Oct 08

Guesting on the Peter Attia Drive (4 of 5) – Energy Status, Risk, Testing the Hypothesis

 

This is a five part series covering my appearance on The Peter Attia Drive podcast. Please skip to the final post to comment. 

Part 1 of 5 – Lean Mass Hyper-responders, Oxidized LDL, All-Cause Mortality
Part 2 of 5 – Cholesterol Challenge, Lipid Metabolism, LDL Receptor
Part 3 of 5 – Remnant Cholesterol, Craig Moffitt, Fasting
Part 4 of 5 – Energy Status, Risk, Testing the Hypothesis
Part 5 of 5 – Comments and Featured Thoughts

In both this and Part 3, I’m going to “let the tape role” as it were. While I considered trying to summarize many of these parts, I quickly realized it’s too unrealistic here as the ongoing context is important to keep together.

The Energy Status Research Phase

Dave Feldman

I suspect I could get my LDL down to 70 if I was willing to go through with it. There’s another part of this conversation we haven’t had a chance to touch on, but that you might find very interesting since we talked about the liver and again, more theory, so about 80 percent of what I’ve talked about is an explanation that I’m trying to fit onto what I know and this is definitely one of those, but I suspect given the data that I have for the whole second phase of my research that actually part of how I’m reducing my triglycerides in the blood through a certain series of experiments I call carb swap experiments, is that I’m just trying to get a certain threshold of glycogen stores up in my liver, which seemed to be at a certain point, meaning that there will be less VLDL secreted and therefore less LDL. That’s the theory.

Peter Attia

I’m sorry to say again. By moving glycogen, you’re doing what?

Dave Feldman

So again, I’m trying to think about it more like as an engineer, whether right or wrong. I think, okay, if I were trying to engineer this body and I were caring a lot about the long-term tank of storage, which is your adipose sites, but it was also to care about the short-term tank. What is the reason why it would make sense from a mechanistic standpoint as to why the body would want to be so adamant about mobilizing these triglycerides for fuel in a low carb high fat athlete, especially somebody is very lean? The short Occam’s razor from my perspective is it comes down to, well, there’s very little glycogen stores relative to somebody who’s on a high carb diet. This isn’t to say that they have bottomed out glycogen stores, but relatively speaking, there’s less play and because of that, it makes sense as to why the body would activate more lipolysis, have more of the free fatty acids moving through, keep making it more available, etc. Okay, so then how could I tweak that?

Peter Attia

But wouldn’t that also just as easily be explained by the fact that when someone’s walking around with 60 percent of the glycogen in their muscle, there’s by definition, assuming they don’t have, you know, a pathologic condition, there’s not much circulating glucose and therefore it’s probably, they’re also in a low insulin environment which is fostering lipolysis.

Dave Feldman

Right, but it’s gradiated, right? It’s going to have to do with … There’s threshold points which are part of what I’m trying to isolate out and there seems to be a threshold point with me. For example, if I have around 90, it seems to be at the last time I tested it. It’s at around 90 carbs per day, net carbs per day. That seems to be the magic threshold that if I do that for about three days, my LDLC will just drop substantially. Now, let’s see, I did 70 net carbs for three days. I’ve already done that, doesn’t do it. I have to get up to a certain threshold and once I get up to that certain threshold, which seems to be somewhere around 90, all other things being equal, like I have to structure my life around this where like sleep the same amount and so forth. That seems to be the point at which there’s an actual drop and I actually wrap that around one of my presentations is I actually had a fat shake, a ketogenic shake for, I want to say three days for a washout period, and then for just two days I added what I thought would be the calculation to demonstrate what I was looking to do. So I swapped out the fat for carbs, kept it isocaloric for two days. I had one that was a lower amount and one of them was a higher amount.

I can’t remember the numbers right off hand, but then to further emphasize this, I switched back to the high fat diet for the next five days and we saw my LDLC drop almost immediately and continued to remain low for the next five days. And in fact, it got to the lowest point, the end, right?

Peter Attia

So it seems to be at least a sensitive on your carbohydrate intake is your fat intake, right?

Dave Feldman

Correct. And this is very relevant because again, I’m still thinking about this from the energy model-

Peter Attia

But hang on. For this to be … I’m not saying this isn’t interesting, but for this to be relevant, it has to be reproducing something that’s going to last over much longer than five days. How do we know if these effects aren’t transient? And also how do we know they’re relevant if they require an extreme condition such as, one of them, I know you talked about how you just have to force feed yourself a ton of fat.

Dave Feldman

Yeah, that was the very first presentation that I did, where I was having just a very high pro-

Peter Attia

That also dropped your LDLC paradoxically. Correct?

Dave Feldman

Correct.

Peter Attia

Right. But the point is … We have to back up for a moment. Why does any of this stuff matter in the long run? If you’re listening to this podcast or if you’re sitting in front of me as a patient, you have a very important question you have to ask yourself if your LDLP is through the roof as a result of what seems to be your diet. Does it matter and do you want to do anything about it?

Dave Feldman

Right. And this is why this is the most relevant question is if you’re right, and I’m not saying that I know for sure either way. Let’s say that you’re right, you, Peter, you’re right that this, regardless of how we got here, if you have a high LDLP because of being on a ketogenic diet, then there was a lot of people who need to know that if they’re at higher risk and I definitely want to be one of the people that brings that to their attention. I have emphasized this several times before and I’ll say once more, I am on a journey of science, not of advocacy. I’m going to be quite a skeptic, but all of that said, if I come to a point in which I can feel convinced the LDLP is in fact atherogenic, absent remnant lipoproteins, absent having a high HDL, low triglycerides-

Peter Attia

But we already know it’s absent remnant lipoproteins. I mean there’s a thousand studies including this to demonstrate that the atherogenicity between these people and these people, I’m pointing to the Garvey study, has nothing to do with what may or may not be remnants. The LDLP alone here … I think one thing that sort of makes sense-

Dave Feldman

I’ve not seen a study yet, where remnant lipoprotein … I mean I’ll send you the ones I have. If you have somewhere LDL particle is more relevant than remnant lipoprotein, I would be very interested.

Peter Attia

Again, we have to be very careful of what we mean by remnant. So there are clearly going to be a subset of remnants that are potentially the most pathologic on a per particle basis. But I think the body of evidence implicating the causal role of ApoB and LDLP is so overwhelming. Is it perfect? Of course not. But I think what concerns me with this culture, when I say this culture, I mean this sort of low carb culture of LDL doesn’t matter, is if I had a dollar for every time I had to see some low carb enthusiast basically dismissing the idea that LDL is relevant and touting the idea that statins are a big conspiracy theory, that’s a really dangerous problem.

Dave Feldman

It, it’s dangerous if we know … Just generally speaking, I think, dismissiveness in general, of evidence is bad, but we do have to care about the quality of evidence regardless.

Peter Attia

We sure do. So, let me offer a very controversial viewpoint that I can’t believe I’m about to voice publicly. I think one of the challenges in the low carb community is you have a group of people who have become very used to rejecting mainstream information because they did so with nutrition, right? If you are on a low carbohydrate diet, on some level you have decided that the ADA, the AHA, the USDA, the NIH and the CDC are full of shit.

Dave Feldman

I think that’s fair point.

Peter Attia

Okay. So, do you know what I think that when it comes to nutrition, that’s largely true. Okay. Now they think they’re coming around, but I think it’s largely true and I think the body of evidence, the body of literature that pointed towards the Food Pyramid was quite shotty. I don’t think it was nefarious. I don’t think this was as much of a conspiracy as people want to make it out to be. I don’t think Ancel keys with some evil dude who was like scheming away to … I just don’t buy that. I think there were strong personalities and lousy science. Those are very different things.

Dave Feldman

And let me go on the record with saying I basically agree. I feel like-

Peter Attia

This is the easy part to agree with. This is the hard part that’s coming.

Dave Feldman

Okay, good.

Peter Attia

Okay. So what happens is a lot of people get in this mindset of, “Well, look over here, I saw an entire body of evidence that was very easy to dismiss, and by the way, look at the results. You don’t have to be a rocket scientist. If you’re sitting there following the food pyramid, getting fatter and sicker and you abandon it and get better. There’s the proof.” The real problem, and, I again, I apologize for getting on a soapbox. The real problem is when people try to look at the last 50 years of lipid literature through that same lens. Nobel prizes have been won in this field. Now I know that somebody is going to start screaming, “Oh, that’s an appeal to authority. That’s a logical fallacy.” I got it. To you, whoever said that, I acknowledge it, but unless you’re willing to go back and read every one of those papers, something even I have not done though, I’ve probably read more of them than most. We’re talking about apples and oranges with respect to a body of literature here.

The body of literature implicating LDL as having a causal role, a necessary but not sufficient role in the pathogenesis of Atherosclerosis is on a different level from the body of literature that gave us the food pyramid and the real challenge I think in this low carb community, this LDL denying community, is they’re throwing the baby out with the bathwater. Now, part of that is because I think there are too many doctors who are too lazy at the other end of the spectrum. They just assume, “Well, statins or what we give everybody. You know, anybody who’s LDLC is about 100 gets to be on a statin”, and these doctors are equally guilty in my mind of being ignorant and not thoughtful and not understanding the pathophysiology of the disease, but somewhere between these, is a measured space that requires a very careful consideration of the literature.

Confounders and Risk

Dave Feldman

With that in mind, to kind of broad base this pretty well, this whole energy model that we’ve been talking about that I’ve been kind of walking you through, and the audience to some degree, it’s the lens by which I came up with the challenge. I didn’t come up with a challenge because I was just like, “I just, today I just want to tweet out something that I think we’ll get a lot of people annoyed.” I believed that. I looked at those two sides of the dotted line and I said, it looks as if you’re insulin resistant, we tend to see that there are high levels of triglycerides. We tend to see the high levels of VLDL, forget even remnant. We can detect VLDL to a certain extent. We can see that people who are down the range of metabolic derangement, they’ve got that and that tends to be highly associated with cardiovascular disease.

This is all on the energy delivery side. On the other side of the LDL, we tend to see on the support side that there can be further problems in the immunological role and oftentimes that can be induced by likewise, lipolysis. That can actually be something that can … you’ll see on the vitamin E studies, for example, this gets brought up quite a bit. For example, if you if you inject lipopolysaccharides into a body, you’ll actually have a higher fatty acid synthesis that’s going on in the liver along with lipolysis, in order to induce that higher response. So again, we see on that side we see higher levels of triglycerides and I kept coming back to, I kept-

Peter Attia

But you’re also, as we talked about, when you inject LPS in somebody, you’re going to see a higher HDL cholesterol too. I mean, everything at that moment. LPS is a terrible toxin. It’s going to kick the body into a four alarm fire. Of course it’s going to want all of the energy substrate it can muster and all of the hormonal precursors it can muster.

Dave Feldman

Agreed, agreed. So when we’re looking at an association between LDL particles and a bad outcome, we want to absolutely confirm it was the cause and not the association, right? But the same reason that if we were to say, I want to confirm ambulances aren’t the cause of death for people who are dying inside of ambulances.

Peter Attia

Yeah, I mean we have to be a little careful with that analogy. So let’s, let’s be clear. Can you get atherosclerosis without having an oxidized sterol taken up by a macrophage?

Dave Feldman

No. We agree on that. If I could take all of the LDL particles out of your body right now, I could feel totally confident that you will not die of atherosclerosis.

Peter Attia

Okay. So does that not imply that LDL is necessary but not sufficient for atherosclerosis?

Dave Feldman

I don’t disagree with that. Without question, LDL particles are-

Peter Attia

It’s important for some people to understand that because I do think, I mean, put it this way, I’ve certainly heard people in this community argue the following, that the burden of proof should be on the lipidology community to demonstrate that LDL is causal rather than the reverse, and I find that comical, if it weren’t for tragic. Right?

Dave Feldman

Let’s go back to the analogy for a second. Are ambulances causal for ambulance related deaths? Absolutely. They’re a part of the-

Peter Attia

That’s not the same thing, because what you’re basically saying is-

Dave Feldman

I’m emphasizing and association over causation. We both realize that, right? So, okay, it could be in this town, you actually are in worse shape if an ambulance picks you up. There’s very incompetent EMTs, and their life saving measures are poorly done and therefore, if you could ban all ambulances in this town, you’d find that actually-

Peter Attia

A mendelian randomization of ambulances would ferret that out.

Dave Feldman

I would agree if there wasn’t anything associated in the ambulance in the medallion randomization with response by ambulances in the first-

Peter Attia

The only way I think you can discount the Mendelian randomization is if you believe that the mutations that you are measuring … So you’re looking at a series of mutations that are affecting a phenotype. In this case cholesterol level. You’d have to convince yourself that each and every one of those is also effecting something else that’s driving the underlying cardiovascular process. But we’ve already went through this, right? It can’t be the LDL receptor because that’s not even ubiquitous and there aren’t LDL receptors on your epithelial cells.

Dave Feldman

I want this tested on a healthy vascular system. However that’s occurring, I want every cell to have-

Peter Attia

Why does a person with FH not have a healthy vascular system when they’re born?

Dave Feldman

When they were born?

Peter Attia

Yeah. Meaning they inherit a clean slate, right? Someone who’s born with FH has a normal, beautiful vascular system, that over time in most of them becomes destroyed.

Dave Feldman

Just answer this question, is there any cell in somebody who has FH that would function like a normal cell in somebody who doesn’t have FH in order to be able to acquire the lipids or lipoproteins it wants to take?

Peter Attia

Yes. There are plenty of patients with FH who do not have defective, completely defective LDL receptors and therefore are not impeded. Put it this way-

Dave Feldman

Their metabolism is not impeded is what you’re saying.

Peter Attia

Not all of them. Again, we have to be very careful when you talk about FH because there are at least 2000 known versions of that disease. It’s a very cumbersome, so that’s why I think FH gets talked about like it’s one disease, it’s a phenotype that has all of these things that can cause it. So, the broader question is, is everyone with FH struggling to make steroid hormones?

Dave Feldman

I don’t know the answer that question.

Peter Attia

No. In fact, FH maybe slightly protective in the case of an infection and in the case of diabetes and one argument for that … The diabetes one’s a little hard to explain. The infection one, because … I mean, FH has stuck around for a long time, so there may have been a time when having the ability to mount an incredible immune response would have proved to have a survival advantage, and if you have four times the cholesterol of somebody else, that’s one moment in when that could come at a huge advantage.

Dave Feldman

Right, which gets back to the immunological response, but to get back to the larger point, I wouldn’t blame somebody who has a poor digestive system for being malnourished. So, as long as we can count and everybody’s tissues to be properly nourished and-

Peter Attia

I don’t understand what you mean by blaming them, help me understand what you mean by that.

Dave Feldman

What I mean by that is, if there was a problem with absorption of lipids or lipoproteins unrelated to total quantity of LDL particles, that’s what I’m going to care about and I hopefully will have an answer on this soon. I’m actually working with a couple of researchers who I’m trying to get an SNP list together that doesn’t include lipid metabolism issues. So Ronald Krauss, who you had on from earlier, he was talking about this, they are looking right now on, for example, the genetic studies and he was explaining the receptor issues associated with … and this is how you end up with higher levels of LDLC or LDLP, right? Is that you end up having less absorption, particularly on the liver side, but I’m especially interested in non-hepatic tissues-

Peter Attia

But there are, there are people with Niemann Pixie, one like one transporter deficiencies. There are people with ATP binding cassette deficiencies who have a huge increase in cholesterol. It has nothing to do with an LDL receptor. It’s a transporter.

Dave Feldman

I’m not pointing just to the LDL receptor, I’m pointing to just the health of the cell. If the health of the cell is not compromised than I’m interested. If the Lipid metabolism difference-

Peter Attia

But why would someone who’s ATP binding cassette in their enterocyte, that is not appropriately excreting cholesterol, therefore driving up the recirculated cholesterol pool. Why? Why does that mean that they’re endothelium is somehow defective?

Dave Feldman

I would have to follow what the path is that we’re talking about. I don’t know that I could give an answer to that until I can actually see the study that’s associated. If you can take a biopsy of anybody who’s going to have this issue and you can basically effectively see that the cells for which would be targeted, there was not gonna be any problems, I wouldn’t have any problem with using it. I mean basically what we really want, is just the means of just an overproduction on the part of the liver without it touching any other part of the lipid system. And your point, I’ll make your point for you. It’s hard to get an SNP that doesn’t in some way touch other parts of the lipid system, but that’s also the point against it. You see what I’m saying?

Peter Attia

So, so let me ask you this. You’re, you’re saying, “Look, I want more evidence.” And I think science is based on skepticism. I completely respect that, but I think we also have to temper that with some modicum of understanding probability theory and saying, “Look, at some point the probability looks disproportionately one way versus the other. So right now, what would your confidence be in the idea that LDL is playing a causal role in atherosclerosis, just as endothelial dysfunction and inflammation play a causal role in atherosclerosis?

Dave Feldman

Let’s make a distinction, the distinction is, if you’re saying, “Is it part of the development of an atherosclerotic plaque?” It’s nearly 100%. If you’re saying, ” Is the total quantity of LDL particles absent any inflammation or anything else along those lines?”

Peter Attia

Nobody is saying that. Nobody reasonable is saying that. So again, listen to what I said, right? So you’ve got three things that we can sort of use a metaphor and say they’ve formed the three legs of the stool. Three things have to happen for someone to get atherosclerosis. Each of them is necessarily, none of them alone are sufficient. That’s just the nature of complicated biology.

