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#34 – Don’t Ignore High LDL, TG/HDL Ratio, Lp(a), Cholesterol Absorption and more with Tom Dayspring, M.D.

How important is TG/HDL ratio? Does LDL cause heart disease? What are the best biomarkers for measuring cardiovascular health? We get into these questions and a whole lot more with world-renowned lipid expert Tom Dayspring, M.D.

Listen on Google Play Music

This Episode Covers:

  • The real deal on TG/HDL ratio and implications for the Black community [2:30];
  • Why LDL is bad for the heart [7:00];
  • LDL with APOC3 [17:00];
  • LDL not designed to traffic TG, but… [20:00];
  • Alcohol and TG levels [30:00];
  • LDL and all cause mortality [39:30];
  • Hyper-absorbers, Zetia, eggs, sterol panels [45:00];
  • Can you reduce cholesterol absorption through diet? [56:30]

Transcript:

Dr. Dayspring: Individualize your recommendations based on what is going on in the person you’re staring in the eyes. It’s nice to know what he did in 10,000 people in this trial or that trial, but I don’t know. Does this person even fit in that trial, or are they on the left side of the curve, the right side of the bell-shaped curve? Are they in the middle? You don’t know because virtually none of our patients meet the exact criteria that all these trials use for enrollment. And whatever therapeutic advice you can come up with, please, in two months, repeat your biomarkers, put them on the scale again, recheck their blood pressure, and that will give you good guidance.

John: Welcome to the “GeneFood” podcast. I’m your host, John O’Connor. Hey, everybody. Today, I’m really excited about the episode. We were really lucky and grateful to have on Dr. Tom Dayspring, who some of you who are interested in conversations around lipids and LDL and heart health and risk will already know Dr. Dayspring is one of the best-known, world-renowned expert in lipidology and somebody who teaches and publishes and is just an incredible resource for all things heart health and cardiovascular biomarkers. So, today with Dr. Dayspring, we got into a number of fun topics, including triglyceride to HDL ratio. I did misspeak at the beginning of the episode and say HDL to triglyceride ratio. It’s the triglyceride to HDL ratio. We talk about that. We talk about why looking at markers like that alone, why looking at HDL alone is not gonna give you the full picture on your heart health. We talk about apoB, lipoprotein(a), cholesterol synthesis, cholesterol absorption, all sorts of good stuff in today’s episode. For those of you who are heart health nerds and enjoy these types of conversations, I think you’re gonna find this one a lot of fun. So, without further ado, here is Dr. Tom Dayspring on the “GeneFood” podcast.

Dr. Dayspring: Ready to roll.

John: Ready to roll. All right. Should we just jump right in?

Dr. Dayspring: Sure.

John: I’m very glad to have you on the show. And it’s a real pleasure and honor to get to chat with you about some of these issues that we’re all trying to learn more about related to heart health and cardiovascular disease. So, I wanted to jump right in and kind of set the table for some of the topics that we’re gonna discuss today by giving you the scenario that’s out there in our world, which is nutrition of people who are on low carbohydrate diets and they’re feeling better and maybe they’ve lost weight. And there’s a theory that’s going on around the internet about how your HDL to triglyceride ratio and, you know, some insulin resistance markers, if they look good, then you don’t have to worry about your LDL and especially your LDL cholesterol. Let’s start there. What say you about this HDL to triglyceride ratio theory of cardiovascular health?

Dr. Dayspring: First of all, I think it’s the triglyceride to HDL ratio, not vice versa.

John: Okay.

Dr. Dayspring: And it’s been used for a long time as a marker of insulin sensitivity. Many people don’t know it has no application whatsoever to African-Americans because they just… Even though they have a high incidence of metabolic syndrome and insulin resistance, they rarely have hypertriglyceridemia reduced to HDL cholesterol. They qualify as insulin-resistant based on hypertension, waist size, and glucose. So, you can’t use it in that crowd. But if you wanna use that as everybody’s getting lifted profile, so if you see the ratios above whatever you think it should be, you should at least be suspicious that insulin resistance is at play. And virtually everybody who’s not on a liquid modulating drug, who has an abnormal triglyceride to HDL cholesterol ratio has elevations of apolipoprotein B. So, therefore, if that liquid marker, which is basically free with your lipid profile suggests it’s out of whack, you should immediately do an apoB. If you haven’t ordered that, at least glance at the non-HDL cholesterol metric on the lipid profile because although it’s not as good as apoB, that would kill you out that wow, you’re drowning in atherogenic glycoproteins.

