#03 – Ron Krauss, M.D.: a deep dive into heart disease

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [upbeat music]

2. 0:04 – 6:23

   Episode Preview and the Case That Prompted the Conversation

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obs- obsessions I've gathered along the way. I've spent the last several years working with some of the most successful, top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] In this podcast, I'm speaking with Dr. Ron Krauss. First and foremost, Ron is a very close friend and an amazing mentor. I was introduced to Ron probably five years ago and have worked with him closely in a number of capacities, and he's always served as sort of one of the three or four lipidologists that when I get stumped on a really difficult clinical case, he's the person that I'm reaching out to, along with a couple of these other folks that hopefully we'll also have on the podcast at some point. So he is certainly recognized globally for his research in lipidology. He wears a ton of hats. He's a clinician, obviously a lipidologist. His interest in nutrition, genetics, drug research is quite profound. He obtained, I believe, both his college degrees and medical degrees from Harvard. He's board certified in internal medicine, endocrinology, and metabolism, and currently he's a senior scientist and the director of atherosclerosis research at the Children's Hospital in Oakland. So in this episode, we talk about a lot of stuff, but obviously we're really focusing on atherosclerosis and cardiovascular disease. I was really excited to have this discussion with him because a lot of these topics I've certainly covered in writing. As some of you may know, I have that sort of nine-part Straight Dope on Cholesterol series on the blog that I probably wrote about four, five years ago. Obviously, some of that's a little bit outdated, and I also was quite deliberate when I wrote that not to be prescriptive, meaning I don't really get into this is the drug treatment you would do for this, and I largely avoided a lot of that stuff. Whereas in this podcast, Ron and I get a little bit into this. This podcast was pretty technical at times, so my hope is that both the curious patient will get a lot out of that and, and hopefully the physician will get a lot out of this, or the person that is also, uh, kind of on the front lines of having to make decisions about how to treat dyslipidemia and reduce the risk of atherosclerotic disease. I think a couple of really interesting things in this. I actually for the first time learned about Ron's motivation for this, both his family history and the five legendary articles that he read in The New England Journal of Medicine that largely shaped his career. This is the stuff we talk about with, uh, Friedrichsen, Levy, and Lees, who I'd written about in the cholesterol series because these guys are sort of the fathers of this space. We certainly get into one of the age-old debates about LDL particle size versus particle number. Lots of controversy here, and I don't represent that we've necessarily resolved it, but I think that's the beauty of talking with really smart, sophisticated, nuanced people is they have the humility to say we don't know the answer sometimes. We really dive deep into the whole statin discussion. For reasons that aren't entirely clear to me, this has become an increasingly controversial area, and somehow it's turned into a binary discussion. Statins are good or statins are bad, and very few things in life tend to be that binary, so I'm sort of surprised that it's turned into that. And I don't remember if I even say this on the podcast, but certainly I've s-- people have probably heard me say this before, and I say it to patients all the time. Statins are tools, and the most important thing when you have a tool is knowing how to use it and knowing when to use it. So if you have a Phillips screwdriver, it's really important to know that it's very good at putting Phillips screws into things. It's not good at putting nails into things. It's not good at cleaning windows. So I hope we can shed some light on that. We talk a little bit about the really interesting and recent stuff around chronic inflammation and the role that that plays in atherosclerosis, even independent of cholesterol levels. And perhaps for me personally, one of the most interesting things we discussed was another very controversial topic, which is around niacin and Niaspan, which is a branded version of that, which those of you who follow this world will know that niacin was basically kicked to the curb a couple of years ago. And I think that Ron's insights into that are incredibly interesting and actually have even made me re-question or re-evaluate, I guess, my willingness to ever consider using it again. Ron does a great job explaining the HDL paradox, meaning why is it that all the pharmacologic efforts to raise HDL seem to also raise heart disease or at best make it no better. And finally, we end with a discussion, uh, of PCSK9 inhibitors, which I suspect we'll have a completely dedicated podcast to this topic at some point. And we touch on Lp (a) , though later on in the release of this podcast, we're going to have a dedicated discussion on Lp (a) . Okay. So with all that said, you can find a ton more information, including a lot of links to the papers that Ron has mentioned, more information about Ron in the show notes, which are at peterattiamd.com/podcast. So without further ado, here is my conversation with Dr. Ron Krauss. [upbeat music] Well, I'm here with Dr. Ron Krauss today, and this is a really exciting topic for me. People know I've written about this a lot. I talk about this a lot clinically, but the genesis of this discussion today is that about a month ago, I called Ron to have a discussion with him about one of my patients in particular. It was a patient who had a pretty elevated calcium score, if I recall, pretty significant LAD calcifications. That's the artery in the, uh, left side of the heart. But he was very hesitant to do any treatment, and, uh, he wanted a second opinion, so I thought we should involve Ron and Ron, I remember I was standing in my kitchen. We spoke for probably half an hour, and at the end of the conversation, I said, "You know, Ron, I wish we recorded that conversation because-

   2. RKDr. Ron Krauss6:11

      Yeah, you did say that

   3. PAPeter Attia6:12

      ... this is exactly the kind of stuff that I think a lot of physicians and patients would benefit from." And so I said, "You know, why don't we do this again more formally?" And that, uh, brings us here today.

3. 6:23 – 12:00

   How Atherosclerosis Develops: From Fatty Streak to Plaque Rupture

   1. PAPeter Attia6:23

      Let's start with a big question, but an important one for where we're going, and that's basically the pathophysiology of atherosclerosis. A, a very recent review article I read described it quite eloquently as a smoldering inflammatory condition fueled by lipids. What does that mean?

   2. RKDr. Ron Krauss6:40

      [chuckles] Well, first of all, thank you, Peter, for, uh, asking me to talk with you today and address this topic, which, as you know, I have a deep and longstanding interest in. Uh, hopefully, I can address the issues that you're also interested in, uh, and we'll have a, a good conversation. Well, atherosclerosis, uh, of course, is the underlying process that leads ultimately to vascular disease, particularly clinical events, heart attack and stroke. It starts in childhood. It's well known that there is, early on, uh, the buildup of cholesterol in the artery wall that forms what's called fatty streaks, and that's a process that's actually a fairly normal condition even in young people, and if it doesn't progress any further than that, it's really not hazardous. It's a way that arterial tissue, um, can put cholesterol in its cells, and some of that cholesterol is actually used for various purposes. So that's not necessarily a pathologic process, but it can progress. And when it progresses, there is a combination of factors that conspire to make that fatty streak into a much more toxic process, and it is fueled by lipids, the same lipids that lead to the fatty streak. But under conditions that many of us live under, there are changes, uh, in the lipoproteins that are taken up by the artery, and we'll talk about those in more detail in a minute. In particular, susceptibility to oxidation and the, a change in the properties that allows them to stick more tightly to the artery wall. Uh, and when that happens, particularly the oxidative changes, it does trigger inflammation, uh, as a very early part of this next phase of the disease process. And inflammation is defined in one way as the accumulation of, uh, cells in the artery wall that deliver various, uh, inflammatory molecules, things that ordinarily, if one, uh, bruises oneself or has some sort of a, an injury, those inflammatory processes cause redness and accumulation, in some cases, of clotting factors. When that happens in the artery, that can convert this fatty streak into something that is much more malignant. And then there is a process that kind of feeds on itself, and it does involve platelets and clotting factors in an important way, and it involves a number of inflammatory molecules. And if there's continuing input of these bad atherogenic, if you will, lipoprotein particles, that can actually change the nature of the plaque, and inflammation comes into play in a very, uh, serious way when that results in a breakdown of the surface of the plaque, which ordinarily protects it from any kind of serious consequences. So even fatty streak can develop-- which can develop into a plaque, and a plaque, in this case, is essentially a larger fatty streak. The plaque has the cholesterol, but it also has all these other cells. It's a much more complex phenomenon. So that plaque is ordinarily under relatively benign conditions, encapsulated by a, a fibrous layer. But inflammation and the release of various molecules can cause that fibrous cap, that protective cap, to weaken and ultimately potentially rupture. And when that rupture occurs, that is the beginning of the end in terms of, uh, the process that we're talking about here. Most cases of heart attack and stroke involve this type of acute rupture and ultimately formation of a clot that blocks the arterial flow. So starting from a relatively benign process, this can develop into something that's much more serious.

   3. PAPeter Attia10:18

      Now, when I was in medical school, I remember in first-year pathology lecture, the pathologist said, "Let's see a show of hands. What is the most common first presentation of heart disease?" And, you know, everybody puts up their hands and says, uh, "Chest pain, uh, left shoulder pain, shortness of breath." And he said, "No, no, no, no, no. It's sudden death."

   4. RKDr. Ron Krauss10:38

      Yeah.

   5. PAPeter Attia10:38

      That was a little over twenty years ago. Is that still true today?

   6. RKDr. Ron Krauss10:41

      The estimates I've heard, and I, uh, and I think this, this is arguable because these are really rough rule-of-the-thumb calculations, somewhere in the range of thirty percent, possibly, possibly upwards of thirty percent, which is still a huge number.

   7. PAPeter Attia10:52

      It's staggering. It means that one-third of people's first brush with the knowledge that they have atherosclerosis is death.

