The Peter Attia Drive - #229 ‒ Understanding cardiovascular disease risk, cholesterol, and apoB

Episode Date: October 31, 2022

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this special episode of The Drive, we have pulled together a variety of clips from previous podcasts about cardiovascular disease to help listeners understand this topic more deeply, as well as to identify previous episodes which may be of interest. In this episode, Peter highlights the importance of understanding cardiovascular disease and why early intervention is critical. He also provides a primer on lipoproteins and explains the fallacy of the terms “good cholesterol” and “bad cholesterol.” Allan Sniderman discusses the metrics measured in routine blood work – along with the limitations of those standard panels – before explaining why apoB is a superior metric for determining risk. Additionally, Tom Dayspring explains the causal role of apoB in atherosclerotic cardiovascular disease (ASCVD) and the therapeutic goals for apoB concentration, and Peter explains how early and aggressive lowering of apoB could change the landscape of cardiovascular disease prevention. We discuss: The importance of understanding atherosclerosis early in life [2:25] Defining ASCVD, its causes, and the role of cholesterol [8:00]; Why early prevention of atherosclerosis is critical [13:45]; Preventing atherosclerosis—two fatal flaws with the “10-Year Risk” approach [16:00]; Intro to lipids and lipoproteins: why there is no “bad” or “good” cholesterol [23:00]; Limitations of standard blood panels [35:45]; How Mendelian randomization is bolstering the case for apoB as the superior metric for risk prediction [39:30]; Therapeutic goals for apoB concentration [58:15]; How early and aggressive lowering of apoB could change the course of ASCVD [1:10:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of the space to the next level. At the end of this episode, I'll explain

what those benefits are, or if you want to learn more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. Welcome to another special episode of the drive. As the podcast is now over four years old, we realize we've covered certain topics in a variety of ways across multiple episodes. We realize of course at times it can be hard to piece together this information and it's also difficult for new listeners to be able to go back and keep track of information that's been covered in great depth in previous episodes.

As a result, we wanted to release another episode that is kind of a compilation of clips from previous episodes. We did this before and it was a huge success. So for this one, we want to focus on atherosclerotic cardiovascular disease, AACVD, cholesterol, and APOB. This episode includes clips on why it is so important to care about AACVD, the role of cholesterol in AACVD, and why I don't think anyone should refer to cholesterol

as good or bad. And finally, we look at why APOB is an important metric to track when looking at your lipids. I put these clips in the order of what we think is the best way to listen to them from top to bottom. And also provide some commentary in between clips to give you a little bit of context.

Our hope is that not only will you understand this topic better, but you will also be able to identify some past episodes you may want to go back to and listen more deeply. Final thing is that some of these clips are taken from AMAs, so if you're not a subscriber, we hope this gives you a little bit of a sneak peek of what's covered in those episodes. This is still a fairly new concept. We've only done this once before. We've got great feedback on that, which is why we're doing it again, so if you continue to like this, please tell us, and if you don't, tell us why. So, without further delay, I hope you enjoy this special episode of The Drive.

What we thought would be important is just answering the first question, which is, why should someone care about this? It's such a complex topic. Why is it important for people to put the time in to really think through and understand it? It really starts with the ubiquity of this disease and it's assault on human longevity. People have probably heard me say this before, but astroslerosis is really the only inevitable disease of our species. Cancer, while prevalent with aging and dementia, while prevalent with aging, do not appear inevitable the way astroslerosis does. So not everybody dies from atherosclerosis, but I think to my knowledge,

everybody dies with it, assuming they live long enough. So you have a condition that, as I said, is inevitable, is ubiquitous. Also, I think based on what you're going to hear me talk about today, we know a lot about this condition and we really have tools to mitigate it. To me, that's the reason you want to really understand this. The impact is huge and the tools that we have

are also huge. So again, we talked about longevity. Longevity has two parts, health span, life span, the life span part comes down to delaying the onset of chronic disease of which this is the most common chronic disease. So you can think of a couple of different pads to get there, but really the two biggest risk factors, I am putting smoking aside for a moment, which is a very straightforward behavioral risk factor. In terms of less clear behavioral risk factors, the two biggest are clearly hypertension, high blood pressure, and lipid abnormalities. And that's the one we're going to focus on here.

So, atherosclerotic cardiovascular disease, we'll just abbreviate A-S-C-V-D for short, is really what we're here to talk about. As we get started on this topic, Peter, I think we have people who listen to this podcast of all ages, young, old, everywhere in between. And I think it's a common thought for people under 30, 40, even some people under 50, where they're just like, this is something that only affects old people. I'll think about this when I'm older, but right now it doesn't really affect me. How do you answer the question in its basic form of, isn't this just a disease of old age? And why should those people who

think that not just shut off the podcast at this point and instead continue to listen and in its basic form of, isn't this just a disease of old age? And why should those people who think that not just shut off the podcast at this point and instead continue to listen and continue to put in the effort? Probably have told this story before, and if not, where if folks haven't heard it, I think it's worth hearing again, right? I remember in sort of my first year pathology lecture in medical school that pathologist said, what's the most common presentation for a first heart attack? So if a person is having their first heart attack, what is the most common thing that they will present with? That's the terminology we use in medicine. And of course the hands shot up chest pain being the obvious. Nope, that's not it. nausea. Nope, that's not it. A left arm

pain. No, that's not it. And it was a trick question, of course. The answer was sudden death. The answer was that over 50% of people's first heart attack is fatal. Now, the good news is today, that number is a little bit less. It's probably slightly below 50%. But that's still a staggering number. Now, another way to think about this is through the lens of understanding the age distribution of people who have their first major adverse cardiac offense. So that is a heart attack, stroke, or sudden death due to one of those. If you don't mind, pull up figure one. This graph shows the age distribution for both male and female in the United States in terms of these incidents. I think the easiest graph for me to look at here is the one on the right total annual events.