And your mission in life, therefore, our therapeutic mission is to attack, reduce apoB. You can certainly start out with whatever lifestyle a practitioner might deem appropriate in a given individual. And sooner or later, if that doesn’t work and you’re at a certain degree of cardiovascular risk, you’re gonna have to prescribe apoB-lowering medications. So, that ratio, it is what it is, and if people wanna use it. But the fact that if you’re going to tell me you have a normal triglyceride to HDL ratio and you’ve done apoB and tie, you don’t have to worry about it, I think you’re deluded. I don’t think there’d be a single trial in the history of the world that would support that. I would suggest everybody pick up this week’s “Journal of the American College of Cardiology” that discusses at what point in life we have to worry about these LDL metrics. And it’s basically in adolescence in the 20 to 30 decade because that’s where the most bang for the buck comes on treating and not to wait till you’re 60 to have a positive coronary calcium score. So, that’s what I would say to that.

You can have that belief. You can have that hypothesis. I would tell you to examine anybody who has familial hypercholesterolemia, familial hyper beta lipoproteinemia. They have no insulin resistance, many of them, and they’re full of plaque, a form of aortic stenosis, at very early ages. So, tell them that apoB doesn’t matter, that fluffy buffy LDLs are protective. It’s nonsense. Not supported by data. So, anybody can say it. And you’ve heard Peter Tio, a longevity guide, discuss this many times. If you are in that crowd and whatever you’re doing is sending your apoB off the chart, but maybe you’ve done coronary calcium or you’ve looked at other things and you don’t see much, that’s meaningless to me. Do me a favor. Call me back in 10 years and tell me what your arteries look like while you’ve been ignoring apoB over that time span. So, yeah, it’s an individual decision.

John: All right. Okay. So, that’s a great point. So, the trick to HDL ratio is not without value because in non-African-American populations it’s a good proxy marker for insulin resistance, but apoB is the controlling factor. So, what is apoB, and why are you such an evangelist for measuring apoB and lowering apoB? For a one-on-one conversation, somebody listening who’s like, “Okay. This is new to me. Why is this bad for my heart? Why is apoB bad for my heart over time?”

Dr. Dayspring: Sure. And it certainly is rudimentary basic to your understanding. If you’re gonna think that’s important, you should know what the heck it tells you. And by the way, it’s me being an evangelist, just virtually every guideline is based on apoB nowadays. The European guidelines want you to measure it early in life. And the new standards they have set for it are unbelievably low compared to what we used to think. But anyway, atherosclerosis there’s one cynic one on for this nightmare disease that’s causing morbidity and mortality in most of the people at least in the United States is a disease where there is a sterol in your artery wall. If you do not have a sterol, of which cholesterol is the most common, but there are many others. If you don’t have any sterols in your arterial wall intima, you do not have the disease called atherosclerosis. Now, everybody would have atherosclerosis smokes. Not everyone is fat. Not everybody has hypertension. Not everybody has a nightmare family history of heart disease. But every single human who’s ever had atherosclerosis has sterols in their artery wall. So, the next question would be, “All right. I hope I don’t have sterols in my artery wall, “but probably most important is, “How the heck do they get there,” because if sterols never get deposited in the artery wall, I cannot have the disease called atherosclerosis.”

And then I can go figure out what else I might be coming down with, which will ultimately do me in any way.
So, of course, sterols are a lipid. It’s a ringed lipid. Cholesterol is the most commonly known. Like all lipids, cholesterol is insoluble in aqueous or water solutions. And, of course, our plasma, our circulation is water, yeah, with some proteins thrown in and everything. So, nobody has lipids floating in their bloodstream as free lipids. So, for lipids to circulate in our plasma, they have to be attached to a protein. There’s a few cholesterol and fatty acids molecules that may be attached to albumin, which is a protein, but it’s a minuscule amount. The majority of sterols and other lipids that might wind up in your artery wall are trafficked inside protein-enwrapped macromolecules. And if you wrap lipids with a protein, all of a sudden those lipids become water-soluble and they can circulate in your plasma. So, the lipoproteins that have the capability of leaving your plasma, entering the arterial wall, and depositing their sterol load in an artery wall are wrapped by a single protein easily measurable called apolipoprotein B. ApoB is a structural protein that provides structure, stability, and solubility to the giant macromolecules, the lipoprotein, and it’s enwrapping.

