The Peter Attia Drive - #129 - Tom Dayspring, M.D.： The latest insights into cardiovascular disease and lipidology

00:00:00.000 Hey everyone, welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.720 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay, here's

00:00:48.080 today's episode. My guest this week is Dr. Tom Dayspring. This name is probably familiar to some

00:00:55.020 of you because back in October of 2018, we released a five-part series with Tom. And that

00:01:00.020 set of episodes, despite being quite technical, are some of the most popular episodes we've released,

00:01:06.680 especially amongst people who really like to get serious about their understanding of

00:01:10.260 cardiovascular disease. So we wanted to have Tom back basically to pick it up where we left off.

00:01:15.680 And in this episode, we try to focus on things that have changed in the last couple of years.

00:01:21.220 And that kind of loosely fell into three categories that we probed. The first is digging really

00:01:28.040 deeper into the recognition of the importance of atherogenic lipoproteins. So kind of revisiting

00:01:34.200 the idea of what ApoB is, why it matters. And both Tom and I discuss a little bit about how our views

00:01:39.720 have changed with respect to the use of ApoB as a laboratory surrogate over LDL-P. And we get into

00:01:46.800 all of the nuance around that with respect to VLDLs, triglycerides, LP little a, et cetera.

00:01:52.720 We also get into why HDL cholesterol is a far less relevant metric, at least why we believe that

00:02:00.160 to be the case. We then pivot a little bit and talk about risk assessment. Basically, how do you

00:02:04.900 understand these metrics? How do you use these metrics? This is a lot of the clinician type stuff

00:02:10.020 here around ApoB and triglyceride rich lipoproteins. We again, revisit the idea of LP little a. And then

00:02:15.880 finally, we bring it home with some discussion around therapies. And in particular, we talk about

00:02:20.300 the continued evolution of the PCSK9s, the evolving data around omega-3 fatty acids, in particular,

00:02:28.700 some of the controversy between EPA alone versus EPA and DHA. And obviously we talk about the most

00:02:34.220 recent addition to the lipid drug story, which is a drug called bimbendoic acid, which has not been

00:02:41.820 around very long. And probably many people are not going to be familiar with that, but Tom does a

00:02:45.860 great job explaining that. Tom's a diplomat of both the American Board of Internal Medicine and the

00:02:51.820 American Board of Clinical Lipidology. He practiced internal medicine in New Jersey for 37 years, the

00:02:57.560 last 17 of which was devoted to consulting patients with lipid and cardiometabolic disorders. Between 2012

00:03:04.480 and 2019, he served as the chief scientific officer at two major cardiovascular biomarker laboratories.

00:03:10.320 Since that time, he has been working with us in our practice, primarily on the research side of

00:03:16.660 things, but also as a consultant advising on most of our cardiovascular cases. He's both a fellow of

00:03:23.360 the American College of Physicians and the National Lipid Association, the NLA. And he's an associate

00:03:28.500 editor at the Journal of Clinical Lipidology. He was also the recipient of the National Lipid

00:03:33.720 Association 2011 President's Service Award. He's authored and illustrated more manuscripts,

00:03:40.300 and book chapters related to lipids than I can count. And so without further delay,

00:03:45.680 please enjoy my conversation with my mentor and friend, Tom Dayspring.

00:03:55.540 Hey, Tom, thanks so much for making time to sit down again and talk about lipids. It's been

00:04:01.100 almost two years since we sat down for what still remains the longest podcast I've ever done,

00:04:09.260 nearly eight hours, which I believe was divided into a five-part series that is still a very popular

00:04:19.220 podcast series. And don't take this the wrong way, but I'm kind of surprised at the popularity of

00:04:25.120 that episode, given that I thought it was really geared only towards people that were really,

00:04:31.660 really diehard lipid fanatics. But it's had a broad enough appeal that I think we've agreed

00:04:38.580 mutually that it makes sense to sit down again. That was amazing. First of all, it's always great

00:04:43.640 to sit down with you, Peter, and chat about my little lipid world. But yeah, I'm shocked every

00:04:49.600 time somebody tells me we've listened to the whole series and I've done it three times and I just

00:04:55.320 can't imagine that, but I'm glad it came across pretty good. You know, one of the things I wanted

00:05:00.020 to do today, Tom, and I can promise you and all the listeners, we are not going to do this for

00:05:04.460 another eight hours today. But what I want to do today is sort of, I think, kind of pick up the

00:05:10.620 mantle from where we were a couple of years ago and talk about what's different since then. I think the

00:05:16.620 last two years has seen a number of things that are actually pretty exciting in the field of

00:05:23.580 lipidology, in the field of cardiovascular disease. Some of it's been at the really nuanced level

00:05:30.040 scientifically. Others have been, frankly, at the broader level in terms of recognition of certain

00:05:34.980 things that you've been talking about and many others. People like Alan Snyderman have been talking

00:05:39.600 about. A lot of this stuff is very clinically relevant. The way I pose this to you, and I

00:05:46.600 think this, unless you're opposed to it, the way I'd love to kind of go through this is

00:05:50.860 maybe use our time today to talk about things that are different today than perhaps they were a few

00:05:58.100 years ago and dive into those things in enough depth that everybody from the layperson to the

00:06:06.000 aficionado will have something to chew on. Yeah, that's a perfect strategy for today. Now,

00:06:11.120 there's no doubt we'll reiterate some concepts that we went over in great depth back then, but

00:06:16.380 we won't have that opportunity today. But, and you know me, Peter, I've always lived on the

00:06:21.480 cutting edge of lipidology science, leading the charge, trying to understand new concepts that come

00:06:27.320 down. But one of the great satisfactions of my career is much of what I've promulgated for the

00:06:33.760 longest time has come to fruition. And that's what's really happened in the last two years. There are

00:06:39.620 certainly some new concepts and some abandonment of some other issues, but it's just the, you know,

00:06:46.600 my whole mantra for a long time, you know, we've known each other a decade probably, is that

00:06:51.740 atherogenic lipoproteins are really the issue behind clinical atherosclerotic vascular disease.

00:06:59.660 And although many of us have known it for a while, the data has just become so overwhelming

00:07:04.700 that virtually all of the guidelines have signed on to that premise now that atherogenesis is

00:07:11.580 certainly a sterol mediated disease, but sterols are trafficked within ApoB containing lipoproteins,

00:07:19.160 which provides the vehicle that transports them into the artery wall, where they can in some start

00:07:25.300 a pathological process. So it's the recognition of atherogenic lipoproteins that is now in the

00:07:31.320 guidelines. And, you know, atherogenic lipoproteins are still diagnosed using various

00:07:37.000 cholesterol metrics, but there are things beyond LDL cholesterol matter in the guideline. And even

00:07:43.120 ApoB is certainly within every of the contemporary guidelines in the last two years. And that's,

00:07:49.980 of course, the Alan Snyderman thing that he's been harping about for a long, long time. So it's

00:07:55.900 atherogenic lipoproteins. Within that category, though, the things that are also

00:08:00.820 emerging is what contributes to the atherogenicity of an ApoB particle. Triglycerides has really taken

00:08:08.220 center stage, how they affect lipoprotein concentration and quality or functionality,

00:08:14.560 whatever adjective you want to ascribe to. It's the loss of the ability of at least the HDL cholesterol

00:08:22.880 metric to be terribly informative to us. And it's the emerging significance.

00:08:29.820 For a lot of reasons of lipoprotein little a. So those are the big areas where changes really

00:08:37.460 become important and is really useful at the bedside. Of course, pharmacology and intensity

00:08:42.880 of pharmacology has also advanced. And we'll touch a little bit on that today, I'm sure.

00:08:49.060 To sort of summarize that, we're going to talk about kind of double-clicking on ApoB slash LDL

00:08:55.500 particle, basically the atherogenic lipoproteins front and center in the pathogenesis of cardiovascular

00:09:01.680 disease. We're going to talk about the modification of our risk assessment. And I like that you brought

00:09:07.620 up HDL because I want to have a pretty interesting discussion about that. And obviously, we're going

00:09:12.480 to talk about what's happened in therapies. There have been actually quite a number of things,

00:09:16.320 including the continuation, more data around ezetimibe and PCSK9 inhibitors, much more data since

00:09:23.320 we last spoke around omega-3 fatty acids. I spoke with Bill Harris about that, but I think we can go

00:09:29.700 a little bit further. And there are a couple of other therapies. So let's start with maybe a little

00:09:36.740 bit of a reminder for people as to what ApoB is. People like you and I sometimes use ApoB and LDL-P

00:09:46.780 interchangeably as shorthand. That's not entirely correct. And when we last spoke, we probably

00:09:53.900 disproportionately spoke about the number of LDL particles. And now we're going to focus on ApoB.

00:09:59.560 So do you mind explaining what the difference is, both from a biology standpoint, but also from a

00:10:06.520 laboratory standpoint? And those are critical points, Peter, because it's one thing to talk

00:10:11.360 about ApoB. But almost what you're saying about it depends. How did you analyze it? What laboratory

00:10:17.120 metric did you order that you think is telling you something about ApoB, whatever that encompasses?

00:10:23.700 So to make a story very simple and short, you know, lipids go nowhere in aqueous plasma because

00:10:30.060 they're hydrophobic. So for a lipid to be trafficked throughout plasma, it has to attach to a protein.

00:10:36.280 Now, a few molecules of any lipid can attach to albumin, but that's not the primary way lipids

00:10:41.660 get anywhere. Serious collections of lipids, hydrophobic substances, attach to fairly significant

00:10:49.620 proteins, which solubilize them. And these Apo proteins, as they're called, proteins that wrap

00:10:56.860 collections of lipids, provide structure and stability to this macromolecule that we're going

00:11:02.960 to call a lipoprotein. So the main structural protein that enwraps lipids in our body is

00:11:09.880 apolipoprotein B. It's a 500 kilodalton molecular weight protein, so it's pretty big, and it has a

00:11:17.940 great ability to attract a lot of lipids to bind to it. But once the lipids are bound to it, this is a

00:11:24.060 water-soluble lipid transportation vehicle. There's basically one other class of lipoproteins,

00:11:31.600 and that is the HDL particles that you mentioned, and they have no ApoB on them. Their structural

00:11:37.340 protein is apolipoprotein A1, capital A dash, either Arabic or Roman number one. So right away,

00:11:45.760 we have a double classification of lipoproteins. The ApoB containing, they're often called beta

00:11:51.940 lipoproteins, or the ApoA1 are called the alpha lipoproteins. So now within that ApoB family,

00:12:01.500 it always gets a little more complex in lipidology. The two tissues in your body that can make ApoB are

00:12:07.840 the liver, hepatocytes, and of course the small intestine, which is absorbing a lot of lipids,

00:12:13.060 so it has to put them in something if those lipids are going to get into your plasma.

00:12:16.820 So the ApoB that's made in the liver is a big 500 kilodalton protein that I mentioned,

00:12:24.740 and it's called ApoB100. Now why do they add the 100 on it? Because the intestine also produces ApoB,

00:12:32.240 but it produces a truncated version that has 48% of the molecular weight of the hepatic-produced ApoB.

00:12:39.060 So that's called ApoB48. So if the liver makes an ApoB particle full of lipids, it's got one

00:12:46.320 molecule of ApoB100 on it. If the intestine makes a big lipoprotein, and it does, they're called

00:12:52.860 chylomicrons, that has one molecule of ApoB48. The intestine can put it in your lymphatics,

00:12:59.820 it enters the systemic circulation, the liver just secretes it directly. So those are the two types

00:13:06.080 of ApoB. We're not going to talk a lot about chylomicrons. They're in most people without a

00:13:10.460 pathological, genetic pathological issue. It's not your chylomicrons that are the major problem

00:13:17.580 here. They're a postprandial lipoprotein. So the liver makes these ApoB100 particles,

00:13:24.060 and they can go out, the liver can secrete them, but some of the particles that the liver secretes

00:13:29.120 can be catabolized into smaller and smaller versions, even though they're still ApoB proteins.

00:13:34.100 So if we're going to talk about the ApoB100 family, and I'm probably not going to use the

00:13:39.300 term 100 anymore, we're talking about very low-density lipoproteins, intermediate-density

00:13:46.420 lipoproteins, and low-density lipoproteins. And of course, part of the LDL family is lipoprotein

00:13:53.960 little a, if you happen to produce that. Not everybody does to significant amounts. The names of those

00:14:00.840 particles, as you know, they were originally discovered via ultracenification. So the ones

00:14:06.480 that floated on top of the tube were the very low density. The ones that sank to the bottom were the

00:14:11.200 high density, and the in-between were the IDLs and LDLs. Now, so the ApoB family is VLDLs plus IDLs

00:14:20.300 plus LDLs plus LP little a, if you have it. Well, that's true, but here's the reality. We have to

00:14:27.160 look at plasma residence times. How long do these things float around? How long are they in your

00:14:31.400 system? Because that's important, because these are the particles that have the potential to crash

00:14:35.940 your artery wall and traffic sterols and whatever else into the artery wall. The chalomicrons I

00:14:42.180 mentioned, their half-life is in minutes. Their plasma residence time, a few hours. The VLDL particles,

00:14:49.640 their half-life is two to four to six hours, depending how rapidly they're catabolized.