And what you can focus on is the first two bars. That is the bars that are for people up to the age of 65. So if you look at the male bars, which are the darker bars, you can see that the summed total of those two bars, slightly below 25%, slightly above 25%, the implication of that is over 50% of men who are going to have a cardiac event in their life will have it before the age of 65. And for women, you do the same exercise, you can see that it's one third of women. So it's clear that there's a shift in time and that women, while subject to the exact same burden of disease, seem to experience it about a decade later

Still fully one third of women are going to have their first cardiac event Which is going to be part of tax stroke or death as a result of those things before the age of 65 and a little over 50% of men will be in that camp so As we're going to talk about in this episode That's not the whole story. It's even more compelling to care about this when you're young, when you understand how long it takes for this disease to take hold, and the implications therefor for prevention. The most sobering thing for me when you look at this is it's not even the 50% under 65, it's almost the, especially for males, the almost 25% under 54. And especially when we get to what we get to later, which is

for that to happen to someone who's 45-50, it doesn't mean it started two years earlier, right? And so I think it's pretty crazy when you see these type of stats laid out, how it creates that shift in your mind around why you should care about this. in your mind around why you should care about this. What we need to do is first, almost step back and look at what exactly is ASCVD. I think people have to understand what it is to then really understand how it comes about, how to think about prevention. So what do you think the best way to walk people through in a relatively simple form, what this disease is? I'll explain it at a high level now,

and then I think we should go through it in some detail in a moment. The precy on this would be that the ASEBD disease state characterized by the deposition, for the buildup of cholesterol, more clearly, or more rigorously sterile, which include cholesterol and phytosterol in the artery wall. It initially starts as something called a fatty streak,

which I'll explain in a little bit more detail later. And then it later consolidates into things called plaques. And these can ultimately lead to a reduction in blood flow. And of course, it's this reduction in blood flow that leads to what's called ischemia. Ischemia is the reduction in blood flow, and therefore the resulting tissue damage that occurs to the heart is what results in a heart attack, which can be fatal depending on the amount of the cardiac tissue that is impeded from appropriate amount of oxygenation. To have this disease, you don't have to be obese, you don't have to have high blood pressure or things of that nature. It's

really a question of the cholesterol in your blood. That's really what defines the disease. So the essential condition of atrosplerosis is the presence of cholesterol in the artery wall, which by the way is not necessarily related to the measure of cholesterol in circulation, which we will talk about in great length. And although these often co-exist, patients with cholesterol in their arteries do not necessarily have to have co-aggravating factors such as high blood pressure, diabetes, obesity, family history, smoking all these things that exacerbate it. You mentioned cholesterol a few times, and obviously it's a topic that's been talked about on more podcasts than I can even counter recall right now.

But for this conversation, can you define cholesterol just in its simplest form? So everyone's aware of exactly what we're talking about as we're going to get into kind of the more nitty-gritty. Cholesterol is an organic molecule that resides in the lipid family. So we typically characterize these molecules by their solubility in water, and this is a not soluble in water molecule. So it is a hydrophobic molecule.

And I think the easiest way to sort of picture those things is to think about oils. So if you took an oil like olive oil and you poured some of it into a cup of water, you would immediately see what it means to have a hydrophobic substance in contact with something, which is the ultimate hydrophilic substance water, right? So they repel each other. Now, of course, cholesterol is about one of the most important molecules in the body.

To be clear, if we didn't have the ability to make cholesterol, we would cease to exist. In fact, you couldn't be born without the ability to do this. There are rare genetic conditions that impair the ability to make cholesterol, and these are uniformly fatal. Why do we need cholesterol? There are broadly two things that cholesterol is essential for. The first is that they contribute heavily to the cell membrane of virtually every cell in the body.

So cells are actually kind of fluid things, spherical things, and what allows them to have that fluidity and what allows them to have membrane channels that allow things in and out of them is the cholesterol layer that forms the membrane. And secondly, cholesterol is an essential substrate for the production of some of the most important hormones in the body, cortisol estrogen, testosterone. It's also essential for the creation of bile acids, which are necessary to be able to digest food. So the mantra that I like to say is no cholesterol, no life. Period. You should put that on a bumper sticker on your car.

Just roll around Texas with that guy. No, I think that's great. Why don't we look at and discuss Peter, how does A.S. CBD come about? So before I jump to the figures, I want to make one other point that I should have made a moment ago. And that is the necessity of the body to make cholesterol. So I think most people, when they think of cholesterol, will probably first think of what it is that's floating around on their bloodstream, but will very quickly turn to cholesterol within food, because it turns out that when you eat certain foods, you can also eat cholesterol. So everybody knows, for example, eating eggs means eating cholesterol.

And a natural question is, what is the relationship between the food that I eat that contains cholesterol and cholesterol you're measuring in my bloodstream? And the short answer is very little. And the reason for that is the cholesterol that we eat is in a form that the fancy term Ford is called as a sterified. So it has a chemical bond that swings between an intermediary oxygen and then another side chain. From just a straight mechanical problem, that is too large for the receptors in our gut to absorb. So most of the cholesterol that we eat is in fact excreted out of our

backside. We don't bring it into our body. And therefore most of the cholesterol that we are going to talk about today is actually cholesterol that we have made and that's transported between cells through these things called lipopropies. One of the things I remembered from Pathology A, so it's the first of the three major classes you take in pathology, was something that the professor said, which is he said, no doctor has more experience with what it is to have heart attacks than pathologists, because 50% of the people who have a heart attack die on their first heart attack. So he said, I'm seeing 50% of the people

who have a heart attack and their first presentation is death. So I kind of remembered that and it's a very sobering fact to think that half the time. And again, I don't think that's true today, but I think 25 years ago that was the case. The numbers are probably a bit better today. It might be a third of first events or fatal, but nevertheless it was sobering. So you have this sort of weird factoid that's again often the recesses of my brain somewhere. And then you had me this textbook and it actually made sense with what he said because in addition to going through in great detail the pathological staging of atherosclerosis,

it was littered with autopsy sections of coronary arteries of people who had died for other reasons. Now, notably, they were quite young. So here's a 26-year-old male victim of a gunshot wound. Here's a 27-year-old female who died in a motor vehicle accident. Here's a so-and-so-and-so-and-so. And when you look at their coronary arteries, you realize they already have atherosclerosis. They already have oxidized apoB bearing particles engulfed by macrophages and thickened intima and while they may not have calcification in their arteries yet

or the types of plaque that would rupture within the ensuing weeks or days or months They nevertheless had atherosclerosis and they were in their 20s and in their 30s. So all of a sudden, what this professor said 20 some odd years earlier made sense, which is this was now an explanation. This was a bridge to explain what otherwise seemed hard to understand. Atherosclerosis is a disease in the tissue, and almost everything that lipid people talk about is in plasma.

And if we don't understand the natural history of the disease, how can we construct a strategy to prevent it? And although much of my work has been on EpoB, the more important part, I think, has been on understanding how the natural history of atherosclerosis should direct our prevention strategy. What that leads to is that every major guideline in the world bases their selection of subjects for statin prevention on the tenure risk of disease. And that was a huge step forward in 1980 and 1990,

but it totally, or not totally, but it very fundamentally makes prevention of premature disease almost impossible. When you plug in the numbers to calculate somebody's risk for any of the risk algorithms that American College of Cardiology, 2019, AHA, multissociety. You plug in numbers that belong to that particular patient and what comes out is what you think is the risk for that particular patient. It actually isn't, but what drives that calculation is the age and the sex of that patient. Things like cholesterol, blood pressure, they contribute minimally

to the actual calculation of 10-year risk. So what that means is if you're 35, well there is an even risk calculator for you, but if you get to 40, almost everybody's risk is low at age 40. And it is until you get to about 55-60 that risk gets you over the threshold for the American Prevention Guideline Treatment. So prevention really starts at 55-60, but half, almost half of all infarcts and strokes, occur before the age of 16. So, how can that be?