Of your apoB family of lipoproteins, we have very low density, a very transient particle called an intermediate density, and a low-density lipoprotein. In the LDL family is a genetic lipoprotein [inaudible 00:10:01] LP(a) which most people don’t have but some do. So, if you’re measuring apoB, and any lab in America can do it, it’s all well-standardized essay, you are measuring the total sum of VLDL particles, LDL particles, IDL particles, and if you have them, LP(a) particle. But here’s the truth. One of those particles have different plasma residence times, half-life, so to speak. VLDL’s last two to six hours in the bloodstream. They’re mostly a postprandial [inaudible 00:10:33] lipoprotein. LDLs, whether they be produced and over by the liver or they’re a result of VLDL metabolism, hang around for three to five days, IDLs hang around for an hour or two. So, of all your apoB particles, 90% to 95% of them are LDL particles.

And I said on the unfortunate part about apoB particles of which the vast majority are LDLs, the number one criteria as to why they might invade your artery wall rather than going back to the liver and being cleared, which is what they’re supposed to be happening, it’s particle number. There are other attributes to the lipoproteins that affect their ability to become “atherogenic” or entity artery wall, but far and away is particle number. Now, there are other factors at play. The health of your arterial wall, your endothelial integrity, and many, many other factors make it easier for an LDL particle to enter the artery wall, but particle number, the odds are it’s going in. Once it’s in, that particle has to be entrapped by the proteoglycan tissue. It has to be oxidized by reactive oxygen species, then it gets engulfed by monocytes and macrophages. Then you have [inaudible 00:11:52] cells. Bingo, you have atherosclerosis. But that’s why apoB is important because they are the lipoproteins that deliver sterols through artery wall.

As a quick aside, everybody knows there is another class of lipoproteins called high-density lipoproteins or HDL. They have no apoB on them. They’re enwrapped by a different family of proteins, primarily apoprotein A-1. So, they’re not the ones that are polluting your artery wall with sterols, but it’s the apoB particles, of which the overwhelming majority are LDL particles. So, when you measure apoB, although technically you’re measuring VLDLs plus LDLs plus IDLs, blah, blah, blah, because 95%, 90% of them are LDLs, apoB is basically an LDL particle test, which makes it a far superior metric to LDL cholesterol, which is simply the entire cholesterol mass traffic by all of the LDL particles that exist in a deciliter of your plasma. It’s like counting the dump trucks going down a highway or counting whatever the hell they’re carrying in the back when a thing that matters is truck number, particle number. And that’s why you can have a normal LDL cholesterol and a high apoB or vice versa.

John: And so to kind of riff on that, there’s this feeling out there in the community as well that there’s a distinction to be made between the large fluffy apo B lipoproteins and some of these insulin resistance lipoprotein markers like small dense LDL and VLDL. Can you speak to the difference, you know, big fluffy particles versus small dense particles and how you view that in terms of risk?

Dr. Dayspring: Yeah. First of all, stop using the double adjectives, small and dense. It’s like calling an obese person fat and heavy. One adjective is all you need.

John: Okay.

Dr. Dayspring: So, lipoproteins, every sub-particle classification glycoproteins is a heterogeneous mixture of larger particles and smaller particles. Smaller particles because they’re carrying less crap are always denser because they lose lipids and they keep their protein, so they’re denser. You heard a fluffy buffy when we first discovered lipoproteins, they were discovered in centrifuge, so they were classified by their buoyancy. So, the ones that were big and fat and full of lipids were buoying and the ones that had no lipids basically there’s some proteins and miniscule amount of lipids were denser. So, there are large fluffy LDLs, small dense LDLs. There are large fluffy HDLs, small LHDLs. There are large fluffy VLDLs, small VLDLs. So, you only need to say small. Most people don’t understand buoyancy to say buoyant or dense, so small has invaded the literature. So, all apoB-containing particles are potentially atherogenic. And whether they are or not, meaning are they gonna crush your artery wall or are they not, depends primarily on particle number, but a multitude of other factors I just told you.

Hey, endothelial health, vascular wall health, blood rheology factors, the location in the artery due to stress, and things like that. So, there are other factors that determine whether that apoB particle is gonna crack. So, for people in the insulin-resistant community, and that’s a gigantic fraction of the United States population, just look at the waist sizes as people walk down the street. You don’t need a triglyceride-HDL ratio in many of them to know who’s insulin-resistant. Just take their blood pressure. It’s all. That’s what you’re probably dealing with or so. And the people who are most apt to have what you’re calling the small, dense, I’m just gonna call it a small LDL or a dense LDL, are insulin-resistant. And what does every insulin-resistant person have in addition to high apoB? About 20 other metabolic abnormalities that make their arterial health quite poor.

