Cardiovascular disease & why we should change the way we assess risk | The Peter Attia Drive Podcast

1. 0:00 – 0:10

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive Podcast." I'm your host, Peter Attia. [upbeat music] Hey,

2. 0:10 – 14:32

   Problems with the current 10-year risk assessment of cardiovascular disease (CVD) and the implications for prevention

   1. PAPeter Attia0:10

      Allan. Thanks so much for, uh, making time to sit down today. This is, uh, kinda one of those discussions I've been meaning to have for over a decade, and I suspect much of what we speak about today will be reminiscent of things we've spoken about, uh, usually in person over a meal over the past decade. So, uh, welcome to the show, and, uh, sorry that we can't be doing this in person.

   2. ASAllan Sniderman0:32

      Well, thank you so much.

   3. PAPeter Attia0:34

      So I think listeners of the show will be pretty familiar with your name because certainly I've brought it up before, um, as have other people on the show, most notably probably Tom Dayspring. I've also probably referenced on at least one or two occasions the textbook you gave me, God, probably about eight years ago. Do you remember, do you remember what book you gave me?

   4. ASAllan Sniderman0:55

      Uh, I'm trying to remember which of the two it was. I think it was the book I did with Jacqueline de Graffen.

   5. PAPeter Attia1:02

      W- No, the, y- that, that is one of them.

   6. ASAllan Sniderman1:05

      Or Paul Ridker.

   7. PAPeter Attia1:05

      But the one I'm, the one I'm referring to is actually, I think it's Herbert Starry, the pathology book.

   8. ASAllan Sniderman1:10

      Oh, right, right, right, right, right, right, right. Oh, now I'm with you. Yeah, yeah.

   9. PAPeter Attia1:13

      Yeah.

   10. ASAllan Sniderman1:13

       Yeah, yeah.

   11. PAPeter Attia1:14

       Which, which I, you just kind of immediately blew my mind. And, um, I then went out, you know, and bought as many of them as I could find on Amazon, and they were prohibitively expensive. Um, but tell me, uh, well, tell me and tell, tell the listeners why, why did you give me that book?

   12. ASAllan Sniderman1:33

       I'm trying to rec- [laughs] I'm trying to recall. Um, atherosclerosis, it's a disease in the tissue, and, and almost everything that l- 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 ApoB, the more important part, I think, has been on understanding how the natural history of atherosclerosis should direct our prevention strategy. And what that leads to is that every major guideline in the world bases their selection of subjects for statin prevention on the 10-year risk of disease. And, and that was a huge step forward in 1980 and 1990. [laughs] But, but it totally, or not totally, but it, it, it very fundamentally makes prevention almo- of premature disease almost impossible. Do you want me to explain why?

   13. PAPeter Attia3:09

       Yes, definitely.

   14. ASAllan Sniderman3:12

       When you plug in the numbers to calculate somebody's risk for any of the risk algorithms, the American College of Cardiology, 2019 AHA multi-society, y- you plug in numbers that belong to the p- that particular patient, and what comes out is what you think is the risk for that particular patient, and it, it actually isn't. But what c- 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 isn't even a risk calculator for you, but if you get to 40, almost everybody's risk is low at age 40. And it isn't till 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 to 60, but half, almost half of all infarcts and strokes occur before the age of 60. So how can that be? What Starry and 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 the lesions 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 is a, are the two fatal flaws in the 10-year risk approach, and we, we published a paper pointing this out in, in JAMA Cardiology a few years ago. Bo Nordestgaard and his colleagues have done exactly the same thing with the European guidelines. Beat-- You can't beat these numbers. So rather than what Stary taught me, and it took some years before we could develop the methodology, was that we should be basing prevention... 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 could 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 100 people at 4.1%, 4.1 of them will have an infarct. 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... Do you know the philosopher A.J. Ayer?

   15. PAPeter Attia8:03

       No.

   16. ASAllan Sniderman8:03

       The English, the logical positive? He wa- he was actually darn good on probability. And, and 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. So I either am or I'm not. And if, 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 have a risk, 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 gonna happen. So the way we can deal with this, and what we've done, is develop what's called a causal benefit model, is we measure non-HDL or ApoB and, 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. So when I gave you that book, I was starting my own journey on trying to construct an alternative to the present risk model, and which, with the help of my colleague here at McGill, George Thanassoulis, and Michael Pencina from Duke, and Carol Pencina from Harvard, we've done.

   17. PAPeter Attia10:35

       Now, something about it, Allan, um, that also brought home another message that had been somewhat left in the garage of my brain. Um, [clears throat] as, as you may recall, I trained in general surgery, so the kids in med school who are gonna go into surgery were not the sharpest tools in the shed like the kids that go into internal medicine, right? So, um, but I still remembered a couple of things from my pathology class, and 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, um, "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."

   18. ASAllan Sniderman11:42

       Right.

   19. PAPeter Attia11:43

       So I kind of remembered that, and it's a very sobering fact, right? 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. Uh, it might be a third of first events are fatal. But nevertheless, it was sobering. So you have this sort of weird factoid that's, again, off in the recesses of my brain somewhere, and then you hand 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 had many... I mean, it was littered with autopsy sections of coronary arteries of people who had died for other reasons. Um, and, and notably, they were quite young, right? So here's a 26-year-old-

   20. ASAllan Sniderman12:32

       Yep

   21. PAPeter Attia12:32

       ... male victim of a gunshot wound. Here's a 27-year-old female who died in a motor, 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, this was now an explanation. This was a bridge to explain what otherwise seemed hard to understand. That, that's the thing I took away from it in the-

   22. ASAllan Sniderman13:28

       Yeah

   23. PAPeter Attia13:28

       ... in the instant you handed it to me, as we were li- literally looking at it in the restaurant.

   24. ASAllan Sniderman13:33

       And, and it, and it's, and it's how... The thing I'd emphasize is how when you have atherosclerosis, I mean, as a cardiologist, and you, we're so used, used to looking at angiograms. We say, "Oh, there's a, there's an LAD lesion." Well, there's an LAD lesion, but the whole damn artery is diseased. And when you destroy the normal architecture of the artery, you can't restore it. So a lot of our statin prevention therapy is to prevent the complications of disease, not to prevent the disease. And statins lower ApoB particle number. That's how they work. Fewer ApoB particles in plasma, fewer get into the arterial wall, fewer get trapped. It's not that complicated.

3. 14:32 – 22:07

   A primer on cholesterol, apoB, and plasma lipoproteins

   1. PAPeter Attia14:33

      So let's back up for a minute because I think everything we've just talked about for the last, whatever it's been, 10 minutes, is in many ways the advanced, advanced seminar on prevention of atherosclerosis. So now let's go back and set the stage for this, because there are going to be a number of people listening to this who perhaps have not heard previous discussions I've had on this subject matter. So let's back way up and start with what is cholesterol, and how does it relate to this thing called ApoB that you've mentioned a number of times already? Because, uh, most people would have heard of cholesterol, and most people understand that you can measure it when you take somebody's blood. But this ApoB thing might be new to some people.

   2. ASAllan Sniderman15:22

      Cholesterol is obviously a fat, a lipid. It's a critical element in cell structure. Uh, it's in all cell membranes. Uh, the amount that's in the cell membrane is, is, is determinative of the function of the membrane. Uh, all the cells in the body can synthesize cholesterol. Only the liver can really break it down in any amount and, and excrete it. So for reasons that aren't... When, when we eat, we absorb cholesterol and, and fatty acids in the form of triglycerides, and they get resynthesized in the intestine into particles. You can't, you can't transport cholesterol and triglyceride. Triglycerides are the fatty acids tacked onto a glycerol backbone. They don't, they don't mix with water. They're not soluble. So you have to put them in particles, like soap bubbles, and there are a variety of different particles. The ones from the intestine that take the, the fat that we absorb, the cholesterol and the triglyceride, they're very large particles. There are very few of them. They have a protein called ApoB 48 on the outside surface, which gives integrity to the particle, structural integrity. There are also a bunch of other proteins. The chylomicrons deposit. They go to skeletal muscle, adipose tissue, and the heart, and the fatty acids are taken out, they're liberated from the triglycerides and rapidly taken up by the, these three tissues. The particle that's left is now much smaller because most of the triglyceride has been taken out of it, and it goes to the liver and drops the cholesterol off. So the cholesterol we eat in the diet goes to the liver, and it tends to reduce the synthesis of cholesterol in the liver. The liver gets inundated with fatty acids and cholesterol from all over the place, chylomicrons, uh, HDL, uh, LDL particles, and it, and it, and it, it... There's a system to regulate the mass of cholesterol and triglyceride in the liver, and that's the VLDL ApoB system. VLDL particles have a molecule of ApoB 100, which is longer, twice as long as ApoB 48, and that gives the structural integrity of the particle. It does one other thing I'll get to. And that particle removes triglyceride and cholesterol from the liver to maintain the balance in the liver. The triglyceride, just as in the case of chylomicron, gets dropped off in adipose tissue and skeletal muscle and cardiac muscle. So the VLDL particle gets smaller and more cholesterol-rich, and it eventually becomes an LDL particle. And an LDL particle is a cholesterol-rich particle with relatively little triglyceride in it. When we measure the cholesterol in the blood, the total cholesterol is the cholesterol in the VLDL particle, the LDL particle, and the HDL particle, the good guys, quote-unquote. The non-HDL partic- cholesterol is the mass of cholesterol in VLDL particles and LDL particles. Now, isn't that enough? Isn't that all we really need to know? And the answer is it tells you a lot, no question. But I'm gonna give you two people. One pers- they both have the same LDL cholesterol. Their cholesterol's 125. One of them tends to have larger LDL particles. One of them tends to have smaller LDL particles. In order to carry the same amount of cholesterol, there gotta be more little ones than big ones. So their LDL cholesterol's the same. Is there any difference in their atherogenic risk? And the answer is yes, yes, yes, and yes. The one with the increased number of particles has higher atherogenic risk because any cholesterol in the artery only got there within an ApoB particle. It doesn't just float in. It gets there within an ApoB particle, either VLDL or LDL, that gets into the arterial wall and gets stuck there. That's the cause of atherosclerosis. There are lots of things that contribute to me- multiplying or diminishing the cause, but that's the cause, sticking of an ApoB particle within the wall. And because cholesterol gets in there within the particles, knowing the number of particles is more important even than knowing the cholesterol level.

   3. PAPeter Attia20:57

      Allan, when did that, um, historically become apparent? If we, if we take a step way, way, way back, right, if we go back into the 1950s, Ancel Keys was potentially one of the first people to utilize the then nascent assay for measuring total plasma cholesterol. So to your point earlier, that number, let's say you measure 200 milligrams per deciliter, that's simply telling you that that's the sum total of cholesterol in all of the lipoproteins. And what Ancel Keys and others observed, and this was by now we're probably into 1957, 1958, was, hey, if you stratify people at the bottom 5% and people at the top 5%, so that might be people whose total cholesterol is less than maybe 100 milligrams per deciliter and people whose total cholesterol is more than 200 milligrams per deciliter, there's a stark difference in their, uh, mortality, or rather in their risk of cardiovascular disease. And that became very

4. 22:07 – 28:45

   Pathophysiology of CVD and the impact of particle cholesterol concentration vs. number of particles

   1. PAPeter Attia22:07

      interesting. Um, it turned out that there wasn't a great way to predict that, so, uh, the amount of cholesterol a person ate did not seem to predict that. But nevertheless, other dietary factors, saturated fat, uh, intake for one, seemed to predict that difference. It would be, what, maybe 20, less than 20, 15 years later that Friedrichs and Levy-Lease and others would start to fractionate those lipoproteins and realize that, well, actually, there's different versions. As you alluded to, there are some that have low density, there are some that have high density, and it's not, I don't know exactly when it became clear just how nuanced that was that, you know, that ApoA is on one and ApoB is on the other. But when did it become clear that there was a discordance between the cholesterol concentration in the LDL particle and the number of LDL particles?