00:14:55.460 The IDL particles are a transient in-between particle between a VLDL and an LDL. They're

00:15:01.820 around for an hour or two. They're not, other than an unusual genetic condition, a player in this

00:15:07.580 ApoB game we're talking about. And finally, we have the LDL family. Now, LDLs have a plasma

00:15:14.280 residence time of two to five days, and there are other attributes to the LDL that determines,

00:15:20.380 is it going to just hang around for two days or five days? Clearly, the longer it hangs around,

00:15:25.020 you're going to have a lot more LDL particles than if you could rapidly clear them. So when we talk

00:15:30.900 about whatever ApoB metric you're doing, technically, you are measuring VLDLs. They're

00:15:38.360 remnants. They're smaller VLDLs, IDLs plus LDLs plus LP little a. But because of the half-life,

00:15:46.120 90 to 95% of your ApoB particles are LDL particles. So that's why many people say,

00:15:53.720 hey, ApoB is just another way of getting an LDL particle count. And that's true. Even in people

00:15:59.900 who might have a lot of remnants, the remnant particle number is quite small. It is still

00:16:06.420 way more LDL particles floating around in these people who might have these remnant VLDLs that

00:16:12.920 cause issue. Not to say a VLDL remnant might not be a very injurious ApoB-containing particle. It

00:16:19.680 certainly is in some people. But if we're looking at the number, which is the primary driving force

00:16:25.600 as to how an ApoB particle enters the artery wall, LDL is king. And that's why our metrics of ApoB or

00:16:33.880 LDL particle count are what are at the top of all the guidelines. And of course, the metric most people

00:16:40.600 use are LDL cholesterol and non-HDL cholesterol.

00:16:43.320 I mean, Tom, on a personal level, the reason I have switched to ApoB in our practice, which is

00:16:50.540 obviously heavily influenced by the work that you've discussed, the work that people like

00:16:56.060 Alan Snyderman have been doing for many years, frankly comes down to a consistency factor. So we

00:17:02.120 had historically relied on LDL-P, LDL particle number, as a concentration count. But frankly, in the

00:17:10.920 span of eight years, we went through three technologies to do that, right? Two generations

00:17:17.400 of NMR coupled with electrophoresis. And while in the end we felt the electrophoresis provided

00:17:25.240 the most accurate measurement, you always have a problem when you don't know what you're comparing

00:17:31.420 it to. So if we have Gen 1 NMR, which is probably still being used by LabCorp and Quest today, that is

00:17:42.300 probably quite inaccurate compared to Gen 2 NMR. But the percentiles, meaning the populations of people

00:17:50.840 that were measured, are still what we use to understand where someone lies. It puts you in a bit

00:17:57.960 of a dilemma as a clinician or as a patient, you want to continually upgrade your technology. In other

00:18:03.500 words, if you're talking about getting a new iPhone, you don't really care that your phone is so much

00:18:08.460 better than two generations ago's phone because all your metrics are better and there's nothing to be

00:18:14.580 gained by comparing yourself to how much better you are. But when you're talking about diagnostics,

00:18:20.480 it does matter where your reference range is and if you're moving it. So do you agree with my logic

00:18:26.520 for switching to ApoB a year ago as now being a much more homogeneous way to assess patients even

00:18:34.380 across labs? So especially now in light of COVID, we can't always use the same lab to measure ApoB.

00:18:41.540 So I might be sending a patient to one lab versus another lab and I just feel like we're getting

00:18:46.360 better results this way. Does that jive with you? No, that makes total sense. And a real important

00:18:52.440 take-home point for listeners is pick your favorite metric. Peter's right now is ApoB. Mine right now is

00:19:00.060 ApoB. And stick with it. Don't do ApoB this time in an LDL particle count via NMR. Peter didn't even

00:19:07.200 mention Quest has a particle number technique called ion mobility transfer that people, they're not

00:19:13.460 comparable. All biomarkers you should consistently try and use. Of course, the same lab, not always

00:19:20.560 possible, but the same assay. And the ApoB immunoassay is pretty standard throughout the

00:19:25.600 industry. It's not like everybody's got their own ApoB assay. The NMR can vary widely. The other big

00:19:32.260 reason to do that, consistency of results over time, is sooner or later, yourself, you're going to read the

00:19:39.880 guideline or maybe your patients are going to go. All the guidelines talk about ApoB. There is no

00:19:44.820 guideline telling you to do a NMR LDL-P or an ion mobility LDL-P. So it's another reason to just stick

00:19:52.960 with the ApoB. And I think there are less false positives with the ApoB. It's just been my personal

00:19:59.440 experience. I've been an NMR guy all my life. And as we got better and better, we just so often saw

00:20:06.620 a totally unexplainable discordance between LDL-P and ApoB. The data is overwhelming for ApoB. So I

00:20:14.320 think that's where you should be in today's world as your marker of atherogenic lipoproteins.

00:20:19.840 Yeah, I think we saw that, especially with the second generation NMR. It was almost like it had

00:20:24.380 become too sensitive. We were seeing discordance that far exceeded what the Framingham or MESA data

00:20:31.320 predicted. The discordance should have been. And that's really actually what took us to the

00:20:36.020 ion mobility assay. But again, I'm actually very, from a diagnostic and management standpoint,

00:20:42.080 I'm actually quite comfortable with where we are. I think the final point I'd add to that,

00:20:46.120 Tom, is just the economic one. Frankly, I think the cost of an ApoB is, at least in Canada,

00:20:51.900 and the only reason I know that is because Alan Snyderman is at McGill and he's been pounding

00:20:56.480 this for a while. I mean, we're talking about a $3 or $4 test. So there is no excuse for any

00:21:02.880 physician to say, we're not going to order your fancy ApoB because it costs too much.

00:21:07.900 I'm going to order the LDL cholesterol. I think that excuse has lost all of its water.

00:21:14.340 It's so true. And Alan just published a beautiful paper where he's researched the cost of ApoB

00:21:19.460 assays. Because, you know, even some of the people in the guidelines always, oh, we can't say ApoB,

00:21:24.600 it's so expensive. That's an old excuse that is no longer applicable to 2020.

00:21:29.820 So of all the technologies to quantitate atherogenic lipoproteins, ApoB is the most

00:21:36.140 affordable. And even, you know, look, labs sometimes change crazy, but if you tell a lab you want to

00:21:42.160 pay a cash price, it's really pretty cheap. Yeah. Let's go back to kind of the macro point

00:21:48.980 here around ApoB, which is a greater coalescing around the idea that ApoB concentration matters.

00:21:56.620 So I think it's very well understood that two of the biggest risk factors for cardiovascular

00:22:04.540 disease are smoking and hypertension. I don't think there is any ambiguity that cigarette smoking

00:22:10.860 and high blood pressure increase the risk of cardiovascular disease. And they both appear to do

00:22:16.900 so through a mechanism that weakens the endothelium or creates an injury to the endothelium.

00:22:22.700 The question now becomes, as you put it, Tom, how ironclad is the story that it's the ApoB

00:22:32.400 bearing particle in the presence of injured endothelium that is the Trojan horse that begins

00:22:39.960 this destructive trajectory of taking that cholesterol into the subendothelial space,

00:22:47.280 becoming retained, undergoing this chemical oxidation process, which then kicks off an

00:22:54.140 inflammatory response that paradoxically, as an attempt to repair the damage, results in what can

00:23:01.660 be a fatal injury. There are other hypotheses. For example, there are people who note, and we have,

00:23:08.100 I mean, look, I have a patient in our practice, Tom, you've weighed in on her case,

00:23:11.640 walks around with a total cholesterol of 300 and something, an LDL cholesterol of 220 milligrams per

00:23:19.540 deciliter, an ApoB of 170 milligrams per deciliter. She's in her late 60s and her coronary artery

00:23:28.040 calcium score is zero. We have elected to not treat her with any lipid lowering therapy. In other words,

00:23:34.000 there are exceptions to this. How do we reconcile that? Well, it's the human body in medicine. As you

00:23:43.180 know, not all smokers are going to come down with lung cancer or chronic obstructive lung disease.

00:23:47.980 Why not? If that's such a horrible risk factor. I try to explain this, and I've certainly seen cases

00:23:54.700 like you say, where, oh my God, if I was just going to say, give me your ApoB or whatever cholesterol

00:24:00.220 metric, you're going on three drugs right now, you've got no choice. And maybe the old days we

00:24:05.620 approach people that way, but no more. I think you have to individualize your whatever risk factors

00:24:11.540 you discover that might wind up causing atherogenesis and then figure it out. So particle number is

00:24:19.120 certainly a major factor that might force it in, but not always. Endothelial function, although you can

00:24:25.500 certainly, if you review the history of this and how do you really determine endothelial function,

00:24:31.100 not everybody has serious endothelial dysfunction who winds up with atherosclerosis. So particle number

00:24:36.700 itself in some people can just make the particles go in. I think if we take most adults, who's not going

00:24:43.420 to have a little bit of endothelial dysfunction. So I agree with you. It's a combination of something

00:24:50.060 about atherogenic particles, be it their number, endothelial dysfunction. But I'm talking more and

00:24:56.040 more now when I discuss any type of lipoprotein, I don't care which subgroup you want to talk about.

00:25:01.760 I think we certainly have to know its particle concentration, but I like to talk about particle

00:25:07.320 quality. So what are the other attributes of any lipoprotein that might contribute to its

00:25:14.080 atherogenicity or in some perhaps not understood make it relatively, it's not going to generate

00:25:21.240 atherosclerosis. And there certainly have to be things like that going on. So as we're getting

00:25:26.000 smarter, we're looking at other components of the lipoproteins that could be other proteins that are

00:25:31.760 on them. That could be their complex lipidome and trying to see, aha, can that help us discern

00:25:38.220 whether in you a given particle concentration is more worrisome than it is in the next person.

00:25:46.340 So there's a lot going on. And also from the gist of this conversation, listeners will know

00:25:52.100 atherosclerosis, atherogenesis is a multi-complex, multi-factorial disease. And that's why even when

00:26:00.280 Peter and I, if we consult on a case and we realize in this person, we have to beat up ApoB and get their

00:26:06.820 particle numbers to a more physiologic range. We don't stop once we do that. We examine in great

00:26:12.880 detail for other things that might be injuring the endothelium or the arterial wall and see are any of

00:26:18.700 those treatable or so. So we're getting a little bit smarter on lipoproteins, but there certainly

00:26:23.640 is more to it than just particle number. Do we think that there's a limit to where the benefit of

00:26:30.100 reduction becomes diminishing or even J curves in the other direction? So we discussed it in the

00:26:37.300 first episode significantly. We did so again with Ron Krauss. It wouldn't be the worst idea in the

00:26:44.720 world a couple of years from now to sit down and do it again and re-examine the data. But again,

00:26:49.300 I think the causal relationship between ApoB and atherosclerosis is as strong as virtually anything

00:26:56.260 we see in medicine for which you can't do the perfect experiment where you have to rely on natural

00:27:02.080 experiments. Nevertheless, maybe it's not entirely clear what the dose response looks like. So if you

00:27:10.300 have somebody whose ApoB is 160 milligrams per deciliter, there's a risk reduction that comes to

00:27:16.480 lowering it from 160 to 100 and lowering it from 100 to 80 and lowering it from 80 to 60. What do we know

00:27:24.460 about the risk reduction in lowering it say from 60 to 40 to 20? And I ask both what we could infer

00:27:33.180 pharmacologically and non-pharmacologically. In other words, from the Mendelian randomization

00:27:38.580 versus the pharmacologic. Well, even using pharmacologic trials and Mendelian randomization,

00:27:45.640 the concept you're going to come across with is lower is better. And with the pharmacologic thing,

00:27:52.000 we're modulating things that either have clinical trial proof that if you lower them, it's good. Or

00:27:57.180 the Mendelian randomization, looking at genes where that drug might be doing something, it works. Now,

00:28:04.280 you do need a few ApoB containing lipoproteins. They do traffic other lipids. They traffic fat-soluble

00:28:10.660 lipoproteins. But we must never confuse A-beta lipoproteinemia where nobody or that person can't make

00:28:17.920 them. Or hypo-beta lipoproteinemia where they make a few enough to traffic those other things that a

00:28:24.500 lipoprotein might have to traffic. But even the guidelines where they examine people looking at

00:28:31.280 their baseline ApoB or LDL cholesterol, the first thing they suggest, at least in the higher risk

00:28:36.800 people, is try and get a 50% reduction. And that's where most of the bang for the buck is going to be.

00:28:42.580 Now, if you still have options that you can lower it further, yeah, the trials show, yeah,

00:28:49.020 there is incremental reduction events, but it's a much smaller absolute risk reduction and dropping

00:28:55.200 at the 50% or so. So I don't know if that answers your question. So most people don't have the type of

00:29:03.220 levels where with modern therapeutics, with modern lifestyle, we can more often than not attain

00:29:11.000 physiologic concentrations. And if I want to talk about ApoB, that's probably under 50 milligrams per

00:29:17.520 deciliter if we can get there. That's what the newborns have. That's when you go in clinical

00:29:23.580 trials. If you take it down that low, you see your most risk reduction. And so far, at least with

00:29:29.400 pharmacologic lowering of ApoB with the currently FDA-approved drugs, there is no signal of harm.

00:29:36.640 Yeah, again, it's funny because I was just about to say, with the current crop of drugs,

00:29:42.920 specifically the PCSK9 inhibitors, we are routinely seeing patients who easily can get an ApoB into the

00:29:52.280 20 to 40 milligram per deciliter range. You and I actually sat down a couple of months ago and did a

00:29:59.360 calculation to estimate how much cholesterol is actually contained in the circulating lipoproteins

00:30:08.020 versus that which is in cell membranes. Do you remember doing this with me?

00:30:13.060 Not per se, but we're developing equations. You're the master of that.