Dave Feldman

Let me help you with the question. I think this would be a better way of asking it. If given the same quantity of oxidative stress, whether it’s low or high, would you rather have 1,000 nanomoles of LDL particles, or would you rather have 2,000 nanomoles of LDL particles? I think-

Peter Attia

Yeah, well, you don’t need to ask me that question.

Dave Feldman

Right.

Peter Attia

I think the question is, what would you rather have?

Dave Feldman

I used to think that I would say the first. That I would rather have 1,000. I would say last year it was probably more like, it could be about the same difference. Learning what I’ve learned, especially with the antioxidative defense system and so forth, and particularly given my own data, especially with the CIMT data that I’ve presented recently. I don’t know if you’ve seen that one as well. I was getting carotid intima-media test every six months. And during those six months in the beginning of this diet, and through the experimentation, I was running at LDLC levels of 200 or higher, LDLP levels of 2,000 or higher. For four tests in a row you can actually see the regression that’s happening on both the left and right side of the carotid arteries. Now-

I’m referring to the Carotid Artery Updates which I’ve been doing every six months and how it was showing a regression. However, that changed following my four-week SAD diet experiment — worth a read!

Peter Attia

Now, again, I don’t wanna get started on CIMT, which is hopefully it’s the same tech doing it the exact same way. I mean, I’m guessing your CIMT initially was pretty good and it may have gotten a little bit better. But, I don’t know. CIMT is even worse than calcium scoring, frankly.

Dave Feldman

Sure enough. But, what-

Peter Attia

But again, Dave, we’re putting a couple of N of how manys, we’re saying, “Look, these three little interesting anecdotes are basically calling us to suggest that the null hypothesis around this topic should be what you’re discussing, rather than what I think is a remarkable body of scientific literature, that is not without its problems, and that is not absolute in its inference.” But-

Dave Feldman

That’s not what I’m saying. What I’m saying-

Peter Attia

That might not be what you’re saying, but it’s certainly what a lot of people are using your words to say.

More on Cholesterol Synthesis and Recirculation

Dave Feldman

I have an energy model that a lot of people are utilizing probably over-simplistically. But, if my energy model is right, it would suggest as to why, the answer of why-

Peter Attia

But, David, you haven’t even described it correctly to me today. I mean, you’re … I mean, I guess it depends how liberal we wanna be with the term model. But, there is no evidence that the LDL is there to carry cholesterol. You have yet to explain to me where Moffett got his cholesterol.

Dave Feldman

You’re talking about to the quantity that he has it at?

Peter Attia

Yes.

Dave Feldman

I-

Peter Attia

You guys got three times the amount of LDL cholesterol.

Dave Feldman

I think it typically tracks with the total particle count. The people-

Peter Attia

You have to give me the mass balance. You’re an engineer, you know this stuff just as well as I do.

Dave Feldman

If you are a hyper responder coming to cholesterolcode.com right now, and you turn over your lab, I can look at your LDLC before you-

Peter Attia

No, no, no. That’s fine. That’s just pattern recognition. That’s not the interesting thing to me. I’m asking a very important physiologic question, which you have yet to provide an answer to, and it seems to be the central tenant of your belief system. Where did Moffett get his cholesterol? Why does he have three times more than he had before?

Dave Feldman

The short answer to that is, he synthesized it and he’s recycling it. Now, there’s some degree with which he’s synthesizing-

Peter Attia

Okay, so this is a totally different answer than before. He has now increased his synthesis of cholesterol. He doesn’t have the same circulating pool. This is not a shell game with boats. Right?

Dave Feldman

I was talking about circulating before.

Peter Attia

No, but I don’t think, what I certainly didn’t hear you say before was that he has actually increased his own endogenous production of cholesterol.

Dave Feldman

There’s some amount where you’re increasing it in order to meet that existing demand. I don’t know how much that is.

Peter Attia

But, this is different from what I understood you to say earlier, which is the reason he has more cholesterol is it’s just along for the ride with the boats, and he has to have more boats, which defies-

Dave Feldman

No, that is correct.

Peter Attia

But, that defies the principle of mass balance. You can’t create matter out of nothing.

Dave Feldman

I’m not saying he’s creating matter, okay.

Peter Attia

So he had to make more cholesterol. I don’t see a way around that.

Dave Feldman

I’m not disagreeing with him making more cholesterol. I think where we’re disagreeing is, I think you’re saying in total, he’s making three times more every day. Am I wrong on that?

Peter Attia

On average, he is making three times more, or reabsorbing three times more. But, just based on what I’m seeing-

Dave Feldman

Reabsorbing at the liver, or reabsorbing in non-hepatic tissues?

Peter Attia

Probably in the gut. That’s where the majority of the reabsorption is taking place.

Dave Feldman

Okay, in other words, he is sending it back out the other side.

Peter Attia

Well, again, this is what we look at these sterile numbers for. When the desmosterol goes through the roof, plus or minus the phytosterols, that tells you these patients are making more cholesterol.

Dave Feldman

Okay.

Peter Attia

But, here’s the question. If this were purely about energy, he shouldn’t be making any more cholesterol. He should have more particles perhaps, but they should be cholesterol depleted.

Dave Feldman

I’m interested in this, I have no … You answer this question for me. When does somebody make more cholesterol-depleted [lipoproteins]… because everything that I’ve read in Clinical Lipidology and so forth, is it’s like a standard quantity on the non-triglyceride side of the ledger. If you’re making cholesterol on a per particle basis, it can vary on a per particle level, but generally speaking, it tends to hit averages that are fairly consistent.

Peter Attia

But, this is an unusual circumstance you’re describing. Right? This is the whole purpose of this experiment, is you’re describing people who-

Dave Feldman

It’s not unusual-

Peter Attia

… who’s demand you’re saying is so great for triglycerides, but they’re doing-

Dave Feldman

That you make more boats. But, the boats, if they already have a standard composition, why would they change that standard composition per boat?

Peter Attia

Well, think about … So are you telling me you’re saying that the large LDL particle and the small LDL particle in the insulin resistant versus the insulin sensitive patients have the same cholesterol composition?

Dave Feldman

No, that’s my point. My point is getting back to remnant cholesterol. Why is it that I think there would be something that would happen on that dotted line, something before and after. Right? Why would there be … Why would there be a problem with somebody who’s metabolically deranged with their cholesterol relative to one of these people that are theoretically metabolically flexible. Why would there be a difference? And the short answer to that, the short answer is, I don’t know fully all of the aspects to it. I do know though, there seems to be a longer resonance time with VLDLs, and we see that because that’s the [crosstalk 02:57:36].

Peter Attia

Yeah, we know that that’s explained very clearly by APOC-III, the resonance time on the LDL for that matter as well in pathologic states.

Dave Feldman

So if I became more insulin resistant, and therefore, ended up with higher VLDLs I couldn’t, say two years later, have healed that and then have less VLDLs.

Peter Attia

No. I mean, look back to the Garvey study. There’s a reason I printed this up, because I knew we’d be talking about this over and over again. There’s very little difference. To try to impute or infer something about remnant cholesterol from VLDL is as complicated as trying to assess Lp(a) by looking at LDL cholesterol. Think about that for a moment. When you look at LDL cholesterol, if it’s directly measured, do you agree that it’s the sum total of LDL cholesterol plus Lp(a) cholesterol?

Dave Feldman

Yes, I believe that’s how it does work.

Peter Attia

And it excludes VLDL cholesterol and IDL cholesterol because they contain ApoE, whereas the Lp(a) and the LDLP do not. So if you have a direct cholesterol measurement, the LDLC is technically LDLC plus Lp(a)C. But, there is no way on God’s green Earth that you can look at that and infer what the Lp(a) is.

Dave Feldman

Right, without testing directly.

Peter Attia

Yeah, and similarly, we don’t know what’s going on with these VLDLs, meaning in Moffett, because we haven’t measured it. But, we’ve measured this in patients that span the spectrum of insulin sensitive to diabetic, and that doesn’t appear to be the answer. The difference in the atherogenicity, the difference in the resonance time, and the difference in the total ApoB load appears all driven through the LDL particle, not the VLDL particle. So something else explains why they have more LDL.

Dave Feldman

That’s what I wanna find out. Again, I’m very up front about what it is that’s theoretical and what isn’t.

Peter Attia

But, we kind of already know the answer to that question. It’s the triglyceride content.

Dave Feldman

But, until we can actually test it on people who are fat adapted, or [kinetogenic], we can’t say that we do. When we can do a kinetics study … When we can do a kinetics study on VLDL secretion with people who are particularly likely mass hyper-responders, then we’ll have some idea.

Peter Attia

But, Dave, that will only offer you an explanation. It will not change the question.

Dave Feldman

Of risk?

Peter Attia

Yes.

Dave Feldman

Right.

Peter Attia

Let’s say you can do a kinetic study, and hopefully someone wants to fund this, because it is an interesting question. Again, I’ve done the kinetic study on myself, you’ve seen my data.

Dave Feldman

Right.

Peter Attia

I lose triglyceride, not cholesterol.

Dave Feldman

Right.

Peter Attia

Which, I would expect. Right? I am seeing cholesterol basically stay the same in those cells, and it’s during the periods of extensive exercise and fasting, we’re seeing triglyceride movement within the cell. But, the point is, even if this theory turns out to be correct, it’s an explanation not a reason. It’s an explanation for something, but it’s not a reason to ignore it, is it?

Dave Feldman

This is where I think we’re getting circular. It’s an explanation as to why it could be benign or even beneficial, and that’s where we’re disagreeing ultimately, which I figured we would be. Why would you have high LDL for a good reason? And you’re answer would be, “There wouldn’t be one.”

Peter Attia

No, no, that’s not true. There wouldn’t be a good reason with respect to cardiovascular disease, there are plenty of good reasons to have high LDL, we just talked about them. The FH patients obviously get some benefits from their high LDL. But, from a cardiovascular standpoint, I don’t think there is a single good reason to have high LDL, and I am not aware of a single card-carrying lipidologist or member of the community that spends a lot of time in this literature that could come up with one, and I’ve been asking. I mean, it’s something I’ve been very interested in. Give me a teleologic reason to have high LDL from a cardio protection standpoint. I mean, I was asking this question seven or eight years ago, and there is no answer.

So again, doesn’t mean that having high LDL is always bad, but it’s really important to understand this distinction. The other thing to keep in mind is, lots of things in biology are not linear. So look at Gilbert’s syndrome, Gilbert’s syndrome is a very common condition. 10%, maybe not 10%, 2% or 3% of people listening to this have it and probably don’t even know it. But, they have elevated unconjugated bilirubin, but very slightly elevated. So if you’ve had a blood test done, you probably know down at the bottom it says, ALT AST bilirubin. And normal bilirubin would be less than one.

But, these patients with Gilbert typically get to about two. Well, in half a dozen studies, these patients have an enormous risk reduction in cardiovascular disease. Why? Why would having a slight doubling of bilirubin, which by the way, at high levels is toxic. So if you walk around with a bilirubin of 10, you’re not gonna be around very long. And those patients present, they get sick, they have obvious symptoms, they’re jaundiced, and they usually have some pathology that’s leading to it. But, these patients can walk around with a bilirubin of 1.6 to 2, and they seem to be getting a benefit from it. And they also seem to have lower LDL, and even if they don’t have lower LDL, because the literature is mixed on this, they always have lower Ox-LDL. And it may be that the best explanation is that bilirubin has anti-oxidative properties. So they get this protection from cardiovascular disease, but it’s a U shaped curve, or an inverted U shape curve rather. Meaning, as that bilirubin gets higher and higher, they start to lose any of that benefit, meaning, whatever oxidative benefit they get, it’s more than being outweighed by the damage that comes from that elevated bilirubin. So I guess my point here is, even if there’s an explanation for why this is happening, from an energy trafficking standpoint, which again, I really wanna be clear, I do not think there is. I do not think that energy trafficking explains this phenotype. I think that is not the Occam’s Razor answer, I think the Occam’s Razor answer is, they’re making a boatload more cholesterol, because I think we have pretty good data to suggest that.

Dave Feldman

Which I’m dying to test, by the way.

Testing the Hypothesis

Peter Attia

Yeah, yeah. We should make sure that you can, and that other people can do this. But, of course, the point here is, it still won’t actually answer the question, what should you do about it? Just because there’s a reason for something doesn’t mean that it’s a benign condition, or that it should be ignored.

Dave Feldman

I agree, and not only that, separate subjects. I’ll even go a step further and say, it could be a U shaped curve on this end as well. It could be that you could have an LDLP of say, 1800, and it turns out that’s actually the bottom of the curve, and people at 1800 don’t turn out to be as high a risk as people that are like the one you just showed me, above 3500. I not only grant that, I also further tell lean mass hyper-responders, “I may turn out to be right on my cautious optimism, as far as the risk of cardiovascular disease, but it could turn out that there’s something else we haven’t yet determined.” That’s a problem with this phenotype, which is another reason why we should be sharing all of the symptoms that may be coming along with it as well. But all of that said, all of that said, the larger question is, why then, would I be able to identify a certain set of parameters that, when studied, seem to suggest that high levels of LDLC, I want some with high LDLP, doesn’t prove to be problematic. And that’s why I want to get a hold of something, I want to get a hold of really large-

Peter Attia

But, how will you demonstrate that?

Dave Feldman

By stratifying. Stratifying for high HDL, stratifying for low triglycerides.

Peter Attia

No, no, no. How-

Dave Feldman

Stratifying for high level-

Peter Attia

How will you know if they do or do not have, if they’re not at increased risk for cardiovascular disease? How long will you need to follow them to know that?

Dave Feldman

Well, that depends on the data set I can get a hold of. I’m not in your space so I have to work with other people who are researching-

Peter Attia

Oh, you’re saying you wanna do this with retrospective data.

Dave Feldman

Correct.

Peter Attia

Okay, so meaning this is your challenge to say, “Don’t give me genetic data, don’t give me drug data.”

Dave Feldman

I like just normal non-drug, non-genetic stratified people preferably. And I like to stratify just on those three, just on HDL, LDL-

Peter Attia

Even though your patients probably have some genetic SNPs that are explaining their phenotype?

Dave Feldman

Oh, I would definitely wanna know that as well. That’s why I’m trying to actively get the 23andMe, I would love to send it your way for obvious-

Peter Attia

But, the point is, you’re excluding anybody who has anything that could be called the genetic alteration, even though the patient population you’re trying to understand this is, almost assuredly has a genetic alteration that’s rendering them susceptible.

Dave Feldman

I’m not trying to exclude that.

Peter Attia

But, you just said you don’t wanna consider any of the genetic drivers of FH.

Dave Feldman

Let me emphasize. If you’re making a study that is gene specific, then it’s the gene that drives the detection, the discovery of those people. Right? I don’t wanna do that. I wanna actually see if I can get a broad base study of people who happen to already have high HDL, low triglycerides, and high LDL, and see if they have high rates of not only cardiovascular disease, but all-

Peter Attia

But again, I come back to the FH patients. You can’t find a more broader demographic of people in terms of variable genetic inputs that produce a phenotype similar to what you’re looking at.

Dave Feldman

I think we’re just gonna end up in one of these gotta agree to disagree moments. Until I can-

Peter Attia

Which is fine. I totally respect that. But, I just want you to understand what it sounds like from over here is, you’re looking for six footers, you’re looking for a six footer and you’re not gonna be happy until you see a six footer, and gosh doggone it, you’re not gonna leave the kindergarten classroom until you find one.

Dave Feldman

I would argue the opposite. I would say, “Look, why shouldn’t I be able to grab …” If I could right now just grab a million people in the United States, just absolutely randomly determined. Why would that not be significant data if I found that there was this stratification for which high LDL did not result in high levels of cardiovascular disease or all-cause mortality?

Peter Attia

Well, because if you’re gonna do that honestly, you’re gonna say, “Well, they can’t have a single genetic mutation, they can’t be taking a single drug, and they can’t be on any funky diet.”

Dave Feldman

Let’s say all of that turned out to be true.

Peter Attia

And what if they don’t exist?

Dave Feldman

If I found that out, that would be definitely something I think would be very interesting to my followers. I would turn that back around.

Peter Attia

But, you’ll never know if you found that out or not, Dave.

Dave Feldman

Well, I’ve already found two studies that do stratify for those three. And of the two that do, high LDL does not result in high rates of cardiovascular disease.

Peter Attia

Wait, wait, you’re talking about these glycogen storage disease cases?

Dave Feldman

No, no, no, Framingham Offspring has one study where they stratified by three, and unfortunately my computer is dead or I’d show you the other one. There’s another one that stratified discreetly between below 170 LDLC and above 170 LDLC. And the high HDL, low triglyceride group, when compared to above and below, were nearly identical, both on the high side and on the low side.

The two studies I’m referring to are:

Peter Attia

Yeah but, this study didn’t stratify by ApoB.

Dave Feldman

Right. I would love to have ApoB.

Peter Attia

Okay, but, that’s the Quebec Heart Study for you right there.

Dave Feldman

The Quebec Heart Study has the stratification by all three of those metrics?

Peter Attia

The Quebec Heart Study, here I printed it up here. I mean, basically it’s showing it has nothing to do with the LDLC once you know the ApoB. Look at the risk.

Dave Feldman

Okay. You have to understand, what I’m trying to get is … Sorry. I’m trying to get those three in conjunction. I want to specifically stratify those three. And in software, this is where I get a bit frustrated, because I feel like there’s such a cultural difference between medicine and software. We’re used to having just loads and loads of free data, just we’re awash in free data. Google can’t wait to give me everything that I wanna see. I requested, I’ve actually applied-

Peter Attia

No, I’ve heard you talk about it. Are you being denied that, or did they not have the data?

