didn't matter how much cholesterol was

in the HDL. The HDL was unbelievably function. Do you know anything about their APO Bs? I think even if they have high APOB, they don't get, I don't know that. Yeah, so that's probably out there. I can't answer. Yeah, so there maybe we'll look that up. But they're high functioning apo A's. Yeah, and they just, so I doubt if apobede matters because some of them probably would. You know, although they're all on that Mediterranean diet and stuff, so maybe they don't have that or junk parts. So I can't answer that. So that led pharma to, hey, let's just invent

either synthesize APOA1 or a truncated APOA1 and commercialize that. Well, at least for people who have had a Q-Carnace in Jones, we'll infuse that into them. It'll delipidate 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-h-yield cholesterol but had coronary atherosclerosis. But there is a bunch of people out there

who are very high-h-yield cholesterol who don't have carny. I'm going to theorize in retrospect maybe APOE's got something to do with that, but I don't know that because that would enhance their clearing. But what is one of the genetic conditions that would give you high-heat-shell cholesterol? Remember, I just taught you what APOE is CETEP. It takes the cholesterol out of your HDL and gives it to an APOB particle. So theoretically, that would lower your HL cholesterol. But if I inhibited C-TEP, your HL would get to keep all its cholesterol.

What would go through the roof, your HL cholesterol? And a genetic model was at least some people with certain C-ETP variants had very high HL cholesterol and they didn't seem to get much heart disease. Although what I'm confused by, Tom, is that in 2011-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? It's a nature paper and we'll pull it. But CETP and the investigation drugs

long before the Mendelian randomization. Absolutely, yeah, yeah. So they didn't have that data that Mendelian randomization shows not necessarily so that with high HL cholesterol, you're protected whereas nowadays most of that data would show it's not. Yeah, yeah, my recollection is that the MR came out in 2010, 2011, and it basically validated what had

at the time been seen in two trials, which was, wow, inhibit C-TEP, things don't get better. Well, yes. So I think Mendelian randomization had that data first. They might have never invented drugs. They might have never made the drugs. Yeah. And which is why they did chase PCSK9 inhibitors because the genetic model told them this can't fail unless there's a downside to the drug that we all know about.

And that's always a problem. What 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. Oh, I can't wait till we're gonna talk about PCSK now. So let's inhibit CETPD, HLs get to keep all their cholesterol, HL cholesterol straight roof. That's good epidemiologically, right?

And it's up on first principles. It doesn't even make sense in light of what you just told us. No, but they didn't know that then either. Remember, this whole HDL story has evolved too. Oh, wait, 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?

No, there was theories on it. Guys like Dan Raider was always talking about it, but you don't know how much you're interrupting the system with that and everything. You know, they're so heavenly focused on basic lipid biomarkers like LDL cholesterol and HDL cholesterol. LDL cholesterol.

And it's the same the nice and story. How could it not work? It raises HDL cholesterol and turns out NIS and doesn't work if you want to take legitimate trials to show it works. And is there a price for using NIS and even if you don't believe the legitimate trials? So that's another story which we'll probably get it.

We will definitely get into that. Because this is one area where your peers will argue with you. Some, many will not. Other than all right, I've tried everything else, nothing else is where I call me. And look, I'm a guy who took an ice in myself for a bunch of years.

So before I knew what I knew now, and it didn't unfortunately work for me anyway. So this CETP, it's gonna raise HL cholesterol, but how much it raises, it really depends on the potency of this CETP inhibitor. And there potency of the CETP inhibitor. In our different degrees of CETP inhibition, we have weak inhibitors and we have super strong inhibitors. The first one that came out of Pfizer had developed a drug that inhibited, thought it was going to be a multi-billion dollar drug because it raised the cholesterol

Pfizer. Many other companies already proved lowering APO-BL, the alcohol, cholesterol works, it really works well. Imagine if we can take those people with residual risk because their HL, HL cholesterol is still low and we could raise their HL cholesterol. That nice and angiographic trial would really support doing that. Okay, so they said let's inhibit CETP

and raise HL cholesterol. Suffice or went to market, many people were buying it, stocking it's infancy, thought they'd make a zillion dollars. I remember where I was standing 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 feta-complete that this drug would work and Pfizer-Stock was going to

skyrocket. Oh, look, we all knew the company of Spirion had developed that and we knew there guys we had heard them lecture many, many to talk about. Everybody was banking on that, boy, this is real. I mean, you never know in a clinical trial, but it looked like a slam. I never really did. And I remember whenever I found out, I forget the weather that day, but it was late at night. And I think the internet was even, and I saw a little thing. It was like 11.30 at night. I don't even know why I saw it. that Pfizer terminates Torsetropib Tri. Well, in fairness, you were actually seeing it in real time.