   2. ASAllan Sniderman23:11

      I think Bob Lees in 1971, he had a paper in Science and, and, and he, he was measuring LDL ApoB, the number of LDL particles, and, and he showed it had no clear relation to plasma triglycerides or to the cholesterol. I mean, there was sort of a relation, but it wasn't exact. And, and Ron Krauss, of course, and his colleagues, and, and I did, uh, at least one paper, one or two papers with him at the very beginning, were the ones who actually showed, becoming in the John Goffman, uh, tradition from Berkeley, showed that the g- the, the, the, there were important differences in size, and these related to differences in the amount of cholesterol mass per particle. So Ron Krauss and the group there, and then a whole bunch of other people and, and deserve, I think, the, the credit, but, but, but we're, we're way back in the '70, late '70s. Um, 1980 was my first paper, uh, clinical paper ... showing with Peter Kwiterovich, the late Pete Kwiterovich from Hopkins. And, and we looked at, um, a bunch of patients with coronary angiography, and we compared people with clean coronaries, like clean, to people with diseased coronaries, like diseased. A- a- and there wa- there was a little difference in triglyceride, there was a difference in cholesterol, but there was a marked difference in ApoB. And, and that was the first, I think, clinically solid observations, along with w- an Italian group that had much, uh, close to the same observations, uh, slightly ahead of us for that matter, uh, saying that, "Look, particles could be more important than cholesterol." And it seems like forever since then, 1980 to now, trying to, and I think largely now succeeding, in developing the evidence that you can say incontrovertibly, particles more than cholesterol. Now, that hasn't moved the American guidelines. But on the evidence side, uh, there, there are, there are a handful of studies that show that non-HDL cholesterol may be equal to ApoB. There are more studies that actually show ApoB is better. But we developed an, a way of looking at it called discordance analysis to identify people who had a high non-HDL cholesterol, which is the total cholesterol in the ApoB particles, but a low ApoB total number of particles versus low non-HDL, high ApoB. So if you're a cholesterol maven, you gotta bet on the one with the high non-HDL. If you're an ApoB aficionado, you bet on the one with the lower non-HDL, higher ApoB. They all show it's ApoB.

   3. PAPeter Attia26:56

      Now, is the argument-

   4. ASAllan Sniderman26:57

      Then-

   5. PAPeter Attia26:58

      ... Allan, i- if, sorry to interrupt. If the, if the-

   6. ASAllan Sniderman27:00

      Yeah

   7. PAPeter Attia27:00

      ... if one argues that n- in the at least equivalence of, if not superiority of non-HDL cholesterol as the superior metric or at least equivalent metric, is it because you're arguing a different mechanism of action that it's... Or does everybody agree on the mechanism of action, and they're simply saying measuring cholesterol content is a good enough proxy for counting the number of particles?

   8. ASAllan Sniderman27:27

      Uh, n- nobody suggests there's a different mechanism. Uh, there are some people who argue that VLDL particles are more atherogenic than LDL particles, and I think they've got a long way to go to prove that. What people did argue was there were problems with the ApoB assay, and that it costs money. And the reality is the ApoB assay was standardized back in 1994. The measurement of HDL cholesterol is not standardized. The measurement of LDL cholesterol, not standardized. [laughs] The measurement of triglycerides, not standardized. And there are-

   9. PAPeter Attia28:05

      Well, the other argument, I, i- in, in terms of the cost argument, because I actually had-

   10. ASAllan Sniderman28:09

       Yes

   11. PAPeter Attia28:09

       ... that argument with a physician as recently as three months ago, who-

   12. ASAllan Sniderman28:15

       Yep

   13. PAPeter Attia28:15

       ... accused me of getting ApoB on patients as a way to upcharge them, even though I don't make any money on labs. But I actually called the lab that we use and said, "What's your cash price for ApoB?" You wanna know what it was?

   14. ASAllan Sniderman28:33

       Please.

   15. PAPeter Attia28:34

       About $2.50.

   16. ASAllan Sniderman28:37

       Right.

   17. PAPeter Attia28:38

       That's a, it's a real-

   18. ASAllan Sniderman28:38

       You know how much it is in my hospital?

   19. PAPeter Attia28:38

       It's a real money, it's a real money maker.

   20. ASAllan Sniderman28:41

       Yeah, yeah. You know how much it is in my hospital? It's $2, okay?

5. 28:45 – 33:10

   Limitations of standard blood panels

   1. ASAllan Sniderman28:45

      It, the, the, the... There's a, there's a... I'm trying to say this moderately.

   2. PAPeter Attia28:54

      [laughs]

   3. ASAllan Sniderman28:55

      This cost argument has been used without documentation as a, as a killer argument. And, and there were labs that charged way too much. Welcome to America, okay? Uh, your, your, in general, your, your charges are higher than ours in my little country. But that's a function of how much somebody's billing, not a function of what the assay costs. And, and ApoB, it really ticks me off because i- if, if you take India for a moment or, or almost anywhere, 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? If he try, 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.

   4. PAPeter Attia30:14

      Well, l- let's explain that to people, Allan, because you and I know the ins and outs of that very well, but I think most people here don't understand the difference, um, 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 deciliter. Is that actually what it is or is that an estimation?

   5. ASAllan Sniderman30:52

      That's an estimation. It's, 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. Uh, LDL cholesterol can also be measured directly. That assay has never been validated in diseased 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 VL, very low density lipoprotein particles, the particles that come out of the liver. That cholesterol is atherogenic, and 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 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. And 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 the triglyceride itself is proatherogenic. What's atherogenic is the cholesterol inside the VLDL particles, and it's the number of those particles that get into

6. 33:10 – 39:26

   Remnant type III hyperlipoproteinemia—high cholesterol, low Apo B, high triglyceride

   1. ASAllan Sniderman33:10

      the wall. Now, there's a c- a complicating reality, because in general, all I need to know is the ApoB. But there is a disorder called Remnant type III dyslipoproteinemia, 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 and 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.

   2. PAPeter Attia33:59

      Can you explain that condition? Um, w- walk us through what's happening pathophysiologically. How does that person have high cholesterol, low ApoB, high triglyceride?

   3. ASAllan Sniderman34:13

      Uh, I said before that the, the, the... I'll try. The, the normal metabolism is the VLDL particles get broken down sequentially as the triglyceride is removed and they get converted to LDL particles. Some of them are removed by the liver along the way. In type III, that process breaks down, and for reasons that are not well understood, around the age of 30, 35 or 40, people develop high triglycerides and high cholesterol because the VLDL particles aren't being broken down to LDL particles. That process stalls. Those particles circulate a long time in the blood, and while they're circulating, cholesterol gets deposited into them, so they become very cholesterol rich, like really, really cholesterol rich. And those people have a very high risk of coronary disease, peripheral vascular disease. It's a commoner syndrome than familial hypercholesterolemia that gets day and night press, day and night. This one is easily treatable almost all the time. FH needs to be treated, much more challenging. But type III cannot be diagnosed in most patients in the United States because ApoB is not measured. The technology that we used to use to diagnose it, it's all gone. Nobody uses it anymore. It's old-fashioned. But, but it can be diagnosed based on the triglycerides, total cholesterol and ApoB. There's a formula that we m- that we devised. So we can recognize those people and say, "Hey, you may be 38 years old, but you got a big problem here. And, and with treatment, we can take your big problem away."

   4. PAPeter Attia36:23

      And so the phenotype of that patient is that they have relatively few particles, but they have so much cholesterol because the VLDLs are so large and so cholesterol full.

   5. ASAllan Sniderman36:37

      Yep, that's right

   6. PAPeter Attia36:39

      So what is it, given the relative lack of particles, that makes that such a dangerous condition?

   7. ASAllan Sniderman36:47

      I'm not sure we know really, okay? Uh, there, it- it- it, there, compared to normal, there are 40 or 50 times as many of these particles, but I'm not sure I understand why it's so dangerous in terms of particle number. I do know that it means you can't just use the ApoB when you're trying to make a diagnosis.

   8. PAPeter Attia37:15

      It seems that an analog-

   9. ASAllan Sniderman37:16

      When I fol-

   10. PAPeter Attia37:17

       Uh, go ahead, Alan, sorry.

   11. ASAllan Sniderman37:18

       Yeah. No, when I follow a patient, I really just look at the ApoB, for normal patients that I'm treating with statin. I only have to get one number right.

   12. PAPeter Attia37:30

       It, it seems that those particles are more atherogenic, sort of in the way that an LP little A is more atherogenic. So i- if you did a thought experiment and you said, you know, you take three people who all have the same ApoB concentration, but they could have three very different predicted risks, if one of them has a very, very high LP little A concentration, another one has a normal phenotype, and another one has a type III, as we've just described-

   13. ASAllan Sniderman38:00

       Yeah, yeah

   14. PAPeter Attia38:01

       ... the, the, the first and the third have a much higher risk, suggesting that on a particle per particle basis, they have more atherogenic particles.

   15. ASAllan Sniderman38:11

       Or, or particles that contribute to clinical events, yeah, agree.

   16. PAPeter Attia38:15

       Yeah.

   17. ASAllan Sniderman38:16

       The, for, for, for me and, and, um, for my practice, uh, I measure a lipo pr- a lipid panel, I measure an LP little A in everybody, and I measure ApoB. I measure the LP little A once. When LP little A is high but ApoB is normal, LP little A may not add that much to risk, but when you got two of them, it's a double whammy, and that I use to, as a, another piece of information in trying to frame for the patient the potential futures that they face.

   18. PAPeter Attia38:55

       And so Alan, what is the treatment for the patients that are type IIIs, these patients with, um, many cholesterol-rich VLDLs despite a normal ApoB?

   19. ASAllan Sniderman39:08

       Statins and/or fibrates.

   20. PAPeter Attia39:11

       And the, the f-

   21. ASAllan Sniderman39:12

       And they, they usually respond very well

   22. PAPeter Attia39:14

       And the, and the, the fibrates in that patients, remind me, their triglycerides are normal or elevated?

   23. ASAllan Sniderman39:20

       No, their triglycerides are elevated.

   24. PAPeter Attia39:22

       They're, they're quite elevated. Okay.

   25. ASAllan Sniderman39:23

       They, they, they're VLDL particles, so the triglycerides are elevated.

7. 39:26 – 42:57

   Using apoB to estimate risk of CVD

   1. ASAllan Sniderman39:27

      Um, we made up a, a, a algorithm that's, um, I think it's the W, the ApoB app, ApoB app, where you could plug in the total cholesterol, triglyceride, and ApoB, and you get the diagnosis of any of the atherogenic ApoB dyslipoproteinemias.

   2. PAPeter Attia39:47

      Yeah, that was a fantastic app. I can still use it on my desktop, but for some reason it stopped working on the phone. Does that... Am I the only one to have that issue?

   3. ASAllan Sniderman39:55

      That's right. It stopped working on, on Google and app, but it's on the web.

   4. PAPeter Attia39:59

      Yeah, and remind me, remind everyone-

   5. ASAllan Sniderman40:01

      It's directly available from the-

   6. PAPeter Attia40:02

      Yeah, what's the, what's the URL?

   7. ASAllan Sniderman40:04

      www.apobapp

   8. PAPeter Attia40:07

      .app, right? A-P-P, I think.

   9. ASAllan Sniderman40:11

      No, I think it's just ApoB app-

   10. PAPeter Attia40:13

       Okay

   11. ASAllan Sniderman40:13

       ... will do it.