So, all I know is… So, if you took a population, let’s say, they just had the larger, more buoyant LDLs, but they’re not insulin-resistance, that’s a terrible risk factor. They have the same insulin to heart disease if not more than any diabetic. But the diabetic or the insulin-resistant person with a small LDL, however, you’ve determined that they got 14 other things that are wrecking their vascular wall going on. So, if you wanna tell me that the small LDL is particularly dangerous, I’ll say fine, not that I wanna denigrate the big, more fluffy LDL, but that’s a person who has a multitude of cardiovascular abnormalities. So, as a clinician, yeah, I’m gonna be trying to lower their apoB but I’m gonna do everything in my therapeutic armamentarium to combat insulin resistance in those people also. So, small LDL is just a little flag saying, “Hey, there’s a lot of crap going on in this station and you better look beyond apoB.” If you ignore apoB, mission number one is apoB. Mission number two is correct all the other things.

John: So, here’s a nerdy follow up just on the lipid focus for the small LDL. My understanding is that small LDL expresses APOC3 proteins at a greater frequency and therefore they have a longer residence time and they’re more prone to oxidation and damage. Is that true? Am I wrong about that?

Dr. Dayspring: APOC3, of course, is another protein that can attach to a very…it can really join any lipoprotein. It’s in your circulation. It could be on VLDLs. It could be on HDLs. And it certainly could be on LDLs. So, although it’s a minority apoprotein on LDLs, most of the time it’s under VLDs. It might be some of the parents of the LDLs. But APOC3 has a number of atherogenic effects. And part of it is the laying particle clearance. So, if you happen to have LDL particles, remember, every LDL has got one apoB on it. But what’s gonna happen if you have some APOC3 on it? It’s a particularly atherogenic LDL particle because it’s gonna have a much longer plasma residence time. But LDLs with APOC3 on it would still be an extreme minority particle. Even for a person who has LDL particles with APOC3 on it, the overwhelming majority of their LDLs would not have APOC3 on it. But if they are small particles, man, how do the LDL apoB particles get cleared? Well, with LDLs, it’s the liver, which is the organ that expresses by far the most LDL receptors, which have the ability to bind to the apoB on an LDL particle attached to it, pull it into the liver where it can be catabolized, etc. And how good is that LDL receptor at recognizing and attaching to the apoB molecule on the LDL particle? Believe it or not, if that LDL particle doesn’t have a normal size, the configuration of apoB changes.

So, the binding domain on apoB that is looking to attach to the LDL receptor or, conversely, the domain on the LDL receptor that’s looking for a certain segment on apoB, they don’t find each other so readily when you have a smaller. But believe it or not, if you have a big fluffy LDL, your apoB is distorted, and this is one reason why people with FH have less clearance of their LDL particles also. You and I pray… I hope we have not only normally-sized LDL particles, which would enhance clearance, but, you know, that you have the proper amino acids on your apoB. Yeah, we all have different genetic inheritance on that. And the one last thing that will affect attachment of the LDL particle to the LDL receptor is what we call the composition of the LDL particle. All lipoproteins have a one-molecule fixed surface consisting of usually phospholipids and some unesterified cholesterol. The core, which is where the overwhelming majority of lipid molecules live, because remember the volume of a sphere is a cube, a third power of the radius, or are based… There could be thousands of different rare-lipid species in there. Most are gonna be either triglycerides or cholesterol ester, a very hydrophobic form of cholesterol that has a fatty acid attached to it. And a normally composed the LDL particle and this is, usually, would be somebody with perfect genes, perfect diet who’s not insulin-resistant, you would have four to five times more cholesterol than triglycerides within your LDL particles. LDLs are not meant to traffic triglycerides. So, they said it’s not a vehicle [inaudible 00:20:42] your VLDLs and chylomicrons to traffic triglycerides, supply the energy to tissues.

So, if you have a normal re-composed and sized LDL particle, it’s got maybe 20%, triglycerides, and 80% cholesterol. But for whatever reason genetics or your insulin resistant, you have what we call a triglyceride-rich LDL. You have three to four times more triglyceride in the core of that LDL particle than you should be normally. That totally changes the composition of the LDL particle. It changes its shape. It changes its thermodynamics. So, if you change any of those properties, all of a sudden that triglyceride-rich LDL can now attach readily to an LDL receptor and be clear. So, people who have triglyceride-rich LDLs almost all have high LDL particle counts. I’ve discussed it many times. I wish we were measuring LDL triglycerides rather than LDL cholesterol because it would be a much better marker 10 times better than your triglyceride-HDL ratio of telling you who likely has insulin resistance or at least the triglyceride issue at play. And then we could take therapeutic avenues to reduce triglycerides again. And last but not least, and maybe to go back to your original question, one thing that will certainly make it likely that your LDL is gonna be triglyceride-rich and cholesterol-poor is APOC3 because every part of lipolysis of that particle are removal of triglycerides. So, I’m gonna say that so many things going on, but you can’t make the statement and say, “Oh, these people that have APOC3 on their LDLs is an extreme minority.”