What Staryan, his colleagues, established was, for the first three decades or so of life, the disease begins, gets a foothold in the artery. But it's only in the fourth decade that you start to develop delusions that can actually precipitate a clinical event. But risk is low and yet the event rate is high. How can that possibly be? Well, the answer is stunningly obvious, which we've published.

There are a ton more people under 60 than over 60. So the rate of events is low, but the absolute number of events is high. That's problem number one. Problem number two is, say you get to 60 and you didn't have an event. Well, the disease was developing and extending during your 30s, 40s and 50s. So by the time we start to try and prevent an event, the disease is well advanced in the arteries. That to me are the two fatal flaws in the 10-year risk approach. We published a paper pointing this out in JAMA cardiology a few years ago. Born Nordiskart and his colleagues have done exactly the same thing with the European guidelines. You can't beat these numbers. So rather than what Stereo taught me, and it took some years before we could develop the methodology, of

course risk is a good concept. Of course it is. But we should be selecting people also based on causes. I can measure your APOB pretty precisely. I can measure your non-HDL cholesterol a little less precisely, but pretty well. And I know it's yours. When I calculate the risk, if I said, okay, Peter, you're my patient, you're a healthy guy,

I calculate your risk is 4.1%. Now, what does that number mean? Is that your risk? Nope, it means that out of a hundred people at 4.1% 4.1 of them will have an infar, but we know that within that category There's a tremendous variance in real risk Not everybody's at 4.1 some are higher some are lower some are dead on So if I had two risk algorithms the philosopher AJ air

English the logical positive He was actually darn good on probability There's a real challenge predicting singular events. I'm either gonna have an infarct in the next year or I'm not. It's not really a probability. It's either I'm or I'm not. If one algorithm said I had a 10% risk and another one said I had a 15% or 20% whether I have an infarct or not, both of them were right because they said there was sort of a chance you could and there was a far larger chance you wouldn't. When we say people should be treated with a risk above 7.5%, that means 92.5% of the time nothing will happen. Well, that's not a great incentive I think for helping people understand what's truly going to happen.

So the way we can deal with this and what we've done is develop what's called the causal benefit model. We measure it non-h-l or apob, and we can project the risk over 20 or 30 years. If you're 30 years old, the period of time you should care about is up to age at least to 60. And so if you were in a group, let's say, and let's say I make you 35 again, and I say, your chances of having an infarct or a stroke before you're 65 are 30%. Now that's a number you can deal with.

That's a number that has meaning. And we could also calculate how much the risk can be reduced by starting at age 35 or how much you lose by starting at age 45 or how much more you lose by starting at age 55. This next set of clips is a deeper dive into cholesterol, the limitations of the standard cholesterol blood panel, and an important segment on why I think no one should ever refer to cholesterol as good or bad. So I recently posted something on social media about my frustration with the way that the press and frankly even sometimes the medical establishment writes about cholesterol, referring to good cholesterol and bad cholesterol.

Now, if you've ever listened to me on podcasts, you understand that I talk about this in great detail. But a number of the comments suggested that there were a lot of people that are kind of new to this discussion. They haven't necessarily followed me. They certainly haven't heard the, I don't know, literally 25 hours worth of content on cholesterol over the last four years on my podcast. And they were kind of looking for a little bit of call it the TLDR version of cholesterol. And I thought this would be a great excuse to do it.

So if you want to understand why I whale on people when they say bad cholesterol and good cholesterol, you have to really understand what cholesterol is and why that type of imprecise language is unhelpful to put it mildly. Okay, so let's take a second fact, what is cholesterol? So cholesterol is a lipid. It is synthesized by every cell in our body. That means every cell in our body makes cholesterol. Okay, so why do we make this stuff? Well, this stuff is super important or every cell in our body wouldn't make it. It's essential for the creation of a cell. So a cell, when you look at a picture of a cell in a book or online or something, they look like two dimensional structures, right?

They're sort of these flat things, but really that's not what cells look like. That's kind of a cut open cell projected onto 2D. The reality of it is cells are three dimensional and they are fluid. They have to be able to be more than just perfectly open spheres. So what gives them that fluidity is their membranes. And it's the cholesterol within the membrane that provides that fluidity. It's also what allows transporters to go across the surface of cells. These transporters are what allow various things like glucose, ions, hormones, etc., to

traverse cell membranes. So it's important to understand that if we didn't have cholesterol, we wouldn't have cells. If we didn't have cells, I wouldn't be making this video and you would be here to watch this video. No cholesterol equals no life, full stop. There are things that are almost equally essential for life that go beyond that. Colesterol is the precursor to some of the most important hormones in our body, which ranges from things like vitamin D to cortisol, to estrogen, to testosterone,

progesterone, et cetera. It's also essential for bile acids. We wouldn't be able to digest most of our food without bile acids, especially fatty foods. So the list goes on and on as to why cholesterol is essential. So why does the story not end there while we're having this discussion? Well, when it comes to something as essential as cholesterol, not every cell in the body is capable of making enough cholesterol to meet its individual needs.

So the body has to be able to traffic cholesterol. So there are certain cells that tend to be net exporters of cholesterol, the liver, for example, as a general rule, the liver makes more cholesterol than it needs, whereas there are parts of the body that need more cholesterol than they are typically capable of making, especially during periods of high stress. So those parts of the body need to receive cholesterol, and this poses a little bit of a problem because the main channel that we like to use in the body to transport things back and forth is of course the circulatory system. It is not the only system, we have a lymphatic system, but the circulatory system is the system that we tend to use most to

transport things like this. Now, there are lots of things we transport in the circulatory system and we do without any difficulty. We transport glucose about any difficulty. We transport electrolytes without any difficulty. We transport lactate without any difficulty. Why? Because all of those things that I just stated are water soluble. And of course, the circulatory system is made up of plasma and proteins. That's what your blood is. The plasma being basically the water of the cell. And so things that are water soluble, like all of the proteins, hemoglobin, and things

like that, things that I already stated because electrolytes, they are soluble in water, and therefore they transport easily. But as I said at the very outset, cholesterol is a lipid. And if you remember a little bit from a chemistry class, you'll know that a lipid is not water soluble. It is hydrophobic, as opposed to what we say, is hydrophilic. So things that are hydrophobic can't move in water. Just as you would dump olive oil into a glass of water, you would quickly realize how much

they repel each other. So we have this totally essential thing that we have to move around the circulatory system. Otherwise, we would die. And we can't do it directly because the medium through which we need to transport it repels the thing we're trying to transport. Aha, there's a solution. We need to create a vehicle that we can transport this in. And that vehicle is called a LIPO protein. And as its name suggests, LIPO and protein, it's part lipid, part protein. And it's engineered in a way that the lipid part is on the inside. The protein part is on the outside. Protein is water soluble.