Dave Feldman

They just don’t return my emails. I mean, there’s even people that I would think would be sympathetic inside the low carb community, and I’m not gonna try to call them out, who I’ve also tried to get this information from. And I just can’t get it, and I want just a nice, clean regression on three axes, that’s all I want. That’s nice and fat.

Peter Attia

So the three axes being triglyceride-

Dave Feldman

Triglycerides, HDL, and preferably LDLP. Now, there is an important distinction we’ve gotta make with ApoB, because ApoB can, in theory, also include remnant lipoproteins.

Peter Attia

Yeah, LDLP is more accurate than ApoB.

Dave Feldman

Right. And LDLP would be extremely fantastic. If you could help me get in touch with that data set I would be very interested, and not with any major adjustments, I mean, whatever Cox proportional might be fine. But, just generally speaking, if I could get a big fat data set and stratify on those three axes, I think that would say a lot as to whether there’s any validity to the energy model overall.

Peter Attia

So when you look at the Mesa data, which stratify on a Kaplan-Meier curve, the difference between LDLC and LDLP. You’re saying that that’s not relevant because why?

Dave Feldman

The thing we’re dancing around here is, obviously when you have high HDLC and you have low triglycerides, it suggests a number of different things. But, more broadly, it’s suggesting a properly functioning lipid energy system, and probably not being in a state of challenge-

Peter Attia

HDLC tells us absolutely nothing. If we’ve seen enough from Mendelian randomizations and in other, how many more CTEP failures do we need to see? HDL cholesterol tells us nothing about HDL function. In fact, any time you increase HDL cholesterol pharmacologically, you seem to make patients worse.

Dave Feldman

I know, but these are modifications to the existing lipid system. If you block cholesterol-

Peter Attia

I get that, Dave. But, boy, if you’re gonna hang your hat on it’s all about HDLC triglyceride, I mean, wow, we are so far beyond that in the lipid world at this point. If you’re gonna go through this brain damage, make it for something worthwhile.

Dave Feldman

But, wouldn’t you predict right now, that if I did hang my hat on those two things, on those two markers, against LDLC or ApoB or LDLP, that it would fail. That if I were to say, “Hey, I wanna get a stratification just of high HDLC and low triglycerides.” That you’d say, “Sure, Dave.” I’ll bet you $10,000, I’ll give you 100 to 1 odds, those people with high LDL, even if you stratify for those two, will still have high rates of cardiovascular disease.

Peter Attia

Again, I’d have to completely see the patient population before I could even hazard a guess.

Dave Feldman

But, right now, you would assume that. Right?

Peter Attia

I am going to assume that LDLP is going to be a stronger maker of prediction than HDLC.

Dave Feldman

And that’s not what I’m making the case on. What I’m making the case on is, whether or not there’s a properly functioning lipid metabolism, which would be indicated by all three of those.

Peter Attia

No, you have absolutely no understanding of the lipid metabolism by looking at HDLC and triglyceride.

Dave Feldman

I think-

Peter Attia

Not even close. No, no, no, we can disagree on things that are nebulous. This is not nebulous, Dave. I mean, you do need … Again, I hate that I’m saying this, because I sound like a jerk and I don’t mean to. You’ve got to spend more time with lipid people, you really do. . . . You’re not dealing with your peers at this. You have to go and figure out … I mean, HDLC is just categorically not a useful metric. It is like a first order term on a … No, it’s not even that. In engineer-speak, it’s the fourth order term on a fifth order polynomial.

Dave Feldman

That hurts, Peter, that hurts.

Peter Attia

No, I mean, come on. It’s just not that.

Dave Feldman

I’m just kidding, I’m just kidding. Look, I-

Peter Attia

It’s super crude. And don’t confuse the ubiquity with its utility. The ubiquity of it is, “Yeah, it’s cheap. It’s easy. Everybody’s got it.” But, let’s not let people listen to this and get lulled into a false sense of, “Hey, if my HDL is high and my trigs are low, who cares what my LDL is.” And unfortunately, that-

Dave Feldman

I wanna prove that right or wrong.

Peter Attia

Well, first of all, you’ll never prove anything in science, so let’s be really clear on our lingo.

Dave Feldman

Okay.

Peter Attia

No, no, no, it’s very important. It’s important for your listeners to understand that.

Dave Feldman

Fair enough, fair enough. But likewise-

Peter Attia

But, nothing is proved, it’s about probability.

Dave Feldman

Sure, but likewise, would you say the lipid hypothesis is proofed?

Peter Attia

Absolutely not. I just said, “There’s nothing outside of mathematics that exists in a proof.” Nothing. And I have the basis of the luxury of having been a mathematician once, so I get it. There’s a luxury of being able to write QED at the bottom. We will never do this here, and if people are sitting there saying, “Well, I’m gonna keep eating my bacon and eggs like it’s mainlining, and ignoring my LDLC because my HDLC is high and my trigs are low, because I’m on a low carb diet, and somehow that makes me special, because no one’s proved that this is wrong.” Wow. That’s not the legacy I want.

Dave Feldman

So what if I continue to find more data sets that actually support that? What do I do?

Peter Attia

I mean, I don’t know. I don’t know what that means. What do you mean by more data sets? Meaning more anecdotes?

Dave Feldman

No, I’m talking like, say I do actually get a hold of Framingham Offspring, let’s say I get a hold of … I forget what some of these larger data sets are, and [inaudible 03:15:01] have to go-

Peter Attia

Mesa.

Dave Feldman

Mesa, sure. Let’s say I can get Mesa and I can stratify for those three and it’s showing the same thing, without doing a lot of adjustments or anything along those lines. What would I tell my followers? I would say, “No, it looks as if, still there’s further evidence that’s showing high LDLC, in this case, is not problematic.” Mesa did actually stratify for LDLP, didn’t it?

Peter Attia

Yes.

Dave Feldman

Yeah. So that’d be a great example. Mesa would be fantastic data to get a hold of. Is that something that you think I would ever actually be able to see or be able to run regressions against?

Peter Attia

I mean, I’ve never thought of it, but I agree with you. That would be great. I don’t know who owns the data.

Dave Feldman

But would that be compelling to you? If it turned out that we could run regressions on it, let’s say that it was in the next room right now and we worked it up on the computer, and sure enough, I went by the stratification I was looking for that are identical to somebody who’d be … And they were typical to somebody who is already a lean mass hyper responder, and it would show that they didn’t have high rates of cardiovascular disease. Would that be compelling data to you?

Peter Attia

I think compelling is the wrong word. The question is, how would it add to the existing body of literature that informs a decision we have to make every day with a patient. And the answer is, “I’d have to see the strength of it and decide, how does this fit into the existing body of literature?” I mean, that’s the only way I can imagine thinking about this. But, everybody listening to this, and you and I, all have to put our heads on a pillow at night with a null hypothesis, against which we have to challenge existing data. I’m not convinced that the null hypothesis here should be anything other than the lipid hypothesis. Now, the lipid hypothesis gets bastardized all the time, it gets misstated all the time, it gets based on LDLC and a whole bunch of other stuff.

But, I’m talking about the real honest to goodness, no bullshit, LDL hypothesis, which again, I’ve written about eloquently, and people have written about it far more eloquently. I should say I’ve written about it in a kluge way, others have written about it eloquently. The lipoprotein, the endothelial damage, the inflammatory changes, all of these things cascading, that’s my null hypothesis. And in the end, if there’s data to counter that, I’m all for it.

But, for example, even when you look at the IL-1, IL-6 agonists, the [inaudible 03:17:19] methotrexate studies that showed you could delay or reduce cardiac events without changing lipoproteins, I don’t think I’m being delusional when I say that doesn’t change the model. It actually feeds into the model. The model is, there are three things that are driving this pathology, if you reduce one of them, things get better. All things equal, if blood pressure goes down, do outcomes get better?

Dave Feldman

I believe they do.

Peter Attia

Absolutely they do. Very potent. Why? Endothelial function. All things equal, if you stop smoking, do outcomes get better? Absolutely. So when you start to look at all these things, and again, with those-

Dave Feldman

But by outcomes get better, you’re specifying-

Peter Attia

Cardiac outcomes.

Dave Feldman

Right, cardiac outcomes.

Peter Attia

The all- cause outcome is a much more complicated question that probably is a podcast in and of itself. So to your question, yeah, Dave, of course. I’d be incredible curious to see this. Who wouldn’t be? But, don’t think that one regression analysis on Mesa is gonna turn over 50 years of data, regardless of what it shows. The question is, how does it alter our understanding and thinking of the problem?

Dave Feldman

Sure. Look, the whole reason I’m even pursuing this particular strata is because of the model in the first place. I had to have something that I could conceive of, that would inform the decision by which I would be looking for what the data is that would disprove it. That’s why I’m in pursuit of disproving it. At the end of the day, Peter, I can’t emphasize this enough. I’m not looking to talk to the echo chamber or looking to just maneuver around inside a number of people that are gonna congratulate me. I specifically-

Peter Attia

But, I think you’re better off going to an NLA meeting than a low-carb meeting.

Dave Feldman

Sure, but they’re freaking expensive. I’ve looked at all of them.

Peter Attia

Get the low-carb community to fund you. If they wanna know the answer, because I don’t think they do, if I’m gonna be brutally honest. I think the worst of that crowd just want their confirmation bias. They have seen these incredible benefits of low carbohydrate diets, and their belief is, nothing can be wrong with this. Like we somehow live in a mono-dimensional, monochromatic world, where it’s that black and white. And if the diet is good for this, it can’t be bad for anything. And they are so wed to that they construct these crazy arguments. But, if they share your passion for truth, then they should happily fund you to go to an NLA meeting and spend a week there, and actually start hanging with these guys who are way smarter than me. I’m a knucklehead, I know a lot about lipids for a knucklehead. But, I’m talking about, the smartest people in the world are the ones you need to be talking to on this topic. And they’re not at low-carb conferences, I promise you that. They’re not on Twitter, and they’re not playing patty cakes on their high-carb, whatever, low-carb blogs. It’s just not about that stuff, man. And again, I think what you’re doing is really interesting. I don’t agree with the model, but I’m glad that you’re pursuing it. I wish you the best in pursuing it with the right people.

Dave Feldman

Absolutely. Perhaps you’ll be able to help me set up with the right people. I would definitely be more interested in finding those voices that can help tear at this model.

Peter Attia

I would be more than happy to help in any way I can.

Dave Feldman

Great. Well, I can’t emphasize enough as I anticipate, I was gonna ask you more questions than you asked me. I’m really appreciative that you took the time to chat with me about this.

Peter Attia

No, my pleasure, Dave. Thank you very much. I apologize if this just took longer than we thought it might’ve, and I know we went off on tangents all over the place. I guess, this will be one where the show notes are probably quite helpful. But, nevertheless, it was great meeting you in person. I didn’t realize it’s only been three years since you’ve been at this. It feels like a lot longer actually.

Dave Feldman

It certainly does for me. And my wife would say its felt twice as long for her. You have to realize something, almost nobody knew about me a year and a half ago, and I knew almost nothing about cholesterol three years before that. So this is absolutely been a fresh journey, and that’s why I have to oftentimes emphasize that I’m not a formally trained biochemist, and I really have a lot of gaps, I’m sure, in my knowledge that I’m looking to fill and find as fast as I can.

Peter Attia

All right. Well, it was great to meet you. Enjoy your time in San Diego. Oh, by the way, for the listener, this is being recorded on July 26th. It will be a long time before this goes up, Dave, so hopefully the listeners will understand that whatever has transpired since then is just … We prerecord these things many months in advance. We may have to bump it up a little bit, depending on maybe we can re-shuffle it and get it out before the end of the year, which is probably right now where it sits in the pipeline. But-

Dave Feldman

You’re gonna subject me to quite a hell, because I guarantee every single follower I have is gonna be knocking on my door until this thing is opened up, so that will be pretty funny.

Peter Attia

Well, we’ll do what we can. Anyway, man. All right. Thanks so much.

Dave Feldman

Absolutely.

Peter Attia

Awesome to finally meet you.

Next part: Guesting on the Peter Attia Drive (5 of 5) – Comments and Featured Thoughts

Oct 08

Guesting on the Peter Attia Drive (3 of 5) – Remnant Cholesterol, Craig Moffitt, Fasting

 

This is a five part series covering my appearance on The Peter Attia Drive podcast. Please skip to the final post to comment. 

Part 1 of 5 – Lean Mass Hyper-responders, Oxidized LDL, All-Cause Mortality
Part 2 of 5 – Cholesterol Challenge, Lipid Metabolism, LDL Receptor
Part 3 of 5 – Remnant Cholesterol, Craig Moffitt, Fasting
Part 4 of 5 – Energy Status, Risk, Testing the Hypothesis
Part 5 of 5 – Comments and Featured Thoughts

In both this and Part 4, I’m going to “let the tape role” as it were. While I considered trying to summarize many of these parts, I quickly realized it’s too unrealistic here as the ongoing context is important to keep together.

Remnant Cholesterol

Dave Feldman

Let’s circle back to remnants real quick.

Peter Attia

Okay.

Dave Feldman

This is why I pause a little bit on the case study that you showed me where you had the triglycerides a bit higher. Now, as you know, what is the poor man’s version of remnants is you basically can just take your triglycerides divided by five. You probably actually …

Peter Attia

No, no, no. We got to be very clear on this stuff. We’re going to confuse the hell out of people.

Dave Feldman

Okay.

Peter Attia

That’s the poor man’s version for VLDL cholesterol.

Dave Feldman

Correct.

Peter Attia

Very important distinction.

Dave Feldman

Fair point. Yes.

Peter Attia

The poor man’s version, which should never be done because it is such an abomination is to take the triglyceride level divided by five, and that number would be an estimate of your VLDL cholesterol.

Dave Feldman

Now, what would you, Peter Attia recommend as the most effective means by which somebody could determine their remnant cholesterol?

Peter Attia

We can’t. It’s impossible. We have no way of knowing remnant cholesterol. Let me be clear. I think I know what you mean by remnant, which is why I’m asking that question. You’re asking pathologic remnant. You’re asking VLDLs that have shed their triglyceride and are now basically pathologic, small. Started out as big, triglyceride rich, and now have shed that through their ApoC-II II LPL pathway, and now have the potential for atherosclerosis, is that what you’re meaning about remnant?

Dave Feldman

No, I now think we may think of it differently. Straight up Wikipedia right now would define remnant cholesterol as basically all cholesterol that’s not in either an LDL particle or in a HDL particle. If you were to just subtract HDL cholesterol [crosstalk].

Peter Attia

If you directly measure total cholesterol, which you can and you can directly measure LDL cholesterol and you can directly measure HDL cholesterol, you subtract those two and you have the amount of cholesterol that is virtually all in a VLDL, and presumably some IDL, if it stick around.

Dave Feldman

Some IDL possibly chylomicrons remnants if you ate recently, but you shouldn’t have any chylomicrons remnants.

Peter Attia

Yeah, that’s very easy to exclude.

Dave Feldman

Right, but effectively, if you’ve had a fasted cholesterol test, pretty much all your remnant cholesterol, pretty much will be in VLDL has longest residence time relative to the IDLs.

Peter Attia

That’s correct, but that’s like telling me outside a very few pathologic states, like [inaudible 01:46:01] and type-III Bs, that’s as interesting to me as your eye color.

Dave Feldman

The remnant cholesterol?

Peter Attia

Yeah.

Dave Feldman

Really?

Peter Attia

Yeah. I mean it’s generally going to be very low. It tracks quite well with triglycerides, though there are lots of examples where it’s been … Actually, I think I brought a copy of one of my other goofy experiments. I don’t know. I probably won’t find it anytime soon, but there is an example of how mine was so far off. It was like a 700% delta between actual versus predicted in one of these studies, but now, the point is yeah, directionally speaking, I would love to see a VLDL cholesterol below 15 milligrams per deciliter as calculated by taking non-HDL cholesterol subtracting the LDL cholesterol, but if you have a direct LDL, cholesterol is your best measurement of that.

Whether it’s 10 milligrams per deciliter, 15 milligrams per deciliter, 20 milligrams per deciliter, that just tells me the sum of cholesterol in all of my VLDL remnants. It tells me nothing about the pathology of them. It tells me nothing about what they’ve done or where they’re going.

Dave Feldman

But, that said, the question then becomes even for as much as what you just qualified, does that become a more powerful predictor relative to something like say LDL cholesterol?

Peter Attia

Maybe, but that’s like saying is rubbing two stones together better than rubbing two logs together to start a fire? It’s like why not just use a Zippo lighter? It’s like we could split hairs on whether non-HDL cholesterol or remnant cholesterol is a better predictor of cardiovascular disease than LDL cholesterol, but again, given that LDL cholesterol is such a crappy predictor of cardiovascular disease, I prefer not to really even think about that.

Dave Feldman

We do have now a situation where this particular phenotype where lean mass hyper-responders will have very low levels of LDL or I’m sorry, of …

Peter Attia

VLDL cholesterol.

Dave Feldman

VLDL cholesterol, have very high levels of LDL cholesterol, will have very low levels of remnant lipoproteins.

Peter Attia

But we don’t know that. There’s no way you’ve measured that. I’ve never measured that. That’s not measurable. In a commercial, I say that’s worth its salt. I think VAP does a vague ass version of that, but it’s bunk, but look at this. Look at Garvey’s studies. We’ll link to this as well. This is actually measuring the number of particles. This is an insulin sensitive person. Their a total LDL-P is about 1,200. Their VLDL-P is about 80. You go to someone whose insulin resistant, but not diabetic. Their LDL-P goes up to 1,435 on average. Their VLDL goes to 84. Their IDL is counted. It’s around area, and then you take the population with type 2 diabetes. Their LDL cholesterol’s up to 1,600 nanomole per liter and their VLDL goes up to 100.

