The Peter Attia Drive - Qualy #106 - Does LDL cause heart disease？

00:00:00.000 Welcome to a special bonus episode of the Peter Atiyah Qualies, a member exclusive podcast.

00:00:16.100 The Qualies is just a shorthand slang for qualification round, which is something you

00:00:20.120 do prior to the race, just much quicker. The Qualies highlight the best of the questions,

00:00:25.320 topics, and tactics that are discussed in previous episodes of The Drive.

00:00:30.000 So if you enjoy the Qualies, you can access dozens more of them through our membership

00:00:33.520 program. Without further delay, I hope you enjoy today's Qualies.

00:00:40.640 Let's talk a little bit about a paper that you were an author on this year. It was the

00:00:44.720 European Atherosclerosis Society consensus statement. Now, you and I were joking about

00:00:49.320 this a while ago that you almost couldn't believe this paper needed to be written, but sometimes

00:00:54.520 there's a benefit in writing it. And what was the conclusion of that paper? Or more to the

00:00:57.820 point consensus statement. It was more than just a paper. I mean, it was really a tour

00:01:01.340 de force.

00:01:01.600 So this paper assembled multiple lines of evidence addressing the question, does LDL cause heart

00:01:09.820 disease? Is LDL a causal factor for heart disease?

00:01:13.020 And just to be clear, the counter-argument is, sure, people with high LDL are more likely to

00:01:18.720 get heart disease. That can't be disputed. The epidemiology is clear. The counter-argument

00:01:23.600 is, but LDL is not a causal role. That's right. And it's associated with that. Efforts

00:01:28.760 to lower LDL cholesterol are not fully justified as a means of attacking the cause. I don't want

00:01:35.460 to be responsible for having stated that incorrectly because I still can't quite believe anybody would

00:01:41.880 hold that opinion. But that was my understanding that led to the group coming together to counteract

00:01:49.000 that perception that lowering LDL was not beneficial.

00:01:52.100 But there are many people. I mean, not that I spend terrible amounts of time on Twitter, but

00:01:56.180 it's a pretty commonly held view, at least in the vocal minority that love to write about this and

00:02:02.240 talk about this, that, hey, LDL cholesterol is a myth. Like heart disease has nothing to do with this.

00:02:07.040 And the problem is, and it did come out in the paper to some extent, but I'll tell you, there is a

00:02:11.500 second component to that effort that is still being written. It was planned and will be a two-part

00:02:17.580 series. The first part is assembling all the evidence from epidemiology, clinical trials,

00:02:22.600 genetics, et cetera, that speak to the causality. And the second one was really relating all of

00:02:29.040 this information to the role of LDL in the pathophysiology of atherosclerosis. And that paper

00:02:34.020 is a work in progress, but it collectively, those two papers assemble just about all the evidence one

00:02:41.180 needs to support the use of LDL cholesterol.

00:02:44.740 And when will that second paper be out?

00:02:46.580 I can't tell you.

00:02:47.280 We don't even know.

00:02:47.680 It has taken longer than we thought.

00:02:49.880 Well, we'll certainly link to the first one in the show notes because that was published in

00:02:53.860 early 2018.

00:02:54.780 Yeah, yeah. We expect it in the next year or so. But one thing I do want to say, because

00:02:59.000 there's a caveat and part of my life as a researcher, as well as a clinician, is recognizing

00:03:05.140 the complexity of what we're dealing with. In discussions such as this, it's important to

00:03:10.560 keep the concepts straightforward and understandable to the best degree possible. But the flip side

00:03:17.280 of that is the risk of oversimplifying a complex situation. So when I just said that the evidence

00:03:24.340 is that lowering LDL cholesterol is beneficial, that's not always true. And so one can point,

00:03:31.200 if one is so inclined, to the evidence that under certain conditions in certain populations,

00:03:37.460 with certain approaches, lowering LDL cholesterol does not result in reduced heart disease risk.

00:03:43.240 And to the extent that you consider that to be a fatal flaw in the argument, that can be,

00:03:48.380 I think, very misleading because it's not. The fact is that LDL is causal, but there are other

00:03:54.220 circumstances that modify that causality to the extent that some forms of LDL under certain

00:03:59.960 conditions, and this may not be uncommon, can be elevated without pathologic consequences.