00:30:19.200 Well, it was one of these things, right? It was sort of like, look, when you look at a person's

00:30:23.380 plasma glucose level, you realize pretty quickly it represents a tiny fraction of total body

00:30:30.100 glucose. And similarly, there's such a concern about plasma cholesterol level, but given how

00:30:38.200 essential cholesterol is, it's understandable why people would be concerned that low cholesterol could

00:30:43.560 be problematic. But once you do the calculation and realize virtually all of the cholesterol in the

00:30:49.280 body is contained within the cell membrane or within the steroidal producing tissue, the circulating

00:30:57.160 amount is a very narrow window into the total amount of cholesterol and therefore a reduction of say

00:31:05.260 60 milligrams per deciliter to 50 milligrams per deciliter of ApoB or even something more extreme,

00:31:13.540 like a full 50% reduction of total cholesterol, 200 milligrams per deciliter to 100 milligrams per

00:31:20.920 deciliter does not represent a significant reduction in total body cholesterol. This is a very important

00:31:26.540 point, right? Let me repeat it. You have a total body cholesterol that you measure in the plasma that

00:31:33.020 says, oh, it's 200 milligrams per deciliter. That goes down to 100 milligrams per deciliter. Let's say

00:31:38.160 the LDL fraction reduced from, you know, 150 to 75 or something. Someone might say, God, you just cut

00:31:45.040 cholesterol in half. That can't be good for you given the importance of cholesterol. But my point is,

00:31:50.820 no, you simply cut the amount of cholesterol being carried by the lipoproteins in the plasma

00:31:55.660 in half. That doesn't capture the majority of the cholesterol. Yes. Thanks for refreshing my memory,

00:32:02.400 what you're talking about now. It's really pools of cholesterol throughout the body.

00:32:07.240 And I think I'm so glad you brought this up because this is just not even understood,

00:32:12.280 even in the lipidology community. We have a total body cholesterol. There are basically three pools.

00:32:19.200 There's your brain and nothing we're talking about today has anything to do with brain cholesterol. It's

00:32:24.260 a separate system. It doesn't interact with the other cells in your body or certainly with the

00:32:29.320 cholesterol in your plasma. So if it's not in your brain, where is cholesterol in your body? Well,

00:32:34.960 it's either in all your peripheral cells, perhaps some more than others, or it's circulating in

00:32:40.720 your plasma. And if it's in the plasma, where is it? There's an itsy-weensy amount bound to albumin.

00:32:48.700 There's more bound within all of the lipoproteins that are trafficking in your body,

00:32:53.720 meaning your ApoB and your ApoA1 particles. But believe it or not, if I wanted to search down

00:33:00.160 blood cholesterol for you, I would suck out your red blood cells and extract cholesterol from them.

00:33:05.240 Red blood cells carry far, far more cholesterol than do all of your lipoproteins put together.

00:33:12.540 And the other crucial point you made subtly, and I hope everybody understood you,

00:33:17.240 the amount of cholesterol within your lipoproteins has no correlation with your cellular cholesterol

00:33:23.720 or even your red blood cell cholesterol. So however you're modulating some LDL, total cholesterol,

00:33:31.960 HDL cholesterol metric, that tells you nothing about what might you be doing to the cholesterol

00:33:37.440 content of your cells. So don't have a panic attack if you're making LDL cholesterol 30,

00:33:44.580 because I can assure you virtually every cell in your body, even if that's your plasma LDL cholesterol,

00:33:50.440 has more than enough cholesterol because it can de novo synthesize it. It can put it in its cell

00:33:56.020 membranes or other organelles that require cholesterol. If it's a steroidogenic tissue,

00:34:01.640 it can produce a little more or perhaps delipidate some. So there's no cell that's being deprived of

00:34:07.700 cholesterol in the periphery when you are modulating lipids through lifestyle or drugs.

00:34:14.220 Tom, what's the best explanation for why it's not the red blood cell that is the primary driver of

00:34:21.760 atherosclerosis, given the fact you just stated, which is red blood cells contain within them a lot

00:34:30.180 of cholesterol within their membranes. And red blood cells clearly traffic to and from past the

00:34:36.900 endothelium. I certainly have my own answer for this question. I think the histology makes it abundantly

00:34:42.920 clear, but is there any thought you would add to that? No, I think histologically we know it's foam

00:34:49.020 cells. And where do foam cells get their sterile content from ingesting oxidized lipoproteins carrying

00:34:55.780 cholesterol? Is the vasovasorum, which supplies the arterial intimate with blood cells, dumping red blood

00:35:02.640 cells in there that are contributing cholesterol? Maybe a few molecules, but I don't think we have any

00:35:08.340 evidence. It's that's a driver of cholesterol that's resulting in arterial wall pathology.

00:35:14.440 Yeah. This is one of those moments where sometimes a picture just serves a thousand words and maybe

00:35:18.760 this will be one of the best. I mean, we're going to obviously accompany this podcast with a lot of

00:35:24.300 figures and diagrams of yours, but what we're basically talking about is you have to differentiate

00:35:29.200 from the vasovasorum side, which is the non-luminal side of the vessel, where of course you have to have

00:35:36.980 blood vessels to keep the artery itself alive versus the luminal side, where the endothelial

00:35:44.440 lining is damaged by everything, including just daily life, but certainly high blood pressure,

00:35:51.040 smoking, uric acid, high glucose, high insulin, sheer forces, you name it. And that's what's allowing

00:35:57.700 these lipoproteins in. But you're right. It's really this histologic examination that makes a very

00:36:02.540 clear, unmistakable case that it's not the cholesterol in the membrane that's doing this.

00:36:10.240 It's this trafficked cholesterol that ultimately becomes a foam cell through the macrophages

00:36:16.280 ingestion of the lipoprotein that is the insult. That's a pretty good tour de force on this topic.

00:36:25.000 One more little caveat, Peter, with that vasovasorum, as you know, as you have an evolving plaque,

00:36:30.620 it gets bigger and bigger and it becomes prone to erosion or rupture and the coagulation system.

00:36:36.420 So there's nothing to say that even in a minuscule histologic rupture of a plaque that the vasovasorum

00:36:42.840 can't be contributing some clotting factors or something else to that pathological process.

00:36:48.100 It almost assuredly does. At some point, once you have damage, I would fully expect coagulation

00:36:54.140 factors to be coming from both sides, the luminal side and the vasovasorum side. It's an all-hands-on-deck

00:37:00.420 war.

00:37:00.800 And the uric acid too, probably, you know, which can crystallize just like cholesterol.

00:37:05.640 You touched on it in the outset, which is what have the guidelines stated with respect to other

00:37:15.000 lipoproteins? So if we take a step back and we went back to the early 1980s, right? In the early 1980s,

00:37:22.620 when we were just beginning to talk about the sub-fractionation of cholesterol. So

00:37:27.640 little history lesson for people, it's 1959-ish, early 1960s. Ansel Keys is clearly onto something

00:37:38.320 and he is identifying a relationship between serum cholesterol and coronary artery disease. He's

00:37:44.500 correctly identifying a relationship. And at the time, they're doing very rudimentary assessments

00:37:49.600 saying, hey, if you take the people who are in the top 10% of serum cholesterol and you compare them

00:37:56.420 to the people in the bottom 10% of serum total cholesterol, there's a profound difference in

00:38:01.620 atherosclerosis. Most people aren't familiar with how that history went and, you know, where it got

00:38:07.260 taken off the rails a little bit by what might be the root cause of those things. But nevertheless,

00:38:12.060 it was pretty clear into the 1960s and 70s that something about serum cholesterol mattered.

00:38:19.720 Eventually people began to, as you pointed out, Tom, begin to fractionate those things. So it wasn't

00:38:24.900 just about total cholesterol. It became about different densities of those cholesterols. And

00:38:30.420 these lipoproteins, some of them were lighter, some of them were heavier and really light and heavier,

00:38:35.580 the wrong words. They had different densities. But one that emerged pretty quickly as a contrast

00:38:41.340 to the low-density lipoprotein was the high-density lipoprotein. And through all of the epidemiologic

00:38:50.020 work that emerged in the late 70s and into the early 80s, and that also, by the way, continued

00:38:57.260 into the 90s through the work of Jerry Riven, as he was in the early stages of identifying what would

00:39:03.360 be called metabolic syndrome at the time called syndrome X, it became clear that higher levels of

00:39:10.420 cholesterol in the HDL particle, which unfortunately is erroneously often referred to as high good

00:39:17.360 cholesterol, had a positive association, the opposite of what we have just been describing,

00:39:23.320 which is high levels of cholesterol in the LDL particle. There's a lot less talk of that today,

00:39:29.880 at least amongst the people who know what they're talking about. Unfortunately, there's still a lot of

00:39:33.820 people who talk about that on social media. But why is it that we aren't sitting here in the guidelines

00:39:39.520 talking about HDL cholesterol, the so-called, quote-unquote, I hate to use this word, good

00:39:46.320 cholesterol?

00:39:48.460 And you know I'm in your corner on that one. Folks, there's one cholesterol molecule. I don't care

00:39:54.660 whether it's in your cell, whether it's in any lipoprotein in your brain. If I drew you the

00:39:59.820 structure of cholesterol, it's identical. So how dare we put an adjective on it like that's good

00:40:05.440 and that's bad? How do you know? So you don't. So they're silly terms, but they sort of evolve for

00:40:11.140 a good reason. And this is a wonderful historical journey that you really have to do to figure out

00:40:17.220 why did HDL have like such importance and now it's an afterthought. Although it's an afterthought,

00:40:24.320 I must say virtually all of the current risk algorithms that are used to classify you as

00:40:29.860 are you at high, very high, moderate, or low risk still use the metric HDL cholesterol to determine

00:40:37.060 that because the data is just 40, 50 years old. The problem with HDL cholesterol as a metric is all

00:40:45.720 those studies that seem to suggest a higher is better or lower is worse were never adjusted for

00:40:51.320 anything else. So, you know, observational type data. Aha, I found the answer. Here it is. You got

00:40:57.880 blue eyes and everybody with blue eyes gets this, that, or whatever. And of course you never adjusted

00:41:03.420 for, oh, wait a minute. Everybody with the blue eyes has this lethal thing going on also. So in

00:41:10.480 retrospect, it turns out that the overwhelming majority of people who might have low HDL cholesterol

00:41:17.320 have a high ApoB level and that's what drives their atherosclerosis. So all guidelines, even though

00:41:24.100 they might do your baseline risk using an ApoB metric like total or LDL cholesterol, they'll use HDL

00:41:31.760 cholesterol as trying to figure out the lipid component to your risk. They use smoking and blood

00:41:36.960 pressure and other things Peter talked about also. When they get to goals of therapy though, only because

00:41:43.660 we have multiple trials now where for decades people have been trying this, that, and everything

00:41:48.440 to raise HDL cholesterol because if high is better than low, raising it has to be fantastic. And not a

00:41:55.680 single trial has ever panned out that what you do to HDL cholesterol results in cardiovascular benefit.

00:42:01.580 Let's pause there for one sec, Tom, and just make sure people understand that.

00:42:05.080 There have been multiple trials using at least two, maybe more technical approaches to raise that

00:42:14.660 number that is unambiguously associated with better outcomes. Is that correct?

00:42:20.920 No, there are no clinical trials that would support raising HDL.

00:42:24.120 No, no, no, no, no. I'm sorry. There have been multiple clinical trials that have attempted to

00:42:27.480 raise HDL cholesterol.

00:42:28.860 That's true. Yes. And it's more than two drugs. There are other drugs that-

00:42:32.680 Yeah. Yeah. I was saying more than two mechanisms of action.

00:42:35.080 Correct.

00:42:35.520 At least two that I can think of. There might be, there's probably three mechanisms of action

00:42:39.260 that have been, that would all raise HDL cholesterol. But the point that you made that

00:42:44.180 should not be lost on anyone is at best, those trials have been neutral.

00:42:52.280 As have the Mendelian randomization trials looking at genetic surrogates of HDL and cardiovascular outcomes.

00:42:58.900 Yes.

00:42:59.100 And at worst, those trials have been harmful.

00:43:02.740 Yeah. There are plenty of people, and you know them, you've seen them in your practice. Certainly

00:43:07.200 I have when I was practicing with high HDL cholesterol who are full of plaque. And we do see people with

00:43:14.020 low HDL cholesterol who, just like you said, you see some people with high LDL or total cholesterol

00:43:19.120 don't have plaque. There are plenty of people with low HDL cholesterol who, my God, you don't seem to

00:43:24.120 have much cardiovascular risk. So there has to be, if HDLs are important to the cardiovascular system,

00:43:29.580 and I maintain they are, the metric HDL cholesterol is useless.

00:43:35.060 Yeah. And this is really where I think I want to go with this. And just, I mean, there's so much we could

00:43:39.660 say on this, but I think it's worth maybe even just explaining this very important point, right?

00:43:45.300 Which is HDL cholesterol, the number that everybody sees when they look at their lipid panel, that if

00:43:51.580 it's below 40 milligrams per deciliter is probably flagged as being too low. If it's above 70, your

00:43:59.100 doctor gives you a high five, that is measuring the concentration of cholesterol within an HDL

00:44:05.700 particle. Now it doesn't tell you anything about the functionality of that particle. And this is

00:44:12.160 where I think, I don't remember if it was Ron Krause that said this, but someone said this to me and

00:44:17.240 I've never forgotten it. It might've been Alan actually. They said, this LDL biology stuff is trivial.

00:44:24.320 All you got to do is lower it. It's the HDL biology that is really complicated. That's what the 21st

00:44:33.080 century is going to be about. We don't have a clue what we're talking about with HDL. We've been using

00:44:38.900 this idiotic crude metric of how much cholesterol it contains. It is now completely clear that that was

00:44:46.380 the wrong metric. Then any attempts to increase it were futile. We've count the number of particles.

00:44:52.600 We can even measure the size of them. That also appears to be almost as crude as what the

00:44:57.720 cholesterol concentration is. But to come up with an assay that truly measures functionality may be

00:45:03.800 beyond the scope of laboratories. Whereas with the APO-BLDL side of the equation, it really appears to be

00:45:10.820 a stochastic problem. The more of these things you have to the first order, the more problems you have,

00:45:16.480 you've already alluded to other attachments to them that can add second and third order terms. But

00:45:22.220 I mean, do you agree with my assessment, Tom, that this HDL problem is way harder and we don't have

00:45:28.320 a clue what we're talking about? Oh, it's just so perfect what you've just said in the last few

00:45:33.780 minutes. It's, you know, we all use laboratory metrics to try and figure out what a given biomarker

00:45:39.900 tells us and what we can do about it. And the only metric that's really available to the world now is

00:45:46.540 HDL cholesterol, which Peter says that's the collective cholesterol mass within all the HDLs

00:45:52.500 that exist in a desolator of your plasma. If you are doing ion mobility or NMRs, you can get an HDL

00:45:59.760 particle count. But that, although it might be a tad better than HDL cholesterol telling you something,

00:46:05.860 there's so many exceptions to that rule that it's not a useful bedside metric either. But presuming,

00:46:12.360 again, HDLs must perform some function in the human body. And part of that function might be

00:46:19.360 either preventing or putting out arterial wall plaque fires that have many etiologies.