You’re right, the VLDL is going up as you get more insulin resistant, but it does not appear very clinically relevant, because remember this is all the burden of disease, is from these ApoB bearing particles, and so the increase in VLDL particle number is not what’s driving the risk of the disease. You actually had a really nice graph in one of your figures that you titled that is remnant that was going up. You know the figure I’m talking about?

Dave Feldman

Yeah.

He’s referring to this one:

Peter Attia

We’ll link to that as well, but you had a graph that showed I think as people were becoming more insulin sensitive, their pool of remnants was growing. What you perceived as remnants.

Dave Feldman

Well, I actually want to qualify something real quick. If I think it’s the graph that you’re talking about, it was the one downside to that is it was non-fasted remnants, which I’ve been trained to find [crosstalk 01:50:02].

Peter Attia

Oh, got it. Got it. Okay, okay.

Dave Feldman

Which I have a problem [crosstalk].

Peter Attia

It was in one of your talks.

Dave Feldman

It was in one of my talks.

Peter Attia

But anyway, my point is what’s missing from that analysis is ApoB or LDL-P. In other words, the expansion of that … See this study, which is I mean the most elegant study of this ever done shows that if you only saw the top line, this to this to this, everyone would be like wow. The more insulin resistant you get, the more your total burden of ApoB goes up. What this is showing is where is that burden coming from. The VLDL only increased by 20 nanomole per liter, but the LDL-P increased by 400 nanomole per liter.

Dave Feldman

Right, and the point I’m coming to is this is where we’re in uncharted territory because I believe will apply to people who are ketogenic fat adapt. I don’t believe this will apply to people who are very ketogenic fat adapted, and particularly who have these phenotype.

Let me see if I can come at it this way, right now, if I were to be able to get the data set for Framingham Offspring, because that is one of the studies that I was showing out for before, and I could basically just do this basic calculation of remnant cholesterol the way they were talking about, and conceding the point of your time that you said earlier that’s there’s no way to truly know. Would I still come up with a more valuable metric for subtracting HDLC, particularly when associating to all-cause mortality? Relative to say …

Peter Attia

Let me make sure I understand what you’re saying. You’re saying if you could develop an [inaudible 01:56:54] to distinguish between the pathologic remnants of VLDL versus the physiologic remnants …

Dave Feldman

I’m not even developing that. Let’s say I’m not even developing. I’m just taking the existing HDLC and LDLC metrics as they’re recorded right now. I’m just grabbing the data says it is right now.

Peter Attia

Yeah.

Dave Feldman

Will the remnant cholesterol that I get from that subtraction, will that actually be more relevant to all-cause mortality than say LDLC?

Peter Attia

I don’t know, but it would certainly rival it. I mean, again, the data are probably more clearer on non-HDL cholesterol versus LDL cholesterol, that’s typically what the literature talks about, but as you can tell that non-HDL cholesterol and LDL cholesterol are two of the three variables you would need. There’s a strong correlation between non-HDL cholesterol and remnant cholesterol, and yes, I believe non-HDL cholesterol is more predictive than LDL cholesterol.

Dave Feldman

But there’s one problem with non-HDL cholesterol I definitely want to bring up for people who are on a low carb diet. If you’re going to be powered much more by triglycerides directly, literally triglycerides being brought to you in VLDLs, then that is going to be relevant. Now, again conceding Peter, what we talked about before, I can’t know if I can stake my flag on it just yet, but I’d be willing to bet if I’m right on the energy model that if fact you are being powered more by triglycerides found in VLDLs, then you can have a higher resulting LDL particles.

Peter Attia

But, wait. That’s a … sorry, I’ll let you finish, but I think your missing something. Go ahead.

Dave Feldman

No, no. Go ahead.

Peter Attia

No, no. I’ll remember it. I feel bad I interrupted you.

Dave Feldman

Okay. No worries. Effectively, the bigger question is, are particular lean mass hyper-responders show casing directly that they’re being powered much more by triglycerides brought on these VLDL boats, if you will, and therefore having more subsequent LDL particles.

Peter Attia

Okay. My hypothesis is that that is not the case.

Dave Feldman

That it’s the higher degree of synthesis, right?

Peter Attia

Yes.

Dave Feldman

Going on with the cholesterol.

Peter Attia

That’s correct. That it is the higher degree of synthesis, which may or may not also be matched by a higher degree of absorption.

Dave Feldman

How would, if you were wanting to, if you’re going to suggest a way that we could test this, how would you suggest that?

Peter Attia

Before I do that, let me unpack where I think energy is moving from. I think we all agree that someone who is very insulin sensitive on a low carbohydrate high fat diet is utilizing a lot of triglyceride. We agree on that, right?

Dave Feldman

Yes.

Peter Attia

Okay. Let’s take an artificial construct and separate endogenous from exogenous triglyceride. Meaning someone on a low carbohydrate diet is eating themselves, and they’re eating triglycerides from the outside world.

Dave Feldman

Right.

Peter Attia

Assuming they’re in the phase of getting leaner. They’re losing weight or even someone who’s weight’s static, they’re utilizing their own internal stores of triglyceride that they’re replenishing. If they’re staying weight stable, right?

Dave Feldman

100%.

Peter Attia

Okay. The exogenous triglycerides enter the body through chylomicrons that’s a pure lymphatic play through CTAP that’s rapid hydrolysis. I think we all get that. I think it’s this other endogenous pool that’s interesting.

Dave Feldman

And if I could just interject this one thing, because this is one thing we’re dancing around that we both know that probably somebody’s who’s not familiar with my work should be aware of. Chylomicrons, they drop off these triglycerides and they’re just gone. Almost like depending on who reading within minutes or hours [crosstalk 02:00:31]. If you’re taking a fast cholesterol test, Peter, we were talking about it earlier, you shouldn’t see any chylomicrons or chylomicron remnants, they should be gone, and the cholesterol payload on those chylomicrons should be gone.

Peter Attia

That’s correct.

Dave Feldman

With that in mind, go back to the endogenous triglycerides.

Peter Attia

Endogenous means we’re dealing with the pool of triglycerides that are coming out of you as the person. You have adipocytes, adipocytes stored triglycerides, and those triglycerides are hydrolyzed such that you have free fatty acids that will be transported. Where do they go? When they come out of the adipocyte, who picks them up? Albumin. Albumin then does two things. It can take it directly to the muscle, so that the muscle can use in the highly fat adapted athlete, or it can take it back to the liver, and it can be repackaged in VLDL or it could be turned into a keto, if we’re getting into an extreme state of someone who’s ketotic.

Let’s talk about, what’s the guy’s name you said, Moffitt?

Dave Feldman

Craig Moffitt, yes.

The Craig Moffitt Example

Peter Attia

Okay. I remember seeing this in your presentation. He looked like a runner, great athlete, super lean dude, right?

Dave Feldman

Mm-hmm (affirmative).

Peter Attia

Do you have Moffitt’s number handy? Can you give it to me?

Dave Feldman

You, know what? I probably can. Glad you mentioned that.

Peter Attia

Even just directionally. I mean, I remember seeing this a few weeks ago.

Dave Feldman

Got it. Okay, just one second. This is perfect.

Peter Attia

Okay. I’m going to read this off to everybody, so Craig Moffitt who looks like a super fit dude, who’s running around, has a total cholesterol of 457 milligrams per deciliter. His LDL cholesterol is 335. His HDL cholesterol 109, and his trig is 67. I’m assuming you did the math correctly. I’m not going to check it, but if that’s presumably the LDLs direct, his remnant cholesterol is 13 milligrams per deciliter, and by the way, that’s not terribly far off from what you would get by the trig by five formula. He’s not that far off. Okay, fine.

Where is he getting his energy. Let’s say he’s out for a run. He’s not eating anything and he’s fat adapted, and he’ll say he’s fasted, let’s make it even easier. He’s fasted going out for a run. His adipocytes are releasing free fatty acids to albumin. The albumin is taking some fraction of that to the muscle directly, and they’re undergoing beta oxidation there. The albumin’s also going back to the liver, and some amount of that is being converted into beta-Hydroxybutyric, which goes down its own metabolic pathway, and some amount of that is being packaged in either a VLDL or an IDL because remember there’s still de novo ILDL production in the liver, just as there’s the novo LDL production.

Those VLDLs and IDLs are leaving the liver and dropping off their payload of lipid to the tissue. The tissue’s basically getting ketones from the liver, triglyceride from albumin directly to the muscle and triglyceride through the VLDL and IDL directly to the muscle. Do we agree on that?

Dave Feldman

We do. I’m just going to expand a little bit on what you just said. So, yes, it’s full body lipolysis, and that he’s releasing the free fatty acids. In the literature they’re usually calling it, NEFA, non-esterified fatty acids, but we’ll just keep it to free fatty acids. It’s getting released from all [crossatlk 02:04:32].

Peter Attia

We usually measure them by the way as one.

Dave Feldman

Yeah. It’s a little frustrating because a lot of these terminology gets interchanged, but the free fatty acids are ultimately making it back to its liver getting packaged into the VLDLs. What we’re talking about the target sites of the muscles for which are making use of triglycerides. I should emphasis that I believe that the primary purpose of the creation of those is to replete everything. It’s not just to fuel the muscles, it’s also to put it back into the adipocytes that just now released it as well.

In other words, Craig Moffitt like many people who are lean mass hyper-responders, if we could install a little turnstile into their adipocytes. We would see that turnstile just spinning like crazy. They barely park the triglycerides there before it’s heading right back out, and that’s because there’s less total adipose mass overall in Craig Moffitt compared to somebody who’s a lot heavier, and therefore there needs to be more global supply of VLDLs relative to somebody else who has a lot more fat mass.

Peter Attia

But this depends on his energy requirement?

Dave Feldman

Absolutely.

Peter Attia

I mean, of course while he’s running, and again, I wrote a blog post on this a lot time I ago, which I guess we ought to link to. It’s something about fat flux. I don’t remember the name of it exactly, but the gist of it was over simplifying a fat cell as having two input doors and one output door. The two input doors as being the de novo lipogenesis door, which is still an esterified entry door, but I separated as a different storage. Meaning it’s coming from a carbohydrate, not from a fat, and then you have the re-esterification door, which has the turnstile that allows fat to go right back in, and then you have the lipolysis door, which allows the fat to exist. A person who is in fat balance has a situation where L, lipolysis equals the sum of the esterified de novo lipogenesis plus the re-esterified fatty acids. Agreed? That’s just straight up math balance.

Dave Feldman

Yes, yeah.

Peter Attia

When Craig’s running, he’s in negative fat flux. Make no mistake about it. His de novo lipogenesis is zero at that moment. His esterification is something, and his lipolysis has to be something bigger.

Dave Feldman

Right.

Peter Attia

If he’s not depleting glycogen, which if he’s highly fat adapted, he’s not.

Dave Feldman

And maybe it’s worth putting on a distinction. I’m not talking about whether they were successfully at the moment that he’s running. Successfully re-esterifying these fatty acids back into the adipocytes.

Peter Attia

And they might be though. That’s my point, because we don’t know. What we know is that in, which goes back to the question …

Dave Feldman

But do we know that it’s the job of the liver to keep maintaining that buffet? To keep putting that energy back out there, and generally speaking, we do know that. It’s just to what degree?

Peter Attia

No, I mean my hypothesis is yes. My hypothesis is, which is not by the way, I don’t think is a commonly held view. I think a lot of people would disagree with me, but my view is that the liver is the an ergo stat of the body. I borrowed that term from Mark Friedman, who wrote an amazing chapter on this in 2008. That has been one of the most influential things in my thinking on appetite, but he described the liver as the an ergo stat. It was, an engineer will appreciate the nomenclature. It looks kludgy to someone who’s not an engineer to say why would he call it an ergo stat, but in engineering speak, that makes perfect sense, but that the liver is probably most susceptible to detecting some currency of circulating energy and circulating metabolites.

ATP would be the most logical thing for it to be sensing. Probably ratio the ATP to ADP, or ATP to AMP, or ADP to AMP, something like that, but yeah. I think the liver … I mean, I think most people appreciate how impressive the liver is in general. I was just talking to a patient this morning, and I said, “Look man, here’s the deal. Anything that goes wrong with you can be supported extracorporeally. You get into a coma, no problem. You need to go on a left ventricular assist device, okay it sucks, but it’s there. You need dialysis, you need a ventilator, all that stuff, we do not have extracorporeal support for the liver. It is too complicated.

Dave Feldman

Anybody who follows me knows just how much I’m loving this because you’re the preacher’s preaching to the choir by far. I’ve often referred to the liver as the straight laced partner, who always puts up with your crap. Whatever you’re giving it, it’s having to pour us out and figure out, and balance the ledgers, and get everything in.

Peter Attia

No, no. That’s a great point, and that was part of the other point I made to this patient, who was not in any way opposing that view. He was just asking if the elevation we’d seen in his liver function tests, which was mild could explain a synthetic issue to which the answer is not a chance in hell under normal circumstances because the liver has an enormous capacity to do its job under even the most ridiculous stress.

Yeah, but going back to Craig, at the moment that he is running, which is the same as saying if someone’s losing weight while they’re on a low car diet, they are in negative energy balance. They are in negative fat flux, and again, when I say losing weight, let’s ignore the water weight and stuff. I’m talking about legitimate weight loss or shedding of …

Dave Feldman

Metabolism exceeds.

Peter Attia

Yeah. Yeah, but that’s what it means, right? On a practical level, it means lipolysis, the amount of fat that is leaving the fat cell has to exceed that which is reentering it, and again, I don’t know that this is entirely relevant, but you’ve eluded to it, so worth reiterating. Not all of that is oxidized. Some of that free fatty acid leaves doesn’t get oxidized, and guess what? It’s mopped back up provided the hormonal mill you still permits it.

Dave Feldman

Yes.

Peter Attia

We agree on the completely. I look at his remnant cholesterol of 13 milligrams per deciliter, and say okay, it doesn’t tell me anything. I apologize. Your question was looking at that, what could we infer?

Dave Feldman

Yes, actually, and this probably gets to just a larger problem that I feel like remnant cholesterol is helping us to address is why is it that anybody would have high triglycerides at all? Why aren’t all triglycerides making their way to either the tissue that’s using it immediately, the skeletal muscle or the cardiac tissue, or to the adipocytes if the body means to not have it sitting inside of lipoproteins part in your bloodstream.

Peter Attia

That’s a totally separate question. I want to come back to this remnant cholesterol question, though.

Dave Feldman

But this is why the original graph that we talked to, this is why I draw that dotted line. I draw a lot of people’s attention to it is …

The dotted line I’m referring to as shown in this graphic, which was up on the screen we were using.

Peter Attia

Can you go back to that?

Dave Feldman

I’m sorry. I’m trying to find another one. Okay, yeah. This is the core emphasis.

Peter Attia

This is the energy delivery support diagram for the person who’s going to be looking at this later?

Dave Feldman

Right.

Peter Attia

Okay.

Dave Feldman

I mean, if I’m going to way oversimplify it, but not by too much – chylomicrons’ job deliver fat-based energy.

Peter Attia

Yeah, and is so far gone that it’s not really entering the discussion we’re talking about outside a very, very rare diseases.

Dave Feldman

HDL, not to deliver energy will just say, things not related to delivering energy, but I just call it support, generally speaking. Operations not related to delivering energy.

Peter Attia

I agree with that.

Dave Feldman

Okay. Last line. Liver, this being the ApoB containing lipoprotein is the one lipoprotein that clearly is pulling double duty.

Peter Attia

No, no, but hang on. Remember this is where your diagram at which you acknowledge is over simplified. The over simplification is hurting you. The liver has three purple arrows coming out of it, the VDL, IDL, LDL.

Dave Feldman

Agreed, which is why earlier I was emphasizing that I believe there’s a higher secretion of VLDLs overall for those people with lean mass hyper-responders, which is very relevant to our discussion.

Peter Attia

How do we know that?

Dave Feldman

It’s a theory. I’m not saying that. What I’m saying is as if this area was fatter, if the VLDL secretion is at a greater degree, it would make sense why there would be more remodeled final LDL particles remaining, and why would we see the inversion pattern in the first place? Because it originated in order to deliver more of those triglycerides, which was brought about.

Peter Attia

Why the excess cholesterol? If that were the case, Dave, wouldn’t you hypothesize that the LDL particle would be very high because you have more VLDL particles, but they’re shedding all of their triglyceride in an effort to deliver their energy payload, but you shouldn’t have an increase LDL cholesterol. You should actually have a reverse discordance from what we see in the insulin resistant patient where we typically see the LDL particle number, being this proportionately higher than the LDL cholesterol by percentiles, of course, and absolutely members, that’s always the case. In other words, if I was buying your hypothesis I would say the LDL cholesterol should be very low. You should have very cholesterol depleted skeleton particles that were mostly used to shed triglyceride as VLDL.

Dave Feldman

But instead, we see the concordance. We see the LDLC and the LDL-p very concordant in people who don’t appear to have other types of diseases.

Peter Attia

Well, at that point they’re so high. It’s hard to know, but clearly not discordant in the direction that would make sense given your hypothesis. In other words, what I’m getting at is, why is there so much cholesterol in those LDLs.