   12. PAPeter Attia40:14

       I, I saved it in my browser 'cause I remember it was a counterintuitive-

   13. ASAllan Sniderman40:17

       Yeah

   14. PAPeter Attia40:17

       ... place. I just actually relied on it to... I, I looked, I looked something up a month ago on it, so it's a great little-

   15. ASAllan Sniderman40:23

       Yeah

   16. PAPeter Attia40:23

       ... and it, and it walks you through all the diagnostic steps.

   17. ASAllan Sniderman40:26

       It walks you through all those diagnostic steps.

   18. PAPeter Attia40:28

       Yeah.

   19. ASAllan Sniderman40:28

       And, and it, and it... Look, a lot of peop- the part of the argument against, um, ApoB, people say it makes things too complicated. If I explain to a patient that they've got a lot of bad particles, cholesterol particles, they get it. When, when I review the results of how well somebody's doing on statins, if their triglycerides were high to begin with, they're unlikely to normalize. The HDL cholesterol's unlikely to normalize. I, I, so their ApoB is good. They're good. That's my target of therapy, and because it's the total number of, um, uh, uh, of atherogenic particles, and Nordiskard had a lovely paper recently in, uh, uh, was it JAMA Cardiology, uh, on, on a discordance analysis of non-HDL cholesterol and ApoB, and showing that ApoB was a more accurate index on statin treatment than non-HDL cholesterol. It's a lovely paper.

   20. PAPeter Attia41:41

       Yeah, I mean, frankly, I find it much easier to explain to patients what ApoB is than to explain what non-HDL cholesterol is.

   21. ASAllan Sniderman41:51

       I do too. I mean, a non-number is hard to explain. [laughs] Uh, and it's interesting to me that with all the emphasis that so many of the lipid guidelines have put on non-HDL cholesterol, they all still say LDL cholesterol. And the American guidelines clearly state ApoB and non-HDL are better than LDL. But the world is, has remained, and it, uh, it's a phenomenon that I'm, that I don't really understand, how resistant, um, the lipid world has been to change. But I think it's important to understand 'cause we'll understand things like Afghanistan- And the financial crisis in 2008 and a whole series of bad decisions by good people thinking as hard as they could. But when everybody in the room has the same opinion going in, it's a bad way to solve problems.

8. 42:57 – 53:47

   How Mendelian randomization is bolstering the case for ApoB as the superior metric for risk prediction

   1. PAPeter Attia42:58

      Yeah. I mean, are you optimistic? I mean, is this just a, a question of time? I mean, in, in 10 years, will kids in med school be learning about ApoB instead of LDL?

   2. ASAllan Sniderman43:10

      I'm pessimistic. Uh, Europe, the 2019 guidelines were very pro-ApoB. And the, the evidence from Mendelian randomiza- like the newer technologies, Mendelian randomization, they've just been slam dunk for ApoB.

   3. PAPeter Attia43:27

      Let, let's explain that to folks, uh, because I wanna talk about the causality of this, and this might be the perfect way to, to, to actually explain the causality of ApoB in the context of this tool. So can you explain to folks what a Mendelian randomization is? The word... People see this all the time in studies, but I don't, I don't, I don't think it's entirely clear for the average person what it means.

   4. ASAllan Sniderman43:50

      I'll try, okay? It's not my expertise, but I'll try. The, the conventional ways of taking things apart with prospective observational studies like Framingham, there's a, there's a limited amount you can, um, of the certainty of your conclusions because of confounding you can't deal with. You, 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. And so you, your inferences are probable but not causal. What Mendelian randomization allows you to do is to come a lot closer to causality. 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, uh, lump together a bunch of those different genes that can have different makeups 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 in, that's fixed at birth, and you see is that associated with a difference in outcome. Then you're [chuckles] you've gotten rid of a lot of stuff in the middle. And what, what a number of Mendelian randomizations have shown is that ApoB includes all the information in triglycerides, L- LDL cholesterol, and even HDL cholesterol. It sums them, which in the sense of VLDL and LDL makes perfect sense. So this is a very high... It, it's a, there's a, there are caveats in Mendelian randomization. You, you can't just push a button and say, "Give me the answer." Um, but George Davey Smith, uh, really arguably one of the founders of Mendelian randomization, or not arguably-

   5. PAPeter Attia46:20

      Yes

   6. ASAllan Sniderman46:20

      ... he was. He's the author of a number of the Mendelian randomization saying ApoB incorporates and therefore beats triglycerides and LDL cholesterol. So that's a huge level of information that isn't even mentioned in almost any of the guidelines.

   7. PAPeter Attia46:47

      Yeah. So let's, let's make sure people understand everything you just said, 'cause 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 LDL-C or whatever metric it is that you are trying to determine, um, 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 LDL-C, higher non, uh, HDL-C, and lower HDL-C all have a higher risk of developing atherosclerosis 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, 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. And therefore, if we-

   8. ASAllan Sniderman48:44

      That's right.

   9. PAPeter Attia48:45

      Yeah

   10. ASAllan Sniderman48:46

       No, no, go ahead. You're doing, you're doing much better than I am

   11. PAPeter Attia48:48

       Yeah. So, I mean, I think 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, there's some pretty big ones.

   12. ASAllan Sniderman49:10

       Yeah. Before we get there, HDL cholesterol was the rage, okay? The total rage because the epidemiological evidence couldn't be clearer.

   13. PAPeter Attia49:22

       In fact, it was four times more clear. My recollection was that Framingham demonstrated low HDL-C was four times more predictive of cardiac events than high LDL-C. Am I, am I remembering that correctly?

   14. ASAllan Sniderman49:38

       Oh, y- y- y- y... I, I'm not sure it's that multi- Yeah, but it's, it's multiples. And, and it turns out, as we know now, at least from the CETP 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 they show ApoB is.

   15. PAPeter Attia50:05

       Those are two very important studies, Allan. I mean, th- and both of those have been in the last 10 years.

   16. ASAllan Sniderman50:12

       Yeah. And, and it, it's, it's, um, a incredibly technical advance in being able to examine questions that... And look at numbers of people that are, would be unimaginable in conventional studies. The Mendelian random, they're always talking hundreds of thousands of people because they've got these huge data banks with genes and, and those numbers get you around the confounding of things. You have huge numbers, so you get... But it's like any methodology, uh, no method is perfect, and this one can mislead you, too, when you've got, particularly when you've got a sequence of associated variables. For example, people showed using MR that triglycerides were, quote, "causal" or associated with increased risk. But when you took into account the non-HDL cholesterol or the ApoB, it 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 dra- persona dramatis.

   17. PAPeter Attia51:34

       Which is why it's surprising that HDL didn't, at least at the first order, demonstrate causality because there's-

   18. ASAllan Sniderman51:42

       Yeah

   19. PAPeter Attia51:42

       ... no doubt that phenotypically, the high triglyceride-

   20. ASAllan Sniderman51:46

       Right

   21. PAPeter Attia51:46

       ... low HDL phenotype is so associated with metabolic syndrome that it makes up two of the five criteria.

   22. ASAllan Sniderman51:55

       That's an incomplete description.

   23. PAPeter Attia51:58

       Sure.

   24. ASAllan Sniderman51:58

       Okay? That's like you describing yourself as six feet tall-

   25. PAPeter Attia52:06

       I wish

   26. ASAllan Sniderman52:07

       ... I wish, okay, and, uh, and, uh, and not giving your weight and, and letting me guess your BMI. You cannot characterize any phenotype without the ApoB. It really drives me around the bend.

   27. PAPeter Attia52:23

       [laughs]

   28. ASAllan Sniderman52:26

       [laughs] And I, and I mustn't go around the bend on your podcast. When people speak saying, "I got somebody because I got their triglycerides and their HDL," well, I say, "Okay, what's their ApoB?" How, how can you pretend you've evaluated the system when you haven't counted the number of atherogenic particles? Because they could be normal, they could be high, or you could have a type III. They don't know, and it's not a phenotype. There is no phenotype without putting an ApoB in there because they're lipoprotein particles. They're disorders of lipoprotein particle metabolism. Of course, the triglycerides and cholesterol are important. But my analogy, I didn't do a good analogy there [laughs] but it, it's so fundamental, uh, that it, it, it drives me to distraction as to why you wouldn't want to know a core element of knowledge. And, um, but it doesn't seem to bother many of my friends.

9. 53:47 – 1:05:49

   Hypertension and CVD risk

   1. PAPeter Attia53:48

      So let's talk about another way that people try to stratify risk. Um, actually, no. Before I do that, I want to go a step backwards and talk about something else that you've alluded to, which is y- you walked through the, the, 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 atherosclerosis than ApoB, or is that not the case?

   2. ASAllan Sniderman54:38

      Well, it, 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- no question. But then you say, "What is hypertension?" Now, 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 anymore, but the basic science goes on in rats. Uh, it just is 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 is hyper- what is hypertension? It's a higher blood pressure than we should have, and where is the disease that produces that higher blood pressure?

   3. PAPeter Attia55:58

      I, I don't think we-

   4. ASAllan Sniderman55:59

      Is it, is it resistance?

   5. PAPeter Attia55:59

      I don't think we know. I mean-

   6. ASAllan Sniderman56:00

      We don't have a clue.

   7. PAPeter Attia56:02

      Yeah.

   8. ASAllan Sniderman56:02

      Okay? We don't have a clue, and, and, and, and, and it strikes me it's the same thing as much of the debate in lipids about ApoB or the, the, the, the drunk looking for the key under the light because, like, this is where the light is, not where he lost it. There's a... The, the-- everybody who's anybody has the same viewpoint. My bet is it's in the proximal aorta. My bet is that it's, it isn't that complicated. We lose elastance in the proximal aorta, and that's systolic hypertension. Thank you very much. And, and what could, what could accelerate that process, okay?

   9. PAPeter Attia56:45

      By the way, what's the m- what's the mainstream view, that this is renal?

   10. ASAllan Sniderman56:49

       Well, I'm not su-- it, it-- when I read hypertension, I get lost because I, I get page after page after page of, uh, peripheral arteriolar tone and very complex metabolic studies and very sophisticated animal models. Uh, so there's some renal left. Uh, it, it's a miasma for me, an absolute miasma.

   11. PAPeter Attia57:17

       I hadn't heard about the proximal aorta, so, so say a bit more about that. What would... I mean, what's-

   12. ASAllan Sniderman57:22

       Well, this is me.

   13. PAPeter Attia57:23

       Okay. Well-

   14. ASAllan Sniderman57:24

       This is just what I think, okay?

   15. PAPeter Attia57:26

       Ta- say more.

   16. ASAllan Sniderman57:28

       The, the proximal aorta is the, is, is elastic, so that... And, and, and if you look at a, at a flow curve, a hydrostatic pressure curve, when we're young, it, it, it's rounded because as the left ventricle ejects blood rapidly into the aorta, the aorta expands, so it absorbs some of that energy. And then you get, you know that wind kessel that they mentioned in school? It's not that big a deal, but the energy is, is partially captured, partially regained, but the wall isn't battered. The wall can give way. I, me personally, just in the middle of my brain, imagine that i- if those elastic fibers start to go, then the walls stiff. So now when the left ventricle ejects blood, the pressure goes up more rapidly, and it falls more rapidly in diastole, and that's why you get systolic hypertension with normal diastolic pressures. So my bet would be, if I was not the age I am, 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 aorta 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.

   17. PAPeter Attia59:13

       And so you think it's, it's this, it's the, it's the actual increase in the pressure of the plasma-

   18. ASAllan Sniderman59:20

       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.

   19. PAPeter Attia59:27

       Does it also damage the endothelium? Do you think that plays a role that makes it-

   20. ASAllan Sniderman59:30

       Well, that's right, but I, I just... 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, but I-- and I know it, it gets-- it functions abnormally, and that's endothelial dysfunction. How that fits into the overall thing, I don't know. I, I-- my bet is ApoB particles are part of the process of inducing endothelial dysfunction, but I don't know that clearly experimentally.