   8. RKDr. Ron Krauss10:59

      And I have patients, and I'm sure you do as well, who have died and come back. And so there is this process where there's an, uh, an acute event that causes an irreversible change, but for some people, fortunately, we can bring them back. But together, that represents really the basis for calling this disease the silent killer because, as you were saying, we don't, and most patients have premonitory symptoms. Sometimes in retrospect, they are there.

   9. PAPeter Attia11:26

      Yes.

   10. RKDr. Ron Krauss11:26

       And I think that's the important reason for educating the public as organizations like the American Heart Association does as to the first signs of heart disease because it may be, and it probably is true, that a significant component of that thirty percent-

   11. PAPeter Attia11:40

       Right. Upon further querying, there was some exercise intolerance or other things.

   12. RKDr. Ron Krauss11:44

       Didn't recognize it, yeah. And it's very hard sometimes. One, one of the things that we'll be talking about is ways of assessing risk, and, uh, those are still imperfect. I mean, we can't, with a hundred percent certainty, use any kind of risk predictor to know if somebody's destined to have a heart attack with certainty.

   13. PAPeter Attia11:59

       Yeah.

4. 12:00 – 15:23

   Age, Exposure, and Early Lesions

   1. PAPeter Attia12:00

      You said something at the outset, which is this is a disease that begins in infancy, and I, I-- One of the I have very few textbooks and/or papers that are-- I refer to so frequently that they actually sit on my desk in my office so that every time I'm with a patient, I can pull them out. But one of them was a, a book that was given to me by one of my mentors. I consider you a great mentor, Tom Dayspring a great mentor-

   2. RKDr. Ron Krauss12:20

      Sure

   3. PAPeter Attia12:20

      ... Alan Sniderman a great mentor. And Alan gave me this textbook of, of pathology.

   4. RKDr. Ron Krauss12:25

      Hmm.

   5. PAPeter Attia12:25

      I think, believe it's Starry is the, uh, the author.

   6. RKDr. Ron Krauss12:27

      Uh-huh. Uh-huh.

   7. PAPeter Attia12:28

      And while I believe the data, uh, represented there are somewhat dated 'cause it was largely based on the Vietnam cohort and-

   8. RKDr. Ron Krauss12:34

      And Koreans

   9. PAPeter Attia12:35

      ... Yes. Where-

   10. RKDr. Ron Krauss12:36

       Yeah

   11. PAPeter Attia12:36

       ... obviously smoking would have been a higher prevalence than today.

   12. RKDr. Ron Krauss12:39

       Right.

   13. PAPeter Attia12:39

       The fact remains that when you look at autopsies of young people who died of unrelated reasons, homicides, accidents, et cetera, and you look at the histologic sections of their coronary arteries, it's amazing how many of them have lesions that are type III or beyond. Type III meaning, uh, obviously a type of pathological region where you go beyond fatty streak.

   14. RKDr. Ron Krauss13:02

       Yes, indeed. Yeah, that's right. So a subset of these youths will have more advanced lesions, and the studies that have been done, uh, have linked all of the usual risk factors, uh, smoking, uh, certainly diabetes, hypertension, uh, and, and dyslipidemia, all of-- and, and a lipid disorder, all of those, uh, have been associated with the more advanced, uh, lesions in, in those individuals. So as you're pointing out, even, even a more significant plaque development can occur in childhood.

   15. PAPeter Attia13:30

       I think the thing that's hard for m-people to understand, uh, and I think it's true of most chronic diseases, but I don't think any disease-- in any disease, it is as clear as it is with atherosclerosis, which is the compounding nature of the disease. You know, another great example of one of those questions that the professor asks that gets everybody stumped, which is, "What's the greatest risk for heart disease?" You know, is it smoking? Nope. Is it high blood pressure? Nope. Is it dyslipidemia? Nope. It's age.

   16. RKDr. Ron Krauss13:55

       That's right.

   17. PAPeter Attia13:56

       It's age.

   18. RKDr. Ron Krauss13:57

       That's right.

   19. PAPeter Attia13:57

       I mean, and, and why is it age? Because it's exposure.

   20. RKDr. Ron Krauss14:00

       Yes.

   21. PAPeter Attia14:00

       It's time, it's area under the curve.

   22. RKDr. Ron Krauss14:02

       Yeah, that's exactly true. You know, age regrettably is a risk factor that cuts across, uh, many of the diseases, chronic diseases that we, uh, have to deal with, cancer, for example. Uh, and yeah, that's right. It's a cumulative process that can progress at various rates depending, uh, the condition. So people, as you know, and we, we may talk about who have genetically elevated, severely elevated cholesterol levels, will have that process accelerate and have the disease show up clinically early on, uh, sometimes with these severe genetic disorders, um, in the teens, whereas others, uh, most of the population, fortunately, who do have risk factors, show a gradual increase in the manifestation of disease as a result of those risk factors as a function of their age.

   23. PAPeter Attia14:47

       You know, at last check, and I, I can't remember if it was JAMA or another journal, but it was about a year ago, and they looked at some actuarial data for people out through being past centenarians, and the only disease, o-once you normalized for a few things, the only disease that increased monotonically by decade in risk was atherosclerosis.

   24. RKDr. Ron Krauss15:05

       From childhood, yeah.

   25. PAPeter Attia15:06

       Yeah. Even cancer actually, you know, by, I think by the ninth decade, it started to come down.

   26. RKDr. Ron Krauss15:11

       I see. Yeah, yeah. Yeah. You know what? Yeah, that's right. No, it's a definitely different-- I mean, the latency period for cancer also, uh, is a factor there as well. So there's this sort of latency period-

   27. PAPeter Attia15:20

       Yeah

   28. RKDr. Ron Krauss15:20

       ... where nothing happens, and then all of a sudden, in older age, it pops up.

5. 15:23 – 28:27

   Lipoproteins, LDL-C, LDL-P and ApoB Explained

   1. PAPeter Attia15:23

      I'm sure a lot of people listening to this are gonna say, "Okay, well, God, I'm really confused by half the terms you guys just used." So let's unpack some of them, beginning with we use the term sometimes lipid, cholesterol-

   2. RKDr. Ron Krauss15:34

      Right

   3. PAPeter Attia15:34

      ... lipoprotein. We, we throw those terms around interchangeably, but I think it's probably important to give the average person a sense of an understanding. So what is LDL-C versus LDL-P versus ApoB and things like that?

   4. RKDr. Ron Krauss15:47

      Sure. The underlying concept that we are going to address is, is cholesterol because that's really the compound. It's the, it's the molecule that winds up causing plaques. So cholesterol is indeed an important component of the, of the plaque, and it gets into the plaque by uptake of cholesterol from lipoprotein particles. And so lipoproteins are complex spherical macromolecules, big guys, which come in varying sizes, and are composed of cholesterol along with other lipids, uh, such as triglyceride, and most importantly, perhaps for distinguishing the various types of lipoproteins, is their protein content. So there's a, a variety of different proteins that form, uh, the package that, actually a capsule around the lipid, and so that's-

   5. PAPeter Attia16:36

      And, and let me interrupt you for one second.

   6. RKDr. Ron Krauss16:37

      Yeah.

   7. PAPeter Attia16:38

      Is it just a point of clarification. The reason we even need these lipoproteins is that cholesterol is hydrophilic, uh, pardon me, hydrophobic. It repels water.

   8. RKDr. Ron Krauss16:48

      Right.

   9. PAPeter Attia16:48

      And so therefore, to move cholesterol through the bloodstream-

   10. RKDr. Ron Krauss16:52

       Right

   11. PAPeter Attia16:52

       ... you have to package it in something that is-

   12. RKDr. Ron Krauss16:54

       Right

   13. PAPeter Attia16:54

       ... hydrophilic or-

   14. RKDr. Ron Krauss16:55

       Right

   15. PAPeter Attia16:55

       ... dissolves in water. Is that correct?

   16. RKDr. Ron Krauss16:56

       Right. Right. Yeah, and for the, the technophiles here, um, it's the, it's the cholesterol ester. So there's a-

   17. PAPeter Attia17:01

       Yes

   18. RKDr. Ron Krauss17:01

       ... there's two forms of cholesterol, and it's the, the fatty form of cholesterol is cholesterol ester. The other form is more waxy.

   19. PAPeter Attia17:08

       Mm-hmm.

   20. RKDr. Ron Krauss17:08

       So the fatty form is transported right from one tissue to another, and that is the purpose of lipoproteins, not just cholesterol, of course, but triglycerides, as I mentioned, even perhaps more importantly for m-many functions, energy metabolism, w- and other compounds such as phospholipids, as well as passengers on the, on the truck, uh, uh, certain vitamins, et cetera. So these are, uh, packages that, uh, serve an important biologic function. They're not here to cause heart attacks. Uh, we divide them into various categories, but the common parlance, the sort of the most typical way that we think about cholesterol as a pathologic factor is when it's on LDL. So that's called LDL cholesterol. It's-- And that measures the amount of cholesterol on an LDL particle.

   21. PAPeter Attia17:47

       And LDL stands for-

   22. RKDr. Ron Krauss17:48

       And LDL is low, is low-density lipoprotein.

   23. PAPeter Attia17:50

       Right.