00:46:27.740 How can we measure what Peter referred to as the functionality of the HDL particle?

00:46:33.500 You know, being a fireman's son, if you listen to that last podcast, I look at HDLs as fire engines,

00:46:39.860 but I know any fire department has about 10 different types of different fire trucks,

00:46:44.980 and they all supply something different that firefighters can use to extinguish a fire.

00:46:50.620 Some might carry chemicals, some might carry ladders, axes, water, some carry more firemen than others.

00:46:57.200 So what type of fire truck do you need at a given scene? Well, it depends what the heck the scene is

00:47:02.180 all about. So what do HDLs do? They certainly traffic some degree of cholesterol, which it turns

00:47:09.820 out is probably just there for stoicometric reasons, making a spherical particle to which other things

00:47:15.480 can attach. The other things that are in that HDL, remember HDLs are tiny, so they don't carry a lot

00:47:21.620 of cholesterol. Here's a stat that will astound a lot of people. If I took the average HDL particle,

00:47:27.900 the average size HDL particle out of your plasma, how many molecules of cholesterol would be inside

00:47:33.000 of it? About 45. How many molecules are in the average size LDL particle? About 1500, 2000. So the

00:47:41.880 volume of a spear is the third power of the radius. What might influence even the cholesterol content of

00:47:47.780 45 cholesterol molecules within an HDL? Well, it's a spear. There's only so much can go in there.

00:47:54.240 What if that HDL was carrying extra triglycerides for whatever reason? Well, it couldn't carry very

00:47:59.140 many cholesterol molecules, so that would be a cholesterol-depleted HDL. What if that HDL,

00:48:05.140 if I had five groups of HDL particles, same size, same cholesterol content, but they all had different

00:48:11.340 phospholipids on their surface lipidome, or they all were transferring different proteins? They all

00:48:18.480 have APOA1, but what else are they carrying? And those proteins have a multitude of functions.

00:48:24.780 Dan Rader, years ago, always told me, Tom, HDLs are part of the innate immune system.

00:48:29.700 They're little fire engines. They're carrying God knows what that could go into wherever there's

00:48:35.320 inflammation in your body, a swollen knee, any in-tissue injury, or your arterial wall,

00:48:41.100 and they could maybe help what's going on there because they're trafficking immunomodulatory

00:48:47.300 functionality molecules, or they could go in because, oh my God, these are corrupt HDLs.

00:48:54.800 They're carrying bad junk, which is further inflaming it. We have no way of measuring those now. I mean,

00:49:01.800 researchers can do lipidome analysis of the phospholipids, the sphingolipids,

00:49:06.940 the ceramides that are in HDLs. They've identified over 150 different proteins that

00:49:13.900 might be on an HDL. Now, they're not all on one given HDL, but some HDLs may have two of this

00:49:19.500 protein, none of that, and you have different groups of HDLs. In my analysis, there are different

00:49:24.380 types of fire engines carrying different things. Peter, in our lifetime, there will never be an

00:49:28.820 affordable, reproducible, high-throughput way of evaluating anything. People are hanging their

00:49:35.920 hats now on the ability of HDLs to efflux cholesterol from a cell. And hey, if an HDL

00:49:42.300 can suck some sterols out of your foam cells, yeah, I'm kind of thinking that's pretty good,

00:49:47.380 but it's probably a minuscule function of the hundred other functions that HDLs can do.

00:49:52.780 So what if the HDL is pulling out some cholesterol, but it's dumping other crap in the process?

00:49:57.960 So if we ever had an HDL function panel, it's going to be a dozen or more type tests,

00:50:03.600 which we're not going to see because nobody's going to pay for them. The research to be done

00:50:08.280 to prove that these have relevance in a large clinical trial is just not going to be done.

00:50:12.680 So that's the dilemma. There are such panels, right? I mean, I feel like I've seen a couple

00:50:17.540 of commercial panels that attempt to subdivide the HDL particles even further. I've never personally

00:50:24.360 been able to know what to do with such panels. And these days, I don't even look at APO A1 anymore.

00:50:30.580 I'm really focusing most of my efforts on VLDL cholesterol as a poor man's proxy for remnant,

00:50:38.620 triglyceride basically as a strategy for how to lower APO B, APO B, LP little a, and then focusing

00:50:46.080 just frankly, much more on the metabolic stuff that we've talked about. The obviously glucose,

00:50:50.760 insulin, homocysteine, uric acid, much more aggressive stance on blood pressure. But in some

00:50:56.280 ways, my lipid world has become a little bit easier in light of this discussion we're having.

00:51:01.580 It is because you've got the ability based on analysis and understanding of things to not order

00:51:08.960 these silly hocus pocus HDL panels that are being offered by people as a way to generate revenue.

00:51:15.300 Now, look, I've been associated with labs all my life. I'm not at the present time. I don't work for

00:51:19.520 any lab that does or doesn't do any of these tests you're talking about. But mostly those panels that

00:51:25.360 you look at, they're looking, they're reporting HDL size. They're reporting APO A1. Peter knows there

00:51:32.480 can be from one to five molecules on APO A1 on your various HDL species. So you have just a few HDLs

00:51:40.620 carrying a lot of APO A1, or do you have a ton of HDLs that carrying little APO A1? And that could

00:51:45.940 be a misleading metric. People are looking at some of these phospholipids now. Some labs are

00:51:51.160 offering ceramide levels or syngocene levels. But again, you can find something that might support

00:51:58.220 that. But then you have to weigh it against the APO B and the things that are almost beyond discussion.

00:52:03.820 And you would realize this is contributing nothing to me. Why am I even ordering this? Am I trying to

00:52:09.320 impress some patient that I can use big words and this means anything? So they're silly. I'm an

00:52:15.000 all for doing research on HDL functionality and looking into it so we all get a better

00:52:20.120 comprehension of it. I'd love to have a test that tells us what I talk about, the flux of HDL particles,

00:52:27.560 how do little eensy-weensy HDLs mature, fill up, and what do they do with that cholesterol?

00:52:33.800 And are they catabolized? Are they not catabolized? Are your HDLs pulling cholesterol out of an artery

00:52:40.160 wall and then sharing it with an LDL that might take it right back into the artery wall?

00:52:44.180 So there's just so many phenomenal issues to get into with HDL. But right now, don't waste your

00:52:51.340 money. You're going to get an HDL cholesterol. Everybody's going to be doing a lipid panel.

00:52:55.540 Do not waste your money, time, or your brain energy on trying to figure out these HDL metrics.

00:53:02.100 So let's at that junction pivot now to more of the risk assessment stuff. We have talked probably on

00:53:10.760 at least two podcasts about LP little a. You and I spoke about it during our marathon podcast. I think

00:53:17.880 we had an AMA segment where Bob Kaplan asked me a lot of questions about LP little a. It's still on

00:53:23.940 my list of things to do. I'd love to have Sam Tamikas on the podcast. For people who don't know,

00:53:30.040 Sam is certainly among close to the world's experts on LP little a. And I think, frankly,

00:53:37.300 a dedicated podcast on this topic is warranted given that directionally one in 10 people listening to

00:53:45.140 this podcast has an elevated LP little a. And it represents, unless you correct me, Tom,

00:53:50.940 I believe it would represent the single greatest genetic driver of atherosclerosis.

00:53:57.520 So here we have this thing called LP little a that tragically most people don't know they have.

00:54:02.740 You know, I'll tell you a funny story. Have you ever heard of this reality TV show called Alone?

00:54:07.980 No. I don't think I've watched TV in 12 years, but it now shows up on Netflix. And I do watch

00:54:13.560 Netflix from time to time. So a friend of mine mentioned to me the other day, he goes,

00:54:17.360 you've got to check out this, this show called Alone. It's right up your alley. People, they take

00:54:22.300 these people who have remarkable survival skills and they throw them out in the world's worst

00:54:26.920 environment, 10 of them separately, of course. And basically the person who last calls uncle wins

00:54:33.480 half a million bucks. So I'm into season six right now, which is, it's the first one I've watched,

00:54:39.620 but it's, it's clearly into a really nasty part of the Arctic. So I'm watching this and I'm just

00:54:45.380 humbled by the fact that these people can survive any length of time. Anyway, one of the guys in the

00:54:51.800 show, you know, you learn their backstory and he's, this guy looks as impressive as anybody I've ever

00:54:57.300 seen, but somehow it comes up that part of his motivation for doing this is he had a heart attack

00:55:01.820 like the year before. And I think he's 39 on the show implying that he had his heart attack at the

00:55:07.860 age of 38 or thereabouts. Now, if you looked at this guy, Tom, you wouldn't think this is the kind

00:55:13.020 of guy that could have a heart attack. I mean, he looks, he is a specimen. And of course, what's the

00:55:20.060 first thing that comes to my mind? Well, I've seen this story play out 50,000 times, right? I mean, I,

00:55:25.420 my, my wife's grandfather died at 40. He was a firefighter, fit as a fiddle, dropped dead of a heart

00:55:31.060 attack at 47 in my mom's dad's arms when he was 16. So I know the story very well. And it's, to me,

00:55:39.960 it's LP little a until proven otherwise. Anahad O'Connor wrote a great story about this in the

00:55:44.960 New York Times several years ago, disclosing that he himself found he's a carrier of LP little a. So

00:55:51.180 always want to make sure everybody stops, reevaluates, make sure that they aren't a

00:55:56.020 high LP little a carrier. What else is on our list of real risk assessment here? And, and by the way,

00:56:02.620 feel free to just pile on to more LP little a stuff. Cause this to me is, I mean, this, this is

00:56:08.380 interesting stuff. And I do think, unlike my pessimism around HDL, where I don't think

00:56:13.220 we're going to learn a whole heck of a lot about it. I think we're just scratching the surface of

00:56:18.360 differentiating between really aggressive LP little a's versus not as aggressive LP little a's. And

00:56:24.800 I'm optimistic there. Well, you're right. And of course, on the favor of LP little a being dangerous

00:56:31.620 is the, a bunch of Mendelian randomization trials, which don't exist for any HDL metric or so.

00:56:37.740 So right away, it's a, a marker that requires more serious evaluation or so.

00:56:43.800 You want to remind people again, what it is? I guess I glossed over that. Yeah.

00:56:47.240 Sure. For those new to this, a low density lipoprotein is a collection of cholesterol,

00:56:55.140 triglycerides, fossil lipids wrapped by a single molecule of apolipoprotein B. Because of the size

00:57:00.920 and density, it falls within a certain fraction of that centrifuge tube and it's called low density.

00:57:06.380 But all lipoprotein subclasses are heterogeneous. They consist of big particles, small particles,

00:57:14.560 or maybe a particle carrying something else that doesn't really change its density that much. So

00:57:20.180 it separates with the LDLs. And LP little a is basically, you have your LDL part of this

00:57:26.640 macromolecule, but coattached to the apob structural protein is another protein that shouldn't be there.

00:57:33.480 And it's called apoprotein little a. And by little a, we mean small case, not a capital A.

00:57:39.760 And that molecule that attaches APOA, you know, can vary in molecular weight, size, length, etc. But

00:57:47.380 that's beyond this discussion. So it's an LDL that's carrying an extraneous passenger.

00:57:52.240 And here's the problem. We know people with high LP little a that, God, they don't seem to be

00:57:59.440 bothered. They're not coming down. There's no premature family history in them. And other

00:58:03.300 people's, the example Peter just gave, my God, there are atherosclerotic wrecks at young ages.

00:58:09.020 So I also just, as I've sort of iterated about other lipoproteins, I think when we're talking about

00:58:15.460 LP little a in the year 2020, we are talking about, all right, let's, what's its mass? What's

00:58:21.140 its LP little a particle number? But I also think we have to be smarter on understanding the quality

00:58:27.940 or other attributes of this LP little a particle. What makes this APO little a attachment may be

00:58:35.560 terrible for that guy who had his heart attack at age 38, but here are other people who they're

00:58:40.520 coming in at age 80 and they got high LP little a and they're not full of plaque or so. And one of

00:58:46.740 the things we're beginning to understand is look, APOA has potentially some thrombogenic properties,

00:58:52.600 which perhaps get expressed in some people more than others. But more and more, one of the functions

00:58:59.160 perhaps even of APOA, why it even evolved is a little scavenger protein that attaches to oxidized

00:59:05.760 lipid moieties, specifically oxidized phospholipids, oxidized sterols. They bind to it with great affinity

00:59:12.500 and maybe that little garbage truck full of oxidized particles, if it could bring it back to the liver

00:59:18.820 or some other tissue that could catabolize it, those oxidized lipid moieties, which tend to be destructive

00:59:24.720 to cells, are not getting to cells. So we are beginning to have metrics that are starting to appear and

00:59:33.060 available in the real world that we can measure the oxidation, the oxidized lipid moieties that are

00:59:39.180 on APOA. They're actually, it's called oxidized PL phospholipids on APOB. And if you say, well,

00:59:48.960 these oxidized phospholipids are on all the APOB particles to a minuscule degree for, because of the

00:59:54.780 affinity of oxidized lipid moieties to APOA, the overwhelm, if you have a positive oxidized

01:00:00.920 phospholipid APOB, the overwhelming majority of APOB particles trafficking those oxidized lipids

01:00:06.760 are LP little a particles. So if two people came to consult me tomorrow, they both have an elevated

01:00:12.580 LP little a metric. One has a normal oxidized phospholipids on APOB, but the other one is

01:00:18.980 elevated. Based on Sam Samikis and others' work, I'm going to be a little more worried about that

01:00:25.440 person who's, my God, not only do they have this undesirable particle, but this particle is loaded

01:00:31.220 down with injurious other lipids that are potentially very harmful. So that's one aspect

01:00:36.820 of it. We're nowhere near being able to test for the thrombogenicity if that's a big factor of APO

01:00:43.500 little a and everything. So there are other ways of doing this. I mean, I, all the time when I get my

01:00:49.540 weekly email from Peter Atiyah, here's the podcast this week. I'm waiting for Sam Samikis. But for

01:00:55.500 those of you who are still waiting for Peter to nab him, he's pretty active on Twitter and he really

01:01:01.320 tweets a lot of good information on the cutting edge of what's coming down with LP. I think it's

01:01:07.020 LP little a dash underscore doc, something like that. But go on Twitter and Sam Samikis, T-S-I-M-I-K-A-S,

01:01:15.140 and you'll be happy you followed him. So there's just a lot to understand, Peter. So it's who has

01:01:20.980 it? And by the way, the new guidelines are, the European guidelines suggest that everybody ought to

01:01:27.280 have it once in their life as they approach adulthood. And you never need repeat it unless

01:01:31.940 somehow you're trying to modulate it or maybe you go through menopause where it can go up a little bit.