   21. PAPeter Attia1:00:02

       So, so going back then to the question at the top, h- does it make sense to even compare hypertension to ApoB? They both seem to play a causal role. Um, is one more causal than the other, or is that a silly question because they're not binary and static?

   22. ASAllan Sniderman1:00:22

       I think that's not the right question. I think that... Like, our blood pressure goes up as we age. I mean, hypertension involves so much of the population, it's not clear to me what the word disease means. The, the prevalence as we age is so high that, that to me it, it's, 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 aorta and it, it gets a little progressively less able to deal with it. And then so by the time we're 50, what percent, 60% have higher blood pressure? I mean, the figures are staggering.

   23. PAPeter Attia1:01:12

       Is it really that high? So if we're, if we're gonna use-

   24. ASAllan Sniderman1:01:14

       I'm not sure

   25. PAPeter Attia1:01:14

       ... if we're gonna-

   26. ASAllan Sniderman1:01:15

       Don't, don't quote me on that.

   27. PAPeter Attia1:01:16

       Okay.

   28. ASAllan Sniderman1:01:16

       But it, but it's high, high, high. It's high, high, high.

   29. PAPeter Attia1:01:20

       But doesn't ApoB also rise with age?

   30. ASAllan Sniderman1:01:23

       A, a bit. It does rise with age, uh, but not that much. When we, when we look at people at age, uh, 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 got about a 95% chance of staying high. 5% will go u- out of the high zone. They won't go low, low, okay? So if you're high at age 35, hmm, I wouldn't bet anything's gonna move you down [laughs] . That's why I think it's such a good signal for when we should start thinking about treating people, 'cause it's, it's... And if you're low, some people go from low towards high, but, but it's, but the majority don't, and we keep following them. But if you're high, no, we've published a, a fair amount on this. If you're high, it's not 100%, but it's about 90% that you're gonna be high.
10. 1:05:49 – 1:11:37

    Factors influencing the decision to begin preventative intervention for CVD

    1. PAPeter Attia1:05:50

       So let's talk about smoking for a second. Do you have a sense, I know it's, again, not the thing that you study day and night, but what is it about smoking that drives risk of atherosclerosis so much?

    2. ASAllan Sniderman1:06:03

       Truth is, I don't know. Uh, it certainly does. Um, and it, and it drives the treatment decision. Now, I think, I think smokers are wonderful human beings who deserve to be treated as human beings, but I, but I don't think that if you choose to continue smoking, that should prioritize you for statin treatment, whereas based on my concern about people who have high ApoB levels, they should be treated because of their longer term risk. Well, you know, smoking gets you up the category to have your life saved, so bad behavior gets you closer to having your life saved.

    3. PAPeter Attia1:06:44

       Is that a Canadian thing?

    4. ASAllan Sniderman1:06:45

       I don't think it's... No, it's an American thing. It's in your, it's in your risk calculator. If you're a smoker, your risk goes up.

    5. PAPeter Attia1:06:51

       Oh, I see what you're saying. Not based on-

    6. ASAllan Sniderman1:06:53

       Okay

    7. PAPeter Attia1:06:53

       ... a coverage issue, but simply based on-

    8. ASAllan Sniderman1:06:56

       No, no, no, no, no

    9. PAPeter Attia1:06:56

       ... a change in prioritization. I see.

    10. ASAllan Sniderman1:06:58

        That's right.

    11. PAPeter Attia1:06:59

        Yeah.

    12. ASAllan Sniderman1:06:59

        Because everything is risk Bad behavior indu- increases risk, so you get more medical attention. Now, I think bad behavior is our responsibility to help people deal with, but I don't think it should put you to the head of the line for preventive therapy.

    13. PAPeter Attia1:07:19

        I mean, I would argue there is no line. Anybody who wants preventative therapy should be getting it, right? Is there, is there... I, I don't view it as a... Are we resource limited on that front?

    14. ASAllan Sniderman1:07:29

        No, but what we... But we're, we're, we're, we're not using the-- We're not giving patients the information that they deserve. We pa- we published a paper in circulation, I think it's 2019, which I referred to before, looking at what are the costs of delay of intervention starting at age 35, 45, and-

    15. PAPeter Attia1:07:50

        Mm-hmm

    16. ASAllan Sniderman1:07:50

        ... 55. And, and if your non-HDL is low, y- yes, you'll get some gains starting at 35, but it's not a lot. It's actually quite small. Your gain is in the people with a high non-HDL. [laughs] So we don't have to be giving pills to everybody at the age of 35. If we use our physiological and epidemiological knowledge, there's, there's, uh, a- about 20% of the population is, is at demand-- is at evident high risk, and they should consider it. And part of the information they need to know is, how much do I gain now? How much is gained now versus how much is lost by waiting? And that's, that, that's why these methodologies of calculating benefit are so important.

    17. PAPeter Attia1:08:51

        Do you have a sense, Allan, of what fraction of the population has relatively normal ApoB, relatively normal triglycerides, and yet has accelerated atherosclerosis through some combination of yet to be identified polygenic risk factors? So you see atherosclerosis that runs in families, and they, they-- there's not an obvious cause, right? They don't have FH.

    18. ASAllan Sniderman1:09:20

        Right.

    19. PAPeter Attia1:09:20

        They don't have Lp little a, and frankly, their ApoB is harboring around the 20th or f- sort of call it the 50th percentile of the population.

    20. ASAllan Sniderman1:09:27

        Yeah.

    21. PAPeter Attia1:09:27

        But they disproportionately, uh, get afflicted young. So they're all having first events before 60.

    22. ASAllan Sniderman1:09:35

        And I, and I think... I don't know. I think that's where, that's where research needs to be done, and I would look at factors that affect the trapping of the ApoB particle within the arterial wall. I think Kevin, John Williams from, uh, from Philadelphia, they've done an amazing job, amazing job in putting this all together.

    23. PAPeter Attia1:09:56

        And wouldn't that factor into our decision-making then? I mean, would we-- if we, if we had two people that had the-- who were both, say, 40, and they both had the same-- let's just say they were identical in terms of lipids and lipoproteins. They both had the same blood pressure. They birth-- they were both not smokers, et cetera, but one had that family history, the other did not. Are you treating them different?

    24. ASAllan Sniderman1:10:19

        Pro-- I would, I would-- It would factor into my decision, okay? Um, if, if the ApoB is actually low, I'd be less inclined to let it influence me.

    25. PAPeter Attia1:10:32

        Let's say they're both at the 50th percentile.

    26. ASAllan Sniderman1:10:35

        If they're, if they're 50, 60th percentile, I'd get-- that makes me more antsy, okay? The higher they are, the more antsy I get. And a lot of these decisions at the individual level actually aren't that difficult when you're speaking to a particular patient because they have their own objectives and goals. And we gi- if we give people medications, our medications have risks associated with them. I don't think we fully understand the relationship with statins and diabetes. Uh, we just-- I don't think we do. Um, so statin therapy is, like, amazing, but it's not a no cost. Um, so but when you talk to a individual human being, it, it, at least at this stage of my career, it's been easier to make clinical decisions individually than to write rules for groups.

    27. PAPeter Attia1:11:35

        Yeah. And, and there's no question about

11. 1:11:37 – 1:23:27

    Using the coronary artery calcium (CAC) score as a predictive tool

    1. PAPeter Attia1:11:37

       that. Um, let's now look at yet another predictive tool, um, which is the coronary artery calcium score. So, um, maybe tell folks what, what a CAC is. Uh, I suspect a number of people listening to this will have had it, but enough will not have, so it's worth explaining what the test is.

    2. ASAllan Sniderman1:12:00

       Coronary calcium is a, uh, an important step forward in cardiovascular imaging, and it's a process where you can accurately and, and pretty safely determine using X-ray techniques whether there's calcium, bone in the coronary arteries. And calcification is part, is a feature of advanced atherosclerosis. And so there are-- there's very strong evidence that people who have coronary calcification are at higher risk, uh, of a heart attack or stroke than people who do not have coronary calcification. And, and that's a, that's an important piece of information But there's several, uh, a- facts you also have to appreciate. First, the, the frequency of a positive coronary calcium goes up as we age, and so does the risk of disease. [laughs] So by the time a man is 60, all American men are at high risk according to your current guidelines. Women are five to 10 years later. So at the point where the test is most commonly positive, I don't even need it because that person... We were talking a while back about the natural history and stary and stuff, that stuff is for real, [laughs] okay? Um, our arteries in, uh, the majority of us have become substantially transformed in bad ways by the time we're 60. Now, in people who are younger than 60, can this give you extra information if you're on the cusp of saying should you be treated or not? And I think the answer is yes. If you or the patient says, "I want more information, I'm not convinced that I personally am in a situation where I should be taking medications," a- and you have a positive coronary calcium, I think that can be extremely helpful. It's the, it's, it's what's taken as the corollary that if your coronary calcium is negative, you're okay, and that's the problem. For me, from my knowledge and interpretation of literature and the pathological studies, coronary calcification is a advanced si- disease, means advanced disease is present. When people have a heart attack, they don't just have one little area of their arteries that are abnormal, m- that's the area where the plaque broke or the endothelium eroded. But the, the artery's diseased and, and there, there's a chance of an event a sonometer down or a sonometer closer. So if somebody has a high ApoB, the fact that their coronary calcium is negative doesn't mean they don't have a lot of disease and that the disease isn't developing at a rapid rate, it could well be there. So there's an argument saying, "Well, if your coronary calcium is negative, nothing's gonna happen to you in the next five or 10 years," and, uh, maybe, but the disease is gonna develop and we can't make the disease go away. We can modify the effects of the disease, modify the consequences. But when we talk about... I mean, LDL cholesterol and ApoB levels are now so low, th- but, but you still have an artery that's destroyed. You're going to have a substantial number of events. And there's a paper Do- John Wilkins and Don Lloyd-Jones from, uh, Northwestern, they have a paper in JAHA and it's a, it's a terrible paper to read, but because it's so complicated and I wish they hadn't presented it in as complex a form as they did. They're friends of mine, so I can criticize them. But within it are the observations that starting to treat waiting for a coronary calcium is a bad idea. So I'm a conservative physician. That may not be my politics, but as, in that I want to protect patients, give them the option, because it's the patient's choice, of course it is, give them the option to have the best outcome possible when it's, they appear to be in danger. So I wouldn't use a negative coronary calcium to change my clinical decision when I have a high ApoB or another cause of vascular disease present. So I think it's a good test, but relatively limited utility for me.

    3. PAPeter Attia1:17:59

       Yeah, I, I, the way I've sort of talked about it, maybe even on the podcast, but certainly the way I talk about it with patients every day it would seem, is I, I describe it as a two-by-two matrix. Um, so we think about how this test is helpful in people who are young and people who are old. Now, I usually use 50 as the cutoff. It sounds like you use 60 as the over-under, but let's just say it's somewhere in that sixth decade. And then is it zero or is it non-zero? Um, and I, and I, I, I, I agree with what I'm hearing as your assessment, which is in the older patient, the positive score is not very informative. So when I have a 70-year-old patient whose calcium score is 50, it's sort of like, so what? Like, you're, you're normal. It, that doesn't tell me much. Um, and conversely, when I have, uh, an older patient whose score is zero and they're adamant about not getting treatment, it becomes an easier um, decision to accept because you can say, "Well, gosh, you're pretty fortunate to be 73 years old, and despite having an ApoB of, you know, 140 milligrams per deciliter, your, your, your, your calcium score is zero. There must be some other protective mechanisms in you."

    4. ASAllan Sniderman1:19:28

       Yeah. Our, our, the, the bounds of our knowledge are really quite limited.

    5. PAPeter Attia1:19:33

       Yeah.