John: Right. I mean, one of the things that I think of when I think of these triglyceride-rich particle discussions in the context of nutrition, which is kind of how we approach things, is the last scene from the vegan documentary “Forks Over Knives” where the host goes on a 60-day, 90-day plant-based diet, and you see his bloodwork at the end, and his trigs are at 169. And we don’t have as apoB. But I know you see this as thousands of phenotypes, but can you… Is there any way we can loosely assign a phenotype to the person who becomes dyslipidemic based on poor carbohydrate and sugar metabolism relative to somebody who might be just naturally more insulin sensitive?

Dr. Dayspring: No. I think you have to look at other biomarkers that better reflect insulin resistance. By the way, if you are doing more advanced lipoprotein studies, here are the lipoprotein signatures of insulin resistance that can help me… In the old days when we used to get these full NMR reports that gave us all different VLDL sizes, IDL, LDL, HDL metrics, not the triglycerides in it, but different attributes of it. So, here are the signatures of lipoproteins that tell me God, you’re insulin resistant. Number one, you have big VLDL particles, more than you should have. A normal human produces big VLDL particles. The only way your body produces big VLDLs if your liver has too much fat in it, too much triglyceride. It’s gotta get rid of the fat, so it makes your VLDLs split. Okay. So, big VLDLs, either VLDL diameter or large VLDL particle concentration.

Other clues would be an increased LDL particle count. Especially if you were doing the NMR, you’d see that your small LDL particle count is elevated. Small LDL and 99% if you have an excess of small LDL is a signature of insulin resistance. So, why else would you have small LDL other than some bizarre lipase abnormality yourself? HDL particles… If you don’t have big HDL particles, they’ve undergone lipolysis by various light bases. That would be a signature of your insulin resistance. So, LDL size, HDL size, VLDL size, increased big VLDL, increased small LDL, and lack of large HDL. If I just had an NMR showing you all that, I don’t need an insulin level in you. I don’t need other biomarkers of insulin resistance, adiponectin, that sort of stuff, hydroxybutyrate. So, there were already… Now, if you’re not doing [inaudible 00:25:00], and less and less people are for a whole variety of reasons, then I think you gotta do an insulin level at anybody at least or some other marker of insulin resistance, aside from the obvious, waist size, blood pressure, glycaemic abnormalities.

John: Right. So, my question is I’m hearing all these biomarkers associated with insulin resistance. And what I wanna know is, and we’ve talked about this a little bit previously off the show, how much of this can we assign to de novo lipogenesis? How much of this insulin resistance can be assigned to that conversion of excess? You can’t store any more glycogen, so you’re just converting these carbohydrate sources into triglycerides.

Dr. Dayspring: Since none of that is measurable, that’s all good hypothesis and discussions of pathophysiology, what might be going on. But I have no idea.

John: What do you got?

Dr. Dayspring: [inaudible 00:25:54] given individual. First of all, you can get that metric, so I don’t know.

John: Okay.

Dr. Dayspring: All I know is I can have a good idea by looking at other biomarkers whether you have triglyceride-rich lipoproteins, and I certainly can get apoB or other particle enumeration metrics that are available via other methodologies or so. So, that’s all you need. So, I don’t know how to answer your question.

John: Okay, good.

Dr. Dayspring: How much is production? How much is it these particles that are coming out triglyceride-rich are not undergoing rapid removal of the triglycerides? That’s called lipolysis. What are they evolving into? What other cargo are they carrying that may enhance or decrease those lipolytic avenues? I don’t know. We’re not measuring all these other lipoproteins. So, you’re right back to where you probably look at it now. And by the way, and this is where you even get into trouble using triglycerides as your metric, because what’s the standard? Okay. if you got a trig above 150, you’re in trouble. And if it’s lower than that, you’re not. It was in the last two weeks, there’s just a tremendous article in the “Journal of Clinical Lipidology,” which I implore everybody to… And they’ve looked at long-term follow-up of the Framingham offspring study and the ARIC trial, Atherosclerosis Risk in Communities, a giant epidemiological trial.