   24. RKDr. Ron Krauss17:50

       So that's, uh, and so this is a form, uh, of lipoprotein that, uh, is characterized by size, and it's also characterized by its density, which is related to its capacity to float, 'cause there's-- when there's fat in anything, it causes the thing to float, and that, to varying degrees, defines different classes of lipoproteins, and it's the LDL that is the most strongly connected to cardiovascular disease risk, and L- and the cholesterol in LDL, which is measured commonly, clinically as LDL cholesterol, is what has been most widely associated with cardiovascular risk and forms the basis for many of our recommendations for lowering risk. But it's important to recognize that this is a tag on a, a much more complex substance, a, a particle, and this we'll talk about, I think, very shortly. Particle is what causes, uh, the plaque to develop, and it brings the cholesterol with it.

   25. PAPeter Attia18:46

       So the LDL particle, the low-density lipoprotein itself, a spherical molecule or macromolecule which carries around cholesterol ester, phospholipid, triglyceride, it has a signature on it, doesn't it? Uh, something called ApoB 100.

   26. RKDr. Ron Krauss19:02

       That's right. The key protein that holds this particle together, that allows it to form a sphere and to encapsulate the lipid cargo, is called apoprotein B. Uh, there are two major forms of ApoB. Uh, the one that's found in LDL particles is called ApoB 100, and oftentimes, uh, that is used as a surrogate for measuring LDL particle concentration, as we'll talk about.

   27. PAPeter Attia19:30

       And this is a big clinical distinction. I, I think it is safe to say, at least in my, you know, re-relatively modest sampling of physicians, most physicians, let alone most patients, are not really clear on the distinction between the number when they say LDL is 100. They don't necessarily realize what they're saying is the LDL cholesterol is 100 milligrams per deciliter, meaning if you took all of the LDL particles in the body, smashed them apart, gathered the cholesterol ester, the mass per unit volume is 100.

   28. RKDr. Ron Krauss20:01

       And free cholesterol. Both. Both.

   29. PAPeter Attia20:02

       Yes.

   30. RKDr. Ron Krauss20:02

       Both forms.
6. 28:27 – 30:47

   Metabolic Syndrome, Framingham, and the NIH Lipid Era

   1. PAPeter Attia28:27

      Yeah. And, you know, I'll tell you, it's a very interesting historical footnote. Uh, Gary Taubes, a mutual friend of ours, and I don't know if this actually was in any of his books, or I might have read this in one of the outtakes, but it was an interesting footnote, which was basically at the time of the Framingham study, which I'm talking about the very, very first Framingham study, which was really a two-part study, of course. One of the things that came out of that study was that low HDL cholesterol and high triglycerides was four times more predictive-

   2. RKDr. Ron Krauss28:56

      Mm-hmm

   3. PAPeter Attia28:57

      ... of atherosclerosis than elevated LDL cholesterol.

   4. RKDr. Ron Krauss29:00

      Mm-hmm.

   5. PAPeter Attia29:00

      Now, that rings true with what we just said about metabolic syndrome. Nowhere in the five criteria of metabolic syndrome was high LDL-C. It's low HDL-C and high trig. But it's interesting that the LDL cholesterol story really took off, and at least Gary argued, I believe, if I'm remembering the argument, that part of that had to do with the fact that the... God, I'm blanking on the name of the tr- the first trial. There was the LRCCP, but then there was the one before it, uh-

   6. RKDr. Ron Krauss29:28

      Oh, uh, uh, uh, yeah

   7. PAPeter Attia29:29

      ... it had a funny name, like Improve It or something, but it wasn't.

   8. RKDr. Ron Krauss29:32

      No.

   9. PAPeter Attia29:32

      It was like, uh-

   10. RKDr. Ron Krauss29:33

       No. It, it, it was a trial of fibrate. The fibrate trial you're thinking of?

   11. PAPeter Attia29:36

       The fibrate trial was LRCCP.

   12. RKDr. Ron Krauss29:38

       No, that was, that was cholestyramine. So I think that's when you're thinking of.

   13. PAPeter Attia29:40

       Oh, okay, okay, okay. Yeah, yeah, yeah.

   14. RKDr. Ron Krauss29:40

       I think you're th- I think you're thinking of this, the LRC.

   15. PAPeter Attia29:42

       Yeah.

   16. RKDr. Ron Krauss29:43

       I was, I was at N... So part of my training-

   17. PAPeter Attia29:45

       You were at NIH.

   18. RKDr. Ron Krauss29:45

       Yeah, that's where I got my training in, uh, lipids, uh, before I came out to Berkeley, actually. That's, that's how I got my first dose. And, uh, that study was going on at that time, and there was a lot of, uh, nail-biting.

   19. PAPeter Attia29:55

       Well, and, and, and, and the argument here was, look, we kinda spent a, we lost a decade and a half-

   20. RKDr. Ron Krauss30:00

       Yeah

   21. PAPeter Attia30:00

       ... between, say, nineteen eighty and nineteen ninety-five when we missed the role of insulin resistance because we really went down this LDL cholesterol-

   22. RKDr. Ron Krauss30:10

       Right

   23. PAPeter Attia30:10

       ... rabbit hole-

   24. RKDr. Ron Krauss30:11

       Right

   25. PAPeter Attia30:11

       ... and didn't necessarily see the bigger picture.

   26. RKDr. Ron Krauss30:13

       Yeah.

   27. PAPeter Attia30:13

       And, and one of the things I hope we have time to talk about today, because it's actually something that I spend more time scratching my head about than anything else, is you look at a drug like niacin Which lowers ApoB, LDL-C, and raises HDL-C. So in theory, it's doing everything in the right direction, and yet when it comes to outcomes, it's a very confusing picture. So maybe later on this afternoon we can get to that, 'cause I think that's, there's gonna be some rich info in there.

   28. RKDr. Ron Krauss30:40

       Okay. If you put that on the table, I'll be happy to pick it up when you're ready-

   29. PAPeter Attia30:42

       [laughs]

   30. RKDr. Ron Krauss30:43

       ... because I'm, I'm, I'm ready to launch into that anytime.
7. 30:47 – 35:56

   Does LDL Cause Heart Disease? The European Consensus Statement

   1. PAPeter Attia30:47

      So let's talk a little bit about a paper that you were an author on this year. It was the European Atherosclerosis Society consensus statement. Now, you and I were joking about this a while ago, that you almost couldn't believe this paper needed to be written.

   2. RKDr. Ron Krauss31:00

      Right.

   3. PAPeter Attia31:00

      But sometimes there's a benefit in writing it. And what was the conclusion of that paper, or more to the point, consensus statement? It was more than just a paper. I mean, it was really a-

   4. RKDr. Ron Krauss31:08

      Right

   5. PAPeter Attia31:08

      ... tour de force.

   6. RKDr. Ron Krauss31:08

      So this, this paper assembled, uh, multiple lines of evidence addressing the question, does LDL cause heart disease? Is LDL a causal factor for heart disease?

   7. PAPeter Attia31:20

      And just to be clear, the ar- counterargument is, sure, people with high LDL are more likely to get heart disease. That can't be disputed. The epidemiology is clear. The counterargument is, but LDL is not a causal role.

   8. RKDr. Ron Krauss31:33

      That's right, and it's associated with that. Efforts to lower LDL cholesterol are not fully justified as a means of attacking the cause. I don't want to be responsible for having stated that incorrectly, uh, because I still can't quite believe anybody would hold that opinion.

   9. PAPeter Attia31:50

      Mm-hmm.

   10. RKDr. Ron Krauss31:50

       But that was my understanding that led to the group coming together to counteract that perception that lowering LDL was not beneficial.

   11. PAPeter Attia31:59

       But there are, there are many people. I mean, not that I spend terrible amounts of time on Twitter, but it's a pretty commonly held view, at least in the vocal minority that love to write about this and talk about this, that, "Hey, LDL cholesterol is a myth." Like-

   12. RKDr. Ron Krauss32:11

       Right. Right

   13. PAPeter Attia32:12

       ... heart disease has nothing to do with this.

   14. RKDr. Ron Krauss32:13

       Yeah, and the problem is, and it did come out in the paper to some extent, but I'll tell you, there is a, a second component to that effort that is still being written. It was planned and will be a two-part series. The first part is assembling all the evidence from, uh, epidemiology, clinical trials, genetics, et cetera, uh, that speak to the causality. And the second one was really, uh, relating all of this information to the role of LDL in the pathophysiology of atherosclerosis, and that paper is a work in progress, but it... Collectively, those two papers assemble just about all the evidence one needs to support the use of LDL cholesterol.

   15. PAPeter Attia32:51

       And when will that second paper be out?

   16. RKDr. Ron Krauss32:53

       I can't tell you.

   17. PAPeter Attia32:54

       We don't even know yet.

   18. RKDr. Ron Krauss32:54

       It has taken longer-

   19. PAPeter Attia32:55

       Yeah, yeah

   20. RKDr. Ron Krauss32:55

       ... than we thought. [chuckles]

   21. PAPeter Attia32:57

       Well, we'll certainly link to the first one in the show notes because that-

   22. RKDr. Ron Krauss33:00

       Yeah

   23. PAPeter Attia33:00

       ... was published in early 2018.