    6. ASAllan Sniderman1:19:33

       And it's important that we admit that to ourselves as, and, and to our patients as well. Uh, I, I look at it maybe a bit differently. I say, "Yes, I would say the same thing," and I would say, "Yeah, but even so..."

    7. PAPeter Attia1:19:49

       Well, yes. Uh, to me, there's an asymmetry, which I want to come to in a moment. On the flip side of things, the young patient who has a positive calcium score, really that's a four-alarm fire-

    8. ASAllan Sniderman1:20:02

       That's a no-brainer

    9. PAPeter Attia1:20:02

       ... regardless of the ApoB, right?

    10. ASAllan Sniderman1:20:04

        Yeah.

    11. PAPeter Attia1:20:04

        So if you're-

    12. ASAllan Sniderman1:20:04

        Yeah

    13. PAPeter Attia1:20:05

        ... if you're under 50 and you have a speck of calcium in your coronary arteries-

    14. ASAllan Sniderman1:20:10

        Yeah

    15. PAPeter Attia1:20:10

        ... even if it's a low enough speck that it would predict a 10-year risk of 4%, that's still utterly unacceptable.

    16. ASAllan Sniderman1:20:19

        Oh, no. Y- y- if, if, if it's, if it's positive, it's positive, and it m- it's gonna, it's only gonna go up.

    17. PAPeter Attia1:20:29

        E- e- exactly.

    18. ASAllan Sniderman1:20:29

        You know that.

    19. PAPeter Attia1:20:30

        And, and more to your point, it's what it says about the milieu of the entire system. So-

    20. ASAllan Sniderman1:20:37

        Yeah

    21. PAPeter Attia1:20:37

        ... that might be the one area in the middle of your left anterior descending artery where you're at such an advanced stage that you've already laid calcium there. Um, but y- you know, it, it's sort of like looking at the concrete that's been poured over Chernobyl and trying to infer what's going on in the 10 miles around Chernobyl. It's, it's all bad.

    22. ASAllan Sniderman1:21:02

        Yeah. Yeah. That's correct.

    23. PAPeter Attia1:21:04

        Where I find the most challenge is in the, the, there's, there's the, there's the groupthink that says if a person's calcium score is zero, no treatment is needed. Um, and this kind of gets back to your, your paper from JAMA, I think, 2018, maybe 2017, looking at the, the 30-year risk, the causal model, which I want to come back to. You, you mentioned it very briefly at the outset, but it's so important that I want to now use this as a, as a jumping point to go, to go there, which is you take that 45-year-old person who you expect their calcium score to be zero. It is zero, but their ApoB is higher than it should be or you would like it to be. The calcium score of zero hasn't really added much information to my decision-making.

    24. ASAllan Sniderman1:21:57

        No, 'cause your time horizon is different. And, and I, and I think that that's what w- in those studies are we, we use 20, 30 years, okay? I think the 10-year... If you're 45, you want to get to further than 55. Your, your career, your children, your, your, uh, enjoyment of things, surely you're not just planning to age 55. And you should be thinking, "Well, what am I gonna be like at 65 or 75?" That's reasonable. A- and it's also by taking it out to that, you can get to numbers that are really meaningful. When somebody's at a 30% chance, like one in three, that's a, that's a number most people can understand, and it starts to become a truly individually meaningful, a meaningful number for an individual. When somebody's at 7.8% risk, I, you know, that's, that's, that's tough to absorb i- in a, in a, in any way that means something. So when you're in one of these higher risk groups, it doesn't mean you're doomed, but you're in company with [chuckles] a lot of folks who are, and, and we can say that absolutely accurately. And yes, it's limited. It may not be you. M-

12. 1:23:27 – 1:26:30

    The challenge of motivating individuals to take early interventions

    1. ASAllan Sniderman1:23:27

       m- make your bet.

    2. PAPeter Attia1:23:28

       But, but, uh, you know, it's funny, Alan, I would, I would even... I, I'm, I'm maybe a bit more of a, of a... What's the word? I, I might even be more risk-afraid. So y- you're saying that if a person's 10-year risk is 5%, how can you get somebody excited about a 5% event in the next decade if somebody's 50? So somebody's 50, and you say, "You've got a 5% event risk by 60," and you're saying, "Well, the two things that are wrong with that are, one, you shouldn't just be thinking about being 60. You should be thinking about being 80," which I completely agree with.

    3. ASAllan Sniderman1:24:06

       Yeah.

    4. PAPeter Attia1:24:07

       You, we expect you to live a minimum of 30 more years, if not more. Um, and secondly, you're saying, "Well, 5%'s not that much to get excited about." Well, let me, let me turn the table. I want you to pretend you're 50, Alan, and I say to you, "Alan, there is a 5% chance that in the next decade you will die on a commercial plane." How would you change your behavior as a result of that?

    5. ASAllan Sniderman1:24:33

       Don't think I would.

    6. PAPeter Attia1:24:34

       You wouldn't stop flying?

    7. ASAllan Sniderman1:24:35

       I don't know. No, because there's a 95% chance I won't.

    8. PAPeter Attia1:24:40

       Okay. So I, I mean, I think 5% is a bigger risk than people realize, and, and-

    9. ASAllan Sniderman1:24:46

       No, no, I, I, I get it. It's, it's bigger than one in a thousand, okay?

    10. PAPeter Attia1:24:50

        W- well, not only that-

    11. ASAllan Sniderman1:24:51

        But-

    12. PAPeter Attia1:24:51

        ... in the, in the case that I just gave you, the treatment would be don't fly for 10 years, which is a real impediment to your lifestyle-

    13. ASAllan Sniderman1:25:01

        Yeah

    14. PAPeter Attia1:25:01

        ... versus the treatment to lower lipids, which is far less of a burden, and the risks-

    15. ASAllan Sniderman1:25:10

        Okay. Let me come back to you

    16. PAPeter Attia1:25:10

        ... of it can be combated. Yeah.

    17. ASAllan Sniderman1:25:12

        Let me come back to you. What are the confidence intervals on that number of 5%?

    18. PAPeter Attia1:25:19

        Well, that's a good question.

    19. ASAllan Sniderman1:25:21

        Excuse me?

    20. PAPeter Attia1:25:21

        Yeah. No, that's a good question.

    21. ASAllan Sniderman1:25:23

        It is. Excuse me? Excuse me?

    22. PAPeter Attia1:25:24

        Yeah. I'm gonna s- let's, let's say I can tell you it's plus or minus 2%.

    23. ASAllan Sniderman1:25:28

        How do you tell me that? Where's that number? Have you ever seen that number?

    24. PAPeter Attia1:25:33

        At the population level. Let's pretend I'm able to tell you that at the population level.

    25. ASAllan Sniderman1:25:36

        No. No. You've never seen it. I've never seen it.

    26. PAPeter Attia1:25:40

        Well, well we can't do it at the individual level, of course.

    27. ASAllan Sniderman1:25:42

        No, no, no, no, no. I'm saying, what are the confidence intervals for that prediction? Have you ever seen them published? And the answer is nope. Okay? And, and as ... I'm not sure how much of your audience does confidence intervals and this kind of thing, but as scientists, for any result, we get the result, and we get the range of possible results. Then we know how accurate the prediction is. If the confidence, let's say it's 5%, the confidence interval is 4.5 to 5.5, well, you're there. If the confidence interval is zero to 70, [laughs] which it, it could be, by the way,

13. 1:26:30 – 1:33:24

    How medical advancement is hindered by the lack of critical thinking once a “consensus” is reached

    1. ASAllan Sniderman1:26:30

       maybe it isn't. So I'm saying we got an industry that captured clinical care that doesn't include error.

    2. PAPeter Attia1:26:40

       Well, why is that? That seems, now that you mention it, a- almost impossible to believe.

    3. ASAllan Sniderman1:26:45

       Well, it, but I, but I [laughs] it's true. Please, please reassure your audience I'm telling the truth. [laughs] Because we've become less critical. This, this process of forming opinion in, in, in medical care that's, that's, that's, that's, that's appeared over the last 30 or 40 years, has damped down the essential element of science, which is challenge, different viewpoints, um, the contention of ideas, the, the creation of an experiment to say, "This is the right way," or the, the ser- someone with a different view creates a different experiment. Science is a democratic activity, where differing views that are legitimate have, have a chance to contend. I'm not saying every crazy theory has equal... It doesn't.

    4. PAPeter Attia1:27:46

       Well, so, so, so that's exactly what I was going to come back and ask you, Allan, is who is the arbitrator of what's a legitimate differing hypothesis?

    5. ASAllan Sniderman1:27:54

       In science, it's called the experiment. That's what's different about science. An experiment is done to test a hypothesis. If the hypothesis is sustained, you can continue to hold the hypothesis. If the hypothesis falls, then you must reframe your understanding. And we do experiments to gain understanding. It's our tool. But it's not as easy as it sounds. The methods could become complicated. The methods we use to analyze them statistically can become complicate- are complicated. And the conclusions we draw from them may or may not be correct. Error is- occurs. When I was a medical student, the major medical meeting of the year was at Atlantic City, and the big professors would contend, the elephants, you know. And there were different views, and they would argue them out, and it was a contentious, open battle. Evidence-based medicine came along, which has lots of pluses, in which it says, you know, we should use randomized clinical trials as part of our knowledge base. But we developed the belief that it was easy to assess knowledge, and it's not. It's not easy to assess experiments all the time. Some of them are straightforward. Most of them actually aren't. Most of them, there's uncertainty involved, and it's important that we acknowledge the uncertainty and say, "Well, maybe there's another way of looking at this that's even better." But we developed tools like statins that we bel- that we ... There's very good evidence can save lives. So this process of consensus came along saying, "Look, it, this is too complicated for regular doctors." And it is. They don't have the time to analyze all the evidence. So we'll analyze the evidence for them and write it out in a way that tells them what's the best we can do now. And, and th- and there's a lot of good in that, but there's potential weakness, and I think where a lot of the weakness is happening. Because you get a view that becomes the conventional view, and it hangs on longer than it should. Science is about change. If we're still saying the same things we said 30 years ago, eh, could be a problem, because we should have learned how to say it better, more accurately. And a consensus, it, it, you could get... In these consensus conferences, I don't know if your li- listeners appreciate, the recommendations are unanimous. The Supreme Court isn't unanimous often. There's a majority view. The minority says this, that, and the other thing. And it can turn out that the minority, over time we see the wisdom in the minority Any process that has unanimous recommendations has a weakness. Any process where the decisions become larger than the individuals who, who propose them has a weakness. Like the recommendations are the American College of Cardiology, American Heart Association, blah, blah, and about 30 other groups. They're actually 100 people. You know? They're good people, but there's only whatever number it is, 100 of them. But by cloaking it in the, the na- the anonymity of the group, they become impervious to criticism even when there's obvious inadequacies, and that's not science. If, if you write a paper, I could do an experiment and try and overturn your paper or confirm it. But when you have the guidelines, they're the judgment that's cast in stone till the next group of guidelines. And, and depending on which people write them, it, it can influence what you see.