Dave Feldman

Correct me if I’m wrong, but as far as the actual drop off rate, the LDLC is still going be relatively standard on a per particle basis in a healthy subject. How much variability is there typically in LDLC per LDL particle because again, correct me if I’m wrong, I thought that the secretion level tends to be fairly standard, like a spare tire is standard for a car.

Peter Attia

Yeah, it’s …

Dave Feldman

The triglyceride levels can be very variable.

Peter Attia

Yeah, but the cholesterol levels. I mean they have capacity to carry a lot, but think about it. If you have large and small particles that even for the same amount of triglyceride have different amounts of cholesterol, but the bigger point is, where is the cholesterol coming from? If we go back and look at my guy, or look Moffitt. Moffitt’s LDL cholesterol was 335 milligrams per deciliter.

Dave Feldman

Right, but that’s what’s in circulation in the blood at that time.

Peter Attia

Hang on. Just to be clear, Dave, is there any point during his 24 hour day when that number is 30 milligrams per deciliter of LDL cholesterol in his bloodstream.

Dave Feldman

I don’t believe so.

Peter Attia

In other words, if you take the area under the curve, if we could get real time LDL cholesterol number on Moffit, and integrate him over 24 hours, we could argue for argument’s sake, he’s going to be always over 300 milligrams per deciliter. Hus AUC would be very high.

Dave Feldman

For the existing traffic of the LDL particle, I mean basically what we’re talking about is what’s, I almost want to say it in terms of birds in the air. You have so many ships that have left the dock, that are continuing in circulation, but I guess here’s a different question that I’ll pose back to you.

Peter Attia

But, wait. I’m actually asking this because I’m trying to understand it.

Dave Feldman

How much of this cholesterol has already made a lap? Are you thinking of this in terms of it all getting synthesized and then reabsorbed, and then recreated it again?

Peter Attia

Let’s go back and make sure we’re agreeing on the same conditions here. Notwithstanding the experiment where they eat a ton of fat and they go from having incredibly high LDL to very high LDL, but let’s just take Mofitt, over the course of a week. Assume you could do real-time LDL cholesterol sampling on him.

Dave Feldman

And specifically, LDL cholesterol?

Peter Attia

Yes.

Dave Feldman

Okay.

Peter Attia

Or everything. Everything that’s on your page. You could sample his total cholesterol, his HDL cholesterol, his LDL cholesterol, his VLDL cholesterol, and his LDL particle number. You could sample all of these things in every second for a week. I think we’re agreeing that he will always have a very high LDLP and a very high LDLC and a low VLDLC. Correct.

Dave Feldman

Unless he eats a lot of fat.

Peter Attia

Okay. Yeah. Let’s, we’ll come back to that after, but yes.

Dave Feldman

Sure.

Peter Attia

Okay. So, given that the half-life of his LDL is a day, where is that extra LDL cholesterol coming from?

Dave Feldman

I believe it’s being recycled.

Peter Attia

Well, it’s always being recycled. How is his being recycled? So, so where is his, where is he deficient in cholesterol that a person who has an LDL cholesterol of 100 is not?

Dave Feldman

I guess I don’t understand the question. Where is he deficient?

Peter Attia

Yeah, if he’s got 335 milligrams per deciliter of cholesterol in his LDL particles, are you telling me that he has less cholesterol in his cell membranes or less of it somewhere else?

Dave Feldman

No.

Peter Attia

So he has more cholesterol in his body.

Dave Feldman

Correct.

Peter Attia

Why?

Dave Feldman

For the same reason that we would have say, life rafts on a boat and once we have more boats, we have more life rafts. So, if we had a harbor just outside this window, right? And you had 100 boats and on those hundred boats, their main job is to deliver something unrelated to life rafts. They’re delivering cargo to the other island. Right? And they deliver, and 100 of them go out, 100 of them come back. And then demand on that island has changed. Now they need to deliver five times as many things as they were delivering before.

Peter Attia

But the problem with that analogy is it assumes a completely fixed number of life rafts per boat.

Dave Feldman

It definitely does.

Peter Attia

But that’s not how the lipids work.

Dave Feldman

How does it work?

Peter Attia

There’s much more flex in the system. And furthermore, you could ask the question in reverse, why isn’t it higher?

Dave Feldman

Why wouldn’t LDLC be higher per boat?

Peter Attia

No, why wouldn’t LDLC be higher in that patient? In other words, what’s regulating it? What’s regulating how much LDL cholesterol he has?

Dave Feldman

The demand for the boats themselves for LDL particles.

Peter Attia

But what’s driving that demand? This is, I think where we differ, right?

Dave Feldman

The demand of the delivery for the triglycerides. The demand is for the cargo, the originating cargo that is clearly getting used.

Peter Attia

Right, but we agree that the VLDL vanishes very quickly.

Dave Feldman

The VLDL remodels to LDL very quickly.

Peter Attia

Yes, but if you go through the kinetics of this, I can’t follow why he should still have that much LDL cholesterol unless he is making more cholesterol. In other words, I’ve tried to think of this 10 ways to Sunday, the only way on a mass balance that I can explain this hypothesis is if he’s making more cholesterol.

Dave Feldman

And not if he’s recycling the same cholesterol? Certainly he’s making more relative to someone who doesn’t.

Peter Attia

Only if he were depleting it in some other store. So in other words, I’m making this up, but if you could say, well, all of us … I mean you probably know this. Everyone loves to quote this fact, right? But red blood cells have more cholesterol in them than LDL particles, right?

Dave Feldman

Right, right.

Peter Attia

So the, the LDL denier loves to say, “Well, we don’t think red blood cells are causing atherosclerosis and yet they have more LDL.” Whatever. But my point is, unless you’ve depleted a pool of cholesterol elsewhere in his body, just on mass balance, you had to make more of it.

Dave Feldman

As far as I understand, the liver can recycle cholesterol as many times as it wants to.

Peter Attia

Again, that’s true, and the liver and the gut have a very clear pathway, which he described.

Dave Feldman

Correct me if I’m wrong, the liver is the only organ that can actually degrade cholesterol, right? Non hepatic tissues can’t degrade cholesterol.

Peter Attia

Well, again, it depends what you mean by degrade. Remember, cholesterol has no caloric value. It’s not a metabolite. It’s not something that we metabolize, right? We turn it into-

Dave Feldman

If you were synthesizing more, you’re saying it’s going to go somewhere if it needs to be synthesized more.

Peter Attia

Right. If you’re synthesizing more, presumably you have a higher growth of the organism. You have more cells, you need more cells because obviously probably the highest demand for cholesterol is for cell membranes. So that’s what I’m trying to figure out. It’s like, where is all this extra cholesterol coming from? If it’s not being synthesized de Novo?

Dave Feldman

And that’s my larger point. The inversion pattern is part of what should bring this to light. Is, why then, when I have an enormous amount of fat over three days, I would see my LDLC dropped by 73. Why would I see my LDLP drop by 1,115 in three days from eating huge amounts of dietary fat? Why would that happen?

Peter Attia

I mean, it’s an interesting question. I’m just not sure. All it’s basically saying is you have a way to perturb those levels. I mean, I’ll give you another anecdote here. So, you know, I did a one week fast, I went Keto for a week and then ate nothing for a week and now I’m actually back on Keto for a week and I’m checking my blood every seven days. So that was my LDLP before I … That was just me. That’s my normal LDLP. So I’m walking around at 920 nanomoles per liter. This is after months and months of time restricted feeding with virtually no carbohydrate restriction other than just I don’t eat crappy carbohydrates.

Dave Feldman

Right.

Fasting Impact on Data

Peter Attia

So then I went Keto for a week and look, my LDLP actually went up. Now I don’t think I would meet criteria for being a “hyper responder” because it went up to 1380, which is not that high, but you know, that’s still a significant jump for me. Right? Okay. What should it have done when I fasted for a week? Shouldn’t it have gone up according to this model?

Dave Feldman

Well, here’s the catch. The catch is, I only know the three day window. I don’t have a lot of data from people who fasted for a week, as in just water fasting.

Peter Attia

I do.

Dave Feldman

Okay. You do? Good.

Peter Attia

Yeah. I’ve done this on multiple patients who have done three, five and seven day fasts.

Dave Feldman

Okay. Who are fully ketogenic and you’re saying it typically goes-

Peter Attia

Not always ketogenic. No. Sometimes they’re just, you know, fat adapted. Sometimes they’re not. Sometimes they’re actually insulin resistant and we use the fast to kick them into a state of Ketosis to make it easier. But, and again, I want to be very careful. This is simply just anecdote because I’ve only done this on maybe 30 people, but this is not uncommon. I mean, look, my LDL cholesterol went from 64 to 37 after the fast. I mean it went way down.

Dave Feldman

Wow. Fantastic.

Peter Attia

And that’s consistent with what I see. Now, that’s not the reason I’m fasting. To be clear. I’m not using a fast to manipulate lipid proteins. I’m doing it for a completely unrelated reason, but my point is I always see, and again I can say always because it’s a relatively small end. Obviously, at a large enough and you’re going to see counterexamples to anything and everything, but the general principle seems to be under caloric deprivation, LDL goes down and under fat deprivation LDL goes down.

Dave Feldman

I’ve got to put in the one footnote and it’s an annoying footnote that I keep putting in. I really need to. And this is why I’m dying to get these parts of the exercise. I need to look at a population that also is not getting any, particularly weight training or resistance training and so forth, because that seems to impact it. Whether it’s my theory or not, that seems to impact overall lowering LDLC numbers. I’d be very interested about this in fasting.

Peter Attia

I’ve got that in my patients. Not every one of my patients lift weights despite my best efforts. So, again, I think the more common thing that we see is that when you put people on a high fat diet, the ones that go on to have this hyper response, as you note, their trigs usually go down, their cholesterol goes through the roof and it’s driven by a doubling, tripling, or even greater output of synthetic biomarkers like desmosterol. Now, for reasons I don’t understand, you also tend to see at least two of their three phytosterols go up. Now, one thing we didn’t talk about though, I wrote about it, so I’m sure you know about this, is this seems reversible. If you eliminate the saturated fat.

Dave Feldman

It does seem to matter in this case, and you’ll like this, at least in our own data with ApoE4s, seems more likely if you’re an ApoE4, you will see a drop somewhat in saturated fats.

Peter Attia

So I don’t think I have a large enough sample size because I’ve only put seven patients through that protocol. Which is, and I wrote about the very, very first one. So that’s probably the only one that you’ve seen that I’ve talked about, but this was a young guy who went on a Ketogenic Diet, was crushing it, meaning like everything was going well. I mean he’d gone through the adoption period. His performance was exceptional, mentally never felt better. He was not an overweight, or metabolically ill guy to begin with. He was just kind of a normal software guy who just decided he wanted to take it to the next level. But then he showed up with labs, not unlike these. He was the first guy I ever saw where there was a greater than sign on the LDLP.

Dave Feldman

Right. It maxes out at 35.

Peter Attia

I was like, “Oh, I didn’t actually realize the assay stopped at 3,500. This guy is my guy.” He looked better on some of the other metrics. He didn’t actually have a lot of the inflammatory stuff. This was before the Ox LDL assay was commercially available. So I didn’t have that. But you know, his CRP and is LPPLA2 we’re okay. But we had the discussion, right, which is the discussion that at the end of the day I’m accountable for having, which is what are we going to do about it? And he was young. I mean the guy was 30, so it wasn’t like we had to do something tomorrow. This is not a guy who’s going to have a heart attack in a week.

Dave Feldman

Because I think when you originally writing about it, he actually pushed back a little bit. Like he wanted to come up with a-

Peter Attia

Well, what he pushed back on was, because I basically said, “Look man, I don’t think the Ketogenic diet’s right for you. These numbers are crazy.” And he was like, “Yeah, I don’t ever want to go back to what I was doing before.” I mean he basically said in not so many words, like I’d rather die of a heart attack and feel this good. And he’s not saying like, “I’m going to die of a heart attack tomorrow”, but he’s like, “Look, I’d rather live to 60 and feel this way, than live to 70 and not.” Which I say totally fair by the way. That’s a very reasonable trade off to make, but let’s also think about this a little more logically. So that was actually probably the first case I ever discussed with Tom and this was I think back in 2011 and it was actually this discussion I think that lead Tom to go on to write the lipidaholics case, even though it wasn’t the patient that he used in that case because he then went out and found others like them.

What we just decided was on biochemistry first principles, our hypothesis was it’s the saturated fat, more than the ketones. Because that was the other thing, this guy didn’t want to leave ketosis. My thought was, let’s just dial this back, get you out of Ketosis. So our hypothesis was both ketones and saturated fat can be readily converted into cholesterol, but if he’s adamant on staying in Ketosis, let’s at least get his SFA down to 25 grams per day. Which was hard. This is a guy that was eating about 100 grams of SFA a day, maybe 80 grams. I mean, it was a lot. We basically just made most of it MUFA. So I said to the patient, I said, “Look, the way we could do this just for no other reason as the purpose of a thought experiment is, you’re going to basically have to become a nonstop olive oil, Macadamia nut eater. Even even the avocado you can’t go hog wild on because eventually you’ll get too much carbohydrate out of it for this purpose.”

And sure enough, I think he came back at like 1300, after eight weeks or something like that. So six more patients have been so adamant about staying in Ketosis and not taking any medication but wanting to go through this experiment and all of them have had the same response. Which is, if you can get them to main line MUFA, you fix the whole problem. Without reducing or increasing to any measurable effect, how much fat they’re consuming.

Dave Feldman

Have you been keeping track of their PUFA levels too? Because it’s hard to add a lot of MUFAs-

Peter Attia

Their PUFA was going up.

Dave Feldman

And you know, the issue with that, with adding more PUFA, is the downside is there’s the potential that you’re actually adding more peroxidation on the particle basis.

Peter Attia

Yeah. Yeah. I mean, I think it depends. This is one of those areas where I’m trying to get a lot smarter and I want to make sure I’m not sitting in the echo chamber. I’ve historically, you know, measured RBC levels of arachidonic acid and all of those things and tried to keep track of the ratio of that to the EPA and the DHA, but ultimately I don’t really think I know the answer to this yet. And I also don’t think … My guess is PUFAs are not as bad as I have historically thought them to be, but they’re probably not as good as MUFA. So not withstanding that, I just want to talk about this from the level of the thought experiment, so to speak. My sample size of those people is too small to know if there’s a relationship to their ApoE gene. To your point, what I’m hearing you say is maybe that’s more … That’s something that you’re more likely to do in someone who’s an ApoE4 carrier.

Dave Feldman

It’s been a proportional kind of thing that we’ve sort of noticed.

Peter Attia

I don’t know, but what I do know is it seems to point back to this idea that the hyper responders … That the Occam’s razor here is that they’re making more cholesterol. Because that makes sense from a mass balance standpoint. Again, I’m still-

Dave Feldman

And I would have agreed with you were it not for this energy inversion that I see. If it were not … The very thing that I said from earlier that I could move my LDLC to where I want to move it. That would be based on me basically arranging for a few days to eat to a certain level and I’d be pushing down my LDLC by eating up to a certain-

Peter Attia

Notice you’re pushing up and down on LDLC within super physiologic levels. Meaning, if I recall seeing your data, do you mind showing me that again?

Dave Feldman

Unfortunately, the computer died. That’s why I’ve had it closed, but yes, what you’d see as an inversion graph and-

Peter Attia

I’m very familiar with it and we’ll obviously link to it, but it was, as I described it, you’re showing that you can move your LDL between the ranges of very high and stupidly high.

Dave Feldman

No, like I’ve, I’ve moved my-

Peter Attia

What’s the lowest you’ve ever got your LDL?

Dave Feldman

98, and I suspect-

Peter Attia

Okay.

Next part: Guesting on the Peter Attia Drive (4 of 5) – Energy Status, Risk, Testing the Hypothesis

Oct 08

Guesting on the Peter Attia Drive (2 of 5) – Cholesterol Challenge, Lipid Metabolism, LDL Receptor

 

This is a five part series covering my appearance on The Peter Attia Drive podcast. Please skip to the final post to comment. 

Part 1 of 5 – Lean Mass Hyper-responders, Oxidized LDL, All-Cause Mortality
Part 2 of 5 – Cholesterol Challenge, Lipid Metabolism, LDL Receptor
Part 3 of 5 – Remnant Cholesterol, Craig Moffitt, Fasting
Part 4 of 5 – Energy Status, Risk, Testing the Hypothesis
Part 5 of 5 – Comments and Featured Thoughts

 

The Low Carb Cholesterol Challenge

Dave Feldman

The part of what this energy model, in particular, that with hyper-responders, specifically lean mass app responders comes back to. I don’t know if you’ve, I know you don’t necessarily hang out on Twitter too much, but you know that I’ve had-

Peter Attia

More than I would like.

Dave Feldman

I have this pinned Tweet, I’ve been pinging lots of lipid-lowering experts on this, I’ve said, “Look, I’m looking for any studies that show people with high LDL will have high cardiovascular disease, if they likewise have high HDL and low triglycerides.” But there’s one qualification, it can’t be a gene or drug study. It’s gotta just be-

<Snip>

https://twitter.com/DaveKeto/status/963437664199352322

Peter Attia

No, I’m seeing that. Here’s my concern with that, Dave. I have no doubt in my mind that you are a truth seeker. I don’t think that’s true of necessarily some of your peers. I do think a number of your peers are deluded and so filled with their own confirmation bias, and so unwilling to acknowledge that their precious low carbohydrate diets could be hurting them. That not with malicious intent, but with blind carelessness, they are absolutely ambivalent to anything.