And they’ve redefined what a normal triglyceride level is. And it’s basically if you don’t have a trig under 50 and certainly, and certainly if it hits 100, your cardiovascular risk is almost going up like a straight line. And if you read through the whole paper, they show you all sorts of intriguing graphs relating it to gender, relating, tying in the association with HDL cholesterol. One idea, if you get to the final paragraph, it says, “As your triglycerides gets to whatever level in a given individual you’re apoB is going up,” and that’s where your therapy must be directed, not per se to triglycerides, although most of the therapies we suggest to improve whatever your triglyceride metric is are gonna reduce apoB, but you just don’t know because of the other factors. So, this is why I prefer not to use triglycerides, but if you are gonna use them, start worrying about it at much lower levels than we ever did.

John: Really? Wow. So, you wanna see a trig at like 50 milligrams per deciliter or 60.

Dr. Dayspring: No. If your trig is 300 but your apoB is normal…

John: Okay. Fine. Take it back to apoB.

Dr. Dayspring: [inaudible 00:28:27] anyways, that’s not a high enough trig to give you pancreatitis. So, I don’t know what your… If I have to worry about, you know, you might have just some defect affecting triglyceride metabolism or lipolysis that’s raising your triglyceride content in the plasma but not your atherogenic lipoproteins or so. Listen, people who know me forever know I, for most of my adult life, was a pretty heavy insulin-resistant guy. I never crossed any diabetic glycemic threshold, but for all intents and purposes, I was a diabetic. I in my life… Maybe the highest triglyceride ever had in my life whether on medicine or not on medicine was 100 and 110. Yet, my apoB and LDL particle counts were ugly as hell. So, in me, all my life including me telling myself, “Don’t worry. Your triglycerides are fine.” But for me, that was a disastrous triglyceride level. And I knew that the second I started LDL particle counts came on the marker or apoB. So, just be careful. In general, yes, there’s a correlation. As apo triglycerides go up, you gotta worry about atherogenic lipoproteins. But this is why, and I think you would agree with me, we have to individualize our advice to every single human. All the wonderful epidemiologic studies are great and that’s all very useful information. But when I’m talking to you or somebody else one-on-one, this is why I need to do a very thorough history, a family history, a good physical examination, at least with body metrics, and I have to have a bundle full of biomarkers. We haven’t even talked about uric acid, homocysteine, other stuff. Well, then, I’ll make an individual recommendation to you.

John: Well, let’s talk briefly about uric acid in the cont… Well, because what I’m thinking when I’m hearing you talk about keeping your trigs in ranges, I’m thinking about alcohol because I feel like, you know, in today’s day and age with COVID, people are stressed out. Alcohol consumption is going up. I feel like the one thing that can blow out your trigs in addition to sugar is probably just drinking alcohol regularly. And maybe that’s the reason…and that ties into uric acid. So, talk about that pathway, alcohol, uric acid, heart health, how you see that.

Dr. Dayspring: Yeah. Listen, once you’ve come to your own conclusion that I don’t like the triglyceride level in this person, the first things before you go diving into your insulin resistance world is you have to get an accurate, trustworthy alcohol history from the patient. You have to rule out hypothyroidism or so. Get those out of the way. Other than that, I think alcohol is a reason why triglyceride is going up. It’s way overblown. It’s just not… I mean, I guess if you’re running an alcoholic clinic where people are drinking three bottles of gin a day, I can’t talk about that crowd. But the average person is having a few beers. I don’t think it’s a major aggravating factor in triglycerides. For sure, if you came to me, and we determined you did have triglyceride-rich lipoproteins, I would certainly suggest you eliminate or reduce alcohol. But I don’t think it’s the major driver of this.

John: Good. Good.

Dr. Dayspring: But [inaudible 00:31:26] objectively you have to consider it.

John: Good. I’m glad to hear that. Okay. But some of these other markers, you know, these residual risk markers like, what is it, LPLA2, uric acid, LP(a), some of these other, you know, C-reactive protein, how do these fit into the equation and how much weight do you put behind them?