   24. RKDr. Ron Krauss33:01

       Yeah, yeah. And we expect it in the next year or so. Uh, but one thing I do want to say, because there's a caveat, and part of my life as a researcher as well as a clinician is recognizing, uh, the complexity of what we're dealing with. In discussions such as this, it's important to keep, uh, the concepts straightforward and understandable to the best degree possible, but the flip side of that is the risk of oversimplifying a complex situation. So when I just said that the evidence is that lowering LDL ch- uh, cholesterol is beneficial, that's not always true. [chuckles] And so one can point, if one is so inclined, to the evidence that, uh, under certain conditions in certain populations with certain approaches, uh, lowering LDL cholesterol does not result in reduced heart disease risk. And to the extent that you consider that to be a fatal flaw in the argument, uh, that can be, um, I think m- very misleading because it's not. Uh, the fact is that, uh, LDL is causal, but there are other circumstances that modify that causality to the extent that some forms of LDL under certain, certain conditions, and this may not be uncommon, can be elevated without pathologic consequences. And so lowering LDL in those cases, uh, may not give benefit, and that we know there is heterogeneity in the clinical response when one looks at cardiovascular protection with LDL-lowering treatments. So I have to absolutely extend the simple notion of LDL causality to, uh, saying that one has to look very carefully at the arguments against LDL causality because they latch on to piece, bits and pieces of information that are really misleading.

   25. PAPeter Attia34:39

       Mm-hmm.

   26. RKDr. Ron Krauss34:39

       Uh, just because lowering LDL cholesterol is not always beneficial doesn't mean that LDL is not pathological. And the second component of that is the focus on LDL cholesterol. That goes back to our initial discussion here today as a marker for a causal mechanism, but it's the particles that are causal, and LDL cholesterol, as we just talked about, does not always mirror the number of LDL particles.

   27. PAPeter Attia35:02

       Now, I don't think we, we should necessarily take the time to go through the paper in incredible detail, but it did touch on eight criteria for causality: plausibility, strength, biological gradient, the temporal sequence, the specificity, consistency, coherence, and then the relative risk reduction or risk reduction-

   28. RKDr. Ron Krauss35:23

       Right

   29. PAPeter Attia35:23

       ... with an intervention.

   30. RKDr. Ron Krauss35:24

       Right.
8. 35:56 – 42:13

   Genetic Evidence for Causality: FH, PCSK9, and Mendelian Randomization

   1. RKDr. Ron Krauss35:56

      Well, you've just touched on probably the number one strongest argument, and it's really where we, [chuckles] those of us who have been in the field for decades, um, started with, uh, being impressed with the role of genetic elevations o- of LDL. Very, very strong evidence. I would put that probably right at the top. And, and you talked about this condition, familial hypercholesterolemia, when, when there's two doses of an abnormal gene, the LDL levels can skyrocket. I referred to that A little while ago, uh, as the condition that can lead to heart disease early in childhood is unequivocal. In fact, the, the reason I got a little bit, uh, I was a little bit taken aback by the need to do this more extensive review, which I think, by the way, was a quite a, a, a good exercise, uh, both for those of us who did it and people hopefully who read it. But all you have to do is look at a eight-year-old child with cholesterol levels that are eight or nine times normal, who's a candidate for liver and heart transplant, to know that that's it, that, that's causal. [chuckles] But the genetics support it beyond that.

   2. PAPeter Attia36:57

      Right. Now, in those cases, the genetic defect is one in the LDL receptor, correct?

   3. RKDr. Ron Krauss37:01

      That's right.

   4. PAPeter Attia37:02

      So closing the loop on how this works, right? The body makes cholesterol. The body... You know, so every cell in the body makes cholesterol. Then cholesterol gets recirculated, ends up mostly back in the liver. It gets secreted, some of it in bile, gets reabsorbed, and this process continues. But it's this LDL clearance, mostly via LDL receptors in the liver, that seems to be where a lot of these genetic things go awry.

   5. RKDr. Ron Krauss37:27

      That's right. Yeah, the liver really is the factory, uh, as, as well as the disposal plant, if you will. Most of the cholesterol that winds up in the blood is, is released in terms of in, in lipoproteins that are synthesized by the liver. And then, uh, they come back to, uh, the liver ultimately after they've done their thing, so to speak, delivered their cargo or interacted with cells in various ways and come back to the liver. And a large portion of that return is mediated by these receptors that latch on to ApoB. It's, it's ApoB that is the kind of the key, uh, that binds to the lock that s-snaps up the LDL in the liver and degrades it and excretes it into bile. Uh, and that's the way we dispo-- one of the ways we dispose of cholesterol. There's, there are other mechanisms involving HDL, but the receptors are a key determinant and do represent a mechanism by which most of the drugs that we use to lower cholesterol act to increase LDL receptor-mediated disposal of LDL particles. And I'm just going to connect that concept to something you brought up earlier, and that is the duration of exposure, uh, to, let's, in this case, high levels of LDL. We talked about it as a function of age. The longer the, greater the number of years, the longer the exposure. But there's also a, a dynamic aspect to LDL metabolism that we just touched on. That is, particles are produced, actually precursors of LDL, which are called VLDL, which carry mostly trigly-triglyceride and apoprotein B as well. Uh, those particles are being actively secreted. They interact with peripheral tissues and receptors and other transporters that, um, handle, uh, various lipids in various ways and lip-- and enzymes, et cetera. There's a lot of processing that goes on. And then what's left comes back to the liver through LDL receptors. Now, if that process happens briskly, if there is a nice fast turnover, if you will, of those particles, you can just see that there is less time for the arteries to be exposed to any of those pathologic, uh, forms of lipoproteins. They're, they can be scooped up. But what underlies, uh, at least to me, a common concept, a, a common underlying factor that connects various lipid traits to heart disease risk is the extent to which they influence the circulation time. That is the length of time that a particle is circulating in the blood. So that if particles are not being cleared by LDL receptors efficiently, they will circulate longer and have more opportunities for mischief.

   6. PAPeter Attia40:01

      What is the typical half-life of a VLDL particle, so very low-density lipoprotein, IDL, intermediate density, and low density?

   7. RKDr. Ron Krauss40:09

      I'm probably going to get this wrong be-- and, and this is where, uh, I don't want to have to go back and look at the textbook and realize how far-

   8. PAPeter Attia40:15

      Uh, well, directionally, though.

   9. RKDr. Ron Krauss40:16

      Uh, yeah. So for, particularly for a larger VLDL triglyceride, the half-life is, uh, half an hour, an hour, two hours. It's, it's pretty rapid-

   10. PAPeter Attia40:23

       Mm-hmm

   11. RKDr. Ron Krauss40:23

       ... because that particle is rapidly subject to enzymatic digestion. Well, let me just jump to the LDL. So the LDL that are formed, uh, from those precursors, you know, more like twelve to twenty-four hours and, and, or longer.

   12. PAPeter Attia40:35

       Mm-hmm.

   13. RKDr. Ron Krauss40:36

       So it turns out that, uh, smaller particles, uh, have a longer resonance time because they are less avidly removed by LDL receptors. So there's a range of circulation times for LDL, in some cases, you know, days actually, and then IDL are somewhere in the middle. The intermediate density lipoproteins or IDL is what you're referring to.

   14. PAPeter Attia40:54

       Mm-hmm.

   15. RKDr. Ron Krauss40:54

       That's the step between VLDL and LDL that is, uh, involved in their metabolism. So it's these longer exposure times, and these intermediate particles can include, and do include very pathologic forms as well. And so there are disorders, and metabolic syndrome, coming back to that, is one of them, where the clearance of those intermediate particles, which also comprise what we call remnants, partial breakdown products of VLDL on the way to forming LDL, those intermediate particles can have much longer exposure times, right? And, and they can be subject to various pathologic effects involving oxidation, the acquisition of partial digestion products of, uh, various lipids that cause them to be more toxic. And those particles can be damaging even with a, a shorter resonance time, uh, because they're so, they're so toxic. So, so that gets into what I was referring to earlier as a somewhat greater complexity of beyond thinking just about LDL cholesterol, thinking about LDL particles, thinking about the types of LDL particles in terms of the pathophysiology, and then also thinking about the role of these remnant lipoproteins. They all participate in this potential risk. And it comes down, in my view, in the end, to the length of time that a particle with certain pathologic effects is circulating in the blood, if caused.

9. 42:13 – 52:14

   Remnants, Fredrickson Typing, and Krauss's Career Path

   1. PAPeter Attia42:13

      And, and this, this VLDL cholesterol, VLDL remnant problem is one that is unfortunately very often missed even by relatively astute clinicians. Um, you know, your textbook cases, these, these type threes, these, these hypertriglyceridemias who have normal ApoB, normal LDL-C, you think they're relatively low risk. You sort of miss the fact that their VLDL cholesterol is seventy-five milligrams per deciliter, and they have these just devastating atherosclerotic plaques.

   2. RKDr. Ron Krauss42:42

      Yeah. A- and that was, again, one of my learning experiences when I was at the NIH, the... When I was at the NIH at a time with, uh, working with, uh, uh, Doctors Fredrickson and Levy, when, um, the various-

   3. PAPeter Attia42:53

      Just, just for the listener, it's important for them, I think, to understand the luminaries that you just described, right? Fredrickson, Levy, and Lees, I mean, let's put these guys in context, right? This is, you had people that figured out that there was this thing called cholesterol, but it was really those three that did the pioneering work in the 1970s that laid the groundwork for fractionating, figuring out all of the different subparticles.