I don’t put you in that category, so I will challenge you in the following way…

Dave Feldman

Great.

Peter Attia

When you say, “Show me an example of something that is not a genetic study, that can point to that phenotype.” The reason I would call issue with that is, why would you limit yourself from genetic studies? That’s sort of like me saying, “I want to know if there are people who are six feet tall. I think they might be, but I’ve never seen one. So, if you can go into a kindergarten class and find me one, I’ll believe it. But, you must limit yourself to the kindergarten class.” In other words, that’s an obscure example. What I’m basically saying is, you’re excluding so much potential data by excluding all of the genetics.

Because when people talk about genetic studies, we have to remember something, most of the genes, most of the snips that lead to alterations in lipids and lipid metabolism, are completely unidentified. FH, for example, familial hypercholesterolemia, which would be the most obviously example to counter that point, you’re excluding because it’s a genetic condition. What the listener might not know is that FH is a phenotypic diagnosis, not a genotypic diagnosis. FH is arguably the most heterogenous collection of genes you can imagine.

So, why would we exclude looking at those people, when that’s, in many ways, one of the richest bodies of evidence for a natural experiment in … To answer the question, can you have LDLC, high HDLC, low triglyceride, and still get atherosclerosis? That’s the question you’re asking, right?

Lipid Malabsorption – Part I

Dave Feldman

Yes, yes. Well, so, we’ll double back to that in a sec, but basically, you’re taking us back to genes, and this is why … This is another hypothesis, fully untested, I’m in the process of trying to collect on it, but I call this loosely, Cellular Lipid Malabsorption. Right, just generally shorten it to lipid malabsorption.

Basically, here’s the issue that I have with the existing mendelian randomizations. For that matter, almost all of the gene-based studies is what we’re trying to get, what we’re trying to get, is as much as we can, the isolation of just a higher gradient of LDL particle count. That’s what we all secretly … We want your wand. You’re talking about where we can wave it, and then there’s just magically more LDL particles in some people, or for that matter, less LDL particles. Without touching any other parts of the process.

The problem is, that I believe … I’m keeping a list of my own SNPs of those genes that are either resulting in higher or lower LDLC. Unfortunately, of the ones that I find in the mendelian randomizations, they don’t just result in the higher LDLC and LDLP, they also come to be that way because there’s a lack of lipids or lipoprotein uptake by the cells.

Therefore, particularly with endothelial cells, you’ve got to be concerned that that could cause dysfunction. And therefore could be a reason for why you’d have higher levels of atherosclerosis. This is why-

Peter Attia

Wait, wait. So, explain that part again. The last part.

Dave Feldman

We would ideally want to-

Peter Attia

No, no, I got that part, but tell me about what you said about the endothelial cells?

Dave Feldman

Endothelial cells being dysfunctional.

Peter Attia

Yes.

Dave Feldman

Would that be potentially problematic for atherosclerosis?

Peter Attia

Yes.

Dave Feldman

Okay, then why would we want to look at any SNP that would in any way impair, inhibit them relative to a normal person endothelial cell?

Peter Attia

Why do we believe patients, or a subset of patients with FH, as a result of their FH have defective endothelial cells?

Dave Feldman

Well, if you’ve got defective LDL receptors.

Peter Attia

There’s not receptors on the endothelial cell. It’s diffusion mediated.

Okay — time out!

Endothelial Cells and LDL Receptors

This was probably the most surreal moment to me in the podcast as I found myself instantly conflicted.

I assumed going into the broadcast that we’d likely agree on all the fundamentals, yet would disagree on the broader interpretations. And should Peter correct me anywhere on a question of fundamentals, he was almost certainly right and I’d be all too happy to concede this on the spot (hence my “stealth interviewer” statement earlier).

Yet… Peter said something that I was 90% certain was in error. Endothelial cells do have LDL receptors… right? Peter said this with such specificity and confidence. Could I be wrong about this? I was suddenly searching everywhere in my head where I learned about endothelial cells and LDLr.

Regardless, the bigger problem is that endothelial cells were just one part of the larger equation to this central point anyway. If I got hung up on this point with endothelial cells, right or wrong, I might also fail to illustrate the larger one. The issue of Lipid Malabsorption was relevant to all tissues, so why not just move the spotlight to the other tissues and fact-check the endothelial cell receptor issue later?

Dave Feldman

Okay. Well, yes, but you’ve got the receptors with the Adipocytes, right?

Peter Attia

Yes, but, at least 20, if not 40% of LDL uptake, is not even receptor bound in the body.

Annoyingly, it was in this moment I remembered where I had first heard about endothelial cells and their family of receptors (including LDLr). But I didn’t want to doubleback as the moment as I really didn’t want to say anything on it until I was 100% sure.

Fast forward two hours…

After the podcast was completed and I got back to my car, I enthusiastically pulled up every reference I could on endothelial cells and LDL receptors. I further had Siobhan redundantly do the same. It all checked out.

Fast forward three weeks later to August 16…

I was at another conference in a lengthy tweet exchange with Nick Hiebert between sessions where at one point I said the following:

https://twitter.com/DaveKeto/status/1030113916540669953

To my surprise, Peter jumped into the debate (something he rarely does on Twitter) with the following:

https://twitter.com/PeterAttiaMD/status/1030124638909673472

Of course, now I was much more confident in the original assertion. But I wanted to keep this lighthearted and friendly so that my answer wouldn’t seem confrontational or curt in any way. So given many were pinging each of us about when the podcast would be released, I decided to insert a joke about that along with the pathway answer…

Peter then ultimately acknowledged this but expressed his reservations that evidence was thin for in vivo studies in particular (even if demonstrated in vitro). We then exchanged a few more tweets back and forth from there before stopping for the day.

Lipid Malabsorption – Part II

We now return the discussion already in progress…

Peter Attia

And not all cases of FH have receptor deficiencies. So, there are at least 2,000 vaguely identified genetic causes of familial hypercholesterolemia. Some of them are lower, they have fewer receptors. So, the PCSK9s are a subset of FH, right? About three to 5% of patients with FH have-

Dave Feldman

Over expression of PCSK9.

Peter Attia

Over expression of PCSK9.

Dave Feldman

Gotcha.

Peter Attia

But that’s how PCSK9 was discovered.

Dave Feldman

Okay, but in that case, you’re impacting a cell’s capability of uptake for lipids, or for lipoproteins, right?

Peter Attia

Yes, you are in that situation. Those patients’ livers, will take up less LDL, because PCSK9 is a protein that does, among other things, degrades the LDL receptors because they have hyper-functioning PCSK9, they are more rapidly degrading their LDL receptors on the livers, so they’re taking up less LDL particles. Which explains why they have higher LDL.

Dave Feldman

But this, again, introduces a dysfunction on the lipid metabolism itself.

Peter Attia

But that has nothing to do with the endothelial. That has nothing to do where atherosclerosis occurs. All that’s doing is giving you more LDL and circulation.

Dave Feldman

But, it’s … Let me put it this way. Why not take anything that results in a higher level of LDLC or LDLP that doesn’t impact any lipid absorption from any tissue at all?

Peter Attia

Right. But that might be a bit of an artificial constraint right? As you pointed out yourself and I think anybody listening to this will appreciate, this is a complicated dynamic system, so it is going to be difficult to have some perturbation in a system that will lower or raise LDL that won’t have some other effect.

The question is, how do we, with some reasonable degree of certainty, look at those other effects, and ask whether or not their germane to the question of atherosclerosis and the causality of LDL to atherosclerosis. So, I think the PCSK9 example is not an unreasonable one, because we have a pretty clear understanding of what that gene does. We have a very clear understanding of where that protein lives, and what it’s doing-

Dave Feldman

But if anything, that’s resulting in the other direction. Where, if you have lower LDLC or LDLP from under expression PCSK9. That actually results in a hyper-absorption of lipids, for example.

Peter Attia

In the liver, yeah. They have enhanced hepatic clearance. So both ends of that though, right? So, if you have hyper-functioning and hypo-functioning PCSK9 patients out there, both of whom exist, I believe the hyper-functionings were discovered first. But they hypo-functionings are kind of the ones that gave the drug companies the desire to go in … Not the desire, the idea to go and create a drug to mimic that phenotype. But these patients walk around with LDL cholesterol of 10 to 20 milligrams per deciliter, and as far as anybody can tell, there’s no other side effect of that.

Dave Feldman

This is the thing I want to zero in on. Let’s say that we do that. Let’s that we go “Okay, never mind this side part of the lipid hypothesis end of it. I’m sorry, the lipid metabolism end of it.” We should then be able to look back at these people with the more novel versions of SNPs and assuming there’s at least a large enough population, we should see that longevity. Your mentioning of the APOC-III from earlier, is the first that I’ve been able to find of that one. I’m interested to see if we would see that across the board with these people who have these SNPs.

Peter Attia

Yeah. I mean, I suspect it will have to do with how many of them there are, and how long they’re being tracked.

Dave Feldman

Because, the all-cause mortality, you’d have to understand, I sympathize with your concern, as it’s absolutely the case, nutrition medicine, there’s certainly a lot of personalities that are out there. But, I can understand at least for me, on my end, I like hard endpoints over soft endpoints. Maybe it’s just the engineer in me. I like ones and zeros. Death is pretty easy to diagnose. Whereas, soft endpoints, the downside is there can be arbitrary decision making on the part of the patient and the doctor.

Peter Attia

Yeah, you know, I heard you mention that on one of the podcasts. I gotta tell you. I disagree with that. Having seen more patients in an E.R. when I was in residency with MIs, I can honestly tell you, Dave, never once knew what their cholesterol levels were.

When someone comes in the E.R. with chest pain, I care about the advanced cardiac life support algorithm, which involves oxygen, which involves and EKG, which involves troponin, which involves morphine, aspirin, and potentially a trip to the cath lab. But, we are, and no where in that algorithm, are we asking, “What’s their LDL?” And letting that help us think, is this indigestion versus other things. So, I do take issue with calling MI as soft outcome.

There’s a little bit of a misunderstanding here. The podcast Peter referred to is likely my appearance on ZDoggMD. I have it queued to the specific part here:

To summarize:

  • Person A has high cholesterol and is told regularly by their doctor of this concern.
  • Person B has low cholesterol and is likewise aware of this through their doctor.
  • Each eats the same meal, experiences an intense 30-minute chest pain right afterward.

While I think each have a decent chance of checking themselves into the hospital, I certainly think Person B is more likely to rule it heartburn and take a tums. Person A checks in, gets an EKG, post-cardiac enzymes, etc. So if both A and B are in a study, we can see how their own cholesterol awareness furthered a feedback loop that could potentially bias the data. The only way to guard against this would be for both the doctor and patient to be unaware of the lipid numbers. (File that under Things That Will Never Happen)

Peter was speaking more to the admittance upon entering the hospital, not your primary care physician discussions. But as an aside, I think I could go into any hospital waiting room in America and over half the people there will know off hand if their cholesterol is “high” or not, regardless of why they are there.

Soft vs Hard Endpoints

Peter Attia

It’s not so much whether it’s a soft outcome. It’s whether or not there are things like, say revascularization. That can be determined based on the decision on the part of the doctor and the patient, that may or may not have to do with their knowledge of the lipids, right?

Agree. These are different things. But, I also think we should be careful not to take mortality as the only outcome. I will say this, and I hate putting on the stupid doctor hat, because it sounds ridiculous in this context, but unfortunately, I feel like I have to go back into and out of that world here. I would say at least half the patients that come to me, do not actually find themselves asking for an extension in life span. Right? My interest is longevity. But longevity has two components. How do you increase lifespan? Meaning, how do you delay death? And how do you improve health span? I won’t go into what that means, but, the bottom line is, there are many people who say, “I honestly have no interest in living one day long then I might otherwise live. But I want that quality to be much higher.” So, if we’re going to say … And, again, I don’t necessarily agree with that, I think the bigger issue is a statistical one with all- cause mortality, but, nevertheless-

Dave Feldman

But you go into modality. Like, if somebody has an MI, and it actually impacts their quality of life afterwards.

Peter talks a bit about possible modality outcomes, statin impact on Alzheimer’s and diabetes, and population vs individual-level data.

Dave Feldman

But, getting back to the challenge. In a sense, you’re saying by ignoring the genetic data, that the genetic data basically answers the question, to your satisfaction. To where you don’t need to look at non-genetic-

Peter Attia

Not alone. I think of it as the genetic data, coupled with the pharmacologic data, coupled with the mechanistic data, give me a high enough degree of certainty, that I am willing to act in a certain direction. Remember, everybody, me, you, whoever’s listening to this, they have to make a decision.

Dave Feldman

Sure.

Peter Attia

Indecision is a decision. So, when you showed up with the hemoglobin A1C of 6.1, did you have type two diabetes? Nope. Your doctor said, “Hey, I’m cool just waiting.” But you said, “No. Indecision is not a decision any more, I’m going to do something about it.” Because, presumably, you said, “Look, I have a family history of this. I think I have a sense of what the progression of it is. Quite frankly, I don’t want to wait until I have this disease to do something about it.” So, you decided indecision was not a viable decision.

Sometimes indecision is a reasonable decision. But, the point is, people have to understand they are making a decision whatever they decide to do.

Dave Feldman

Absolutely. Well, and for what it’s worth, as I say outside of here, and as I’ll say on this podcast, as I actually just said it, the speech, I don’t know if you saw the one that I did from last month. I told people, I prefer they not be echo chambering. I prefer they find everything that challenges from every side. So, with that said, going back to the lean mass hyper-responder, you would say, given what you know right now, given everything we’ve just talked about, that they are at high risk of cardiovascular disease. Would that be correct?

Peter Attia

I’d want to know more data. But, yes. If everything … If I didn’t know anything else other than-

Dave Feldman

Let’s say all cardiovascular risk markers say, LDL of 200 or higher, LDLP of typically 2,000 or higher, everything else is just pristine perfect, like CRPs at the floor, their LPPLA may be-

Case Study Talk

To my delight, Peter had a lab to chat about…

Peter Attia

Let’s look at this patient here. So, we’ll link to these labs. I asked this patient, this is a patient I saw last week. So that the only reason I printed this up, because I see this so often, but I’m like, “Let’s just get the last one.”

This is a gentleman who’s been on a low carb diet for a couple of years, is achieving amazing success with it. He’s a new patient to me, but he’s been around the block on this stuff before, and he’s got an amazing history of his labs going back many years. I’ve seen what he looks like on and off all of these therapies. On and off drugs, et cetera. He’s one of these guys where, across the board, looks fantastic, right? His glucose disposal is remarkable, his insulin levels are very low, his c-reactive protein is 0.3. Everything looks good. Read off some of his numbers, just for the folks, Dave. He doesn’t quite meet your lean mass, because his trigs might be a bit higher, but, talk to me about this guy’s numbers.

Dave Feldman

So, total cholesterol is 504.

Peter Attia

Is that high?

Dave Feldman

I know what you’re doing there.

Peter Attia

No, I’m just kidding.

Dave Feldman

I get this all the time where somebody sends me just that number.

Peter Attia

No, no. Okay. Go ahead.

Dave Feldman

Total cholesterol 504, LDLC direct, and it’s worth emphasizing just real quick for the listener, when they say direct, it’s very important to notice that, because usually, LDLC on a typical lab is actually calculated through the Friedewald Equation. So, when it’s direct, that actually is a direct measurement. And that matters for remnant. Hope we’ll get a chance to talk about that.

Peter Attia

We will talk remnants for sure.

Dave Feldman

So, LDLC at 362, HDLC at 94. Triglycerides at 125. The very first question I would ask if somebody was sending this to me is whether it was fasted or not?

Peter Attia

Yeah, this was. But, I’ve gone back and looked at all of his other trigs, and he actually, normally, does reside below about 70.

Dave Feldman

Oh, he does. Okay. So he would be typical for a lean mass.

Peter Attia

Yeah, he might have just eaten dinner a little too late, or something. I’m not sure what was going on.

Dave Feldman

Do you want me to keep going on the particles?

Peter Attia

Yeah, hit the particles.

Dave Feldman

So, Apo-B is 283? That actually is a little higher than I’m used to seeing. LDLP is about 3,500. Small LDLP is at 1,483. Small dense LDLC is at 47.

Peter Attia

All right, so we’ll just stop there and come back to it.I’ve told you that everything else on this guy’s looks pretty good. Is this guy at risk?

Dave Feldman

Well, I’m actually looking ahead, because I would have cared about these other markers. That could indicate inflammation, so, for example, the fibrinogen is very high. LPPLA2 is above 600. I don’t … In fact, I think I just Tweeted about this recently. I don’t know that I’ve seen an LPPLA2 above 300 or 400 of the labs that have been sent to me. I don’t get a chance to interpret oxidized LDL, but you have the LDL as above 135. So, I would say by this lab, as it looks, I would be concerned about the triglycerides, I would ideally want the triglycerides to go down.

So I have to concede, this was an awkward moment. I realized Peter wanted to zero in on whether I’d think the high LDL was an issue. But the whole profile matters. When we see LDL cholesterol levels that high here on the site, probably 90% or more it will end up being a LMHR and I’d fully expect the triglycerides will be below 100 at least (and usually they are below 70). So this profile already didn’t jive with the patterns I’m used to seeing.

The elevated Lp-PLA2 also set off my spidey sense. I’d wanted to know more about their situation, eating habits, and/or possible symptoms of illness.

So I followed up with a lot more Q&A I won’t list out here. We ultimately got to Peter’s key point…

Peter Attia

So, his cholesterol synthesis is through the roof, and his cholesterol absorption is quite high as well.