01:01:37.100 But it's a genetically determined marker. You have it or you don't have it. If you don't have it at age 18,

01:01:41.940 you're not going to have it at age 68. So it's a one-time test and it helps us before we talk,

01:01:48.940 let's do thorough cardiovascular risk assessments, no matter what your APOB is. And this would be one

01:01:54.540 of the tests that at least the Europeans have signed on to now. The National Lipid Association,

01:02:00.180 other people have issued guidelines to it and they're still telling you, well,

01:02:04.040 do it for unexplained heart attacks or strong family history of heart disease. To me, it's,

01:02:09.260 again, it's not a very expensive test. Get it once or for all. But there's so much to talk about

01:02:14.180 this, Peter. And in the future, I mean, there are ways, what would you do for somebody with high

01:02:20.800 LP little a? We have strategies, which is mostly attacking APOB right now and any of the other

01:02:26.060 cardiovascular risk factor. But there are drugs in the pipeline that may give us better alternatives to

01:02:32.340 perhaps stop your liver from making APO little a. Let's talk about that a little bit. So up until

01:02:38.920 I would say a few years ago, the only strategy for patients, let's assume that we've confirmed that

01:02:46.520 a patient's LP little a is elevated. And furthermore, let's confirm that we have reason to believe

01:02:51.660 that in that patient, the LP little a is also problematic. And again, this usually shows up in

01:02:57.840 family history. It's not a subtle thing. A lot of times I'm taking the family history from a patient

01:03:03.280 before I've got the blood test. That'll be there. Those could be offset by weeks. And it's because we

01:03:09.540 give our patients the template to work on this. They come in with a very thorough family history.

01:03:15.800 They really know what happened to, you know, the mother's older sister and the grandfather and all of

01:03:21.360 these other things. And, you know, you usually just see this history of heart, lots of heart attacks

01:03:25.920 before the age of 60. Obviously, it can be confounded by people who are heavy smokers and

01:03:31.020 things like that. But yeah, let me just interrupt you for one second. It'll be a minute because

01:03:35.260 published yesterday in the Journal of the American College of Cardiology is a study and a fantastic

01:03:40.620 editorial. And they looked at people with terrible family histories of heart disease and people who had

01:03:47.760 LP little a issues or they didn't. And the conclusion was simple. Don't have high LP little a if

01:03:53.940 somehow you can avoid that, which you can't. Don't have a terrible family history of coronary

01:03:58.660 artery disease. And I don't know how you avoid that. But if you want the worst scenario, don't

01:04:03.120 have both LP little a. So Peter, what Peter is just saying is now backed up by a nice study.

01:04:10.040 Yeah, I love the best advice is choose healthier parents. So let's assume we're in that situation,

01:04:15.640 which is we have high LP little a and we have the family history that is not favorable or something

01:04:21.580 else that's even more germane to the patient, which is a positive calcium score, something to that

01:04:25.580 effect. Well, again, historically, our best bet would be remove all other risk to the extent that

01:04:33.100 it is possible. So we lower all other ApoB maximally pharmacologically. We optimize completely

01:04:41.420 all of the metabolic parameters that we've discussed briefly here, but touched on in greater detail

01:04:47.180 elsewhere. And that includes everything from modulating blood pressure as aggressively as

01:04:52.120 it needs to be to controlling all of these other factors that don't get enough attention in my book,

01:04:57.520 the uric acids, the homocysteines, things like that. But then as you point out, there's a strategy now

01:05:05.000 that says, wait a minute, what if we knock out the liver's ability to make Apo little a and all of a

01:05:12.880 sudden you wouldn't have an LP little a. So what does that strategy look like? And where is that

01:05:18.320 strategy in the pharmacologic pipeline? In pretty early trials. And of course, any cell,

01:05:25.840 and we're talking about the liver here, if the liver is the primary site of production of Apo little a,

01:05:30.540 and it is, if we could mess with the genes through ASO therapy, we could probably stop a cell from

01:05:38.880 making a given protein. If we can stop the liver from making Apo protein little a, if you don't have

01:05:45.660 that, you certainly, the liver can't secrete it. So it can attach to LDL particles, transforming them

01:05:52.200 into LP little a particles. So that's almost like a no brainer. The Mendelian randomization trial says

01:05:58.560 don't have ApoA or LP little a. So let's just exhibit its synthesis as we've done with other

01:06:04.780 things that contribute to coronary artery disease. And that has to work. Yes, provided that protein

01:06:10.600 doesn't screw or that ASO treatment doesn't screw up something else or cause a downside to it. And

01:06:16.680 that's why you ultimately have to do large clinical trials looking at not only event reduction, but

01:06:22.220 safety. But those drugs are in early, you know, and like anything else, the first generation of those

01:06:29.800 anti-sense oligosaccharide drugs that came around, they've perfected them. So there's a second

01:06:35.200 generation of them now that they've made even more hepatoselective so they can dose less of it.

01:06:40.740 And it goes right into the liver, but they're phase one, phase one dash two trials. And Novartis,

01:06:50.020 I believe has now acquired the product that they're going to put it in a major, which has just started

01:06:56.880 enrollment, a phase three trial on let's not. But here's the problem. Peter knows the billions that

01:07:04.820 probably have to be invested when you're developing a drug of that type of magnitude to reduce something.

01:07:11.600 You're not going to do it on every Tom, Dick and Harry who has a trivial LP little a. You want that

01:07:17.100 first trial to work because if it doesn't, that's it. The drug, the drug is dead. It'll never be tested

01:07:22.320 in lesser risk people. So the only way you can get into this current apolittle a synthesis modulator

01:07:29.800 drug is you have to have had an atherosclerotic clinical event, a myocardial infarction, a stroke,

01:07:36.360 blah, blah, blah, stents. And you have to have an astronomical like upper quintile concentration of

01:07:43.680 LP little a. Because Mendelian trials suggest if you're going to get benefit by lowering apolittle a or

01:07:50.000 LP little a, it has to be a pretty significant drop in it. So you're not going to take somebody

01:07:55.280 with a trivial LP little a elevation. And, you know, if you tested 50,000 of them, maybe it would

01:08:02.420 work. But so if they go through this first trial and it'll probably take three, four, five years to

01:08:07.620 show efficacy and safety, then they're going to have to maybe do some sub trial analysis. And then

01:08:14.880 is anybody even going to fund the primary prevention trial with this drug, with the cost that that takes?

01:08:19.980 I don't know. So even if you're somebody who's had a heart attack because of LP little a, and you're

01:08:25.480 waiting for this drug, you got five, 10 years to wait. And for primary prevention, go on to other

01:08:31.600 ways that clinicians are attacking this problem right now, because you're not going to have anything.

01:08:36.960 Why is it that statins, which are probably the most potent drug until five years ago to lower

01:08:45.520 LDL, and by definition, then lower APOB concentration, have virtually no effect on LP little a.

01:08:55.880 But this new class of drug that's been around for five years called PCSK9 inhibitors,

01:09:01.520 while even more potent in lowering LDL, seem to also be able to lower LP little a.

01:09:09.320 I think there's two reasons there. And one, we've gotten enough trials now that seem to show,

01:09:16.200 depending on your APOA makeup, do you produce the large high molecular weight APOA or the smaller

01:09:24.200 low molecular weight APOA, which in epidemiologic trials seems to be way more associated with

01:09:30.080 atherosclerosis, that if you're one who does produce the low molecular weight, short APOA,

01:09:36.340 which means, because it's such a small protein to make, the liver can make a ton of it, secrete it.

01:09:41.420 So they actually, even though their molecular weight of APOA is lower, they have much higher

01:09:46.520 LP little a particle counts. If you have that isoformity LP little a, statins can induce the

01:09:53.020 synthesis of that. Statins do not affect the synthesis of the larger APOA moiety. So in some

01:10:01.100 people, Peter says, statins do not much to LP little a concentrations, but there is a small

01:10:06.380 component where statins will actually raise it a little bit. And people get scared. They go,

01:10:12.260 well, I'm lowering LDL cholesterol, LDL particle counts a tad, but I'm raising LP little a.

01:10:17.480 Even Sam Samikis will tell you, don't worry about it. LP little a, if you learn nothing else about our

01:10:24.640 LP little a discussion is a minority LDL particle. So even though if you have the small isoforma statin

01:10:32.940 may be raising LP little a a tad, it's so blowing away the LDLs that don't have APOA attached to it,

01:10:41.380 that at the end of the day, you have less cardiovascular risk. And that little excursion

01:10:46.260 in LP little a concentration is probably meaningless. Now to go on to the second part of the questions,

01:10:52.120 the PCSK9 inhibitors don't have an effect on the synthesis of APOA in the body. So at least

01:10:59.300 they're not aggravating it in some people, but we're still in our infancy trying to understand

01:11:05.300 how LP little a particles are intercatabolized or cleared. And it's probably due to multiple

01:11:11.680 receptors. The LDL receptor is part of it. And a PCSK9 can give you more LDL receptors than a statin

01:11:19.320 probably can, putting aside the synthetic interference with it. But PCSK9, they're

01:11:26.060 finding has effects now on APOE receptors and three or four other lipoprotein clearing receptors

01:11:33.320 that are expressed in liver and other cells or so. So, I mean, there's got to be better clearance

01:11:39.400 of the particles with the PCSK9 inhibitors than there is with LDL receptor expression with statins

01:11:48.600 or statins plus whatever other APOB lowering drug you're going to add to it or so. So I think that's

01:11:54.720 where we're at right now. Most of the time, these people are going to wind up on statins plus PCSK9

01:12:00.140 unless they can't tolerate a statin or there's another reason not to use a statin. So that's my

01:12:05.660 explanation right now, Peter. I think we touched on that a little bit in the last podcast and

01:12:10.480 we still don't have a lot of info on clearance of LP little a particles.

01:12:15.140 And as you said, it's quite variable. I mean, we've seen patients where

01:12:18.300 they're on a PCSK9 inhibitor for other reasons. And every time I put somebody on one, I recheck

01:12:24.520 their LP little a just for no other reason than to gather our own data on how much of an effect the

01:12:30.020 the drug either Prolent or Repatha is having on LP little a and there's the range is zero to

01:12:38.020 60, 70% reduction. I mean, that's literally how broad it is with probably a median reduction of a

01:12:45.200 third. Yeah. So two important points here. One, LP little a is not an acceptable goal of therapy

01:12:51.780 because there wouldn't be trial dating support, even though we all think that's probably going to be

01:12:55.180 good. But I think most people like Peter, when he prescribes it, I don't sort of likes to at least

01:12:59.540 see what happens to get his own information or so, but realize that's not what you're making a

01:13:05.100 therapeutic decision on per se is the LP little a concentration. So, uh, uh, just keep that in mind

01:13:12.400 when you, when you're following up on these people. One last thing I want to circle in on you with that

01:13:17.800 you and I spoke about a couple of years ago, it was an experimental metric that was being

01:13:24.420 bandied about. In fact, I remember you guys ran it at THD on some of my serum, but I, I don't know

01:13:32.920 that it ever saw the commercial light of day, which was, I think it was like LDL triglyceride

01:13:38.400 concentration. Have those tests ever seen the light of day? I think if you look around enough,

01:13:46.380 you might find the lab. It's a very easy assay. Denka makes it where you could get a,

01:13:51.800 and LDL triglyceride level. And by the way, just another thought jumped into my brain on that LP little

01:13:58.880 a, as I told you, there are other things that attach to even LDLs and HDLs that make them less

01:14:04.380 clearable or more atherogenic. And a very recent study show, believe it or not, there are LP little

01:14:11.860 a particles that carry APOC3. You're not going to clear that particle if you make it. So

01:14:18.020 the double whammy. Yeah. Oh my God. But anyway, back to LDL triglycerides. People, I often tease

01:14:26.220 them if you said, you know what, we're really cost effective. We're only going to allow you to have

01:14:30.880 one lipid concentration on this person, nothing else. I would tell them, give me an LDL triglyceride

01:14:37.120 level, certainly not an LDL cholesterol level. And remember, APOB is a lipoprotein metric,

01:14:42.580 not a lipid metric. So that's what I would really take. But the triglyceride part of the core of any

01:14:49.800 lipoprotein has a lot to do with plasma residence time of that particle. What else might be attached

01:14:59.360 to that particle? Even I alluded to it a little bit in my brief HDL discussion before. Dan Rader calls

01:15:06.740 some fat HDLs. What if your HDL particle is not carrying very many cholesterol molecules,

01:15:12.500 it's carrying triglycerides? Well, he's shown, God, that was a decade ago that those fat HDLs,

01:15:19.320 meaning triglyceride enriched, are dysfunctional. They're carrying some of the bad stuff that HDLs

01:15:24.200 carry that don't allow them to do their cardioprotective functions. So if triglycerides

01:15:30.020 gets into an LDL, number one, what happens to an LDL that's floating around? And it might still be a

01:15:35.920 big LDL because it's full of triglycerides, not cholesterol, but it has a very great affinity

01:15:42.800 for lipase enzymes that line our arteries or the surface of the liver. So hepatic lipase is a very

01:15:49.440 potent triglyceridase phospholipase that is just like a fly trap looking for flies. It's looking for

01:15:56.400 triglyceride enriched HDLs. And if it binds to it, it will extract, hydrolyze the triglycerides.