So now you create this spherical molecule, which on the inside you can package the cargo that is hydrophobic, repels water and on the outside you have a coating that is hydrophilic, that is attracted to water and moves effortlessly through the water and that's how we transport And that's how we transport cholesterol. Now, broadly speaking, these lipoproteins traffic in two types of families. A family that is defined by APOB, which is a lipoprotein that wraps around it, or an APO lipoprotein that wraps around the spherical, larger lipoprotein. And APOA, there's an APOA family, there's an APOB family. Technically, there's two APOB families,

there's an APOB 100 and an APOB 48. I'm gonna ignore the APOB 48 right now. That just exists on chylamicrons and we could do another class on that another day. But for now, we're gonna focus on APOB 100, which defines the lineage of LIPE proteins that are terms you've probably heard of, VLDL, IDL, LDL, LP, LLA. And the APOA LIPE proteins define a totally different class of these called HDLs.

So what do those names mean anyway? VLDL, IDL, LDL, HDL. They all refer to another feature of the lipoproteins that is distinct from the ape of lipoprotein that wraps around them, which is their density. So if you think about a high school experiment where you take various different substances and you put them into water, you might notice

that you can separate how they would float. Now water's kind of a bad example of how that works because things are typically binary behaving in water. They're sink or they're going to float. But I think that gives you a conceptual understanding of the difference in density. Density is mass over volume and a higher density object relative to a lower density object will sink versus float. So if you take all of those life-approachings that I mentioned, all of the APOV ones, all of the APOA ones,

and you put them in a certain type of gel in the lab, you can see a separation of them based on their density. And the highest density ones of those, we just call the high density life-opropane, the HDLs. You have more than one APOA on an HDL and you have different subclasses of HDLs. HDLs are really complicated and we don't even come close to understanding all the ins and outs of them. Which, by the way, is why I get really annoyed when people say having a high, good cholesterol

is good. Again, what they really mean to be saying is having a high HD good cholesterol is good. Again, what they really mean to be saying is having a high HDL cholesterol is good. And while it's true that on average, higher HDL cholesterol is associated with and traffic with metabolic health in a way that low HDL cholesterol tends to traffic with bad metabolic health, you can absolutely not tell by looking at an individual based on how high the HDL cholesterol is if they're in good shape or not. Because that single snapshot of how much cholesterol is in the HDL tells you nothing about the functionality of the HDL, and it's the functionality of the HDL that matters. I'm not going to talk anymore about that because I have an entire podcast coming out on HDL

biology where we'll go into that in great detail. But it should be stated that efforts to raise HDL cholesterol pharmacologically have by and large mostly, not exclusively, but mostly failed in improving outcomes. Okay, so over on the LDL, APOB side, the most abundant APOB 100 or APOB for short, lipoprotein is the low density lipoprotein. That's the one that gets called bad cholesterol. And again, on the APOA side, we have HDL, which gets called good cholesterol. So a couple of things I want to say on this one. If you're talking LDL, you are referring to the low density light-approach. If you say HDL, you are referring to the high density

light-approach. But if someone says what is your HDL, what is your LDL, they're asking for a laboratory metric, they are asking incorrectly. There is no laboratory metric called LDL or HDL. There is HDL cholesterol, LDL cholesterol, abbreviated LDLC and HDLC. There is LDLP and HDLP, which is the particle number of LDL, which can be counted via electrophoresis or NMR. Of course, my preferred way to count the number of these particles is to look at APOB. The APOB concentration, to me, is the most important number you want to understand to predict from a biomarker standpoint your cardiometabolic risk, a CBD risk, because

it captures all of the atherogenic particles. So APOB counts the total of the LDLs, inclusive of the LT-LAs,ays, the ideals, although they virtually never exist. They have such a short residence time and the VLDLs, which can become problematic in people with metabolic syndrome and eye triglycerides. So APOB gives you the total afrogenic burden of those liked proteins. And therefore, I think it's the preferred metric by which we want to assess risk. But if you want to look at LDL, you have to look at LDL C, LDL cholesterol, and HDL,

you have to look at HDL cholesterol. Now, is the cholesterol in the HDL any different from the cholesterol in the LDL? No, of course not. Therefore, it is totally erroneous to say, HDL is good cholesterol and LDL is bad cholesterol. No, instead, what is true is that LDLs themselves, as life-approach teams, are bad actors because of what they do, what they do is they go into artery walls where they get oxidized and they basically dump their oxidized sterile contents into the subendipulial space, which elicits in immune response on a whole bunch of other things that lead to ethos courses, which I'm not going to get into now.

But the point of this discussion that I want people to understand that LDLs and HDLs are like the proteins. If you want to talk about the cholesterol, you talk about LDL cholesterol and HDL cholesterol, but the cholesterol in them is the exact same. And there is no such thing as good cholesterol or bad cholesterol And so you just have to be careful when you see things written that are written through that lens Because what it tells you is the person writing this doesn't understand the basics of Lippitz and like the proteins and if they don't understand the basics of lipids and life of proteins

Because what I just told you guys is literally the 101 on this subject. We didn't get to the senior level class, let alone the graduate level class. And this is complicated stuff once you get into that level. So if someone writing to me is butchering the 101, you can stop reading. Because whatever else they're saying,

they're undoubtedly screwing it up. So there it is. There's the TLBR on lipids. What's the problem? What's the problem? If a doctor gets a report now, he gets total cholesterol, triglycerides, non-HDLC, LDLC, HDLC, five numbers.