00:04:05.360 And so lowering LDL in those cases may not give benefit in that. We know there is heterogeneity

00:04:10.340 in the clinical response when one looks at cardiovascular protection with LDL-lowering

00:04:15.720 treatment. So I have to absolutely extend the simple notion of LDL causality to saying that

00:04:22.600 one has to look very carefully at the arguments against LDL causality because they latch on to

00:04:28.920 pieces of information that are really misleading. Just because lowering LDL cholesterol is not always

00:04:34.960 beneficial doesn't mean that LDL is not pathological. And the second component of that is the focus on

00:04:40.740 LDL cholesterol that goes back to our initial discussion here today as a marker for a causal

00:04:47.320 mechanism. But it's the particles that are causal. And LDL cholesterol, as we just talked about, does not

00:04:52.300 always mirror the number of LDL particles. Now, I don't think we should necessarily take the time to go

00:04:58.220 through the paper in incredible detail, but it did touch on eight criteria for causality. Plausibility,

00:05:04.680 strength, biological gradient, the temporal sequence, the specificity, consistency, coherence, and then the

00:05:14.000 relative risk reduction or risk reduction with an intervention. Among those, I found the Mendelian

00:05:19.980 randomization to also be very compelling. So, you know, when I talk about this with people, I generally talk

00:05:26.840 about the natural experiments, such as the people with PCSK9 mutations, both hypofunction or, you know,

00:05:34.080 gain of function, loss of function, PCSK9, the FH patients, the Mendelian randomization, and the

00:05:39.800 intervention. If you were going to bring up three points from the paper that you think probably are

00:05:46.000 most relevant, what would they be? Well, you've just touched on probably the number one strongest

00:05:52.460 argument. And it's really where we, those of us who have been in the field for decades, started with

00:05:59.780 being impressed with the role of genetic elevations of LDL. Very, very strong evidence. I would put that

00:06:07.360 probably right at the top. And you talked about this condition, familial hypercholesterolemia, when

00:06:12.000 there's two doses of an abnormal gene, the LDL levels can skyrocket. I referred to that a little

00:06:17.580 while ago as the condition that can lead to heart disease early in childhood. It's unequivocal.

00:06:23.440 In fact, the reason I got a little bit, I was a little bit taken aback by the need to do this

00:06:29.240 more extensive review, which I think, by the way, was quite a good exercise, both for those of us who

00:06:35.160 did it and people hopefully who read it. But all you have to do is look at an eight-year-old child

00:06:39.600 with cholesterol levels that are eight or nine times normal, who's a candidate for liver and heart

00:06:44.820 transplant, to know that that's it. That's causal. But the genetics support it beyond that.

00:06:50.080 Right. Now, in those cases, the genetic defect is one in the LDL receptor, correct?

00:06:54.860 That's right.

00:06:55.460 So closing the loop on how this works, right? The body makes cholesterol. The body, you know,

00:07:01.480 so every cell in the body makes cholesterol. Then cholesterol gets recirculated, ends up mostly

00:07:06.100 back in the liver. It gets secreted. Some of it in bile gets reabsorbed, and this process continues.

00:07:12.360 But it's this LDL clearance, mostly via LDL receptors in the liver, that seems to be where a lot of these

00:07:18.640 genetic things go awry.

00:07:20.480 That's right. Yeah, the liver really is the factory as well as the disposal plant, if you will. Most of

00:07:26.720 the cholesterol that winds up in the blood is released in terms of lipoproteins that are

00:07:31.280 synthesized by the liver. And then they come back to the liver ultimately after they've done their

00:07:38.520 thing, so to speak, delivered their cargo or interacted with cells in various ways and come

00:07:43.540 back to the liver. And a large portion of that return is mediated by these receptors that latch

00:07:49.220 on to ApoB. It's ApoB that is kind of the key that binds to the lock that snaps up the LDL in the

00:07:57.080 liver and degrades it and excretes it into bile. And that's one of the ways we dispose of cholesterol.

00:08:02.460 There are other mechanisms involving HDL, but the receptors are a key determinant and do represent

00:08:09.860 a mechanism by which most of the drugs that we use to lower cholesterol act to increase

00:08:16.880 LDL receptor-mediated disposal of LDL particles.

00:08:20.980 Hope you enjoyed today's special bonus episode of the Quali. New episodes of the Qualis are released

00:08:27.320 Tuesday through Friday each week and are published exclusively on our private member-only podcast

00:08:32.980 feed. If you're interested in hearing more, as well as receiving all of the other member-exclusive

00:08:37.080 benefits, you can visit peteratiamd.com forward slash subscribe. This podcast is for general

00:08:44.160 informational purposes only and does not constitute the practice of medicine, nursing, or other professional

00:08:49.160 healthcare services, including the giving of medical advice. No doctor-patient relationship

00:08:54.920 is formed. The use of this information and the materials linked to this podcast is at the user's

00:09:00.600 own risk. The content on this podcast is not intended to be a substitute for professional medical advice,

00:09:06.920 diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical

00:09:14.180 condition they have, and they should seek the assistance of their healthcare professionals

00:09:18.260 for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures

00:09:25.860 and the companies I invest in or advise, please visit peteratiamd.com forward slash about where I keep an

00:09:34.100 up-to-date and active list of such companies.

The Peter Attia Drive - February 05, 2020

Qualy #106 - Does LDL cause heart disease？

Episode Stats

Summary

Transcript