    6. PAPeter Attia1:32:44

       I mean, I, I, I, I, I completely agree with that. Um, I would add even more complexity to it, which is if you go through what the critical steps are in the elucidation of knowledge, the first presumably would be the formation of a hypothesis. The second might be designing an experiment to test that hypothesis, then conducting that experiment, analyzing the results of that experiment, and interpreting it. Again, I'm oversimplifying a little bit, but these are quite discrete steps, and as you pointed out, any one of these steps offers infinite ways to do it wrong and a relatively few rate ways to

14. 1:33:24 – 1:39:49

    PSK9 inhibitors and familial hypercholesterolemia: two examples of complex topics with differing interpretations of the science

    1. PAPeter Attia1:33:24

       do it right. I'll give you an example that's near and dear to both of our hearts. So just yesterday, I was having an email debate with a friend. Um, I forget what spawned it. Oh, he, he had sent me an article about, um, something lipid-related, and it somehow led to a discussion about the, the FOURIER trial, um, which for listeners is the trial that looked at one of the two PCSK9 inhibitors, uh, this was Repatha, and it demonstrated that on patients who were on a very low l- or on a very high level of statins and had a very low LDL-C, I think their average LDL-C was in the neighborhood of 70 milligrams per deciliter, over a five-year period, they had a reduction in cardiac revascularization but no change in mortality. His... Am, am I getting that right? I think that's the gist of the FOURIER trial as it was first published. Um, his point was how can these drugs be, you know, tolerated? How, how is it that we live in a society where insurance companies are paying for these drugs, or people are using these drugs, and doctors are prescribing these drugs where they didn't even demonstrate a reduction in mortality? All they demonstrated was a reduction in revascularization. I can't remember if there was a redu- a reduction in events, uh, 'cause I sometimes confuse ODYSSEY and FOURIER. Um, to which I said, "Well, it's really interesting, um, because the time course of that disease was, or the time course of that study was so short in a group of patients who were already so heavily statinized that it's my interpretation of that study when it came out, which is probably six years ago, it's actually a miracle it showed anything at all. Because if these patients are walking around with an LDL-C that's at the fifth percentile of the population, and then you give them another agent that lowers LDL-C to, you know, the first percentile of the population, and we're talking about a disease that takes at least four decades to take hold, and you study them for just five years, would you really expect to see an event difference? Which by the way, you did see in ODYSSEY probably because using a very similar drug, those patients were started out at a higher level of LDL-C, so you saw potentially a greater risk reduction. So here you could have two relatively smart people looking at the same presumably well-done experiment with the same reasonably legitimate statistics, but we have a different lens for what the disease is and therefore draw a completely different conclusion. Is your point that no consensus can ever basically resolve that, and the way that medicine has to progress is that each of us needs to progress o- on the basis of our own understanding? Or, or how would you sort of referee the debate between my friend and I?

    2. ASAllan Sniderman1:36:23

       The, I, I, I think w- we can only understand as individuals. There is no such thing as a group understanding. We, we, we can't get beyond ourselves really. [laughs] It's, it's not, it's not possible. And when you talk about thinking, I can't think about every issue that's out there that's important, either in medicine or my car or, uh, my woodworking. I have to delegate a lot. I'm writing a paper now about, uh, familial hypercholesterolemia, and there's a study that's, that's the core study for, um, demonstrating that the patients with familial hypercholesterolemia in whom you can demonstrate a genetic abnormality are at much, much, much, much higher risk than people with similar LDL cholesterols but without the genetic abnormality.

    3. PAPeter Attia1:37:31

       Hmm.

    4. ASAllan Sniderman1:37:33

       Now, that study's been accepted by everybody as being well done and decisive. And, um, and I mean by everybody, everybody

    5. PAPeter Attia1:37:45

       Just to make sure I understand what you said, you can have two patients who are phenotypically identical, but the one who has the genetic abnormality of FH, which is simply a phenotypic disease, by the way. It's not a genetic... It's a, it's a... The disease is defined by the phenotype. You're saying they carry a residual r- risk that's not present in the wild type.

    6. ASAllan Sniderman1:38:09

       That's correct. Three to five times that risk. 300%.

    7. PAPeter Attia1:38:13

       That's, that's unbelievable.

    8. ASAllan Sniderman1:38:16

       So what? I thought so, too. And so I, I read the study, and I read it again, and I reread it because I kept... I, I couldn't understand it. So I... Then it dawned on me after a lot of rereadings, I think they made a mistake in their methodology. I think they made a, a, a grade school error. Now, maybe I'm wrong, okay? 'Cause I'm writing this up. I'll subject it to, uh, review and criticism, and I'm... Given that I'm saying every authority in the field is wrong, uh, chances of coming out on positive in this are pretty slim. But, but, but the error in the methodology that I think is present is so simple, it's decisive. And, and I'm just putting... Maybe I'm wrong, but my bet is I'm actually right, uh, is that thinking is damn difficult, and we have to continue to think and discuss with ourselves. HDL cholesterol, everybody believed it till they didn't, okay? [laughs] I mean, how many dissenters were there until everybody said it was obvious there was nothing there? And we're human beings. We, we, we search for validation, but science isn't about that. It... Real science.

15. 1:39:49 – 1:46:07

    Defining risk and uncertainty in the guidelines

    1. ASAllan Sniderman1:39:50

       And, and it turns out that real science-- the world is a very s- slippery thing to get your mind around. I, I gave the example at the beginning of this talk about risk. Now, if I said... If I asked you what risk was, I wouldn't do that to you, 'cause you're the, you're the boss of this podcast. Uh, but risk is the number of events per standard number of people over a defined period of time. We leave out the standard number of people. When we say your risk is 5%, we say, "Well, that's one in 20." Well, it's per standard group of people. That's why I said risk is low if you're under 60. The number of events per 100 people is low, but the number of 100 people is a lot larger than over 60. That's why the absolute number of events is so high. So a difference of words, tremendous difference in action, because it means I don't use the 10-year risk model, okay? And even though that has been published, and even though that has been reproduced by other investigators, that has not changed the guidelines, and that's wrong. When I look at the guidelines, and I have enormous respect for people who serve on them, I can look at the literature on an issue, I can tell you who wrote the guideline. Uh, there was a recent guideline from Europe that was negative about ApoB. One paper cited. One paper, and that became the guideline. So I'm not talking about throwing out the process. The process of reviewing knowledge in a group is positive. I'm saying that we better watch out for the process, and we, we need to do much more to ensure that the process includes a multiplicity of views, so we don't wind up with bad decisions. And if you don't think we can't make bad decisions, just look at all the bad decisions the politicians and the business guys make. We're no different.

    2. PAPeter Attia1:42:35

       So if you did what you're suggesting, Allan, if you brought in a more heterogeneous group of views and greater diversity of priors, by definition, you could probably never arrive at a unanimous decision.

    3. ASAllan Sniderman1:42:53

       So what's wrong with that?

    4. PAPeter Attia1:42:54

       Nothing's wrong with that. My question is-

    5. ASAllan Sniderman1:42:55

       Well, is everything right with that?

    6. PAPeter Attia1:42:57

       Yeah, exactly. My question is-

    7. ASAllan Sniderman1:42:59

       I mean, how long- Yep

    8. PAPeter Attia1:43:00

       ... what does the guideline look like? So now let's take it back to the doctor who has to see 40 patients in a day, will never listen to this podcast, let alone read the show notes of this podcast, which are probably gonna be 150 pages of the backup of everything we've talked about and every citing that-- every study that's been cited, et cetera, et cetera. They literally just want to know what to do in the moment with the person sitting in front of them, and currently, they look to the guidelines, which are unanimous, expert run And, you know, revised often enough that it gives you the feeling that, hey, they're keeping up with the science, right? Every five to 10 years, I'll get a new one of these. Now it's going to be this complicated legal document that's like reading the dissents and reading the in favors and how would they – well, I mean, again, I'm not saying that we shouldn't be doing this, but how does it translate to the, uh, to the field?

    9. ASAllan Sniderman1:44:02

       How do the guidelines read now?

    10. PAPeter Attia1:44:03

        Oh, they're pretty miserable. No, no mistake about it.

    11. ASAllan Sniderman1:44:06

        They're, they're not pretty miserable. They're totally miserable.

    12. PAPeter Attia1:44:09

        [laughs]

    13. ASAllan Sniderman1:44:09

        I mean, you talked about legal documents. No doctor, or I shouldn't say no doctor, that's me being, uh, talking for too long. Uh, no, you ... They're not reading for-

    14. PAPeter Attia1:44:23

        But there's a summary, and that's what the doctors typically read, right? The doctors will read the one-page executive summary that basically says-

    15. ASAllan Sniderman1:44:33

        And, and that gets hammered home. And do you know what that says about ... And that's, I get this rebuttal all the time. "We've got to do this because the doctor who sees 40 patients isn't going to do anything unless we dumb this down." I don't think most doctors are dumb. I think they're caring. I think doctors want to do good jobs. I think we need to learn more about how we present information. I don't think we should ever compromise on truth, because when you do, you say, "I've got to do this in order to get to here." And I don't want to use your political history in the United States negatively. But, but Afghanistan, I can't think of anybody right, left, or center who thinks that the process getting in and throughout it represents the best efforts of the minds of America. It doesn't. You guys are really smart, wonderful people. But it's what happens when you boil the options down to two, and you got to get it down to a one-liner, and life isn't a one-liner. Not real life. And if we're going to learn to make decisions that are to present information to our patients, we're going to have to learn how to deal with doubt.

16. 1:46:07 – 1:51:58

    Making clinical decisions in the face of uncertainty

    1. ASAllan Sniderman1:46:07

       That's what it's all about.

    2. PAPeter Attia1:46:08

       Yeah. It, it's, it, it's, it's funny. Just as you said that, I was about to say the real problem here, Allan, is we are not trained to be comfortable with uncertainty.

    3. ASAllan Sniderman1:46:23

       I think we are. I think that's what medicine's all about.

    4. PAPeter Attia1:46:27

       I think it is for things that can't be measured, and I think it's not ... I think there's a false degree of confidence that comes from things that can be measured. So you're absolutely right. In the olden days when, um, uh, the, a, a, a surgeon went down to the ER to evaluate somebody for appendicitis, so this was long before the days when every one of those patients had a CT scan, right? This is, this is based on the books that I used to read from the, the great surgeons of the '50s and '60s, where this was a purely clinical diagnosis. So you know 7% of people in their lifetime are going to have appendicitis, and you know that the pretest probability on this person is a heck of a lot higher than 7% because they're sitting here right in front of you presenting with these signs or that signs. But you also know that there's an asymmetry in your decision. In other words, there's two wrong decisions that can be made here: operating on the person without appendicitis and not operating on the person with appendicitis. And you also understand that you have to calibrate your decision-making around that uncertainty so that one mistake is more likely than the other. And so I think you're absolutely right. I think most physicians are very good at doing that. Somehow that doesn't translate into the type of uncertainty that I think is necessary to do what you want to be able to do, which is rather than give people a, a sort of unanimously agreed upon consensus that is so distilled down to simplicity that it's, it borders on being incorrect, you'd like to be able to give them the range of thoughts on a subject, acknowledging that you can't tell them which one is correct.

    5. ASAllan Sniderman1:48:20

       Yeah. I, it, it's a, it's a, um ... I think that, for example, even we ta- there are different audiences. There's the practicing doctor, there's the practicing family doctor, there's the practicing internist, there's the academic internist. There are the experts in the field. I think at a minimum, you've got to have a range of opinion in the experts in the field, and I don't think we meet that minimum. And I think that when there's doubt, you ought to be able to write, "I'm not sure about this," which we do when we have weak recommendations, but they're also always unanimous. What, what happens when you put five people in a room, doctors, experts are no different, the one with the loudest voice can carry the day. The one who claims the greatest expertise in the area can carry the day. Um, so these, these ... And then we wind up with documents that are very difficult to read, and, and, and read like, um You know, 20 years ago with minor modifications, you can't say anything was wrong. Well, good gracious, we learned it was. Okay, what's our problem? Who are we here for? Ourselves or our patients and the truth? And so I, I, I think you can write clearly and, and people can read and make informed choices. The, in the end of the day, what this is saying is that people are too stupid to make a real choice, and I don't believe that. I believe that when we tell people, I mean, heaven b- when, when I've treated patients and made recommendations, were they always the right ones? Of course not. Th- they were what I thought was best to advise, but I can't claim they were always right. And in knowing I could be wrong, then I calibrate the safest way through for my patient. That's what keeps me ... That's what makes me, if I was good, that's what helped me, was saying, "I, if I'm wrong about this, how can I set up something to catch it? How can I, how can I hedge my bet here?" Or, "I gotta go a little stronger here because I could be missing this." That's what medicine is. Medicine is, algorithms help us. Of course they do. But when we treat algorithms just by algorithms, then that isn't what's called clinical medicine or clinical surgery. That's, that's algorithms. And, and, and we have good healthcare professionals who are more driven by algorithms and, and more advanced healthcare professionals who can take the algorithms and, and work within them and around them, and, and everybody's doing a good job. But we gotta respect the fact that our understanding is limited, and that science requires different views to contend equally, and that we need to write the truth.