Do you think he actually looks at any of those numbers? He's trying to do a good job, he does. But let's say the triglycerides are high. Can he do anything with that? Nope, because everything is based on LDLC. So he's got, in reality, four numbers that are doing nothing. Let's explain that to people, Alan,

because you and I know the ins and outs of that very well, but I think most people here don't understand the difference between the calculated and measured LDL. So let's start with that. And then let's talk about how VLDL has been estimated. And let's bring this all back in terms of some other work you've done, which is understanding the role of triglyceride in APOB. So let's start with the basic. You go to the doctor, you get a set of labs done,

and the LDL number comes back at 140 milligrams per desoleter. Is that actually what it is, or is that an estimation? That's an estimation. It's almost always a calculation. And there are at least eight different methods to calculate LDL cholesterol. So if there are eight different methods, they don't all give the same answer, or you wouldn't have eight different methods. LDL cholesterol can also be measured directly. That assay has never been validated in disease patients, and no one has ever published a paper showing that it's more accurate in terms of disease identification than calculated LDL cholesterol. And yet people have paid good money for that lab test. There's no question that the number of LDL particles is a more accurate index of risk than the LDL cholesterol. The VLDL cholesterol is a cholesterol

that's in the very low density, like we're protein particles, the particles that come out of the liver. That cholesterol is atherogenic. There's a lot of triglyceride in that particle. So the people who measure triglycerides say, well, the triglycerides are high, that must be the problem. And there's no question that people with measure triglycerides say, well, the triglycerides are high, that must be the problem. And there's no question that people with high triglycerides are at increased risk of

heart disease. But the people with the high triglycerides who are at increased risk of heart disease have a higher number of LDL particles and VLDL particles. It's the particle. When you're measuring the triglyceride, you're just measuring a blob of liquid In a bunch of particles and you need to know the number of them. So It's an important number in the sense of if you're a lipoprotein guy trying to figure things out if it's extremely high It increases the risk of pancreatitis

But I haven't seen any solid evidence that Stragusrite itself is proathrogenic. What's pathrogenic is the cholesterol inside the VLDO particles. It's the number of those particles that get into the wall. Now, there's a complicating reality, because in general, all I need to know is the APOB, but there is a disorder called Bremnant, type 3 dyslipoprotonemia, and that's a very specific highly atherogenic condition that manifests with high

triglycerides, high cholesterol, but get this you know, low APOB. So when I measure my lipids in APOB, I can recognize that. But if you don't measure the APOB, and this applies to most of the people who are listening to this podcast, if they go to see their doctors, that condition can't be diagnosed. A last set of clips will focus on why I think APOB is a superior lipid metric to LDL cholesterol or even non-HDL cholesterol when trying to predict risk. Are you optimistic? Is this just a question of time? I mean, in 10 years, will kids in med school be learning about APOB instead of LDL?

I'm pessimistic. Europe, the 2019 guidelines were very pro-APOB. The evidence from Mendelian randomization, like the newer technologies, Mendelian randomization, they've just been slam dunk for APOB. Let's explain that to folks, because I wanna talk about the causality of this and this might be the perfect way to actually explain the causality of ApoB in the context of this

tool. So, can you explain to folks what a Mendelian randomization is? Were people see this all the time in studies, but I don't think it's entirely clear for the average person what it means? I'll try. Okay, it's not my expertise, but I'll try. The conventional ways of taking things apart with prospective observational studies like Framing Hand. There's a limited amount of the certainty of your conclusions because of confounding you can't

deal with. You take measurements at age 20 and you follow someone for the next 30 years. You take measurements at age 20 and you follow someone for the next 30 years. Well, a lot of things change in the next 30 years that you don't have a handle on. Your inferences are probable but not causal. What Mendelian randomization allows you to do is to come a lot closer to causality. Because, for example, you can identify groups of genes that are associated where changes in the gene are associated with a little lower cholesterol or a little higher cholesterol. And when you lump together a bunch of those different genes that can have different make-ups because you can change the makeup of a gene pretty easily. You can see fairly substantial differences in cholesterol. So what you've got is information on somebody that's

fixed at birth. And you see, is that associated with a difference in outcome? You've gotten rid of a lot of stuff in the middle. And what a number of Mendelian randomizations have shown is that APOB includes all the information in triglycerides, LDL cholesterol, and even HDL cholesterol. It sums them, which in a sense of LDL and LDL makes perfect sense. So there are caveats in Mendelian randomization. You can't just push a button and say, give me the answer. But George Davy Smith, really arguably one of the founders of Mendelian randomization or not arguably he was. He's the author of a number of the Mend in dealing randomization saying, APOB incorporates and therefore beats triglycerides in LDL cholesterol.

So that's a huge level of information that isn't even mentioned in almost any of the guidelines. Yeah, so let's make sure people understand everything you just said, because you said a lot of things in there. When you prospectively follow a cohort, the way the Framingham cohort was followed, or the Framingham offspring, or the Mesa cohort, or any of these cohorts have been followed, you can take a bunch of people and you could measure their APOB, or their LDLC, or whatever metric it is that you're trying to determine if it, in fact, has a causal

relationship to the disease of interest. You can follow them over decades, and you would demonstrate, as has been demonstrated, that the people with higher B, higher LDLC, higher non-HDLC, and lower HDLC all have a higher risk of developing a thruscarosis over time. But it's hard to say that that's causal just based on that information because over the ensuing 20 years that you follow them, they are free to make other choices that may impact those variables of interest and other variables.

So the Mendelian randomization attempts to get around that by saying, at the time of, I was gonna say birth, saying, at the time of, I was going to say birth, but really at the time of conception, we all get randomized to a set of genes. We get assigned a set of genes. I guess they're not perfectly random because they come from our parents, but for the purpose of not changing, they are indeed a random assignment that is fixed. If we can identify which genes map to which phenotype and we can figure out the genes that map to the phenotype of our interest, namely driving up or down a variable of interest such as APOB, then we don't really have to worry

about the confounders that occur in between because the genes can't change. Just to put a bow on that, basically, now when you see a difference in outcome, it's much more likely to be causally related to the phenotype of interest because the gene has not changed that underlies it. Now, what are some of the ways that we can get tripped up with Mendelian randomization? I mean, there's some pretty big ones.

Yeah, before we get there, HDL cholesterol was the rage, the total rage, because the epidemiological evidence couldn't be clear. In fact, it was four times more clear. My recollection was that Framingham demonstrated low HDLC was four times more predictive of cardiac events than high LDLC. Am I remembering that correctly? Not sure. It's that multiple. Yeah, but it's multiples. And it turns out, as we know now, at least from the CTP inhibitors, that you can't manipulate HDL and change outcomes.

And that's one of the elements of demonstrating an overall causal relationship. And the Mendelian randomization show HDL is not causal, whereas the show A will be is. And cholesterol is too, by the way. Those are two very important studies, Alan. I mean, and both of those have been in the last 10 years. Yeah, it's a incredible technical advance

in being able to examine questions and look at numbers of people that would be unimaginable in conventional studies. The Mendelian ran, they're always talking hundreds of thousands of people, because they've got these huge data banks with genes. And those numbers get you around the confounding of things. You have huge numbers, but it's like any methodology,

no method is perfect. This one can mislead you too, particularly when you've got a sequence of associated variables. For example, people show using MR that triglycerides were quote, cause or associated with increased risk. But when you took into account that non-HDL cluster or the APOB disappears. So when you've got a linked metabolic chain, you've got to be careful that you've gone to the end of it. You've got the real actor, not act one leading to that you've got the real persona

dramatic. Which is why it's surprising that HDL didn't at least at the first order demonstrate causality because there's no doubt that phenotypically the high triglyceride low HDL phenotype is so associated with metabolic syndrome that it makes up two of the five criteria. That's an incomplete description. That's like you describing yourself as six feet tall, I wish, and not giving your weight and letting me guess your BMI. You cannot characterize any phenotype without the APOB. It really drives me around the bend when people speak saying, I got somebody because I got to try this rights in their HDL. Well, I say, okay, what's their EPO-B?