Dave Feldman

Are these affordable tests? Because I would definitely want to turn these around to the existing group of lean mass-

Peter Attia

I’m sure, the cash cost on these is not onerous.

But, my point is, I think that the explanation for this phenotype is the up-regulation cholesterol synthesis from the saturated fat. I don’t think this is an energy issue per se. I think this is a sterol regulated binding protein issue, or some sort of regulatory path around what the body is doing with ketones and/or saturated fat.

So here’s the thing — technically speaking, my and Peter’s theories aren’t really mutually exclusive. It’s quite possible this is energy trafficking and there’s higher sterol production overall. The modification I’d make is that this production would likely be dynamic in my model.

Peter went on to discuss a case with Dayspring and some further observations he’d made since.

Peter Attia

Bringing it back to this idea of genes, we might really be dealing with a subset of people, these hyper-responders, whoever, whatever percentage of the population they are, who are the people who are susceptible to this. Because you are not gonna find a leaner person, exercising harder than I was when I went on a ketogenic diet. I never had this response.

Dave Feldman

But there is a distinction that I tend to find and this is Occam’s razor. Again, more theory. I’m actually gonna be testing this myself in the next series of experiments that I’m doing. There is a difference between those people who are doing things like say endurance running, and weight lifting, or resistance training. In that, I think there is a greater overall gradient of receptor-mediated endocytosis for muscle repair and growth. I could be wrong about that, but I’ll be very curious to see if that turns out to be the case when I’m doing it myself.

Two things to mention real quick to the reader…

One — I have since completed that experiment and I was quite pleased with the resulting data! Indeed, it appears intensive resistance training (when everything else is tightly controlled) does reduce LDL cholesterol as predicted. Whether this is as I hypothesize to be receptor-mediated endocytosis on the part of the muscle tissue… well, that’s a bit harder to prove directly.

Two — If there’s anyone I’d expect to have lower LDL cholesterol due to this theory, it would certainly be Peter Attia! He’s no stranger to athleticism with resistance training! Check out this video: Peter Attia Tire flipping, jumping pull-ups, and other fun things you can do without carbs. So yes, I’m rebutting Attia here by slapping him with a fat compliment at the same time.

Do Muscles Endocytose LDL Particles?

This next part gets a bit long, but I think it’s a good read.

Peter Attia

Sorry, a greater amount of endocytosis of which lipoprotein, and for which product?

Dave Feldman

Of LDLP in particular.

Peter Attia

Into muscles?

Dave Feldman

Yup.

Peter Attia

For what product?

Dave Feldman

For repair and growth.

Peter Attia

You’re saying that in these people, they’re relying on their LDL for cholesterol delivery to the muscle?

Dave Feldman

Well, and phospholipids and just about anything else that would be inside of an LDL particle. There is existing studies that are out there, as far as those people who do a lot of weight training will also see LDLC and, this is why I’m saying it’s completely theoretical. I’ll actually be testing this myself over the next few weeks. Because I’m actually gonna be eating too, a very fixed diet, fixed sleep schedule, fixed everything. Then I’ll actually be introducing basically, any way in which I can get my muscles sore in a very fixed fashion, I can then turn around this data. If the hypothesis is true, I would expect that my LDLC, my LDLP might change.

Peter Attia

But, I’m confused. Why is the runner’s muscle more demanding than the weight lifter’s muscle? Or vice versa.

Dave Feldman

The other way around. That I would see the weight lifter actually seeing a difference. Because I think there’s more use of the product of LDLP directly by the cells. I may be wrong about that.

Peter Attia

But, what’s the evidence that that’s happening?

Dave Feldman

The evidence as far as … The keto gains groups. I’m sure you’ve heard of them?

Peter Attia

No.

Dave Feldman

There’s a ketogenic group, that’s keto gains, there’s not as many lean mass hyper-responders that come out of that group. They’ll tend to see their LDLC go up, but not as pronounced as those people who are say, runner-types, or aerobic-types, or even people who are doing yoga. There seems to be actually, a more pronounced difference of higher LDLC, depending on how much you’re doing resistance training, or anaerobic training.

Peter Attia

Yeah, again, I’m not aware of any evidence to suggest that the muscle is relying on LDL for delivery of anything. Including energy.

Dave Feldman

I’m not so sure about it on energy. What I’m thinking about is in terms of just raw material. I mean, as far as damage that can happen to, for example, the membrane of a cell. I realize this is kind of a key difference between us, is that your sense is that effectively, anything that the cell is gonna need, it can basically synthesize on its own, right?

Peter Attia

No, I think my sense is that … Occam’s razor would at least have me start from a place of plausibility. And I’m just not aware of any data that suggests that LDL is functioning to do this.

Dave Feldman

What’s the value of non-hepatic receptor mediate endocytosis from your perspective?

Peter Attia

So, you’re talking about very specifically, the little bit of LDL that gets out of circulation, either with or without a receptor to non-hepatic tissue?

Dave Feldman

Yes.

Peter Attia

My sense is the most important value of that would be to tissues that need more cholesterol to synthesis hormones.

Dave Feldman

But specifically cholesterol and not the phospholipids or anything else that-

Peter Attia

I think the phospholipids probably may be more delivered through others. Certainly, the VLDL delivers far more phospholipid than LDL. But, LDL is really a custom built package for cholesterol. If you look at how many cholesterol molecules fit inside and LDL particle, versus even an HDL particle … Remember, the HDL is the general of RCT. Yet, it can still only carry about 50 molecules of cholesterol. The LDL particle can carry 1,500 molecules of cholesterol. That’s staggering, again, when you consider the size of these things, right? It’s tailor made for that. That is largely conserved.

I don’t want to get us too far in the weeds, but I actually did a very interesting kinetic experiment many years ago. I did three blood tests every day for three days. Like the full NMR panel, but this is with kinetic. So, this is not commercially available. So, what you’re looking at is my ability to track, you’ll  have to lay it down, because I barely remember what I did, but this is pre-work out, immediately post-workout, four hours later, looking at my LDL particles, my VLDL particles, my HDL particles, both in terms of their cholesterol and triglyceride content.

Dave Feldman

So, you see them going down yourself?

Peter Attia

I don’t see any change in the cholesterol content. It’s minimal change in cholesterol content, right? What I think you see here is, “Yeah, wow. Under really periods of super high intense exercise, I actually did take some triglycerides out of this.”

Dave Feldman

Right.

Peter Attia

Minimal out of here. By the way, this backs up Garvey’s data, which is, there’s virtually no way to distinguish what’s going on at the VLDL level. We can’t tell what a remnant here, or what’s not a remnant. I apologize for the listener, we’re looking at a chart, but we’re gonna link to it, so you’ll see it. We’re basically talking about this idea of how much movement of cholesterol is going into, and out of, the LDL particle under these extreme conditions. I just did different types of workouts. So, on this day I did a crazy high intensity interval training. On this day, I did a crazy intense swim.

And I think on this day was the hardest workout of them all, was a crazy intense bike ride.

Dave Feldman

And the listener can’t see this, but I’m smiling ear to ear. It’s almost as if you knew I was gonna-

Peter Attia

Well, I thought you would appreciate … I forgot I did this. I did this six, seven years ago.

Dave Feldman

That’s fantastic.

We chatted a little bit more about the experiment after that.

Next part: Guesting on the Peter Attia Drive (3 of 5) – Remnant Cholesterol, Craig Moffitt, Fasting

Oct 08

Guesting on the Peter Attia Drive (1 of 5) – Lean Mass Hyper-responders, Oxidized LDL, All-Cause Mortality

UPDATE – 10/8/2018: This entire series was written before the podcast was to be released. Many people messaged me this morning about the format change where Peter summarized a rebuttal before the podcast begins in an unusual format change and were quite frustrated about it.

Don’t be!

Just listen to the complete episode and even return to the beginning again to judge for yourself. Again, this is and always will be a journey of science, not of advocacy.

Update 2 – 10/8/2018: I now have a response piece to Peter’s prebuttal at the beginning of the podcast which you can find here.

 

This is a five part series covering my appearance on The Peter Attia Drive podcast. Please skip to the final post to comment. 

Part 1 of 5 – Lean Mass Hyper-responders, Oxidized LDL, All-Cause Mortality
Part 2 of 5 – Cholesterol Challenge, Lipid Metabolism, LDL Receptor
Part 3 of 5 – Remnant Cholesterol, Craig Moffitt, Fasting
Part 4 of 5 – Energy Status, Risk, Testing the Hypothesis
Part 5 of 5 – Comments and Featured Thoughts

 

The podcast link is here

Before diving in, I want to thank Peter for having me on and making note of a couple things he deserves very special credit for:

  1. Since my earliest days, he was kind enough to answer some emails I sent him regarding my high cholesterol before I knew much about the subject.
  2. Having me on at all shows genuine interest in having the discussion. If he were truly fostering an “echo chamber” as some have suggested, then he’d only have on lipid-lowering advocates. Why bother sharing any of the megaphone with a skeptic of the overall theory?
  3. During the show, I complained at one point of the high cost for a National Lipid Association conference. After the podcast wrapped, Peter offered to cover my entry fee for one of these conferences, which is nearly a $1,000 value. This was not only very generous, it was clearly a good faith effort to expose me to higher level lipidologists in the field for the benefit of expert opinion.

I ultimately decided to turn down this amazing offer. But I did so because I realized any appreciation I expressed toward Peter past that point could be seen as influenced by this gift. Or to put it another way, you can be sure everything nice I’m saying about him on this page I genuinely mean as I’m literally paying almost $1,000 to do so.

Also, I big shoutout to Bob Kaplan. He’s Peter’s top researcher and someone I’ve had the pleasure of getting to know through this process. He’s also the reason I have the transcript of this podcast for you. (Insider note: I often tell Siobhan she’s my “Bob Kaplan” as my way of giving her a compliment)

Pre Show

I was excited to finally visit Peter’s office in San Diego. When he arrived, he had a flurry of business to take care of with his assistant, then entered the room to greet me. At first, I was concerned that I might have caught him on a bad day as I felt like my own pre-show chatter wasn’t landing very well. But I soon realized he was just in a very focused mode getting materials together in front of him for the podcast and confirming appointments to follow.

He plugged in the mics and warned me I need to stay very close for optimal capture. He likewise pointed out there will be the occasional plane flying above the office. Just a hazard of the location.

What would come next was unlike any appearance on any video or podcast I’ve ever done…

Opening Discussion

After some short banter, Peter set the stage well and introduced me.

One of the things I wanted to be sure to remember was my being very upfront about not being a formally trained biochemist or medical professional. Everything I know is self-directed learning. The other thing I wanted to be sure to mention is a big thanks to Peter himself for providing The Straight Dope on Cholesterol series.

With both of those out of the way, I launched into my backstory. As I approached the energy model discussion, Peter jumped in:

Peter Attia:

Okay. I think the other thing we’ll want to make sure listeners have done by this point if they want to get really deep on the understanding of this is probably go back and listen to at least one but potentially two or three of the other podcasts you’ve been on. You’ve been interviewed a number of times. I’ve had the privilege of listening to several of them, which is what kind of helped me get more up to speed on some of your arguments.

I think rather than just spend an hour going over those again here, I’d rather we sort of get to it more quickly, which we will, and then let the listener go back and get that way of background.

I was thankful for this statement as I figured Peter was up on my general model and we could just jump into the meat of it right away.

We talked about my numbers pre-keto and how I came into hearing about the term, “hyper-responder”.

Cholesterol Synthesis and Absorption

Peter pointed out that when finding a patient had very high cholesterol numbers he likes to run a Cholesterol Synthesis and Absorption test. The four markers it checks are:

  • Desmosterol (synthesis)
  • Campesterol (absorption)
  • Sitosterol (absorption)
  • Cholestanol (absorption)

After he chatted about this and the mechanisms for a while, he stopped himself…

Peter Attia:

Anyway, I apologize. I’m talking more than I should be.

Dave Feldman

Not at all. For what it’s worth, what you just mentioned … I myself have not gotten a sterol test. I haven’t actually broken down these, but I have been particularly interested in this. For what it’s worth, Peter, I’ve been looking forward to this because I think I may actually be just the stealth interviewer in the room because I think it’s just as possible I may be asking you more questions than you’re asking me.

We returned for a bit to my backstory. Then I eventually worked my way around to how the research began.

The Inversion Pattern, ApoE & ApoC-III

I spent a while discussing my theory on energy distribution through triglycerides aboard Chylomicrons (CM-TG) and aboard VLDLs (VLDL-TGs), with the latter resulting in higher LDLs downstream.

IMPORTANT: If you’re not that familiar with proposed Lipid Energy Model, you might want to watch my Breckinridge 2018 presentation here. You can also check out my new diagram for the Lipid Energy Model theory here.

This is important to bear in mind for the coming exchange…

Peter Attia

I think we do need to get pretty technical on this because I suspect that you and I will draw different conclusions from the data. In my experience, the easiest way to understand where those differences lie is to sort of start to get into some of the things that we would view differently. I’ll start with one thing that you said … I like to be, I think, maybe clear on where I believe the chylomicron, the VLDL, the IDL, and the LDL are coming from, going, and what they’re doing.

Peter then launched into a fairly straightforward view of existing literature and how it ties in the core assumption that the real value of LDL particles is as a part of the reverse cholesterol transport (RCT).

We then chatted about ApoE and ApoC-III for a bit before he rounded back to my energy model.

How Many LDLs Started as VLDLs?

Peter Attia

… So, you have this de novo creation of VLDLs, and you have this de novo creation of LDLs, and they form this circulating pool, but to my knowledge, we can’t really differentiate those when you look at that snapshot. I can’t tell, is that an LDL that came from a VLDL, or is that an LDL that came straight from the liver in that form?

Dave Feldman

And that was actually one of the questions I had for you was how, with a kinetic study, can you actually determine if an apoB100 lipoprotein that was secreted by the liver ever has, say an APOC-II on it? I think you and I would probably be in agreement that we don’t know.

Peter Attia

We don’t have any clinical way to measure that.

Dave Feldman

Right. And in that sense, I fully can see that I can’t be sure, even with the energy model, that the LDL particles that I’m seeing, the LDL-P, that I can say with any level of real confidence how many of the total proportion of those were truly for energy delivery.

Peter Attia

This is where we get into the semantics. I would argue none of them are for energy delivery, because that’s not what LDL does. But I think what you mean is, how many of them came from VLDLs that were trying to deliver energy?

Dave Feldman

Right, originated as VLDLs, for the purpose of doing it. In the morning, let’s say that your job is to deliver pizzas <snip> and you know that it only takes you about an hour to do. And then, guess what, the rest of the next two to four days you’re actually going to be patrolling the neighborhood. You’re the neighborhood watch. And you’re going around, and you’re also helping to fix up people’s houses, or something along those lines. Somebody who comes into the neighborhood and sees a whole bunch of these cars patrolling, they don’t know how many of those people actually delivered pizzas before they got started on that part of the shift.

Here I tried to convey the “Two Jobs” description of ApoB100 lipoproteins. That a large proportion of them deliver energy first as VLDL (the pizza delivery) and then second, remodel to an LDL to take on a support role (the neighborhood watch). If you look at the pathway graphic, you see in that purple line at the bottom the representation of the ApoB100 lifecycle when beginning as a VLDL. The key is that dotted line where I distinguish the “Energy Delivery” and “Support” jobs.

Thus, my explanation is:

  1. Job #1: as a VLDL, provide TG to hungry cells
  2. Job #2: if not taken up by the liver, hang out as an LDL to bind to provide immunological defense and reparative support

The critical question, of course, is just how many LDL particles did indeed start out as VLDL particles?

The Sacks Paper

Peter responds with Frank Sacks’ paper which details a breakdown of both VLDL and LDL secretion from the liver.

Peter Attia

Well, we sort of know. I mean, what Frank Sacks’ paper showed is if you have a triglyceride … If you take patients with low triglycerides, and I believe he used a cutoff of 130 mg per deciliter, 38 percent were de novo secreted by the liver, 62 percent came from either IDL or VLDL, where you had de novo … I don’t think the paper differentiated between which ones went IDL to LDL versus VLDL to IDL to LDL. So that’s an important point.

I think at this point he’s referencing this paper from Sacks 2015, The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia. This is oft cited by Dayspring. You can dig into it to find out where they got that same percentage breakdown Peter cites and it references the earlier study, Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions.

To be sure, each of these papers are very technical, but I’m very, very interested in just how they determine direct secretion of LDL particles that — and this is key — would never fill the role of energy delivery as a VLDL in their lifecycle. In other words, at no time would they ever have an ApoC-II on their hull and be providing the TG cargo within to cells.

The problem with trying to speculate this, even with a kinetic study, is that ApoB100s are the only apo that is “non-exchangeable”. Other apos that are attached to the surface can be provided (such as by HDL particles) and this includes the very relevant ApoC-II. This apo is how cells can specifically bind and combine with LPL to get fatty acids off the lipoprotein through hydrolysis.

Lean Mass Hyper-responders (LMHRs)

Dave Feldman

With that in mind, here’s what I would speculate. This is purely hypothetical, but I would speculate if you were to grab a whole bunch of people who are … We’ll hopefully get into this model that I’m talking about, that I call lean mass hyper-responders. People who are at the far end of the spectrum, they are athletic, they are thin, and they are very, very low carb, and therefore see very high levels of LDL-C and LDL-P, but they also have very high levels of HDL-C and low levels of triglycerides.

I suspect that they would show a very high rate, proportionally, of VLDL secretion, that they actually are trafficking a lot more, for their energy, triglycerides in VLDL particles, and therefore have succeeding LDL particles as to the explanation as to why their LDL-C and LDL-P would be higher.