   4. RKDr. Ron Krauss43:16

      Late '60s.

   5. PAPeter Attia43:18

      Late '60s, early '70s.

   6. RKDr. Ron Krauss43:19

      Late '60s.

   7. PAPeter Attia43:19

      Yeah.

   8. RKDr. Ron Krauss43:19

      No, it was late '60s. Uh, I'll just give you a, a slight anecdote since you, uh, paused me on this. Um, I, I have alw- always been interested in heart disease because it runs in my family. As a medical student, I read a series of five articles that was published in the New England Journal of Medicine, and I think you're referring to the three authors, Fredrickson, Levy, and Lees, that completely transformed me. Uh, it was a epiphany because those five articles describe lipid disorders in terms of genetic sub- genetic types, differing, uh, lipoprotein profiles that had differing, uh, metabolic effects, different consequences, and were influenced differently by various diets, and I thought this was absolutely the most important lead I could imagine. So I made it my business when it came to deciding what I was gonna do after my medical training is to come back, is to come to NIH and work with those guys, and I was fortunate enough to be able to do that. And it was, it was really in the era where what was called the Fre- what was called the Fredrickson typing system-

   9. PAPeter Attia44:19

      Mm-hmm

   10. RKDr. Ron Krauss44:19

       ... uh, identified these various forms. And the one you just referred to, the genetic forms of lipids that, uh, we don't often always consider, it was called type three, and that, uh, was characterized by abnormalities in receptor-mediated clearance of these remnant particles through, uh, a mutation in apoprotein E or variant apoprotein. And, and that also was fascinating. I happened to be in California when the ApoEs were discovered. So I sort of feel like, uh, uh, one of these characters that just, you know, shows up at the appropriate time. [both laughing] Uh, uh, it was called the argirigpeptide initially. The, the history is just... I, I wrote a, uh, we wrote a review actually of the early history of lipoprotein research, which I would commend to the audience here.

   11. PAPeter Attia45:00

       Let's put that on the list here.

   12. RKDr. Ron Krauss45:01

       It was in the Journal of Lipid Research in two thousand and sixteen. In fact, I just got a fan letter for that article-

   13. PAPeter Attia45:05

       Okay

   14. RKDr. Ron Krauss45:06

       ... because, um, anybody that's seriously interested in this field should probably understand the origins. In fact, I got a letter after that paper was published. I got an email from Joe Goldstein, who was the other, one of the other-

   15. PAPeter Attia45:16

       Oh, yeah. Another luminary

   16. RKDr. Ron Krauss45:17

       ... icons in the field, who said, he, he said, "Every- everybody that goes into lipid research should read this paper." So I'm, I'm gonna... Uh, it's not a book. I don't make any money off of it, but-

   17. PAPeter Attia45:26

       We're, we're gonna make sure that the, the, the, the people who wanna get smart on this read it.

   18. RKDr. Ron Krauss45:30

       Anyway, paying back to these remnants, I think particle for particle, the remnants are probably the most pathologic particles of all because of this rampant atherosclerosis when there's, uh, elevation of remnants. You know, fortunately, uh, this condition of type three is fairly rare. It's like one in ten thousand.

   19. PAPeter Attia45:45

       Yeah.

   20. RKDr. Ron Krauss45:45

       But it does illustrate the, the pathology.

   21. PAPeter Attia45:46

       I've seen that.

   22. RKDr. Ron Krauss45:47

       Yeah, I've seen seve- you know, so-

   23. PAPeter Attia45:48

       So you've seen several.

   24. RKDr. Ron Krauss45:49

       Right. So, uh, yeah, what I was trying to say, I, actually, initially, what I was trying to say when I was at NIH in my training, I saw all these things. You know, all the types were there.

   25. PAPeter Attia45:56

       You, you collected them.

   26. RKDr. Ron Krauss45:57

       Yeah.

   27. PAPeter Attia45:57

       Yeah.

   28. RKDr. Ron Krauss45:57

       We had patients who had the type three. We had type one, which was a serious elevation of triglyceride. Type two was familiar hypercholesterolemia. Uh, it goes on and on. So, uh, uh, yes, and, and it's, and it's really, uh, striking. Um, I tell my students, I, I lecture on this to, uh, students at Berkeley, and I show them pictures of, of what are called xanthomas, which are, you know, deposits of cholesterol and lipids and tissues, and you have these very characteristic lesions that used to be rampant in patients before we had adequate recognition and treatment as a manifestation of the underlying pathology that also affects the arteries. The cholesterol that winds up in the arteries can also break into the skin.

   29. PAPeter Attia46:37

       Mm-hmm.

   30. RKDr. Ron Krauss46:38

       And these are just very striking, uh, illustrations of, of the role of genetics. So it gets back to your earlier question about causality. There are so many situations where, where genetics helps in establishing causality, and this, this certainly is, is one of them. Uh, after that, you asked me [chuckles] what, what are, you know, one, two, and three, right? You asked me how many, what my, my top three are.
10. 52:14 – 1:02:32

    LDL Particle Size Versus Number and the Sortilin Variant

    1. PAPeter Attia52:14

       Let's go back to something else you said a few moments ago that I think is... I would say ten years ago, I don't remember when Jim Otvos' analysis came out, but Jim, who's an incredibly thoughtful person in this field, wrote a paper that basically said, "Once you normalize for the number of LDL particles, the size doesn't matter."

    2. RKDr. Ron Krauss52:37

       Yeah.

    3. PAPeter Attia52:37

       Now, a moment ago, you said that your intuition is that actually that's not correct, that particle for particle, a small particle is more atherogenic. Is that a fair assessment of your thought?

    4. RKDr. Ron Krauss52:49

       It, it is, it is definitely an assessment of my thought, and unlike what we've just been talking about, we, we don't have a way showing incontrovertibly that that's true. So one tries to sort of dance around this question by using statistics. Can you use statistics to factor out everything with which the particle size... And, and, and let me clarify one other thing before I go on, and that is the reason particle size got on the map was that r- I wrote a paper, I think in the '80s actually, probably thirty-plus years ago, in which the only test we had was particle size measurement, and we showed that particle size, small particle size is related to risk, but we also said it was associated with lower HDL and higher triglycerides, so that was the definition of this triad-

    5. PAPeter Attia53:31

       Mm-hmm

    6. RKDr. Ron Krauss53:31

       ... that we just talked about, and we never said that the particle size was independent. We never actually said that. We never said it was related to independently to risk. It was a marker for this whole syndrome. The particle size context that I was referring to early on in our discussion today was not the size of the particles but the numbers of particles of differing sizes, and that's a somewhat different concept. So there are techniques that measure, uh, that give a number for whether most of the LDL in the blood is larger or smaller.

    7. PAPeter Attia53:59

       And we typically d- bifurcate this at, like, something like twenty point five nanometers-

    8. RKDr. Ron Krauss54:03

       Right, right

    9. PAPeter Attia54:03

       ... or something like that.

    10. RKDr. Ron Krauss54:03

        And the other thing I'm going to say because, uh, this is lo- [chuckles] I'm going to say it because there's an opportunity to say it.

    11. PAPeter Attia54:08

        [chuckles]

    12. RKDr. Ron Krauss54:09

        If, if, if you measure, uh, those particle sizes correctly, the distribution in the population is bimodal. That means there is a discrete subset of the population that has smaller LDL particles. Now, that says nothing about their heart disease risk. That just, that says that there's something going on that tips in a quantum way towards the small LDL trait, and that is the marker for the metabolic syndrome. So that's not about heart disease risk. That's a metabolic marker. The heart disease risk depends on the magnitude of that Small LDL mode. If you have a lot of, if you have a lot of LDL particles that are small, that's bad. Now, the argument that Afos and others have made using statistics that I will come back to in a minute as to why I think this is a flawed approach, is that the, if you do certain statistical, uh, corrections for interrelationships of various particles with each other, there is a significant relationship to risk of larger LDL as well. So that's not untrue. A larger LDL can be bad for us because-

    13. PAPeter Attia55:13

        I mean, if I recall, as long as something's less than seventy nanometers, it can enter the subendothelial space. So-

    14. RKDr. Ron Krauss55:20

        Yeah

    15. PAPeter Attia55:20

        ... any small... any large or small LDL-

    16. RKDr. Ron Krauss55:22

        That's right

    17. PAPeter Attia55:22

        ... can enter the space.

    18. RKDr. Ron Krauss55:23

        So, so it gets back to residence time.

    19. PAPeter Attia55:25

        Yes.

    20. RKDr. Ron Krauss55:25

        Um, and-

    21. PAPeter Attia55:25

        How long do they stay? How likely-

    22. RKDr. Ron Krauss55:26

        That's right

    23. PAPeter Attia55:26

        ... are they to retain?

    24. RKDr. Ron Krauss55:27

        So, so, so it turns out [chuckles] this is, so this is going to be a little bit complicated, but I'm gonna try... You, maybe you can help me-

    25. PAPeter Attia55:32

        We-- No, no, we, we have an audience that's willing to handle complicated, yeah.