How can you pretend you've evaluated the system when you haven't counted the number of after-genic particles? Because they could be normal, they could be high, or you can have a type three. They don't know, and it's not a phenotype. There is no phenotype without putting any bobi in there. They're lipoprotein particles.

They're disorders of lipoprotein, particle metabolism. Of course, the triglycerides in cholesterol are important. But my analogy, I didn't do a good analogy there. But it's so fundamental that it tries me to distraction as to why you wouldn't want to know a core element of knowledge, but it doesn't seem to bother many of my friends. You walked through the pathophysiology of how the APOB bearing particle wreaks havoc in the artery wall many, many years

before we see clinical events. And you also mentioned that there are other factors that can amplify or exacerbate that. I can't remember exactly how you said it, but that was the gist of it. Well two of those things that are widely accepted to exacerbate risk are smoking and hypertension. In fact, smoking and hypertension probably carry a greater risk for arthroscarosis than APOB, or is that not the case? It all depends the way you think about it.

Because if you just say, what's the risk somebody with hypertension faces, they have high risk, I have no question. But then you say, what is hypertension? The last 30 or 40 years, there have been almost an infinite number of basic science studies on hypertension. And when you were in medical school, and even before that, when I was in medical school,

we talked about pathophysiology of hypertension. And what strikes me is, we don't talk about the pathophysiology of hypertension. And what strikes me is we don't talk about the pathophysiology of hypertension anymore, but the basic science goes on in rats that's healthier than ever. And there isn't anything I know of that's come out of that basic science that's been clinically useful in the last 30 years. The drugs we use, we use them because they work. So what is hypertension? It's a higher blood pressure than we should have and where is the disease that produces that higher blood pressure? Is it resistance? We don't have a clue, okay?

We don't have a clue and it strikes me. It's the same thing as much of the debate in lipids about ABOB and it strikes me, it's the same thing as much of the debate in lipids about APOB or the drunk looking for the key under the light because this is where the light is, not where you lost it. Everybody who's anybody has the same viewpoint. My bet is it's in the proximal earna. My bet is that it isn't that complicated. We lose elastants in the proximal earurna, and that's systolic hypertension. Thank you very much. What could accelerate that process? What's the mainstream view that this is renal? When I read hypertension, I get lost because I get page after page after page

of peripheral arterial or tone and very complex metabolic studies and very sophisticated animal models. And there's some renal left. It's a measement for me, an absolute measement. I hadn't heard about the proximal aorta. So say a bit more about that. Well, this is me. The proximal aorta is elastic.

And if you look at a flow curve, a hydrostatic pressure curve, when we're young, it's rounded because as the left ventricle ejects blood rapidly into the order, the order expands. So it absorbs some of that energy. You know that wind castle that they mentioned in school? That's not that big a deal, but the energy is partially captured, partially regained, but the wall is in bad mood. The wall can give way. Me, personally, just in the middle of my brain, imagine that if those elastic fibers start to go, then the wall stiff.

So now when the left ventrival ejects blood, the pressure goes up more rapidly, and it falls more rapidly and diastole. And that's why you get systolic hypertension with normal dead stolic pressures. So my bet would be, if I was not the HIM, I would be looking at factors like cardiac output again, which used to be way back when, or factors that alter the behavior of the proximal laorta. As much as something that's, to me, pathophysiologically, much more likely to be involved. So once I got hypertension, okay, then I've got a driving force to push particles into the wall. And so you think it's the actual increase in the pressure of the plasma.

And the response of the wall, I think there are responses to the wall, the wall thickens up, it gets harder for particles to go through. Does it also damage the endothelium? Do you think that plays a role? That's right. I don't understand endothelial dysfunction. It's more a language thing to me than it is a reality. I know the endothelium is critically important. It functions abnormally and that's endothelial dysfunction. How that fits into the overall thing, I don't know. My bed is, APOB particles are part of the process of inducing endothelial dysfunction, but I don't know that clearly experimentally.

So going back then to the question at the top, does it make sense to even compare hypertension to APOB? They both seem to play a causal role, is one more causal than the other, or is that a silly question, because they're not binary and static. I think that's not the right question. I think our blood pressure goes up as we age.

I mean, hypertension involves so much of the population that's not clear to me what the word disease means. The prevalence as we age is so high that to me it's becoming almost a aging process because we're lasting a lot longer than we were probably designed to go. So you have this repetitive injury to the proximal laorta. It gets a little progressively less able to deal with it.

So with a time where 50, what percent? 60% have higher blood pressure. I mean, the figure's you're staggering. Is it really that high? I'm not sure. Don't quote me on that, but it's high, high, high. But doesn't APOB also rise with age? It does rise with age, but not that much. When we look at people at age 35, we can pretty accurately categorize the group they belong to at age 35, not that they won't change somewhat. So if you're

high at age 35, you've got about a 95% chance of staying high. 5% will go out of the high zone. They won't go low, low. So if you're high at age 35, hmm, I wouldn't bet anything's going to move you down. That's why I think it's such a good signal for when we should start thinking about treating people. And if you're low, some people go from low towards high, but the majority don't, and we keep following them. But if you're high, no, we've published a fair amount of this. If you're high, it's not 100%, but it's about 90% that you're going to be high. Is there a gender difference?

At least clinically, I seem to see women as they go through menopause experience, dyslipidemia that men wouldn't experience over that same decade or even five-year transition. I think there are changes, and APOB goes up with menopause. I'd like there to be more data. I think part of the reason it's held APOB back is that people didn't measure it.

So they were sort of, well, what I measured has to be important because I can't answer your question. Hopefully more data will be coming. But I agree with you. People can change in the meta-plus. So I'm not saying we don't keep looking at people. But when you have somebody at age 35 to 40 who's high, the odds are high that they're going to stay high. Are we doing a better job treating hypertension than dyslipidemia? I have no idea. The incidence of coronary diseases going up

in the last five years. And that's despite statin therapy. And that's the obesity diabetes. So I think we've been too quick to congratulate ourselves at how well we're doing. There are many reasons that treatment is not succeeding as well as it should. And I think the complexity of the lipid phenotype,

of the lipid model is part of the answer. It's easy for me. I get the APOB where I want it to go. Yeah, I mean, an explanation for your observation would be if in the last five to ten years the incidence of atroslerosis, or major adverse cardiac events is rising, despite the advances we have, you would argue or could argue that if we're measuring LDLC and that's our proxy for treatment, but as dyslipidemia is growing in the metabolic context, meaning if you have

more methamphetamine and more insulin resistance and more type 2 diabetes, we know that those phenotypes are associated with greater discordance between apobian LDLC, suggesting that you'd have a greater and greater portion of the population that is being undiagnosed or being undiagnosed because you're treating their LDLC and you believe that it's lower than their risk actually is because their apobias higher. I know you know what I just said. I hope the listener understands what I just said. Yeah, what you just said was important.