I saw it the next morning. Right. So, and look, there was no Twitter day, and I could call up every lipidologist. I know I emailed a few close buddies. Look at what I just saw. And so they stopped the trial, not because it was harming people. And as it turns out, it looks like that drug

perhaps some other properties that screwed up certain electrolytes and other hormonal levels that, okay, no wonder. So we'd raising HL cholesterol if it's going to bring a downside to the table, goodbye. So, Faisal lost a lot of money in that. But that didn't stop research on a drug. As they developed these other toxicities that maybe were specifically related to that, she tepid inhibitor.

Let's develop better C-teps inhibitors and go with them. So they did. They came up with a very weak one called dalsetropib. Who made that? It wasn't Merck because Merck did the third one. So there's someone in between I keep forgetting. Yeah. Anyway, okay, so we can figure that out.

If I confuse Oli's, I was certainly if they'd consult with them back too. And then two other companies, again, it was Merck and Lillie had super potency ETP inhibitors, but they did all the tests and it didn't have this other toxicity with electrolytes and ranninangia, tensin levels and things like that. So maybe this would work. And of course, the stronger your C-TEP inhibition,

the more you would raise HDL cholesterol. So DowSETRIPIB raised it 20 to 30%, whereas the stronger ones raised it 80, 100% HDO cholesterol. So the Dow Setra Pib, they enrolled the QCarnis Syndrome, a humongous population and we're doing a randomized trial. And after a few years, they didn't see any downside. They weren't killing anybody or... There was no superiority, no superiority. It was futility.

And those are very expensive trials. So to being counter-synced, it's a shooter trial. Forget about it. So that's what you're saying. I think that those trials combined with the MR have put an end to this approach to lipid modulation. They did. And the two other companies, though, said, well, it's a week's C-TEP inhibitor.

We're potent. So we're going to continue our trials, they're well underway, too. So with Anacetra Pib and Eva-Cetra Pib, the remaining things, they did them. Sooner or later, Lily just bailed on their trial. More futility. They weren't going to take it up. But Merck continued their trial. So Lily, with a potent EVA cetropeb,

was seeing not only drastic raisings in HL cholesterol, but LDL cholesterol, but, you know, PCSK9 inhibitors are starting up here, but nobody's going to ever prescribe this drug based on what it does to LDL cholesterol, and we're not so convinced that raising HDL cholesterol matters anymore. So they, and there really, this thing was some futility. So they bailed on their trial too.

People think they should have, some people wish they would have continued that trial. But Mark did continue and Mark did hit its endpoint, did it reduce car and area events. It did drastically raise HDL cholesterol, but it dramatically lowered apobee also. So the dairy came to be, what a C-Tep inhibitor does to the metric HL cholesterol has nothing to do with anything, but if it can lower apobee, it works.

And the trial was it worked, but they're not going to bring it to market because it in stays in the human body for years. And I just are afraid of that. They have no idea what might show up in the human body for years. And I just are afraid of that. They have no idea what might show up in the form. Well, especially when there's no upside. Yeah, relative to what you can do. And we got a lot of other things

that will give you that type of apobeloring that seem to be safe and been around. Yeah. So, Merck is not going to commercialize that product, even though it has a successful trial. So if you want to definitively say, C-Tep inhibition doesn't reduce ather or something, well, it's interrupting

a transfer, but it doesn't actually tell you what happens after the transfer, and that becomes the problem. No, it doesn't tell you. Even though some of the primitive HL functions studies they did on it didn't look like they were screwing up the HL, but there's immense numbers of HL function. You don't know what you're doing. And if that protein is going to stay in your body forever, what other consequences might there be long-term screwing up of other biological systems or something, so it couldn't risk

that. Yeah. Well, kudos to Merck, because I don't, I think the FDA would have approved it, don't you? Not with the retissue residual time I had. Oh, so you think the FDA would have did that based on that? I had that fear. And even if they thought they could get it by their lawyers, probably told them,

Well, Merck, it's funny. I'm not a people don't remember what happened in Merck with the viox. Sure. The failure of the black box warning. And I actually, I got to tell you that. That to me is one example of an overreaction too late versus an appropriate reaction sooner.

So, you know, not that I'm a pharma guy and no much about pharma, but Viox was an amazing drug. I mean, ten times better than the Celebrex ever was. For the listener who's wondering what we're talking about, Celebrex and Viox were the first two versions of these things called selective cox2 inhibitors, which were potent and much more selective anti-inflammatory drugs. So for people with orthopedic issues, joint pains, things like that, but they don't have some of the drawbacks you have with using just non-selective inhibitors of cyclooxygenase

where such as advill or a leave or things like that. Anyway, to make it long story short, it was about 2001 when they saw a small subset of patients and turned out those, I think, that were hypertensive. We're having a higher risk of MI taking viox. The drug got immediately ranked. 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 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 that stuff. Sure. And in today's medical legal world, that stuff comes back to Huanthos companies. One person goes south and it's 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 grave. And while we didn't, we still people. Yeah, those things were the most toxic drugs. But the VPCs disappeared. Yeah. You know,

in so today. Yeah. You got to be careful. So well. You can find all of this information and more at peteratiamd.com forward slash 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 peteratiamd.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

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