    26. RKDr. Ron Krauss55:36

        He- Help me work, help me work through this with you because I, I know what I wanna say, and I just wanna make sure that I say it clearly. Let's talk about larger LDL, so this, in this large LDL mode. That signifies, um, sort of the flip side of metabolic syndrome. It generally identifies people who have not only larger LDL, but, uh, higher HDL cholesterol and lower triglyceride. So that's a low-risk syndrome.

    27. PAPeter Attia56:00

        And often low insulin.

    28. RKDr. Ron Krauss56:01

        Uh, that's, that's right. [chuckles]

    29. PAPeter Attia56:03

        Yeah.

    30. RKDr. Ron Krauss56:03

        And so quite apart from the question, are these particles better or worse, they signify a metabolic profile where there's a pretty brisk circulation of those particles, and the exposure to, uh, the artery wall is very low. Now, if you have an LDL receptor defect, it also causes large LDL. Large LDL accumulate-
11. 1:02:32 – 1:16:43

    Can LDL Be Too Low? Cholesterol Synthesis and Statin Off-Target Effects

    1. PAPeter Attia1:02:32

       So let's go back to something that you've kind of touched on a little bit, which is can LDL cholesterol/LDL particle/APOB be too low? And, and I'm referring specifically to a pharmacologic intervention.

    2. RKDr. Ron Krauss1:02:47

       Mm-hmm. Mm-hmm.

    3. PAPeter Attia1:02:48

       So I think we've already established that the people so genetically blessed to have hypofunctioning PCSK9 seem to be completely fine. But if someone came along and said, "Look, I'm walking around at the thirtieth percentile of the population. I want to walk around at the first percentile of the population. I'm gonna pharmacologically lower it."

    4. RKDr. Ron Krauss1:03:08

       Right.

    5. PAPeter Attia1:03:08

       Is there a downside?

    6. RKDr. Ron Krauss1:03:09

       Right. So I guess I'm, I'm hung up on genetics today because I think the best, uh, scenario to consider in evaluating the pros and cons of very low LDL are genetic syndromes associated with very low LDL. We just talked about one of them. So PCSK9 loss-of-function mutations are an example of what you're asking. Those, those individuals have lifelong exposure to very low LDL and, as far as we can tell, do fine. There are people who have abnormalities in the APOB protein that results in, uh, impaired production of LDL ultimately, uh, and most people do very well. Not only have less heart disease, they tend to live longer. So this is the genetic evidence for the safety and the benefit really of having very low LDL. That doesn't imply that we can extrapolate those genetic observations to all, uh, treatments. Now, for the PCSK9 inhibitors, if we assume that the use of the antibodies that lower PCSK9 therapeutically mimic the genetic effect, then one would have the same confidence that this would not be hazardous. Uh, we don't yet know that there are not other effects of these antibodies that may not necessarily fully mimic the genetic effect. But by and large, I think it is a vote of confidence that those treatments that lower L- that that particular treatment with PCSK9 inhibition, uh, probably does not only lower risk, but have no significant downsides in, in related to the LDL lowering. But we don't know... The clinical trials of any of the drugs that lower LDL, uh, have not been long enough to know, uh, what the lifelong effects might be.

    7. PAPeter Attia1:04:43

       So if you look at the most widely prescribed class of drugs for lipid lowering, it's obviously gonna be statins. And statins really do two things. You know, they have a direct effect, which is they inhibit the first committed step of cholesterol synthesis, and so that directly lowers the burden of cholesterol, thereby lowering the burden of lipoprotein. But in many ways, their indirect effect is at least as strong, which is the liver, in response to this, upregulates the LDL receptor, and you get enhanced clearance. Now, the latter, we certainly have a genetic model to look at. Do we for the former? Uh, do we know of people who have deficient cholesterol synthesis? I mean, outside of the extreme, we know that there are certainly inborn errors of metabolism-

    8. RKDr. Ron Krauss1:05:29

       Right

    9. PAPeter Attia1:05:29

       ... that are uniformly fatal.

    10. RKDr. Ron Krauss1:05:30

        That Smith-Lemli-Opitz syndrome. [chuckles]

    11. PAPeter Attia1:05:31

        Yeah, yeah, yeah. But, but, but sort of outside of those people-

    12. RKDr. Ron Krauss1:05:34

        Yeah

    13. PAPeter Attia1:05:34

        ... are there people walking around with low cholesterol where the defect is in cholesterol synthesis that would give us confidence that, "Hey, inhibiting cholesterol synthesis can't be that bad"?

    14. RKDr. Ron Krauss1:05:43

        I'd have to say I don't know that there is such a genetic variant. There are genetic variants in the rate-limiting enzyme, HMG CoA reductase, that is the target of statins, that affect LDL levels and heart disease risk in the expected direction. Uh, but those variants are, uh, have a modest effect size. They are not big-time-

    15. PAPeter Attia1:06:04

        Mm-hmm

    16. RKDr. Ron Krauss1:06:04

        ... players to knock down LDL to those same very low levels. That, that's what makes the PCSK9 story so exceptional. There's just nothing quite like it. Uh, so the answer is, to my knowledge, no, we don't have that kind of evidence that would apply to very low LDLs that are induced by genetic factors other than-

    17. PAPeter Attia1:06:24

        And, and that's a scenario that I, I think I clinically struggle with, and I, I suspect there's gonna be at least one other person listening to this that's gonna share that struggle, which is I do get a little bit nervous when I have a patient whose risk of atherosclerosis is so high, for example, a patient with significant family history and a very elevated LP little A, just as an example. So you've got, you know, and you know I seem to collect these patients. [chuckles] So you've got these folks, and They've got a clinical burden of disease. So they've, you know, they've, their CT angiogram shows soft plaque, their calcium score shows that they've got calcifications, their Lp (a) is through the roof, and they're tolerating their statins, meaning they don't have the myalgias or CK elevations or any of those things. But to get their LDL where it needs to be, in a patient like that, I'm going to put to the fifth or tenth percentile, I have effectively, by all means that I can measure, almost shut off cholesterol synthesis. In those patients, I panic because of a couple of papers that I've seen that look at the opposite end of the spectrum, which is, you know, they look at markers of cholesterol synthesis in patients who are medicated and then the risk of dementia. In particular, there's a paper that looked at desmosterol levels, and it found that if the level was below .5, which is, you know, generally very low on the scale we look at, and they use that as a cutoff on the receiver operating characteristic curve, the area under that curve, which again can vary from somewhere between about zero point five to one, zero point five meaning it's a useless test, it's a coin toss, one is a perfect test, you know, they're coming in with, with AUCs of the ROC at .87, .89. That's quite suggestive of this. And, and certainly biochemically there's a plausibility to this, right? We understand that every tissue in the body has the ability to borrow cholesterol from elsewhere. That doesn't appear to be the case in the brain. The lipoproteins don't seem to, you know, be able to traffic across the blood-brain barrier. So I guess that's just one area where I certainly don't know an answer, but I, I've become, I think, clinically much more quick to move people to PCSK9 inhibitors when I get uncomfortable with the degree of cholesterol synthesis. Do you think I'm paranoid?

    18. RKDr. Ron Krauss1:08:39

        You've opened up a big topic all by itself, I think, and that is the off-target effects of cholesterol. If we consider the target, that's not even the proper term. It's the off-tissue target because the, it's the tissue targeting of statins to, uh, the liver inhibiting HMG CoA reductase in the liver that is the therapeutic goal, uh, and-

    19. PAPeter Attia1:09:00

        That's right. That's, that's actually all you're really trying to do.

    20. RKDr. Ron Krauss1:09:03

        That's right.

    21. PAPeter Attia1:09:03

        But we can't. We have to hit all of these peripheral tissues as well.

    22. RKDr. Ron Krauss1:09:06

        Well-- Oh, that's right. So there's something called pharmacokinetics. So for the last, uh, sixteen or seventeen years, uh, I have been leading a program in studying statin pharmacogenetics, which is-

    23. PAPeter Attia1:09:16

        I just want to explain this again because I know you and I are sitting here in this session, we understand this, but I want to make sure the listener understands-

    24. RKDr. Ron Krauss1:09:20

        Okay

    25. PAPeter Attia1:09:20

        ... the point you just made. It's so important. In an ideal world, a statin would be a dream drug if it only inhibited cholesterol synthesis, meaning HMG CoA reductase activity in the liver such that the liver would upregulate and you wouldn't impact peripheral tissue metabolism, uh, cholesterol metabolism, you know, for example, in the brain and the muscles-

    26. RKDr. Ron Krauss1:09:42

        Right

    27. PAPeter Attia1:09:42

        ... et cetera. Unfortunately, that's not the case. So-

    28. RKDr. Ron Krauss1:09:45

        Right

    29. PAPeter Attia1:09:45

        ... I'll let you continue.

    30. RKDr. Ron Krauss1:09:45

        Right. So this has to do with, uh, me, uh, with at least my exposure to, uh, this set of issues through the, the world of pharmacology. So I have been hanging out with pharmacologists-
12. 1:16:43 – 1:24:15

    Statin Myalgias, CoQ10, and Long-Term Unknowns

    1. PAPeter Attia1:16:43

       Yeah. I think for me, I am... I mean, I sort of d- you know, talk to patients and I say, "Look, I think there are short-term things that we're generally gonna figure out in three months, which is myalgias, plus or minus a CK elevation."

    2. RKDr. Ron Krauss1:16:53

       Right. Right.