It's another example. An unfortunate sad example. The trying to quantify lipoprotein's base just on lipids is not adequate. You're not capturing all the information that you should. Let's go back to the macro point here around APO-B, which is a greater coalescing around the idea that APOB concentration matters. So I think it's very well understood that two of the biggest risk factors for cardiovascular disease are smoking and hypertension.

I don't think there is any ambiguity that cigarette smoking and high blood pressure increase the risk of cardiovascular disease. And they both appear to do so through a mechanism that weakens the endothelium or creates an injury to the endothelium. The question now becomes, as you put it, Tom, how iron clad is the story that it's the APOB bearing particle in the presence of injured endothelium that is the Trojan horse that begins this destructive trajectory of taking that cholesterol into the subendothelial space, becoming retained, undergoing this chemical oxidation process, which then kicks

off an inflammatory response that paradoxically, as an attempt to repair the damage results in what can be a fatal injury. There are other hypotheses, for example. There are people who note, and we have, I mean, look, I have a patient in our practice time. You've weighed in on her case, walks around with a total cholesterol of 300 and something, an LDL cholesterol of 220 milligrams per deciliter, an APOB of 170 milligrams per deciliter. She's in her late 60s and her coronary artery calcium score is zero. We have elected to not treat her with any lipid lowering

therapy. In other words, there are exceptions to this. How do we reconcile that? Well, it's the human body in medicine. As you know, not all smokers are going to come down with lung cancer or chronic obstructive lung disease. Why not? If that's such a horrible risk factor. I try to explain this a color, and I've certainly seen cases like you say, where, oh my God, if I was just going just gonna say give me your apobie or whatever cholesterol metric you're going on three drugs right now you got no choice. And maybe the old days we approach people that way but no more I think you have to individualize your whatever risk factors you discover that might wind up causing atherogenesis and then figure it out. So particle number is certainly a major factor that might force it in, but not always, end at the allele function, although you can certainly, if you review the history of this and how

do you really determine end at the allele function, not everybody has serious end at the allele dysfunction who winds up with asterscrow. So particle number itself, and some people can just make the particles go in. I think if we take most adults who's not going to have a little bit of endotelial dysfunction, so I agree with you, it's a combination of something about atherogenic particles, be it their number, endotelial dysfunction. But I'm talking more and more now when I discuss any type of lipoprotein.

I don't care which subgroup you wanna talk about. I think we certainly have to know it's particle concentration, but I like to talk about particle quality. So what are the other attributes of any lipoprotein that might contribute to its atherogenicity or in some perhaps not understanding, make it relatively,

it's not going to generate ather sclerosis. And there certainly have to be things like that going on. So as we're getting smarter, we're looking at other components of the lipoproteins that could be other proteins that are on them, that could be their complex lipidome and trying to see, ah-ha, can that help us discern whether in you a given particle concentration

is more worrisome than it is in the next person? So there's a lot going on. And also from the gist of this conversation, listeners will know, atherosclerosis, atherogenesis is a multi-complex, multifactorial disease. And that's why even when Peter and I, if we consult on a case and we realize in this person, we have to beat up APO B and get their particle numbers to a more physiologic range. We don't stop once we do that. We examine a great detail for other things that might be

injuring the endothelium or the arterial wall and See our any of those treatable or so. So we're getting a little bit smarter on lipoproteins But there's certainly more to it than just particle number Do we think that there's a limit to where the benefit of reduction Becomes diminishing or even J curves in the other direction. So we discussed it in the first episode significantly. We did so again with Ron Krauss. It wouldn't be the worst idea in the world, a couple of years from now to sit down and do it again

and re-examine the data. But again, I think the causal relationship between APOB and atherosclerosis is as strong as virtually anything we see in medicine for which you can't do the perfect experiment where you have to rely on natural experiments. Nevertheless, maybe it's not entirely clear what the dose response looks like. So if you have somebody whose apob is 160 milligrams per desoleter. There's a risk reduction that comes to lowering it from 160 to 100 and lowering it from 180 and lowering it from 80 to 60. What do we know about the risk reduction

in lowering it, say, from 60 to 40 to 20? And I ask both what we could infer pharmacologically and non-pharmacologically, in other words, from the Mendelian randomization versus the pharmacologic. Well, even using pharmacologic trials and Mendelian randomization, the concept you're going to come across with is lower is better. And with the pharmacologic thing, we're modulating things that either have clinical trial proof that if you lower them, it's good or the Mendelian randomization, looking at genes where that drug might be doing something, it works. Now you do need a few hypoby containing lipoproteins.

They do traffic other lipids, they traffic fat soluble lipoproteins, but we must never confuse a beta lipoproteinemia where nobody, or that person can't make them, or hypobatal lipoproteinemia where they make a few, enough to traffic those other things that a lipoprotein might have to traffic. But even the guidelines where they examine people looking at their baseline, able to be your LDL cholesterol,

the first thing they suggest, at least in the higher risk people is try and get a 50% reduction. And that's where most of the bank for the book is going to be. Now, if you still have options that you can lower it further, yeah, the trial show, yeah, there is incremental reduction events, but it's a much smaller absolute risk reduction and dropping it the 50% or so. So I don't know if that answers your questions. So most people don't have the type of levels where with modern therapeutics, with modern lifestyle, we can more often than not attain physiologic concentrations.

