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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

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