    3. PAPeter Attia1:16:53

       So either your, you know, your muscles are gonna get sore with or without a ch- an elevation in CK, which is a way that we can measure the breakdown of muscle, and changes in your liver function tests. We look for those elevations.

    4. RKDr. Ron Krauss1:17:03

       Mm-hmm.

    5. PAPeter Attia1:17:03

       I don't know about you, but I see a lot more LFT bumps when combined with Zetia than just statin alone.

    6. RKDr. Ron Krauss1:17:08

       Hmm. Hmm.

    7. PAPeter Attia1:17:08

       I find a lot of patients I have that tolerate any dose of a statin-

    8. RKDr. Ron Krauss1:17:12

       Hmm

    9. PAPeter Attia1:17:13

       ... then you add Zetia, it seems to me like-

    10. RKDr. Ron Krauss1:17:15

        Right

    11. PAPeter Attia1:17:15

        ... twenty percent of people just immediately have an LFT bump.

    12. RKDr. Ron Krauss1:17:18

        I haven't seen it that often, but I have s- I have seen it, yes.

    13. PAPeter Attia1:17:21

        Um, and then I talk about the long-term stuff, which is actually, I think, in many ways what we should be more concerned with-

    14. RKDr. Ron Krauss1:17:26

        Right

    15. PAPeter Attia1:17:26

        ... because the short-term stuff, like you, you figure that out-

    16. RKDr. Ron Krauss1:17:28

        Right

    17. PAPeter Attia1:17:28

        ... in ten seconds, right?

    18. RKDr. Ron Krauss1:17:29

        Right. Right.

    19. PAPeter Attia1:17:29

        But it's the... And the diabetes doesn't worry me as much for all the reasons you've said-

    20. RKDr. Ron Krauss1:17:33

        Right

    21. PAPeter Attia1:17:33

        ... which is it doesn't sneak up on you-

    22. RKDr. Ron Krauss1:17:35

        Right

    23. PAPeter Attia1:17:35

        ... and you can measure the progress.

    24. RKDr. Ron Krauss1:17:36

        Right.

    25. PAPeter Attia1:17:37

        But for... Maybe I'm being overly cautious, and I've had many an argument with many a cardiologist that I share patients with, who, you know, will have a patient on a maximum dose of a statin. You know, I'll give you one example. I've got a patient who came to me on eighty milligrams of Lipitor, still wasn't quite at goal. We added the ten of Zetia, so then he was at goal, and given his burden of disease, goal for this guy is about, uh, seven hundred nanomole per liter of LDLP. But, you know, he had no cholesterol synthesis that we could speak of. So put him on a PCSK9 inhibitor. That took his LDL down to like two hundred [chuckles] nanomole per liter. So I said, "Great, let's back off the Lipitor." And his cardiologist just thought-

    26. RKDr. Ron Krauss1:18:19

        Huh

    27. PAPeter Attia1:18:19

        ... like I w- this was malpractice.

    28. RKDr. Ron Krauss1:18:21

        Hmm.

    29. PAPeter Attia1:18:22

        And, uh, you know, it took many a discussion-

    30. RKDr. Ron Krauss1:18:24

        Right
13. 1:24:15 – 1:33:44

    Statins, Inflammation, and Primary Prevention Evidence

    1. PAPeter Attia1:24:15

       What do you make of the evidence for and against the case that... And this is not a common argument, but it is one that's, that shows up enough, which is, okay, statins do reduce events, but it's not by lowering LDL.

    2. RKDr. Ron Krauss1:24:29

       Right.

    3. PAPeter Attia1:24:29

       That's a-

    4. RKDr. Ron Krauss1:24:30

       Right

    5. PAPeter Attia1:24:30

       ... an unintended consequence or an intended consequence that is true, true, and unrelated, but the benefits of statins actually come from the endothelial health and or inflammatory reduction.

    6. RKDr. Ron Krauss1:24:44

       Right. So this is another deep topic, [chuckles] which is obviously clinically important that people understand what it is they're treating and why. It gets back to a couple of issues. One is the causality of LDL, which we discussed a, a while ago. LDL is causal. That's established beyond doubt. So the benefits of drug-induced LDL lowering, let's say statins Have to be considered as operating in part through that mechanism. Otherwise-

    7. PAPeter Attia1:25:14

       Right. Let, let's at least concede that in part, that's-

    8. RKDr. Ron Krauss1:25:16

       Other- otherwise you're just-

    9. PAPeter Attia1:25:17

       Yeah, yeah

    10. RKDr. Ron Krauss1:25:17

        ... ignoring reality. So that's number one. Number two is, is that the m- is it the most important factor? Is it the only factor? And the answer is, it's certainly not the only factor. There's no doubt, in my mind anyway, [chuckles] uh, I'm not sure how much of this is opinion versus, um, evidence, but well, there are certainly anti-inflammatory effects, and there's a, and there's a lot of work that a good friend, Paul Ridker, has been involved with, uh, to help establish-

    11. PAPeter Attia1:25:39

        Paul Ridker's at NIH.

    12. RKDr. Ron Krauss1:25:40

        No, he's at, uh, uh-

    13. PAPeter Attia1:25:41

        Or he's at Brigham

    14. RKDr. Ron Krauss1:25:42

        ... he's at Brigham.

    15. PAPeter Attia1:25:42

        Okay. Yeah, yeah.

    16. RKDr. Ron Krauss1:25:43

        You know, uh, e- early on establishing, uh, the importance of C-reactive protein as a marker for inflammatory, uh, risk, um, not just of heart disease, but-

    17. PAPeter Attia1:25:52

        And, and we should detour on that topic 'cause it's so important, right? There was a recent trial that looked at low dose of methotrexate-

    18. RKDr. Ron Krauss1:25:58

        That was-

    19. PAPeter Attia1:25:58

        Which is an, that's-

    20. RKDr. Ron Krauss1:25:59

        No, it was an IL, it was interleukin-1-

    21. PAPeter Attia1:26:01

        Well, weren't there two? There was the IL-1 and-

    22. RKDr. Ron Krauss1:26:02

        Yeah, the, the methotrexate isn't out yet.

    23. PAPeter Attia1:26:04

        Oh, okay. Maybe I'm just, uh-

    24. RKDr. Ron Krauss1:26:05

        It's, it's the other one.

    25. PAPeter Attia1:26:06

        Okay. Okay.

    26. RKDr. Ron Krauss1:26:06

        The, the other one's out.

    27. PAPeter Attia1:26:07

        Yeah.

    28. RKDr. Ron Krauss1:26:08

        Yeah. Uh, the, the, it used a, an interleukin-1 receptor-

    29. PAPeter Attia1:26:10

        It was one or six. Yeah, yeah, yeah.

    30. RKDr. Ron Krauss1:26:12

        Yeah, one receptor.
14. 1:33:44 – 1:40:45

    Statins in Older Age, Cognition, and the ATP Guidelines

    1. RKDr. Ron Krauss1:33:44

       No, as a matter of fact-

    2. PAPeter Attia1:33:45

       I'm teasing. I'm teasing

    3. RKDr. Ron Krauss1:33:46

       ... quite, quite the opposite. I've, I've put it in a part of my brain that, uh-

    4. PAPeter Attia1:33:49

       [laughs]

    5. RKDr. Ron Krauss1:33:50

       ... has, has, has made me not forget. That there can be effects, uh, that are, are long term that we simply can't assess easily, and so one of them could be cognitive function. But, uh, having said that, there's no, no evidence, and in our consensus paper that just came out on statin intolerance, no evidence, really-

    6. PAPeter Attia1:34:07

       Well, at the population level-

    7. RKDr. Ron Krauss1:34:08

       There's-

    8. PAPeter Attia1:34:08

       ... I would say it's the opposite. At the population level, I think we see that the risk, if anything, goes down a little bit.

    9. RKDr. Ron Krauss1:34:13

       Yeah, and there's a, a cardiovascular... There's a vascular-

    10. PAPeter Attia1:34:15

        That's exactly right

    11. RKDr. Ron Krauss1:34:16

        ... element to that.

    12. PAPeter Attia1:34:16

        Right.

    13. RKDr. Ron Krauss1:34:17

        There's a vascular element that even contributes to, to classical Alzheimer's disease. But again, the data are really not compelling. Uh, they're not compelling-

    14. PAPeter Attia1:34:24

        No, this is the challenge

    15. RKDr. Ron Krauss1:34:25

        ... in either direction.

    16. PAPeter Attia1:34:25

        This is person-

    17. RKDr. Ron Krauss1:34:26

        Right

    18. PAPeter Attia1:34:26

        ... personalized medicine means-

    19. RKDr. Ron Krauss1:34:27

        That's right

    20. PAPeter Attia1:34:27

        ... at the end, I don't care about the population. I care about the one person sitting in front of me at this moment-

    21. RKDr. Ron Krauss1:34:32

        Exactly

    22. PAPeter Attia1:34:32

        ... when we have to make a decision.