And if I want to talk about APOB, that's probably under 50 milligrams per desolider if we can get there. That's what the newborns have. That's when you go in clinical trials, if you take it down that low, you see your most risk reduction and so far at least with pharmacologic lowering of APOB with the currently FDA approved drugs. There is no signal of harm. Yeah, again, it's funny because I was just about to say with the current crop of drugs, specifically the PCSK 9 inhibitors, we are routinely seeing patients who easily can get an APOB into the 20 to 40 milligram per desolate range. You and I actually sat down a couple of months ago and did a calculation to estimate how

much cholesterol is actually contained in the circulating lipoproteins versus that, which isn't cell membranes. Do you remember doing this with me? Not per se, but I, and where we're developing equations, you're the master of that. Well, it was one of these things, right? It was, it was sort of like, look, you know, when you look at a person's plasma glucose level, you realize pretty quickly it represents a tiny fraction of total body glucose. And similarly, there's such a concern about plasma cholesterol level. But, you, but given how essential cholesterol is

its understandable why people would be concerned that low cholesterol could be problematic. But once you do the calculation and realize virtually all of the cholesterol in the body is contained within the cell membrane or within the steroidal producing tissue, the circulating amount is a very narrow window into the total amount of cholesterol. And therefore, a reduction of, say, 60 milligrams per deciliter to 50 milligrams per deciliter of apobie or even something more extreme, like a full 50% reduction of total cholesterol, 200 milligrams per desoleter to 100 milligrams per desoleter, does not represent a significant reduction in total body cholesterol. This is a very important point. All right, let me repeat it. You have a total body

cholesterol that you measure in the plasma that says, oh, it's 200 milligrams per desoleter, that goes down to 100 milligrams per desoliter. Let's say the LDL fraction reduced from 150 to 75 or something. Someone might say, God, you just cut cholesterol in half. That can't be good for you given the importance of cholesterol. But my point is, no, you simply cut the amount of cholesterol being carried by the lipoproteins in the plasma in half. That doesn't capture the majority of cholesterol being carried by the lipo proteins in the plasma in half. That doesn't capture the majority of the cholesterol.

Yes, thanks for refreshing my memory. What you're talking about now is really pools of cholesterol throughout the body. And I think I'm so glad you brought this up because this is just not even understood, even in the lipidology community. We have a total body cholesterol. There are basically three pools. There's your brain and nothing we're talking about today has anything to do with brain cholesterol.

It's a separate system. It doesn't interact with the other cells in your body or certainly with the cholesterol in your plasma. So if it's not in your brain, where is cholesterol in your body? Well, it's either in all your peripheral cells, perhaps some more than others, or it's circulating in your plasma. And if it's in the plasma, where is it?

There's an easy weathe sea amount bound to albumin. There's more bound within all of the lipoproteins that are trafficking in your body, meaning your APOB and your APOA1 particles. But believe it or not, if I wanted to search down blood cholesterol for you, I would suck out your red blood cells and extract cholesterol from them. Red blood cells carry far, far more cholesterol than you all of your lipoproteins put together. And the other crucial point you made subtly, and I hope everybody understood you, the amount of cholesterol within your lipoproteins has no correlation with your cellular cholesterol,

or even your red blood cell cholesterol. So whatever, however you're modulating some LDL total cholesterol, HDL cholesterol metric, that tells you nothing about what might you be doing to the cholesterol content of yourselves. So don't have a panic attack if you're making LDL cholesterol 30, because I can assure you virtually every cell in your body, even if that's your plasma LDL cholesterol, has more than enough cholesterol because it can denoubo synthesize it. It can put it in its cell membranes or other organelles that require cholesterol. If it's a starogenic, just a reogenic tissue can

produce a little more or perhaps can lipidate some less. So there's no cell that's being deprived of cholesterol in the periphery when you're modulating lipids through lifestyle or drugs. lipid through lifestyle or drugs. So when ASCVD have also become far more aggressive on the timing and magnitude of APOB reduction. So take a step back and ask what are the leading causes or modifiable causes of ASCVD? The big three are pretty unambiguously smoking, hypertension, and hyperbeta-lipoprotinemia, which is just a really fancy word for saying too many lipoproteins that have apoby on them.

So that's LDL, ideal, VLDL, LP little A. By measuring apo B, why I'm such a fan of measuring apo B, as opposed to just measuring LP, LDL, particle number, or LDL cholesterol number, is we have one single number that captures the total concentration of apo B. And while that's pretty well associated with non HDL cholesterol, which is a far better surrogate than LDL cholesterol, it's still better.

And that's been demonstrated than I think we even covered that in a previous podcast where we went over the discordance between non-HDL cholesterol and APOB. So now the question becomes, well, when should you start APOB reduction and how much should you lower it? And I'll tell you, I used to take a point of view that if a 40-year-old had an elevated APOB,

let's just put some numbers to this, right? So the 20th percentile of APOB is about 80 milligrams per deciliter. I used to say that let's say somebody was at the 50th percentile, they're 40 years old, they're calcium score is zero, and they were ambivalent about lipid lowering therapy, and let's assume that they're not insulin resistant, and you've done all the things that you can do reasonably with nutrition. I wouldn't push that hard. I've now taken a very different stand, which is I've basically taken the stand with others that I've taken with myself, which is the evidence is overwhelming that infantile levels of APOB are not deleterious in any way, meaning an APOB of 30 to 40 milligrams per deciliter, which is the level that children would have, poses not only no risk to children

as evidence by the fact that that doesn have, poses not only no risk to children as evidenced by the fact that, I mean, that doesn't require an explanation, but as evidenced by what we see in the literature on adults with levels that have been pharmacologically reduced, tells me that we need to be lower. And the amount of time it takes to see a benefit tells me we don't want to wait until there's an issue. In other words, if the reason we begin therapy is because somebody has a positive calcium score, which again,

we covered this in great detail. So for people listening, we have a dedicated ASCVDMA, which goes into heavy detail for about 90 minutes on all this stuff, where if this is of interest. That's a great AMA that goes super deep on basically all of the reasons why I think my point of view now is treat early and treat aggressively and I will now also make a very bold statement. Again, let's start with the thought experiment, right? A thought experiment for colon cancer was do a colonoscopy every day on a person's life starting at the age of 30 would you eliminate colon cancer deaths? I think the answer is yes. And similarly, I would say pharmacologically lower APO B to somewhere in the 20 to 30 milligram per

desoleter range for everybody in the population, while someone is in their 20s, can you eliminate ASCVD? And I think the answer is probably yes. In other words, I think what you're basically going to do is eliminate death from atherosclerotic causes. And that would need to be started in 20s? I think so, yeah. Very early on. Yeah. So again, how do you take that thought experiment and turn it into a practical implication? Because I don't think it's practical to take every 20-year-old and obliterate their APO-B. Although it's clearly something we do in the subset of patients who have significant genetic

abnormalities, such as the cluster of genetic abnormalities that coalesce around a condition called familial hypercholestralemia. We certainly do medicate those patients usually as teenagers. So this is not some completely crazy idea. But I think practically what it means is basically by the time you're in your late 30s or early 40s, if you have any measure of APOB that's even north of the 20th percentile that should be completely lowered. So in some ways I would view an APOB ceiling of 60 as the limit.

And that's probably at about the 5th percentile. You'd sort of want everybody to be below the 5th percentile. We hope you enjoyed this special episode of the drive. This is one of the most talked about topics, not only on previous podcasts, but also one that we write about frequently in our newsletter. If you want to dive deeper, there's no shortage of content, and we'll link to it all in the show notes. However, we hope this provided you with a little more understanding of ASCVD, cholesterol,

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