17. 1:51:58 – 1:59:58

    How the emphasis on consensus and unanimity has become a crucial weakness for science and medicine

    1. PAPeter Attia1:51:58

       I mean, do you think that we've seen an acceleration of the kind of forcing function around a uniform voice? I mean, it seems to me that the past 18 months with COVID has really amplified what you're describing. Um, I think there are, you know, lots of dissenting views out there for how COVID could be managed, what the potential efficacy is for, um, repurposed drugs, and truthfully, I've struggled to wade through the literature on this stuff. Um, and you know, you'll always find somebody who's made it their, you know, it's their mission to understand how this drug or that drug or this intervention or that intervention is the, is the, is the solution to the problem. Um, but there's no denying that, that such people have been, you know, pretty roundly silenced, uh, for, for this, and it begs the question that, you know, should we be paying more attention to these views, and when do these views become so fringe and marginal that they're actually harmful?

    2. ASAllan Sniderman1:53:15

       Yeah. It's a, it's a, it's... They're... 'Cause they can be. They can be. And, and we've got to be, um... But that's why I think when the, the first level of discussion is, is, should be amongst experts, where you can call out views that are, um, so divorced from experimental, uh, evidence that they're not serious views. I do think we can separate out, um, a- as... I mean, COVID, COVID's a great example. I heard good people express somewhat different views at different times on different issues. The, not the same person, but one person had a view, and you say, "Gee, that's got a good point," and other person had a view, "That's a good point." But, but they were all within a channel that was, um, that made sense to me as a physician, not an infectious disease expert. So I'm not talking about legitimizing any possible view because it's a possible view. I am saying that people were say- were pointing out i- different aspects of a complex problem, and they might put a little more emphasis here and a little... But the result would be, oh, I f- I, I, I understand more clearly that there is a, uh, a series of choices involved and, and, and it's challenging to go through them. In, in Canada, the government, we had much longer periods between the first and second vaccination, so more people got-

    3. PAPeter Attia1:55:06

       Yeah

    4. ASAllan Sniderman1:55:06

       ... their first dose before the second. So I get that. That's a, that's a, uh, decision in real time that's a real challenge, that it's, that you can't be sure that you got it right at the moment you're making it. But you're the responsible person, you gotta deal with it. But it was in the open, so you know it was being done. So I'm good with that process because I know what happened, and we can assess the, the, the outcomes. I, I'm not good with someone just shrieking Uh, and, and I think it's, it's the, what I'm against is saying because we can't have somebody shrieking, we can't have any debate. That's wrong. That's totally wrong. Because it winds up then we make mistakes where we, we don't have to make mistakes. And, and, and the responsibilities we have to make recommendations to our patients are so awesome that we, our humility, we need to, we need to be humble and say, "Okay, give me your best shot. I'll give you my best shot." [laughs] And we're colleagues. We're not enemies. I mean, I disagree with lots of people 'cause I'm, have a scientific viewpoint, but they're not my enemies, and we have ways of discussing this. And if I'm in the room, I can say, "Hey, you said that you show... I'll show you line 26 in your paper, which contradicts you." And he has to respond in front of other people. That's what I believe in, is the testing of the argument in a, in a, in a jury of your peers.

    5. PAPeter Attia1:56:59

       Is that culture being watered down in science? Is it the same today as it was 30 years ago?

    6. ASAllan Sniderman1:57:04

       No, I think that's the weakness. I think that's the, I think that's the crucial weakness. I think inside the room, that's what's not occurring, and I judge that by the product that comes out.

    7. PAPeter Attia1:57:15

       And why do you think that is?

    8. ASAllan Sniderman1:57:16

       'Cause the product that comes-

    9. PAPeter Attia1:57:16

       Why, why has this process become diluted?

    10. ASAllan Sniderman1:57:19

        Because of the, the, the part is that, uh, uh, people get attached to views. I think people select view 'cause there's emphasis on consensus and unanimity. Y- you don't want Sniderman in the room 'cause he's gonna argue for ApoB. You can deal with me. I'm not hard to deal with. You can say, "Okay, I heard you, but here's what's wrong with you, your argument, not me personally. Here's what's wrong with your argument."

    11. PAPeter Attia1:57:54

        But has something changed to make it that ideas are more personal? Like, what, what is the factor that has led to, or factors that have led to that?

    12. ASAllan Sniderman1:58:02

        I think people are invested in what's came up, come out, came out.

    13. PAPeter Attia1:58:06

        In a way that they weren't before?

    14. ASAllan Sniderman1:58:07

        'Cause they're no longer speaking as individual. No, I mean, I think people used to become known for their own science. Now, if you're on the guidelines, that's your science. You- that's your, that's your... You're very prominent 'cause you're on the guidelines, not that you did the science. You, you're on the, you're on the guidelines. And, and we have so much science that's done, like the clinical trials, I mean, I think clinical trials are wonderful, but they're limited tools. And I, I'm not sure... I, I, I think the composition of the committees needs to be reexamined, and I think you ought to be able to criticize what comes out. Like, I've written critiques of the... ApoB's my thing, okay? So I wrote a critique of the 2018 American guidelines. How many references were there on the comparison of ApoB and, and LDL cholesterol and non-HDL cholesterol?

    15. PAPeter Attia1:59:07

        In the guideline?

    16. ASAllan Sniderman1:59:09

        Yeah.

    17. PAPeter Attia1:59:10

        I don't know. Five?

    18. ASAllan Sniderman1:59:12

        There were four, two from a group opposed and t- two from me, and mine weren't even correctly cited. Now, that's one issue. They dealt with a whole bunch of issues, but that's not adequate. That wouldn't get you a passing grade in school. [laughs] Uh, and we're not limited now by space in dealing with issues. We can, we can put anything out on the internet for anybody who wants to read it. And what that represented to me was that I can't tell what happened inside the room, was there wasn't a full discussion, and that... And we didn't have these processes when I was young. Contending ideas could, could contend more easily.

18. 1:59:58 – 2:11:44

    Factors holding back the advancement of apoB for assessing CVD risk, treatment, and prevention strategies

    1. ASAllan Sniderman1:59:59

       I mean, I, I, I think ApoB, I don't think it's gonna happen, and I don't think it's gonna happen because, not because there isn't value, but I think there, there were a group of people who just weren't interested, and that's sad.

    2. PAPeter Attia2:00:14

       And you think that ultimately there are still that many physicians who are gonna defer to the guidelines? Uh, 'cause I don't... Look, I don't think you need the guidelines for... I mean, reimbursement's not an issue, right? ApoB bills your insurance company four bucks and its cash pay is $2.50. I mean, it's, this is not a cost issue. This is really an awareness issue on the part of physicians. That's, that's really all it comes down to at this point.

    3. ASAllan Sniderman2:00:41

       Well, the guidelines present it as a cost issue. That's the argument against ApoB.

    4. PAPeter Attia2:00:45

       Right, but the guidelines must have failed to actually look at the cost then.

    5. ASAllan Sniderman2:00:49

       That's correct. That's correct. I know that.

    6. PAPeter Attia2:00:51

       [laughs]

    7. ASAllan Sniderman2:00:52

       Okay? But, but I can't say that, [laughs] okay? Because the guidelines are the guidelines.

    8. PAPeter Attia2:00:59

       Of course you can say that.

    9. ASAllan Sniderman2:01:00

       That's what I'm objecting to.

    10. PAPeter Attia2:01:00

        That's, that's what we're talking about here. I mean, it, why has... I mean, that might be your next paper, is do a survey of the laboratory cost of ApoB and the average Medicare reimbursement rate on it across the United States or something to that effect and, and in Canada. I mean, it's, it's such a... A- a- again, I, I think it's, it's, those are, those are valuable exercises, right?

    11. ASAllan Sniderman2:01:21

        I, uh, I think they are, and they, they... We did a, a cost analysis on ApoB, I think using a charge of $10, and looking at the cost of care, and I think it contributed .01% to the cost of care. [laughs] Something like that.

    12. PAPeter Attia2:01:42

        Okay.

    13. ASAllan Sniderman2:01:43

        Okay? I mean, the co- the concept that a $10 test really changes the cost of care

    14. PAPeter Attia2:01:49

        Well, uh, furthermore, the whole thing is so idiotic, right? The last time I looked, in the United States, and admittedly we're spending infinitely more than we should and infinitely more than anybody else. So this is 10-year-old data, so y- it, you know it's probably closer to 10,000 now. But 10 years ago, in the United States, our healthcare spending was $7,000 per person per year. That's 10 years ago. So again, I don't see how it's less than $10,000 per person per year in the United States today. So if the ApoB test cost $100, which again, is like 20 times more than it actually costs, so what? Atherosclerosis, when last I checked, is the number one killer of men and women. It kills women at a rate that is more than 10 times that of breast cancer. What, I mean, are we missing something here? Is there some part of this that you haven't told me?

    15. ASAllan Sniderman2:02:51

        Well, I, I d- that's, that's my frustration. That's my, that's my sadness, is because you're, you're absolutely correct. This is penny wise, pound foolish, where it's lives that are being lost. And we've calculated the number of lives and heart attacks that could be, uh, avoided. Lives saved, heart attacks avoided if we switch to ApoB. The American, uh, College of Clinical Chemistry, the European clinical chemists, they have a series of reports saying ApoB can be measured more accurately than LDL cholesterol or non-HDL cholesterol. No question. Is that in any of the guidelines? Accuracy of measurement? No. That's where, that's where, that's what's so hard to deal with when you say you're criticizing the guidelines. Maybe it's just you, you're a ... Who are you? You're a nobody. Which is true. Uh, but I'm saying, look, it's a laboratory test. Surely the quality of the measurement is something that should be mentioned. Not. Not. The diagnosis of type III can't be done without ApoB. So any hydro- hypertriglyceridemia patient needs an ApoB. Not done. Not mentioned, type III. So, um, I can't beat on you with sadness and stuff, but it, it's, it's, um ... I've been incredibly privileged, uh, to have the opportunity to, um, try and understand the world around me. I mean, I, I, my background is not a ... would've led you, would've normally led someone like me to have that chance, nor to work with the quality of people that, that I've had the, uh, privilege of working with. And, a- and I've been able to write and record the images of the world that, that, that, that looked real to me, and, and how few human beings ever get that, um, that privilege. Um, and I'm just sad that it, it, it, it won't help. It won't help people. I'm sad about that. And, and I, and I'm sad that the, um, you go so far in the thinking, and then somebody can take it to the next step. It's not like I've done that much. Somebody can see this and say, "Oh, wow, if that's so, let's go there." And, and i- it's not gonna happen.

    16. PAPeter Attia2:05:58

        I, I don't, I don't agree on two levels. The, the first is I don't, uh, and I'm gonna call you out on this, Allan. For a guy who understands uncertainty and probability and risk, you're using awfully black and light, white language right now. "It's not going to happen." With what certainty can you say that?

    17. ASAllan Sniderman2:06:20

        No, I mean, it, it's ... October, I'll be 80.

    18. PAPeter Attia2:06:24

        Okay. [chuckles]

    19. ASAllan Sniderman2:06:28

        Um, so you're right. You're right. And it, and it, and it, and it's, and it's self-pity, and it's not attractive to me either, okay?