Dr. Dayspring: Well, when you look at other risk factors, adjunctive risk factors or residual risk factors beyond apoB, let’s get out of our lipoprotein world, per se, what other things… Even if two people came to me with a given apoB level that’s a little high, very high, one would tell me that with your apoB you’re even a far more total disaster than I would guess just by your apoB alone. And that would be looking at these other factors. Now, uric acid, I mean, it’s tied in with your fructose and your diet, and your renal function, your genetics, but it’s like… One of the reasons cholesterol is so deadly to your artery wall, it’s one of the molecules in the human body that causes what we call a crystallopathy. It crystallizes. Crystals are toxic to any cell where crystallization occurs. So, in your plaque, cholesterol crystallizes, and it really totally inflames the plaque. It causes plaque to rupture. Uric acid is a major cause of crystallopathy. Most of the time, it crystallizes in your joints and causes arthritic pathology, but it can crystallize in your arterial walls. God knows what other cell, which, of course, is not gonna help sell your health.

So, I think you have to, you know… Peter Tio has got some great podcasts on uric acid. And personally, I believe if you have a uric acid of whatever cause and, yes, if you’re drinking, you have to stop the drink, and that can be a big argument for that. If you have renal failure, I think you’re in trouble unless I got a cure for renal failure and whatever is causing that in your person. But in general, by getting that fructose, especially a low carb type of diet, you gotta reach for uric acid-lowering drugs sooner rather than later. And that’s where you wanna make a case for drugs that might belong in the drinking world. At least for that crowd, it’s allopurinol. And sex would be… I don’t want… You can’t wait for somebody to get padegro [SP], which is inflammation in a big toe or in a swollen knee and say, “Oh, my God, you got gout,” or, “Oh, my God, you’ve had a kidney stone and it’s uric acid.” That is way too damn late. That’s like waiting for your calcium artery score to be positive. Why do you wanna wait for that? So, just fear and treat hyperuricemia. And I would use 6.0 as your, “Hey, I gotta start thinking about therapies,” and certainly not wait for uric acid, crystallopathy symptoms, or what a guideline might tell you is your uric acid is much too high. There are also are gender differences with uric acid that you have to be aware of. So, that’s the uric acid story.

Those other markers you talk about, we should segregate them into, hey, they’re inflammatory markers or they’re insulin resistance markers or they’re something else. LP(a) that you mentioned is basically an inherited abnormal lycoprotein. And what it is it’s an LDL particle, but to which is attached a protein that most people don’t make, and therefore it can’t be on your LDL particle. And that accessory protein is called apoprotein(a). That refers to small case A, not a capital A. ApoproteinA is what’s on the HDL particle. So, if your liver makes this apoprotein(a) peptide, it secretes it. It jumps on the first LDL it cruises by. You have an LDL particle that is also carrying this extraneous protein that shouldn’t be there. Now, that protein has potential pathology attached to it. There may be some degree of thrombogenicity associated with it. You don’t wanna have a procoagulant floating around your artery. And we’re finding more and more that it’s probably a magnetic carrier of what we call oxidized lipid moieties. Oxidized lipid moieties are extremely dangerous cellular toxic liquid moieties, you know, oxidation, per se. It’s not something you wanna brag.

We need oxidation to burn fuel and to help a little bit of healing, but you can’t have persistent too much oxidation in your body. And LP(a) is sort of a garbage truck that maybe even it involves to go around and pick up oxidized lipid moieties and return them to the liver or wherever the heck LP(a) particles get clear. But if you are just generating too many oxidative lipid species and your LP(a) particles become enrich with oxidized lipid buoys, that’s a particularly dangerous LP(a) particle. We do have a metric that is starting to be available in various laboratories that can measure the oxidative lipid per potency of your LP(a) particles. It’s called OxPL-apoB. It’s oxidized phospholipids that are on apoB. And almost all of the oxidized phospholipids, those dangerous lipid molecules, although it’s measuring it on apoB particles, the overwhelming majority are on LP(a) particles.

So, again, two people come to me with high LP(a). I’d worry much more about the person who concomitantly has a high oxidized phospholipid apoB as opposed to one who does not. The LP(a), the contemporary avant-garde, that’s the European guidelines suggest early in life getting an LP(a) test done. It’s a genetic test one time in your life. You either make it or you don’t. If it’s negative at age 20, you don’t have to check it at age 50, unless you got a gene transplant or something, which is not available right now. So, that’s a very important marker. But it just tells me no matter what your apoB and no matter what else is going on with you, you’re even sicker than I thought as far as atherosclerosis, aortic stenosis is concerned. You did mention a couple of inflammatory markers, C-reactive protein, and lipoprotein phospholipase A2, which is another marker that’s readily available. There’s no doubt that those can give you more risk assessment evaluation abilities when you’re looking at people. Again, if I had whatever your apoB is, if your C-reactive protein is also high, you’re probably a little riskier than somebody who doesn’t. But I’ll tell you this. By far the one that has the most data behind it, the one that you can depend on, is C-reactive protein? So, that’s the one I’d do.