01:16:04.860 So if I had an LDL full of triglycerides and I pulled the trigs out, what am I left with? Well,

01:16:11.780 that's an LDL particle that's lost a lot of surface phospholipids as well as a lot of core

01:16:17.140 triglycerides. I have the so-called small LDL or dense LDL. I try not to use both adjectives together

01:16:24.140 because they're redundant. And we have plenty of evidence that, yeah, it's no good to have an

01:16:29.740 increased total LDL particle count. But if, try not to have too many small LDL particles,

01:16:37.700 because the evidence has certainly emerged that particle for particle, they're probably more

01:16:42.360 atherogenic than the more buoyant, larger LDL particles for a variety of reasons. And the bigger

01:16:49.060 non-triglyceride rich LDL might be a better fit for an LDL receptor. It's going to clear it.

01:16:54.720 So LDL triglycerides, basically, if you told me it was high, I know you probably got a high LDL

01:17:01.140 particle count, ApoB. I know you have the small LDL particles. I know where those triglycerides

01:17:06.960 probably came from. Your VLDL triglyceride rich particles, your chylomicron particles.

01:17:13.020 And when they transfer their triglycerides to LDLs, they become remnant lipoproteins,

01:17:18.820 which Peter has alluded to. And you can bet those same triglycerides are invading the HDL

01:17:23.640 particles, contributing to HDL functionality. And last but not least, in the studies where they've

01:17:28.920 looked at LDL triglyceride, many of the inflammatory markers are high because those particles

01:17:35.080 set off the inflammasome in various endothelial cells and elsewhere. So it's a really simple,

01:17:42.600 easy to do metric that could tell us so much. And I think if I saw it was up, the first thing I'm

01:17:48.600 saying, oh, I'm dealing with an insulin-resistant person, because that would be the most common

01:17:52.200 cause, not some genetic triglyceride problem. Right. And again, I think perhaps the reason

01:17:58.580 why people aren't leaping up and down to bring this to market is, you know, frankly, if you're

01:18:03.320 looking at VLDL cholesterol and you're looking at all of the markers of insulin resistance, along

01:18:10.360 with the lipoprotein markers we've discussed, I think you get the story. And look, I mean, taking a step

01:18:17.380 back, let's play devil's advocate for a moment. I think that it's worth doing ApoB over non-HDL

01:18:23.900 cholesterol. There are some people who are so opposed to advanced lipid testing that they will

01:18:30.200 argue as long as you have non-HDL cholesterol, you don't even need to measure ApoB because of course

01:18:36.940 the non-HDL cholesterol is measuring the LDL cholesterol, but somewhat correcting for the

01:18:45.960 additional VLDL by adding the VLDL cholesterol. What is your take on the idea of non-HDL cholesterol

01:18:53.600 versus ApoB as they are somewhat proxies for the same problem? Well, I'm in the Snyderman school and

01:18:59.860 he's published on this extensively. I find it, all right, it probably gives you a little bit more

01:19:05.140 information for the reasons you just described. Versus LDL cholesterol, yeah. Beyond LDL cholesterol.

01:19:10.840 But as Snyderman has clearly shown in several studies, even though non-HDL cholesterol correlates

01:19:18.800 with ApoB a little bit better than does LDL cholesterol, there's still 20, 30% of the

01:19:24.100 population in our diabetics and insulin resistance where they're discordant. And where there is

01:19:29.240 discordance, even with non-HDL cholesterol and ApoB, risk follows ApoB. So why am I wasting my time with

01:19:36.420 it? You know, look, it's all useful. It might help you pick what therapy you want to use. But at the

01:19:42.500 end of the day, I see no need to follow your non-HDL cholesterol and following ApoB because I'd be a fool

01:19:49.120 if I told you I normalize your non-HDL cholesterol and I've eliminated your lipoprotein mediated risk

01:19:54.960 until you measure your quantitate of these particles. And if we ever get a quality test,

01:20:01.540 that's a silly thing to say to a patient. Yeah, exactly. We saved $3.

01:20:08.600 Yeah. And we might spend a little time or you're very good at explaining it. How do you determine

01:20:14.700 VLDL cholesterol in your patients, Peter? You're not dividing triglycerides by five,

01:20:19.820 the old Friedewald formula. No. So we use a lab that is actually giving a VLDL cholesterol. And

01:20:26.960 even if they didn't do that, we would still take total cholesterol and subtract from it

01:20:32.240 LDL cholesterol and HDL cholesterol. Not perfect either because in that situation, sometimes the

01:20:38.040 LDL is calculated. But I always do a back of the envelope trig divided by five. It's not close

01:20:44.840 enough. No, that's true. And listen, you made a key point here, which maybe went over people's heads.

01:20:51.380 You cannot do that calculation if you have a calculated LDL cholesterol. You must have a

01:20:57.300 directly measured LDL cholesterol because total cholesterol is LDL cholesterol, VLDL cholesterol,

01:21:03.680 and HDL cholesterol. So if you subtract a directly measured HDL cholesterol, a directly measured HDL

01:21:10.060 cholesterol, in effect, you have a directly measured VLDL cholesterol, which in our current world is about

01:21:17.520 as close as you're going to get to an evaluation of remnants. I think in our last podcast, we talked

01:21:23.340 why there are exceptions to that rule, and that's a more complex discussion. But please, you can't get

01:21:30.580 VLDL cholesterol using the Friedewald-calculated LDL cholesterol.

01:21:35.820 All right. Let's talk a little bit about therapies. Statins have been around forever. They still

01:21:42.420 take up most of the air in the room. They are the workhorse of lipid-lowering therapy.

01:21:49.060 Is there anything new and exciting to talk about? I would say that there's no new statin on the market

01:21:55.460 today that wasn't there two years ago. Is the most recently introduced statin Livelo?

01:22:00.540 Yeah. And that's probably 10 years ago introduced now.

01:22:04.620 What do you make of that, Tom? Why are we not seeing more statin innovation?

01:22:10.700 Two things. I think third-party payers would never pay for a new branded statin. They're going to

01:22:16.980 always insist you use the cheapest generic that's appropriate to the degree of LDL lowering that you

01:22:22.560 need. And there are seven of them on the market now. So I don't think a bean counter at some farm

01:22:28.860 is looking for, let's get a new statin. We're well aware of potential downsides to statin things. We

01:22:35.440 have to look for who tolerates them, who doesn't. I don't know that they're somehow going to invent a

01:22:40.520 new statin that brings none of the potential downside of a statin to the equation. So they're

01:22:45.780 looking at other therapies that will, now that we understand it's atherogenic lipoproteins, that

01:22:52.700 will reduce that. And if your investment pays off, you'll have a branded product for X number of

01:22:57.560 years and you might get a little return on your investment. So I don't think we're going to see

01:23:01.520 another statin right now. The biggest thing that's happened with statins and in the guideline, you

01:23:07.080 know, in the old days when we had nothing else to do and we didn't know a lot about all this

01:23:12.580 lipoprotein stuff is, hey, you got this most trivial elevation of some LDL metric, mostly LDL

01:23:19.760 you're going on a statin. I want them in the drinking water. In the old days, oh, Tom, I just took a

01:23:24.460 statin because they just reduce heart attacks. You and I know there is an event reduction, but

01:23:30.560 there's plenty of residual risk, even if you're aggressively using the statin. So there always is

01:23:35.460 more to the story. But I think the newer guidelines give you a lot more ability to ascertain in a given

01:23:42.500 individual after you do your thorough cardiovascular risk assessment, you and I do our own risk

01:23:49.760 assessment, which is a little different than what the guidelines might offer. But then once a person

01:23:54.040 crosses a certain threshold of atherosclerotic risk, then it becomes plausible to consider a

01:24:00.300 statin. And there's more to it than per se the LDL cholesterol level. There's all those other

01:24:06.720 factors that go into risk assessment. And there are other adjunctive diagnostics. Now, earlier we

01:24:14.720 briefly alluded to coronary calcium scoring, LP little a, they would be things that current

01:24:20.280 guideline says, Jesus, if you're hemming or hawing, should I give a statin? Should I not? Or the

01:24:24.680 patient, I don't want to take it. At least do a CAC, at least do an LP little a, look at the family

01:24:30.600 history, as you mentioned, look at the blood pressure, other concomitant risk factors, and factor that into,

01:24:37.100 do I want to use a statin or other ApoB lowering therapy? So that's the biggest change with statins.

01:24:44.400 Nobody's saying, hey, they belong in the drinking water. You should carefully choose who you're

01:24:49.120 advocating statin therapy to. Any sort of rules of thumb just in terms of the alchemy of this?

01:24:55.760 You mentioned that there are seven out there. You know, in our practice, we really only pick from

01:25:00.860 four of them. Livolo, Crestor, Lipitor, and Prevastatin. I mean, most of these are generic now. And

01:25:09.760 if you listen to the podcast with Catherine Eban, which I know you did, we are actually still pushing

01:25:15.240 for branded whenever we can get it. And if we're not getting a branded version of those, we cross

01:25:22.460 check with who the generic supplier is. And we've seen differences, right? We've seen that a two

01:25:27.560 versions of resuvastatin can produce different outcomes. So our default position is that all

01:25:33.620 generics are crap until proven otherwise. And that's why we use a tightly controlled list of

01:25:39.180 meds. But I don't think I've ever prescribed simvastatin, for example. What's your take on

01:25:44.460 some of the older statins versus the four? I mean, the reason I think we look at Preva and Livolo is

01:25:49.340 mostly for the sensitive patient and then Crestor and Lipitor, resuvastatin and retorvastatin being

01:25:55.360 kind of the workhorse. Yeah. Well, you're just too young, Peter. And old fogies like myself,

01:26:01.060 alovastatin or mevacor was the first statin that came around. Simvastatin was next. And then

01:26:06.560 Pravastatin, Pravacol came. So we have a lot of experience with those drugs. But as time went on

01:26:13.580 and pretty early on, there was a pretty rational thing that whatever the reason, Pravastatin is a

01:26:21.060 safer statin to use than simvastatin or lovastatin. And it turns out that was mostly related to drug

01:26:28.540 drug interactions where Pravastatin is pretty clean. Subsequent to that, the only statin that is even

01:26:34.660 cleaner than Pravastatin on drug-drug interactions is the Livolo. So Patavastatin would be its generic

01:26:41.180 name. So that's in today's polypharmacy world where, and we're not only even talking about

01:26:47.780 prescription products, but the multitude of supplements or God knows what people wind up

01:26:52.240 taking. We have no way to check on drug-drug interactions. So you're probably going to get

01:26:57.240 into less trouble with Patavastatin or Pravastatin. Of course, along came Resuvastatin many years later

01:27:05.920 after Pravastatin. And it shared some at least pharmacokinetic attributes with the Pravastatin

01:27:12.940 in that it was a hydrophilic statin, kind of hepatoselective, but it was way more potent on a

01:27:18.800 milligram basis than Pravastatin. So it became an over that evolution of all those early statins,

01:27:27.220 you know, every three years we had lower and lower and lower LDL metric goals, which weren't there when

01:27:33.280 we first started. So what used to be acceptable is no longer acceptable. So it was very easy to

01:27:38.640 transform from the hydrophilic Pravastatin to the way more potent hydrophilic Resuvastatin.

01:27:45.100 And that pretty much was my statin of choice thereafter, unless you had a putz around because

01:27:51.040 of statin intolerance, where you would try some of those other things. Personally, once all this was

01:27:57.980 known, and once Resuvastatin hit the market, I don't think I ever prescribed another Lipitor dose

01:28:03.020 again, unless, you know, third-party payers are influences here. They sometimes tell people,

01:28:09.200 you either take this one, or here's what you're going to have to pay if you don't go on our formulae.

01:28:13.240 So that can factor into its use. Now Lipitor is a potent statin. Milligram for milligram, it's not

01:28:19.560 as potent as Resuvastatin, but you can get whatever LDL reduction if you use a higher dose of Lipitor

01:28:27.160 as you can with a somewhat lesser dose of Resuvastatin. So unless a third-party payer is telling me to use

01:28:32.540 it, I'm probably not going to advocate Lipitor. Just there are more drug-drug interactions, and it is

01:28:37.620 lipophilic. There's perhaps other issues at play. You and I have talked about statins, ability to get

01:28:43.680 into the brain and everything, where lipophilic statins might have a little more propensity to do

01:28:49.200 that than hydrophilic statins. So there are other issues at play that would influence where you're

01:28:54.560 going. The other thing that, and I'm going to disagree, and I think it's the way you practice

01:28:59.400 too, all of the guidelines right now say, okay, you've made a decision to use a statin.