    23. RKDr. Ron Krauss1:34:33

        Exactly. Exactly. But what's intriguing and what you've-- what your, what your question opened up, and I have to be careful, uh, because, um, I don't wanna go down the rabbit hole on this one. To the extent that statins influence mechanisms that interact with cholesterol transport in the brain, an Apo protein E, uh, which we mentioned is a variant that causes type 3 hyperlipidemia. Apolipoprotein E is, is a key protein that has a variant, another variant that increases the risk for Alzheimer's disease. Well, we're looking at ways that cholesterol metabolism intersects with that pathway and, um, and conceivably, that's just one example of a gene that could interact with statins. And if the, a-and if the statins are getting past the blood-brain barrier in some cases, and inflammation might be a factor that could predispose to that, you could start to have i-imagined effects that could go either way but, but could perhaps potentiate dysfunction. That's just a completely off the, you know, o-out of left field-

    24. PAPeter Attia1:35:31

        No, no, look, I mean, that's exactly-

    25. RKDr. Ron Krauss1:35:33

        Yeah. Yeah

    26. PAPeter Attia1:35:33

        ... I mean, that's-

    27. RKDr. Ron Krauss1:35:33

        Yeah

    28. PAPeter Attia1:35:33

        ... that's sort of the hand-waving that I use, right?

    29. RKDr. Ron Krauss1:35:36

        Right. Right.

    30. PAPeter Attia1:35:36

        So when I have patients-
15. 1:40:45 – 1:53:36

    Niacin, the HDL Paradox, and Who Still Benefits

    1. PAPeter Attia1:40:45

       I could continue this discussion probably for six more hours, but, uh, there is one other thing I want to go back to that we did talk about, and I, I think it's the niacin question. I, I-

    2. RKDr. Ron Krauss1:40:53

       Right. You haven't forgotten that one.

    3. PAPeter Attia1:40:54

       No, I sure have not.

    4. RKDr. Ron Krauss1:40:56

       [laughs] Sorry.

    5. PAPeter Attia1:40:58

       So what does niacin do, right? So first of all, I don't think anybody actually really understands the mechanism by which niacin lowers ApoB. Do-- I mean, is that, is that generally-

    6. RKDr. Ron Krauss1:41:05

       Uh, yeah. It, it-- That's right. I, I would say that's a fair statement.

    7. PAPeter Attia1:41:08

       But, but niacin is a drug that lowers LDL, particle cholesterol. It also raises HDL cholesterol quite significantly. In fact, I've seen it raise HDL cholesterol more than I've seen anything in those CETP inhibitors. So it seems like the dream drug. It's doing everything right. Now, it does also create some insulin resistance, and it seems to do that at a higher level than even statins do. But-

    8. RKDr. Ron Krauss1:41:30

       Mm-hmm

    9. PAPeter Attia1:41:31

       ... do you think that that's the explanation for why the hard outcome data aren't there and why niacin has fallen so far out of favor that... You know, I actually called in niacin for a patient about a year ago. It was, uh, we were kind of doing an experiment. He couldn't tolerate a statin, couldn't afford a PCSK9 inhibitor. You know, we were really reaching for straws, and we couldn't even get niacin for him. I mean, we literally couldn't even get his insurance company to pay for niacin. So it is persona non grata. Help me understand that.

    10. RKDr. Ron Krauss1:41:57

        Okay. So my disclosure is I still use a lot of niacin. So why do I do that if, in the light-

    11. PAPeter Attia1:42:03

        Mm-hmm

    12. RKDr. Ron Krauss1:42:03

        ... of all of these trials? So, uh, let me just back up then and say that the trials, the high-profile trials that led to the, uh, dismissal of niacin as a therapeutic option, one was, uh, AIM HIGH-

    13. PAPeter Attia1:42:16

        AIM HIGH

    14. RKDr. Ron Krauss1:42:17

        ... and the other was, uh-

    15. PAPeter Attia1:42:18

        It wasn't improved

    16. RKDr. Ron Krauss1:42:19

        ... HPS2.

    17. PAPeter Attia1:42:19

        Yeah, yeah.

    18. RKDr. Ron Krauss1:42:20

        HPS2. Both involved the following criterion, and that is niacin was tested as an HDL-raising agent in the setting of LDL being at a low level as a result of intensive statin, plus or minus ezia, uh, to bring LDL cholesterol levels to a low enough level that it would be considered a non-factor. That is, that the niacin effect due to LDL would be minimized, whereas the HDL-

    19. PAPeter Attia1:42:50

        Right. In other words, how do we assess the level of niacin exclusively on its HDL-raising properties-

    20. RKDr. Ron Krauss1:42:55

        That's right

    21. PAPeter Attia1:42:55

        ... because we've maximized LDL lowering?

    22. RKDr. Ron Krauss1:42:57

        That's right. So it w- they were designed to test whether the HDL increase with niacin is beneficial, and the answer is, from those trials, I'd say unequivocally no. That is, the HDL-raising effect of niacin is not protective. That, that's the conclusion to take away. That In my view, was beating, uh, maybe not a dead horse, but a pretty sick one because I never really was totally convinced that, that raising HDL itself would be, would be beneficial, even though I was part of the earliest study that showed that if you genetically treat mice with, uh, uh, given the gene that raises HDL, uh, you can reduce atherosclerosis. I mean, there is a protective effect, but I was of the opinion that the association of HDL cholesterol across a population with risk fell into the same category as the LDL, small LDL story and the triglyceride story. It's part of a interrelated metabolic syndrome, and I felt that the most important pathologic features of that syndrome are not low HDL, but the high levels of small LDL and, and triglycerides. And, and both of those components have been, not just the LDL, but the triglyceride-related risk, have been pretty clearly shown to be causal, and the HDL was a marker for that. That, that was a-actually my, my guess, just based on my being-

    23. PAPeter Attia1:44:18

        And there could be another issue here, right? Which is to raise... I mean, there are, there are known, uh, you know, HDL lipoproteinemias where very high HDL is actually atherogenic because they're so dysfunctional, they can't actually delipivate, right?

    24. RKDr. Ron Krauss1:44:32

        Exa-exactly. So the simple-minded idea that raising HDL by any means would be beneficial, just like lowering LDL by any means would be beneficial, was disproven by those studies. Um-

    25. PAPeter Attia1:44:43

        Plus all of the CETP inhibitors.

    26. RKDr. Ron Krauss1:44:45

        That's right. None of the CETP inhibi- right. And so there's something fundamentally pathologic about, uh, that effect on HDL that overrides any potential, uh, benefit that may be due to other factors. And in the case of the two major, uh, niacin trials, you know, there was some lowering of, of LDL, but as you point out, the HDL, uh, increase was, was fairly substantial. And, and those particles are basically hung up in plasma. It gets back a little bit to this resonance time issue that I was talking about regarding LDL. Well, here's the situation for HDL, where these particles are just-- it's sort of like the, the toilet is plugged.

    27. PAPeter Attia1:45:22

        Yeah. You, you prevent them from doing their job.

    28. RKDr. Ron Krauss1:45:24

        Right. So you're not delivering cholesterol as efficiently back to the liver for excretion, and those particles are hanging around long enough that who knows what properties they may be acquiring, uh, that might possibly, uh, override, um, some of the benefits of the, uh, LDL-lowering effect. So does that mean that niacin has, has no benefit? Well, there was a study that preceded those two studies, uh, that was carried out by Greg Brown and actually was one that led to the AIM-HIGH study being funded by the NIH, and that was called HATS, a-HDL, uh, atherosclerosis, HDL Atherosclerosis Treatment Study, H-A-T-S. And that was a study-

    29. PAPeter Attia1:46:03

        Almost as good as MR FIT, which I realize now is the one I was forgetting-

    30. RKDr. Ron Krauss1:46:07

        Oh, that one
16. 1:53:36 – 1:56:10

    Closing Remarks and Future Topics

    1. PAPeter Attia1:53:36

       Well, and, and with that, Ron, I wanna say-

    2. RKDr. Ron Krauss1:53:38

       Okay

    3. PAPeter Attia1:53:38

       ... you know, first of all, just I consider you a great friend and an unbelievable mentor. I feel so fortunate to have benefited from your knowledge, uh, and, and, and peers of yours over the last, uh, decade, and your generosity is, is unparalleled in terms of anytime I can pick up the phone and call you and run a tough case by you, you're, you're always there to do so. So I greatly appreciate that. I also think we need to do this again sometime because I literally have twice as many questions as we've got to. I wanted to get into saturated fat, fructose, ApoE. There's all these other things that I know you are just an expert on that I, I know people are gonna wanna hear about. So I'm gonna have to come back to San Francisco-

    4. RKDr. Ron Krauss1:54:19

       Right

    5. PAPeter Attia1:54:19

       ... and we'll have to continue this discussion, uh, hopefully during the Warriors off-season.

    6. RKDr. Ron Krauss1:54:23

       [laughs] Happy to do that, Peter, and, uh, thank you for your kind words. Uh, and, uh, it's been a pleasure talking with you. I, I think the opportunity to help people understand some of these complex issues is something you've been very good at, and I've been glad to c- uh, be able to contribute to that.

    7. PAPeter Attia1:54:38

       Thank you so much, Ron.

    8. RKDr. Ron Krauss1:54:39

       Okay.

    9. PAPeter Attia1:54:42

       You can find all of this information and more at peterattiamd.com/podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at peterattiamd.com. What's a Nerd Safari, you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once-a-week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID peterattiamd. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer, this podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and/or advise, please visit peterattiamd.com/about.

Episode duration: 1:56:13