    20. PAPeter Attia2:06:38

        Yeah, no, no, I'm not, and I'm not saying that to, to, to sort of, uh, to, to belittle the, the point of view. What I'm really saying is, you know, y- I, I forget the, the, the ... There's a, there's a beautiful, you know, story about the, the guy that's hitting the stone, right? The mason who's, who's hammering away on the stone for 10,000 strikes, and on the 10,000 and first strike, when he hits the stone, it finally fractures. Now, to the person watching it, it was that 10,000 and first strike that fractured the stone. But of course, the stone mason knows that it was that strike plus the 10,000, the, the 10,000 that came before it. And so I, I, I think y- you just have to accept the non-linearity of the advancement of knowledge. Now, and it's, it's, it's embarrassing that I would even attempt to try to say that to you because you know that so much better than I do, of course. But maybe in this one situation, Allan, you're just closer to it than I am, and therefore you, you're just too close to kind of the, the, the political environment of it, right? Because at the end of the day, these, these, these, these, these, um- Consensus statements are largely political. Um, they're, they're, they're far more based on who you are and who you know and how long you've been on the committee than, than the strength of the evidence. But I, I just... I wouldn't bet against the truth. I, I, I think that in the end, um, the, the truth generally wins in science. Not always, um, but it also depends on your time course. And it-

    21. ASAllan Sniderman2:08:14

        Yeah. No, I-

    22. PAPeter Attia2:08:15

        Wouldn't sur-

    23. ASAllan Sniderman2:08:15

        Yeah.

    24. PAPeter Attia2:08:16

        It just wouldn't surprise me if in 10 years, 20 years, we're gonna look back at this just as we are looking back today at HDL-C. I mean, th- that was not that long ago, Allan, that people thought HDL-C was everything. And today, thanks to the C-TEPH trials, the MRs, we now know HDL-C is, A, much more complicated than we ever thought, and B, probably not something we should be trying to manipulate in an effort to improve outcomes.

    25. ASAllan Sniderman2:08:51

        No, I, I hope... You know, and I, at the end, at the end of it all, that's what I'll hope for, you know? Uh, and, uh, you need to pick yourself up and keep, keep fighting. We have, uh, we have new, a new observation that we think is even different, more startling than anything you've heard, and we'll try. Uh, it's, it's, it's, um... And it, it's, it's w- to, to quit is wrong, to admit, because then you're... Part of this is t- for yourself just to see c- can you understand the ca- what looks like chaos? Is there any, is there any pattern to what looks like there's no pattern? Uh, how do, how does blood sugar and lipids and how do they, how do they combine to, to hurt us? Uh, so just to have the privilege of, you know, looking at those questions and to write down your thoughts in a manuscript and to publish the manuscript is, that's, uh, so few people ever have that privilege. I mean, I've, I've just been extraordinarily, you know, rewarded for, for the very little bit that I've been able to achieve. So, um, it just... I have a short fuse and it annoys me. Stupidity annoys me.

    26. PAPeter Attia2:10:43

        [chuckles]

    27. ASAllan Sniderman2:10:44

        Ignorance annoys me. And, um, and pretentiousness annoys me deeply.

    28. PAPeter Attia2:10:52

        Look, I think those are all things worth being annoyed at. Um, I think, y- you know, another one of your strengths, Allan, that I've observed over the, I don't know, 10 years that we've known each other, maybe longer, is y- you're, you're, you have an insatiable curiosity about things that are theoretically or, uh, you know, I... In quotes, "theoretically outside of your lane." And we've probably exchanged as many emails on the mechanisms of insulin resistance as we have on everything that's related to, to lipids. So, um, uh, I think that that's a very important part of your success, which you've been very modest in downplaying, is the breadth to which you think about this problem. Um, and I think that, I, I, I think that's why you've been able to sort of spot patterns that are not obvious to

19. 2:11:44 – 2:25:31

    Advantages of a 30-year risk assessment and early intervention

    1. PAPeter Attia2:11:44

       others. Before we wrap, there's one thing I wanna go back to because we spoke about it quite briefly, but I think it is so important. And when we spoke about it at the outset, we hadn't given the listener the full landscape of the disease. But now that we have, I think they will understand more what you mean when you talk about the causal model of risk, this 30-year causal model versus just a risk calculator. So let, let's go back to that. You, you, you go to a Framingham risk calculator and you plug in a few variables, right? "I'm this old. I do smoke or I don't smoke. My HDL cholesterol is this. My blood pressure is this. What is my 10-year risk?" And you hit click on the button and a number comes up, and most of the guidelines say if that number is below something, and a typical response would be, "If the 10-year risk is below 5%, there is no need to treat. Carry on as normal." I'm exaggerating a little bit, but that's, that's the gist of it. I practice medicine a very different way because I have a very different goal, right? I have a, I have an objective for how long a person might be able to live disease-free, and I also tend to be influenced by people like you who have taught me how long it takes for this disease to take hold. So the analogy I would use is imagine there was a, a calculator that told you, [lip smacks] you know, how much money you should be saving for retirement, but it could only predict 10 years into the future. It wouldn't be a very useful tool because a 30-year-old isn't going to be retired in 10 years. So how has your thinking, which has influenced me greatly- How did you come to the 30-year model that is based on the causal relationship and, and what, what are the types of yields that we see there?

    2. ASAllan Sniderman2:14:02

       Part, part of it is utilitarian. 30 years was the longest stretch we had reliable data for. And, and part of it was that the, the, the period of uncertainty is greatest between age 30 and I'm saying 60, but 55, whatever. That's where the tenure falls down. And, and we originally did these models based on tenure risk. And, and, and you could say, "Look, you're right. We're not, we're not g- we're, we're gonna miss most preve- premature disease. Let's just lower the, the risk. Instead of 5%, we'll make it 2.5%." And you could do that. The problem is it's not cost-effective [chuckles] 'cause you're multiplying the number you treat, need to treat more than you would need if you start off with a cause. Now, let's say I, I, I categorize you by your ApoB or your non-HDL cholesterol. Let's say you have a high ApoB. So you're in this group of about 25% of the population, 'cause I, I use 25%, 75% to get you there. So that group has over 30 years a 30% event rate. It's a lot. It's not just the ApoB that's doing it. That group will be fat-

    3. PAPeter Attia2:15:37

       Age is still a big driver.

    4. ASAllan Sniderman2:15:39

       Age is a driver, but they'll be fatter at the start. Their blood pressure will be a little higher at the start. It's not that the other things are being left out. You're catching them. You're just selecting differently. And I would submit you're selecting more accurately, 'cause I can measure ApoB or non-HDL cholesterol a- with much less error than I can measure your risk. The variables that we know Michael Pencina's calculated, we were, account for about 20% of the variance in risk. Okay? [chuckles]

    5. PAPeter Attia2:16:18

       Hmm.

    6. ASAllan Sniderman2:16:18

       That's about it. That's not such a, that's not such a large number. That's a ti- that's a small number. So from a utilitarian perspective, by stretching out the thing and using the idea of cause and, and, and precision of measurement, I, I group you, and then I can present a patient with their ... with the, with the, what we know about the group, and they can make their decision. And, and I, uh, there are people who say, "Thank you. I'll pass." They come back in six months, a year. We can have the same discussion again. I didn't lose anything. They didn't... They might, they've lost some, and we can show that. But, but these aren't decisions that you can't revisit. If you s- if someone starts on therapy, they can decide to stop it. Patients are free agents. I mean, I respect that, and it's up to us to present our arguments and continue to present them as we frame them to their, what we think is their best interest and the best we can do. So I, I, I, I, I like to maintain contact with my patients to, who are in this sort of thing to make sure that they know they can change their mind, but I can also show them progress. If, if their ApoB started at 120 and we're down to 60, A, I know they're taking the medication. I really do. [chuckles] Okay? Otherwise, it would be 120. And they can see and appreciate the extent of change that's occurred. And I, for me and for the patients I've cared for, that tends to work.

    7. PAPeter Attia2:18:14

       O- one of the things that I find very helpful to explain this, because it's nonlinear, and I think nonlinearity is not innate to us. I don't, I don't think evolution needed us to be able to think nonlinearly. I think linear thought was good enough, and that included linearity with time and, and chance. But this problem doesn't lend itself to that, and therefore, I think it's not intuitive to somebody who hasn't fiddled with numbers a lot or hasn't spent time looking at things that compound, that even if you were just to look at a risk-based model that was short term, there's a significant benefit to reducing risk from 4% to 2% over a decade. Because even though that might only mean there's a 2% re- risk reduction over the next decade, the amount that that amplifies over two, three, and four decades is amazingly counterintuitive, just in the way it is if you think about saving for retirement. If you're 40 years old or hopefully younger when you start saving for retirement, if you're 30 years old when you really start in earnest to saving for retirement, and you have one option that's going to generate a return of 7% and another that generates a return of 10% or 9%, there's a two percentage point difference, that's not gonna yield an enormous difference by the time you're 40. But by the time you're 70, it does. Um, I've, I've done the math on these, and you can easily show how you can-- it can literally double the nest egg just based on relatively small changes up front. So I think that's also part of the issue here is just understanding what compounding does and how it works in your benefit when you're talking about investing, but understanding how it works against you when you're talking about a disease like atherosclerosis.

    8. ASAllan Sniderman2:20:16

       And we- we- we've done some of these calculations, and you're right. Uh, uh, s- starting early pays off later. And, and, um, when you start later, what you're doing essentially is to try and modify the disease that's already present. When you're starting early, what you're actually doing is starting... stopping disease from developing. And if you can stop a lesion developing, that's 100% success. Trying to treat, modify through one process a complex set of outcomes at this end, much less likely to succeed. So, stopping disease is perfect prevention. Treating disease is partial prevention, and it has to be partial. Can't be more.

    9. PAPeter Attia2:21:16

       Yeah, I think that's a very important point because although we haven't stated it explicitly, the undertone of everything we've said is not only that ApoB is causal, but, but that it's a necessary but not sufficient driver of atherosclerosis. And I think that's important because necessary but not sufficient creates a lot of confusion in medicine, doesn't it? Right? Necessary means you have to have an ApoB particle traffic a lipid into an artery wall. If that doesn't happen, you don't get atherosclerosis. Sufficient means if that's the only thing that happens, do you necessarily get disease? No, you don't. We can... Each of us could rattle off tons of patients who somehow make it into their 90s with high ApoB and don't have disease. But from a prevention standpoint, it's much easier to go after something that's necessary because you only have to block that, versus once the disease has already taken hold, you're advancing something that's multifactorial. So, uh-

    10. ASAllan Sniderman2:22:20

        Yeah

    11. PAPeter Attia2:22:20

        ... I think that's a very important point you raise, and I, I don't think it's... I don't think it gets made enough. Well, Allan, um, I'm glad you... I know you, uh, you were, you were a little reluctant to sit down. You, you didn't see the, the value in doing a podcast, but I'm glad we twisted your arm a little bit and, uh, I, I, uh... It's funny, I didn't realize until, uh, a little while ago that you were, you were 80. I... You always come across as so much younger to me, so there's, uh... That, that explains to me why you've got lots of, uh, lots of miles left in terms of the, uh, the ApoB work and the crusade here. So I'm, I'm very optimistic.

    12. ASAllan Sniderman2:22:58

        Yeah. Thank you. It was nice to... Dinner would be even nicer, but this was nice to speak with you again.

    13. PAPeter Attia2:23:04

        [laughs] Well, uh, we'll make that dinner happen again at some point soon, Allan. Thanks so much.

    14. ASAllan Sniderman2:23:08

        Okay. You're very welcome.

    15. PAPeter Attia2:23:11

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Episode duration: 2:25:35