01:29:03.980 Pick the two most potent statins. That means you're on Lipitor or Crestor and prescribe it

01:29:10.440 at the maximum dose. Because the way these trials were designed, you know, lower is better. They all

01:29:17.840 stuff, you know, very few trials where they took people with minuscule LDL cholesterol levels and

01:29:23.660 drew statins at them. So they want you to get, hey, the clinical trial shows this statin at that dose

01:29:29.380 works. Maybe there's pleiotropic effects that that statin is doing too. So how do you know

01:29:33.700 you have to be evidence-based? I don't buy it. I think virtually all of the statins contribution

01:29:38.860 to atherosclerosis reduction is ApoB reduction. And I think you've known me long enough that rather

01:29:45.440 than maximizing a statin using the gorilla dose day one, I would prefer to start with a smaller dose,

01:29:52.660 again, dependent on your risk and your metrics. I mean, if you're coming off an acute coronary

01:29:56.980 syndrome and your LDL metric is off the chart, okay, I'll start with a big one. But I'd rather

01:30:02.780 take that baby statin, meaning a lower dose of a statin, and perhaps optimizing it with a second

01:30:09.500 ApoB-lowering drug. And for the longest time, we had ezetimibe, which has since been proven in

01:30:15.600 clinical trials to further reduce benefit and also in Mendelian randomization trials, looking at the

01:30:21.640 Neiman-Pick protein. And now we have the new guy on the street, this bempedoic acid, which is a weaker

01:30:27.740 cholesterol synthesis inhibitor affecting an early on cholesterol synthesis step. Also, that has

01:30:33.740 Mendelian randomization support. And if you can't use a statin, or if you can use a statin, if you add

01:30:39.600 distutostatin, or even the triple therapy, statin, ezetimibe, bempedoic acid, maybe you can avoid the

01:30:45.620 expensive PCSK9 inhibitor. So we have a lot more therapeutic options now today, Peter.

01:30:50.340 And then talk about the differences in the synthetic pathways between these two drugs,

01:30:54.880 or where are they targeting the synthetic pathways and what makes them different?

01:30:58.420 Is one more hepatic selective, or is it really a question of potency with respect to

01:31:03.100 where they're blocking the chain?

01:31:05.440 Yes. The cholesterol synthesis pathway, something like 37 steps, each step has its own different

01:31:11.120 enzyme catalyzing the transformation of these precursor products into the next down the stage.

01:31:18.180 Statins happen to inhibit what's called the rate-limiting enzyme. It's the third step

01:31:23.540 in the cholesterol synthesis pathway. And of course, that's modulated by the enzyme HMG,

01:31:29.280 CoA reductase. Statins, pretty significantly in a dose-dependent fashion, inhibit that enzyme,

01:31:36.660 so you can seriously slow down cholesterol synthesis in various cells. The one cell we really want to do it

01:31:43.460 is the liver, because that's the cell that has the greatest propensity to upregulate LDL receptors

01:31:48.540 that can clear our ApoB-containing particles. So statins do that. Now, if you can deplete cholesterol

01:31:56.020 pools beyond what a statin can do in the liver, you will express more LDL receptors. So when we use

01:32:03.500 ezetimibe, we block intestinal absorption of cholesterol or backflux of biocholesterol into the liver,

01:32:09.880 further depleting hepatic cholesterol pools, you will get more expression of LDL receptors.

01:32:17.500 So now we have this new bempedoic acid. It's called an ATP citrate lyase inhibitor.

01:32:23.700 Well, the first step in cholesterol synthesis is citrate, made in mitochondria coming out of the

01:32:29.800 Krebs cycle, is transformed to acetyl-CoA, which boom, then goes down and becomes after,

01:32:36.820 it becomes HMG and then the subsequent things. So this bempedoic acid is called an ACL, ATP citrate

01:32:47.320 lyase inhibitor, but it's a pro-drug. You swallow it, it's only uptaken by the liver,

01:32:53.280 and it inhibits an enzyme in the liver that you can't make acetyl-CoA. So, hey, the less acetyl-CoA

01:33:02.300 you make, you're going to make less HMG, and then therefore, that's going to, you'll have less

01:33:07.960 substrate for the statin to add onto. So collectively, you get additional ApoB lowering.

01:33:13.600 The cool thing is, because one of our biggest downsides to statin is people get these myopathic

01:33:18.940 symptoms, be they weakness, muscle aches, or whatever, you know that. It's a big problem with

01:33:23.980 statin therapy, probably more prevalent than what clinical trials would show us.

01:33:28.740 But this bempedoic acid does not have any uptake in the muscle cells. There's a specific receptor

01:33:35.720 that pulls it into the liver. So it is hepatoselective. Look, resuvastatin is somewhat

01:33:41.800 hepato-selective because there is a special cellular receptor that pulls in resuvastatin,

01:33:47.520 but other cells can pull in resuvastatin. Resuvastatin can give you muscle aches. So

01:33:51.560 it's not quite as hepatoselective as bempedoic acid.

01:33:55.060 Do you know what they saw, Tom, in the trial versus placebo for muscle soreness? Because

01:34:00.840 even PCSK9 inhibitors still had some noise with respect to muscle soreness, even though

01:34:07.620 mechanistically, it's not entirely clear why. Whereas at least the statin, there's some

01:34:12.820 explanation as to why someone could experience muscle soreness. I'm just kind of curious as to

01:34:16.660 what the head-to-head...

01:34:17.620 Yeah, no, they did look at that, and it's not zero. So there are still people who...

01:34:22.680 But they've also shown studies that you can give...

01:34:24.960 You give a placebo when you have...

01:34:26.340 A placebo when people get muscle aches too. So, but it's, you know, and they did comparative

01:34:30.460 trials versus a statin versus a placebo, and there is definitely less with it or so, but

01:34:35.360 it's not going to be zero. So it's worth a trial if you're really hung up. So I think right now

01:34:40.400 it's use, and the FDA approved it. The FDA says, look, you got to go do a big outcome trial,

01:34:46.800 which the company is doing, but Mendelian randomization suggests it would work. Before

01:34:52.180 we ever had outcome trial with ezetimibe, Mendelian randomization data suggested that reducing

01:34:57.420 cholesterol intestinal absorption would reduce cardiovascular events, and that turned out

01:35:02.000 to be so. So, and they only had to do was a certain amount of phase three safety trial,

01:35:08.620 and the FDA let it come on the market. And its use was, you can add it to a statin in people

01:35:14.980 with familial hypercholesterolemia, who the statin probably is not going to get you to goal by

01:35:19.860 itself, and you can combine it to that, or even very high-risk people, where you didn't blow your

01:35:26.060 LDL-C down to 70 or 50, whatever you're trying to do it. You need a junct of LDL cholesterol

01:35:31.700 ApoB lowering. You can co-prescribe the benpedoic acid, and they also allow you to co-prescribe

01:35:38.340 ezetimibe with it. In fact, the company that manufactures this, and the brand name is called Nexatol,

01:35:43.960 they also have been given FDA approval, because there are a lot of statin intolerant people out

01:35:49.660 there, or people who need triple LDL-lowering therapy, that we're going to give you a combo

01:35:55.940 product, which is benpedoic acid plus ezetimibe. I guess it's priced a little cheaper. So rather

01:36:01.860 than swallowing two pills, you could just take that combo pill, you could add it to a statin or not.

01:36:07.020 And look, I think for the nightmares of the world, you could ultimately, if you had to,

01:36:10.160 add PCSK9 inhibitor. The end of the day, if you're good at individualizing your therapy,

01:36:16.480 I think we have four ApoB options now a day, and you're going to go down a fairly standard path,

01:36:22.500 because not everybody can afford a PCSK9 inhibitor. Not everybody might be at the type of

01:36:28.100 high-level risk that the FDA wants you to be at, or the third-party payer wants you to be at.

01:36:34.000 But it's a fun time to be in the ApoB world. We have a lot of therapies, and we're not even

01:36:39.400 talking about addressing triglycerides, which there are therapies that do that, that might

01:36:43.940 contribute to ApoB lowering also. The statin works a lot by the hepatic upregulation of the LDL

01:36:51.120 receptor. Do we think that's the case here as well, or do we think that this is more about the actual

01:36:58.800 reduction of cholesterol synthesis? But remember, if you inhibit cholesterol synthesis,

01:37:04.140 you're going to deplete hepatic pools of cholesterol, which will, through the sterile

01:37:07.880 regulatory element-binding protein, upregulate LDL receptor expression, perhaps some VLDL receptors

01:37:13.920 or other things like that, ApoE receptors. So who, at the end of the day, probably depleting hepatic

01:37:20.880 cholesterol pools is what you have to do.

01:37:22.580 It's still its primary driver. So really, at least on some level, benpidoic acid is attractive,

01:37:27.540 because it's more hepatic selective, even if it's less potent. And remind me again,

01:37:33.300 what do we think is the relative potency compared to a statin?

01:37:36.620 If you look at its monotherapy trials, it's like ezetamide. You're going to get anywhere

01:37:41.440 from a 10% to 18% lowering of LDL cholesterol by itself, a tad less ApoB, 10% to 12% if you use

01:37:49.640 it as a monotherapy. As you know with ezetamide, with statins, there's a wide range of responses.

01:37:56.300 I think with all these drugs, there are hyper-responders, middle-of-the-road responders,

01:38:01.820 and hypo-responders. And I think that probably has a lot to do with how much synthesis of cholesterol,

01:38:09.680 how much absorption of cholesterol, what type of LDL receptors do you make or express. So

01:38:15.400 there's a lot of factors at play. But if you want a generalization, that's what it is.

01:38:19.540 And now you alluded to it, but what do we think about in terms of what's changed in the last

01:38:25.240 couple of years in terms of our thinking about EPA and DHA specifically?

01:38:29.600 Well, two things. And it's been a long time. And nobody has respected triglycerides more than I

01:38:35.580 have been lecturing about triglyceride-rich lipoproteins forever. And I knew, despite all

01:38:41.180 the nonsense that it doesn't matter what you do to triglycerides, you don't reduce events like you do

01:38:45.580 with LDL cholesterol because of improperly designed trials and enrollment of people who basically

01:38:50.880 didn't have triglyceride issues and giving them triglyceride-lowering drugs. But anyway,

01:38:57.060 we're far enough down the road that not only does the Mendelian randomization trial certainly suggest,

01:39:03.180 look, there are certain genes that are involved with triglycerides that are seriously involved

01:39:07.560 with atherosclerosis. So it's very plausible if, at least through those mechanisms,

01:39:12.320 we improve triglycerides, you're going to reduce disease. So for the longest time,

01:39:17.080 what was our, other than lifestyle, what was our way to lower triglycerides? We had niacin around

01:39:23.000 forever. We had the emerging fibric acid story, which progressed, progressed, progressed until

01:39:29.040 the terribly improvised trials that were done to, let's see if fibrates work. They didn't give them to

01:39:36.180 anybody who had high triglycerides. So of course the fibrate didn't work, but there's always been this,

01:39:41.560 hey, omega-3s really are a potentially triglyceride-lowering drug. And maybe we should

01:39:48.820 use them. Anybody who's known Bill Harris for the longest time, as I have, you have. No, yes,

01:39:55.240 omega-3s, if you really want to get triglyceride-lowering from an omega-3, you better be using

01:40:01.280 serious, serious doses of the, you don't give a gram, you don't give two grams if you want to get

01:40:08.120 rid of triglycerides or better yet, triglyceride-rich lipoproteins. If there are other

01:40:14.020 attributes to omega-3s, we have no way of measuring that. Now, and there almost certainly are because,

01:40:19.800 you know, omega-3s are a crucial part of cell membranes and cell signaling. But if we're just

01:40:24.600 going to deal in our lipid world and you want to have an omega-3 on board to help you combat

01:40:31.080 triglyceride-rich lipoproteins, you want to have a maximum dose, which looks to be 4,000 milligrams

01:40:38.120 a day. So this was the belief Bill used to always, listen, don't tell me that you gave somebody 1,000

01:40:44.520 milligrams of omega-3 and you didn't reduce heart attacks. The odds are strong you could never reduce

01:40:50.620 heart attacks with that drug, you know? So now we got confused because as we started to realize this,

01:40:57.580 they started to do trials with, okay, let's give four grams of omega-3s and let's really not make

01:41:04.840 the fibrant mistake, put them in the drinking water. Let's enroll people into these trials who

01:41:09.380 have high triglycerides. Many of those people also have concomitant low HDL cholesterol, but that

01:41:15.760 necessarily doesn't have to be an entry criteria. But you better have a triglyceride level above a

01:41:20.700 certain degree or we're not going to waste our money giving omega-3s to people with triglycerides of 42.

01:41:25.860 And lo and behold, the first trial that started to come down the pike was done in Japan, so

01:41:31.880 God, probably almost a decade ago, the Japan EPA trial. You know, Japanese people eat a lot of

01:41:38.640 omega-3s, so they have higher baseline levels anyway. So they just gave them, for whatever reason,

01:41:45.080 EPA only on top of a statin. And they didn't necessarily have to have high triglycerides,

01:41:51.660 but many of the people did. And lo and behold, although it was not a blinded trial,

01:41:57.260 the evidence was pretty good that, wow, this is really plausible that EPA at a high dose,

01:42:02.400 four grams a day, reduces macrovascular outcomes when given with a statin that, of course, is working

01:42:09.420 on the LDL metric you're looking at. So, you know, of course, people said, aha, that's proving omega-3s

01:42:17.040 work. Nobody was given a lot of credence, perhaps other than the people who produce it, that,

01:42:22.000 oh, this is unique to EPA. Most people are taking omega-3s, are taking some combination of EPA and DHA.

01:42:30.160 But as long as you're going to take four grams of that, why wouldn't it do exactly?

01:42:33.840 So here's what happened. So after that EPA trial, the company that makes the branded EPA medication,

01:42:43.240 which is Vasepa, Ameren is the company, did a major clinical trial called Reduce-It,

01:42:49.760 where they enrolled people with, who were taking whatever statin they had to take to get their LDL

01:42:56.680 cholesterol below 70. And in general, these were high-risk people. They had some degree of

01:43:01.420 coronary disease or they were full-blown diabetics or had a lot of cardiovascular. So it wasn't a

01:43:06.240 low-risk primary prevention type of study. You had to have a triglyceride above 137 to get into

01:43:14.400 that trial. Most people, it was 150. But, you know, the triglyceride assay always varies plus or minus

01:43:20.640 15 points. So they would let you come in if you had a 137 because they thought in a week you're going

01:43:25.980 to have 150. So they enrolled people. That was the cutoff. You had to have that. And lo and behold,

01:43:33.320 and you were maximized on whatever statin it took to get your LDL-C, under 100 at the time, pretty good.