Peter asked about Virta and PPAR alpha/gamma briefly, but I steered it back to LMHRs for a little while longer and discussed CIMT and CAC markers. Peter went into depth on his opinion of the limitations of these markers, then rounded into many different subjects afterward for a bit.

Oxidized LDL

This is one of those exchanges that I have to leave completely intact and it’s worth reading entirely.

Peter Attia

Now the good news is, today we at least have one laboratory test that can measure that burden of oxidation. It’s called the OxLDL assay.

Now, this has been around for a while, but clinically we’ve only been using it for a couple of years because it turns out some very small percentage of those LDLs, once they are oxidized, escape back into the circulation. By sampling those we can track, indirectly, “Hey, what’s the likelihood that oxidative damage is happening?” For me, this is one of the most important metrics I look at is, because I want to spend some time later on going over some clinical cases. I want to see some of the data on yours. I want to show you some of the data that will explain maybe how I’m thinking about this. But this oxidized LDL, which is well documented and described in different quintiles, right, is giving you a small sample of what’s going on. But for the listener, it’s important to understand that when you get a blood test, that’s not telling you what’s happening in your artery. It’s giving you probabilities of things that are largely stochastically governed, that are going on in your artery. And the OxLDL is no exception. Even though it’s a beautiful marker, it’s still dependent on the idea that a subset of those oxidized sterols are now escaping.

Dave Feldman

Can I actually ask a little more on that one? We already know that LDL particles, specifically apoB100 at the LDL stage, have alpha-tocopherol I think is how I’m saying, basically it’s vitamin E, right, as part of the antioxidant defense system. So they’re actually, I mean, part of the purpose of an LDL particle is to actually provide that as a means to battle reactive oxygen species. Right?

Peter Attia

I don’t know about that. If that were true, if it were solely true, it would make me wonder why people with LDL deficiencies wouldn’t have deficiencies of those processes as well, which to the best of my knowledge they don’t.

Dave Feldman

Because I’ve actually been wanting to get into this a lot more, recently, in that … In fact, I might have the thing up. I’m not sure if I’m allowed to do this. Yeah, this is one of the papers, but I’ve actually been getting into [inaudible]. Correct me if I’m wrong, but basically, there’s a certain degree to which you’ve got vitamin E on board. On top of that you’ve got the potential of the phospholipid shell to become oxidized. So if you get oxidized phospholipids that also can bring about the role Lp(a) that can cleave off the oxidized phospholipids. That’s ultimately what Lp-PLA2 is, right?

Peter Attia

Correct.

Dave Feldman

It’s the enzyme that’s ultimately involved in helping to-

Peter Attia

Yes.

Dave Feldman

And this is also, I don’t know how much of this is actually demonstrated, but is ultimately where a lot of the concept behind why it is you would have a higher detection of small lipoproteins, particularly small LDLs, can come around to, is if you’re getting them constantly oxidized and having to constantly cleave them down to much smaller amounts. And then they constantly remodel.

Peter Attia

Yeah, but we’re getting off into two different things here. So let’s come back to this. It’s not clear to me that there is sufficient evidence to suggest that part of the role of LDL is to combat the oxidative stress.

Dave Feldman

Okay. Then let’s put that as homework that we’ll catch up on after this.

Peter Attia

Yeah.

I actually have a lot of additional research I’ve done on this since the podcast has been recorded, but I’m going to save that for a separate blog post. But for brevity’s sake, my position is still the same.

Dave Feldman

But this is relevant for whether or not we’re detecting oxidized LDLs that had never entered the intima. Right?

Peter Attia

No. The oxidized LDLs that we’re detecting have escaped the intima.

Dave Feldman

Interesting.

Peter Attia

There’s a very small subset that are getting out.

Dave Feldman

Okay. That’s definitely something I would like to follow up, because I’m genuinely curious about this stuff, as to whether or not they can be oxidized sufficiently that they’d get big, because it also may be something that is part of the test or isn’t a part of the test, but I’d be curious as to how it can actually determine that.

Peter Attia

Yeah. What you’re basically asking is, how do we know they weren’t oxidized never inside a subepithelial space, and that’s a fair question. I don’t know the answer. I know very little about this assay. I mean, I know the technical stuff of how the assay works, like it’s an ELISA assay. I know what enzymes it’s looking at, but the broader question is, without a tracer, do we know if that LDL has actually been in the subepithelial space where it was bound, oxidized, and then escaped or liberated? So, fair question.

Dave Feldman

Good, because it’s certainly relevant to this larger question of the value of LDL particles, as to whether they play an important part of the immunological role.

At this point, I was starting to realize how our way of thinking this out was different.

Given everything I learned to that point, I continually imagined free radicals in the bloodstream getting constant contact with LDL particles, but this was by design. Loaded up with anti-oxidants, it would be a core responsibility of LDL particles to donate those hydrogen atoms to reactive oxygen species anywhere and everywhere they could in the serum. And while I know it is anathema to say, I would likewise wonder aloud if LDL particles becoming oxidized were still preferable to the alternative (which is… anything else!) as this could help mitigate chain oxidation events.

[Siobhan Huggins here writes extensively on this blog about the research in this area and I credit her with a lot of my core understanding of it. You can learn more here.]

We’ll be returning to this discussion on LDLs and oxidation a little further down, which will make sense when we get there…

Peter brought up HDL and how he feels it is much more relevant in the support role, particularly with RCT and potentially immune defense.

All-Cause Mortality

As many of my readers well know, this is a subject of enormous importance to me. I was happy to finally be discussing it with Peter…

Dave Feldman

Interesting, but this gets back to the multipurpose value of a vehicle. Is it doing things other than that, that also turn out to be relevant. And I think this kind of gets to the larger and more important question overall. The question that I started with, going back to my November 2015 days, was I thought, very naively, that in a few days I would learn all I would need to about cholesterol and lipoproteins, find the landmark study that had a gajillion people, and it would just show that if you had lower LDL cholesterol you just died less. That was it. End of story.

At first, I thought that I had found that because I had found plenty that pointed to events and pointed to a lower cardiovascular risk, but then wouldn’t necessarily talk as much about all-cause mortality. I then had to learn about all-cause mortality. And then more and more I felt like I couldn’t get to something that really emphasized … I thought for sure at least I would see, for example, an elderly population. Generally speaking, the lower your natural LDL … We can get into snips, for example, on this … the more likely it is that you would just live longer, period.

Peter Attia

But you have to remember how these studies are powered. The challenge with ACM is, I don’t think any study in the history of civilization is going to be powered to detect that. It’s hard enough to detect cardiac mortality in a study. So I think we need to be more clear in what our concern is. If the concern is, if you are less likely to die of heart disease, you are more likely to die of something else, then we should state that explicitly and say, “Hey, low LDL, while may be protective of cardiovascular disease,” I will argue that is unambiguously clear and we can discuss that. But the bigger question is, are you concerned that, well, it’s increasing the risk of cancer or a neurodegenerative disease?

Dave Feldman

A trade-off.

Peter Attia

Yes. So the question there, that’s a question of power. It’s not uncommon in cardiovascular studies to see a reduction in coronary mortality with no change in all-cause mortality, or a non-statistical change. You know, most of the time you just don’t see a change, or it’s a change that’s very slight. And then you have to ask yourself the question, even if it looks, hey, death went up or down of other causes, you have to go back and ask yourself, “Was the study actually able to detect that?” That’s a very hard thing to detect.

This is extremely important to understand, so we need to break this down for a moment into two key questions:

First, do high levels of LDL particles have any positive outcomes of any kind?

I would argue yes, there is quite a bit of evidence linking lower non-CVD mortality to higher levels of LDL (as mentioned earlier). Which leads us back to the “trade-off” question. Let’s assume for the sake of argument that the Lipid Hypothesis is 100% correct. Would it be possible for mortality reductions by non-CVD outcomes to outweigh the increase to CVD itself? Of course it’s possible.

So how do you know when controlling for all other risk factors that someone’s chance of dying by a heart attack is a greater chance of dying overall? You can’t without accounting for death overall. And this is a serious problem with any study that makes a claim on mortality of one type without knowing the balance.

That balance, “death by any cause”, is known as All-Cause Mortality (ACM).

Second, why wouldn’t you always capture All-Cause Mortality?

This is Peter’s point, and for that matter, the constant point of the medical community. To “power” a study to show this difference in mortality, one needs to see a “statistical significance” which is hard if mortality changes are very, very small between the intervention and control groups. It takes more time and expense to accomplish this. So it is commonly argued that we should just assume a net benefit.

However, I find this a very unconvincing position. If I tell you a pill a will reduce your chance of dying by Disease X, but it increases your chances of dying by non-Disease X causes, then I’m creating a false sense of security, even if I didn’t mean to.

(Since we recorded this podcast, I was pleased to see Chris Kresser bring this up this very point in his debate with Joel Kahn on the Joe Rogan Experience.)

But it gets worse. You see, by definition, an increase in death by non-Disease X necessarily means you will reduce your chance of death by Disease X. My simple illustration is the fictitious “Cyanide Diet” where I joke that it will “reduce your chance of dying by heart disease by 99.999999%. In fact, it will have the same reduction with all other major diseases as well, like infection, autoimmune, Alzheimer’s…” Naturally, if something kills you first, other things can’t kill you later.

All joking aside, this is easily detected by having the balance sheet of overall death: All-Cause Mortality.

So yes, I freely acknowledge it takes more money and time to power a study for all-cause mortality, particularly if the margin of difference is small. But so what? Why is medicine, of all places, an area where we wouldn’t want to know the statistically significant risk of all mortality for anything that makes a claim of mortality benefit?

PCSK9 and Twitter Battles

I brought up how I didn’t feel a lot of confidence in these drug trials given the short time horizon (“two or three years”) relative to the total time it takes to build atherosclerotic plaque (years to decades).

Peter talked for a bit about his strong opinion regarding PCSK9 inhibitors and getting into debates online. Of subjects I wanted to talk about that day, PCSK9 wasn’t really one of them. But near the end, we got into the time to exposure question.

Lifetime Exposure and Mendelian Randomization

Peter Attia

So, coming back to this thing about lifetime exposure, this is where the Mendelian randomization becomes a very important tool in understanding LDL’s causality. What you alluded to at the outset, you are correct in noting is deficient. There is no lifetime study where, without a drug, you can prospectively manipulate LDL and follow people for 100 years and determine outcomes. That would be the ideal study. Right?

Dave Feldman

Yeah, that would be. You actually, you talked about this in the [series with use] of the wand.

Peter Attia

I know, I remember sort of going on … That’s right, the magic wand test.

By this, we’re referring to his thought experiment from Part VI in his Straight Dope on Cholesterol series. It’s worth reproducing here for context:

Take 100,000 people and randomize them into four matched groups, A, B, C, and D.  Wave a magic wand (you can see why this experiment hasn’t been and won’t be done) and give the folks in Group A an LDL particle concentration of, say, 700 nmol/L; those in Group B you give 1,200 nmol/L; those in Group C you give 1,600 nmol/L; and those in Group D get 2,000 nmol/L.

In our dream world, due to the randomization process, these four groups would be statistically identical in every way except one – they would, thanks to our magic wand, have a different number of LDL particles.  We would follow them without further intervention for 10 years and then compare their rates of heart disease, stroke, and death.

This Magic Wand example is effectively what Mendelian Randomizations are intending to do with genetics. But put a pin in that, as we’ll return to it at several points throughout the podcast…

We chatted for a bit on the zero LDL hypothesis, a fire & oxygen analogy, and a patient case. I asked about how we can be certain cells need only the cholesterol they produce as opposed to gathering some from the bloodstream via LDL, which led to this part:

Peter Attia

Well, we have natural experiments, right? We can look at the abetalipoproteinemia patients who can’t traffic cholesterol, therefore they would be entirely dependent on their own cellular endogenous production and they seem completely fine. So that’s not proof, because we don’t have proof to your point, but it’s certainly evidence to suggest … I mean, we also know when that’s off. Right?

One of the first things we used to see in the ICU, though at the time I didn’t pay any attention to it, was anytime a patient came in and they were septic or under great stress, so they had what’s called systemic inflammatory response syndrome, SIRS, so you could be a car accident, you were shot, you have a horrible infection, their HDL cholesterol would transiently take a huge bump. And I didn’t think anything of it at the time, other than it was neat. It was like, “Wow, 2X bump in HDL cholesterol, overnight.”

I think I would now look back and interpret those data as huge reverse cholesterol transport. Now the HDL is going out of its way to deliver cholesterol to, probably the adrenal glands first and foremost, because the enormous uptake of glucocorticoid, even epinephrine, norepinephrine are needed. So clearly there are examples of when this is not in a homeostatic balance. So I’ll take your point that …

Dave Feldman

Because the abetalipoproteinemia patients, in theory, should be the ones who are outliving us all. Right? They can take out the whole component of heart disease, of atherosclerotic plaque, everything. They should have massive longevity, relatively speaking, to everybody else.

Peter Attia

So the ones who get the longevity, because there’s only about 12 genes that are well enough studied, we have enough patients that we think we know something. And the most important of the longevity genes in cardiac is the hypo-functioning APOC-IIIs.

Dave Feldman

And that actually shows a net …

Peter Attia

A net longevity benefit.

Dave Feldman

Interesting

Peter Attia

Yeah. Work out of Albert Einstein has identified these, roughly a dozen, genes. And the hypo-functioning APOC-IIIs are, I mean most of those genes are, you know, like GHR, IGF. ApoE would be one, right, so ApoE2 would carry with it protective benefits in terms of longevity, both cardiac and, but more that is neurodegenerative. But it’s those C3s. In fact, as we have kind of alluded to a couple of times, I believe there’s an antisense oligonucleotide (ASO) in clinical trials now, trying to impair APOC-III, so now it’s becoming a therapeutic target.

Okay, let’s pause here and break out the two major categories of what we’re talking about…

Abetalipoproteinemia (ABL) and Familial Hypobetalipoproteinemia (FHBL)

After this podcast, I went back to do more research finding where either ABL and FHBL might result in a net longevity (AKA, lower all cause mortality) with very little luck.

The best positive study I was able to find involved a handful of elderly in their 90s and 100s from three families in Spain. It’s a bit scattershot in trying to triangulate the specific SNPs associated but manages to find some with reduced ApoB. Unfortunately, they excluded out many alleles by design and it’s unclear if they likewise looked at SNPs that increased LDL as well. Moreover, there were no blood tests for further comparison to their genetic data.

However, the negative studies were quite numerous for both ABL and FHBL. Remember how I was discussing a potential “trade off”? This certainly seems to be the case for many who are genetically prone to very low LDL. Many studies detail how ABL and FHBL can suffer severe deficiencies in fat-soluble vitamins A and E (which are brought to cells in lipoproteins), which requires high dose supplementation “to prevent or at least slow the progression of neuromuscular and retinal degenerative disease” among other issues.

Hypofunctioning ApoC-III

I found a reference to the research Peter was discussing here in an article with the headline, “Apolipoprotein C-III gene associated with longevity” which detailed “a team from Albert Einstein College of Medicine has identified a second longevity gene occurring more frequently in people who live to 100 years of age.” This linked directly to the study, Genetics, lifestyle and longevity: Lessons from centenarians.

In the abstract of this paper, it mentions, “APOC3 –641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity.” To be sure, I was instantly disappointed this was associated with both “favorable profile” and “insulin sensitivity”, the latter being well known for its association with longevity. The sciency me wants to get that clean variable without others muddying up the Outcome Waters.

But it gets more interesting… the “favorable lipoprotein profile” isn’t actually about lower LDL cholesterol.

“LDL” only appears five times in the body of the main text, with the key passage describing the profile here:

Relationships between other lipoprotein traits and APOC3–641 CC genotype are shown in Table 1. Due to the dependency of lipoprotein traits on age and their modifiability with medications, we only considered offspring (n = 131) and controls (n = 126) not using lipid lowering drugs in this analysis. In females, triglycerides (TG), high density lipoprotein cholesterol (HDL), and their ratio, as well as low density lipoprotein cholesterol (LDL) lipoprotein particle size were significantly more favorable among those with the CC genotype compared to the CA/AA genotypes. The same trends were observed in most of the associations in men.

(Emphasis mine)

So this was about LDL size, not quantity?

Here’s the Table 1 in question:

Take special note of the very high HDL and TG/HDL ratio (both of which are typically improved on a low carb diet). But notice the LDL cholesterol — something I thought would be low given the higher clearance rate assumed with lower overall ApoC-III. Yet all the averages for LDL-C are above 100 mg/dL, with the women even averaging an LDL of 129 for CC and 134 for CA/AA.

Next Part: Guesting on the Peter Attia Drive (2 of 5) – Cholesterol Challenge, Lipid Metabolism, LDL Receptor


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Oct 05

Podcast Prediction Post – Peter Attia Drive Edition


Peter Attia’s The Drive podcast featuring yours truly is now officially slated to drop in three days (10/8/2018). On the same day, I’ll be releasing a five part series as a companion piece to the broadcast.

On the Record

As many have taken to social media with their predictions of this long-awaited podcast, I thought we’d have some fun and give readers a chance to weigh in here.

Feel free to comment below.

Guess the LDLs in the Podcast Jar!

As a bonus, we’re going to have a contest for who can guess the number of times Peter and I say “LDL” over the course of the podcast. LDL, LDL-C, LDL-P, or pretty much any time we say “el dee el” counts.

The winner will be featured in this space in an update. Good luck!

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