01:43:39.920 And lo and behold, and we haven't come up with much in the world so far. At least it has a big trial

01:43:46.740 saying we lower residual risk with a statin. Azetamide did it in acute coronary syndrome survivors

01:43:53.540 to a certain degree. But this high-dose EPA, two grams twice a day with food, because it is an

01:44:00.900 ethyl ester, theoretically it needs to be de-esterified before it's absorbed. There was almost a 30%

01:44:08.300 residual risk reduction. That's mind-boggling to be honest after taking a statin. But they would still

01:44:15.280 say, oh, that's fantastic. We all have to start using omega-3s at the appropriate dose, way more than

01:44:20.720 we ever did. But a lot of believers, and I think probably Bill Harris and myself said,

01:44:25.780 yeah, but we could also just give four grams of EPA plus DHA. Because deep down, many of us believe

01:44:32.520 DHA is a pretty important omega-3 fatty acid too, if for no other reason than your brain needs it. But

01:44:38.320 I believe all cell membranes need to a certain extent. And not everybody can convert EPA to DHA,

01:44:45.060 although most people probably can. So AstraZeneca had acquired a free omega-3 fatty acid, meaning it's

01:44:54.040 not an ethyl ester, which means it has a better absorption, better pharmacokinetics, more bioavailability.

01:45:01.220 And it was called Epinova. But it was EPA and DHA, but free EPA and free DHA. And they enrolled

01:45:09.040 basically the same type of people. High triglycerides, maybe the HL cholesterol is low.

01:45:14.000 At-risk people. And two years into the study, the company just stopped the study. It's never been

01:45:21.340 published, so we don't know. But the reason was it's futility. We're not seeing a signal at two

01:45:26.940 years that it's going to work. So we're not wasting any more money on this.

01:45:31.540 Yeah. This was last November, right, Tom?

01:45:33.820 Yeah.

01:45:34.500 I got to tell you, this caught everybody off guard, didn't it?

01:45:38.300 It surely caught me.

01:45:39.360 It was certainly announced that the study was being stopped. And I would say most observers,

01:45:48.180 myself included, felt, oh, wow, they're stopping it because the signal is so big.

01:45:53.600 And then they announced at the cardiology meeting, actually, it stopped because there's no signal.

01:45:59.200 I'm a little surprised it hasn't been published yet. Are you?

01:46:02.940 And annoyed, to be honest with you. Is there something they're hiding that

01:46:06.600 didn't come out in that press release or the early discussion about it or so?

01:46:11.020 So are there subgroups in there where maybe, yeah, I understand these trials are super expensive

01:46:17.300 and where they say, hey, we're cutting our losses. We'll have to take this out to five or six years

01:46:22.700 before we ever see a signal. And I wish they had done that, but it's not my money.

01:46:26.460 But then they wouldn't have made the announcement. I mean, I guess to me,

01:46:29.060 the thing I'm trying to understand-

01:46:30.700 Well, they would have announced it if they're stopping it.

01:46:32.620 Yes, yes, yes. Yeah, that's what I'm saying. But if they were going to keep running it,

01:46:35.800 they probably wouldn't have made that announcement.

01:46:37.740 Oh, no.

01:46:38.320 And so the thing that I'm trying to wrestle with, which I shouldn't spend any time on it,

01:46:42.480 I'll just wait till it comes out, is how much of this is the vehicle versus the EPA-DHA split?

01:46:48.820 You know, you got to bring Bill Harris back on. Look, technically that should,

01:46:53.760 if what we want to do is achieve a certain level of omega-3s in our blood,

01:46:59.020 be it in a red blood cell or a cell membrane, where we would measure the omega-3 index,

01:47:04.920 which they did not measure in the Reducit trial, or whether you just want to reduce plasma,

01:47:09.980 free fatty acid levels. And by the way, that they did do in the Reducit trial,

01:47:14.380 and though it's not been published yet, it has been presented, that the efficacy of the EPA-only

01:47:20.060 product highly depends on the level you did achieve with a serum. So again, to me,

01:47:25.840 that supports going with four grams a day. Don't think you can get away with two grams a day,

01:47:30.680 perhaps unless you're really checking the levels, but even that would be guesswork.

01:47:34.960 So to take home points, right now, people ask me, Tom, EPA or EPA-DHA, if I want to be evidence-based

01:47:42.180 and you're in that type of risk category, I think you got to go with EPA four grams a day.

01:47:46.700 What if triglycerides are below 150? What about the person with Triggs 100 who still has residual

01:47:51.880 LAPO-B risk? Yeah, it's an unanswerable question right now. I'm not afraid to keep using EPA-DHA.

01:47:59.280 Whatever the magical mystery effects of EPA are, which are all theoretical at the given moment,

01:48:06.360 and they're checking a lot of biomarkers to try and explain this, and it's all winding up in this

01:48:11.580 massive inflammatory world that's maybe it's do something or self-signaling world. Yes,

01:48:18.100 but your brain needs some self-signaling from DHA too. So if I'm going to throw four grams of EPA at

01:48:25.200 you, I, as you know, am a big advocate of doing the omega-3 index. So if I'm giving you four grams

01:48:31.320 of EPA only, but your omega-3 index shows me you have adequate DHA in your system, I know some of

01:48:38.400 that EPA is being converted, so I'm kind of happy, and I don't perhaps necessarily have to co-prescribe

01:48:44.260 some degree of DHA with you. My worry would be, what about somebody who's taken the four grams of

01:48:50.380 EPA, and the omega-3 index shows you you're still deficient in DHA? Then I think you got to scratch

01:48:57.240 your brain and do what you want to do, and I might be, hey, let's start giving a little DHA.

01:49:03.020 You know, but I can't buy into the concept that a little bit of DHA is negating EPA. Maybe that's

01:49:10.580 true, and that's what the EPA purists will tell you.

01:49:14.260 Well, hopefully we have some published data in the next six months that can at least

01:49:18.300 give us a hint. I don't think this study had enough in common with REDUCE-IT to answer that

01:49:24.200 question, but I think it could potentially give us a clue.

01:49:28.500 Yeah, and we're getting more and more data. They're doing additional trials with EPA,

01:49:32.540 and they're doing more subtrial analysis. They've even shown some angiographic data with,

01:49:38.320 despite that great reduction in residual risk, if you actually look at plaque,

01:49:42.380 it looks a lot better when you're taking four grams of EPA. So that's pretty encouraging

01:49:47.900 of that type of study anyway. You know about predicting what a plaque image shows in event

01:49:54.740 reduction, but it's good nonetheless.

01:49:58.420 Anything else on the pharmacology side, Tom, that's really interesting to you,

01:50:02.480 especially in the last couple of years? Because I like the way we've sort of at least

01:50:06.900 tried to bring people up to speed on what the big changes have been.

01:50:12.420 Listen, I still think fibrates are a widely underused drug. I think for the right person

01:50:17.640 where you've, through whatever method you use, have identified triglyceride-rich lipoproteins,

01:50:23.640 perhaps those where you clearly see insulin resistance, their diabetics, or their insulin levels

01:50:28.840 are high. That's where the fibrate subtrial analysis shows miraculous things, not only with

01:50:36.520 macrovascular endpoints, but with microvascular endpoints, retina, peripheral nervous system,

01:50:43.640 renal function. So even though you might screw up creatinine a little bit, you're actually improving

01:50:48.840 EGFR because of overproduction of creatinine, which in that case is not reflective of EGFR.

01:50:54.920 So I think there still is a group of patients right now where fibric acids, the purest fibric

01:51:02.260 acid, which isn't a pro-drug, is that phenofibric acid, still shows trilipics. So I think if you

01:51:08.820 have to use a fibric acid, if at all possible, that's the one to use. And the good news is there

01:51:15.120 is a new fibrate, permafibrate, pemafibrate, that's being invested in clinical trials. It's called

01:51:21.820 a SPARM, a selective PPAR-alpha receptor modulator that they're really high on. And there's big

01:51:28.620 outcome trials going on with that yet. But, you know, nobody's going to be using that or thinking

01:51:33.440 about it until those trials are stopped for good reasons, bad reasons, or published, of course,

01:51:40.200 and get FDA approval. So I think there's still hope with the fibrates. Niacin is a dead drug. I know

01:51:45.940 there's going to be a lot of people listening to this who, oh, no, it's not. It's out of every

01:51:50.120 guideline. There's not a single guideline in the world that recommends you can use anything you want

01:51:54.660 if you're stuck between a rock and a hard place. And I certainly know there are LP little a advocates.

01:52:00.220 If you bring Sam on, he will still selectively use niacin in certain cases. But few in the lipidology

01:52:08.080 world still agree with that. Yeah. And back to your point on trilipics, we probably have three or

01:52:13.100 four patients on it. And man, it's a world beater. I had one patient who was probably, I mean, he looked

01:52:20.240 like he had FH and he looked like he also had, of course, a familial hypertriglyceridemia. I mean,

01:52:27.380 you couldn't distinguish them. And even though you knew he was going to end up on both a statin

01:52:34.260 and a fibrate at some point, I just out of curiosity wanted to see what ApoB reduction we'd get

01:52:40.180 starting with just the trilipics. So his trigs were about 400 to begin with. ApoB was over 200.

01:52:47.560 The trilipics took him from a triglyceride of 400 milligrams per deciliter to about 100,

01:52:53.480 if my memory serves me correctly. And that took the ApoB from wherever it was, high 100s, 200 down to

01:53:01.560 somewhere between 80 and 100. So that's monotherapy of trilipics, which was not the intention, but

01:53:08.080 just in a stepwise progression showed you the potency.

01:53:11.420 And unless you're dealing with a super humongous high risk and acute carnage, I don't think it's

01:53:15.920 irrational to go down that route. There are plenty of people who you have to bat them over the head

01:53:21.240 with whatever to convince them to use a statin. And maybe they'll say, well, I believe in triglycerides.

01:53:26.040 You're giving me a triglyceride. I'll work with you. Well, let's see what the parameter.

01:53:29.200 Clearly, you picked the right person there, whereas triglycerides were generating the ApoB

01:53:34.380 particles and the multi-mechanisms on how fibrates reduce triglyceride had a beneficial effect.

01:53:41.400 I've actually, with Peter Jones, published data using NMRs on resuvastatin and phenylfibric acid.

01:53:49.480 And in some people, there were pretty nice reductions in LDL particle counts using phenylfibrate,

01:53:55.460 always more. But when you looked at the particle analysis, when you were even combining phenylfibric

01:54:01.400 acid with the fibrate, or excuse me, with the statin, you got way more dramatic remnant reductions

01:54:07.560 with the fibrate than you ever did with the statin. So another reason, and almost certainly that person

01:54:13.660 would have triggered 400. There was some contribution from remnants in that person, you would think.

01:54:19.360 So just don't forget fibrates. A tragedy to me are young lipidologists are not being taught about it.

01:54:25.460 Few of them can give you a dissertation on fibrates and how they work and what is their trial

01:54:31.400 history. God, there's 40 years of trial history that you can always garner a little bit from any

01:54:37.020 trial. So I find that sad that it's not even being taught anymore. And people bad mouthily condemn it

01:54:43.080 without knowing what they're talking about. I always feel lucky to have been trained by dinosaurs.

01:54:49.300 Well, some of us have been around the block for a few times or so. But you know, us old dinosaurs,

01:54:54.660 when we meet you young, brilliant guys, you keep us, if I want to still talk to this guy,

01:55:01.900 I got to keep up with this stuff. Because I know things I said 10, 15 years ago are silly now,

01:55:06.940 because you got to keep learning. You know that. Guys like you are really good for me that I just

01:55:12.600 can't rest on my laurels.

01:55:14.540 Tom, this has been a lot of fun. We were supposed to do this last week, and we had some technical

01:55:18.920 difficulties. So we postponed until this week. And I'm glad we did, because it was worth being able to do it

01:55:24.260 and actually be able to look at each other through a screen, as opposed to just have to do it by

01:55:27.520 phone. And so I want to thank you, obviously, for your continued insight. You make a great

01:55:32.960 difference in our practice. I guess I should fully disclose to people, you are now basically full-time

01:55:38.380 inside ATIA Medical as a practice. You're on the backside of things doing mostly research,

01:55:44.080 but we drag you into at least a third of our patient calls. And we always consult with you on

01:55:50.380 all of our cardiovascular cases. So I hope you're also enjoying being

01:55:54.660 back to clinical medicine somewhat, even though it's at a much lower volume. We certainly enjoy

01:55:59.600 having you.

01:56:00.740 It's been such a wonderful part of, if this is the finish of my career, still being able to do this.

01:56:08.820 And you know, although I know a lot of this lipid stuff, the basic science, I've always been what I,

01:56:14.240 Mike Davis calls a clinical lipidologist. None of this lipid stuff is meaningful if you can't use it at

01:56:19.260 the bedside and make individualized things. So I'm just thrilled to be able to contribute to you.

01:56:26.380 And I think one day, as you know, I'm trying to write and generate and put more and more of this

01:56:31.320 into writing, and that will become available to your followers and subscribers. And so folks,

01:56:37.380 stay tuned for that. And I will say, and maybe it's another podcast and are probably better people

01:56:42.480 than me to talk to, but the one thing we didn't get into today is the emerging genetic world,

01:56:48.440 genetic analysis of lipoproteins, and specifically the genetic lipidoses, FH. Who needs that type of

01:56:55.620 testing? Who doesn't? Whatever you discover, what can you do for it? It's another whole serious podcast.

01:57:02.220 So other than that, thank you for everything, Peter. Meeting you a long time ago in Reno,

01:57:08.080 Nevada was a big day in my life.

01:57:11.040 Oh, mine too, Tom. Thanks so much.

01:57:14.820 Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper

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The Peter Attia Drive - September 21, 2020

#129 - Tom Dayspring, M.D.： The latest insights into cardiovascular disease and lipidology

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