Lp-PLA2 is extremely complex. I would suggest nobody use it. It’s totally useless if you’re on lipid-modulating drugs. It’s not a goal of therapy because we have actually drugs that dramatically inhibit the production of or reduce the activity of that enzyme and they don’t reduce cardiovascular events at all. So, in a drug-naive patient, it can maybe give you some other advice that there is a proinflammatory state here. So, if you wanna use it for that, never use it as goals in therapy. Stop repeating it once you put somebody on the lifestyle or a statin or whatever another drug because it would be meaningless what it turns out to be. There’s not a randomized trial probing it but the CRP has a little bit of data that it’s probably good to see that going down. It’s not level one evidence, but Lp-PLA2 has zero data in that respect. So, you shouldn’t use that. And the other nonsense, let me get it out the way, is people who market this come around and tell you Lp-PLA2 is a cardio-specific inflammatory marker. Nonsense. Lp-PLA2 is produced by macrophages. So, if you have adiposopathy and you have a lot of sick fat shells, they produce Lp-PLA2. Fatty livers produce Lp-PLA2. So, it’s certainly not specific to atheromatous plaque in your arterial wall.

John: Gotcha. And so one of the things that people would say, we’ve listened to these kind of very biochemistry-focused mechanistic discussions about these different particles and how they’re working in the body. And what a lot of people will say out there is they say, “Well, that’s great.” Well, if you look at the studies on heart disease, your lower cardiovascular events by targeting, you know, LDL cholesterol or apoB or whatever the case, but it doesn’t equate with dropping all-cause mortality. So, what do you say to those lines of thinking?

Dr. Dayspring: Well, if you look at the extenuation of all the standard trials that have been done for 20 and 30 years, they do. But if you’re looking at two or three years, they rarely do. But let me just throw this at you. If I could tell you I could make you go through life and you’d never have a myocardial infarction, heart failure, a bypass, hospitalized sort of CCU with angina, and I have no clue whether you’re gonna live longer or not, would you not say, “Yeah, I’ll sign up for all of that?” And there’s no argument that statin or other apoB lowering therapy do all of the above. So, do I really care what it does to mortality? There’s certainly no evidence that it increases mortality in anybody through any pathological measure. That’s the stupid stuff you see on the internet. All right, where’s their mortality data? Who gives… In New Jersey, who gives a you know what? Who gives a darn is what I would likely say to your audience. So, it’s one of those meaningless things.

If you wanna slam, criticize some lipid-modulating therapy, and bring up that nonsense, it doesn’t matter. You can’t show me trials where I’m hurting anybody, but I can show you all those other hard endpoints called MACE, Major Adverse Cardiovascular Events, none of which can be faked. You either have an MRI or you don’t. You either have a bypass or you don’t. You either have a stroke or you don’t. You either have heart failure or you don’t. That’s not somebody’s opinion. They all get significantly reduced, not to zero. That’s why the newer concept, again, just unbelievable. And I gotta share with you when we’re done with this. I’ll email you an article in an editorial published yesterday in JAC, that we would do far more to the public health if we will discover whatever you wanna use as an LDL metric. And, of course, they used LDL cholesterol, but it would apply to apoB, and determine you have it abnormal when you’re age 20. If I treat you between the ages of 20 and 30, rather than waiting until you’re 60 with a positive CAC or God forbid, an MRI, I would so, so enhance public health. It’s not… And you know what? If I treated you for 10 years in your second decade, that may mean you don’t even need treatment for the rest of your life because atherosclerosis takes decades to occur.

John: Right.

Dr. Dayspring: It’s never gonna happen. Nobody’s ever gonna do a 40-year study showing, “Yes, that’s the proper thing.” You would wind up treating some people who maybe don’t have to be treated, but without much for a downside. Why not? So, these are the provocative new ideas that are coming down, but you at least ought to be aware of that. So, again, if I’m a 20, 30-year old and all of a sudden my apoB or lipid surrogate of apoB is out of whack, I think you need to seriously consider, of course, a better lifestyle. And I wish everybody would do it. But whatever you can achieve or cannot achieve with your lifestyle, then you have to look at pharmacology. Maybe one day you’re not even working on it for a long time. We may have a vaccine to prevent atherosclerosis. And most of us who still have some degree of sanity left have not abandoned the vaccine world.

John: Yeah. I mean, you can make the case, I think, which you just did, which is, like, these studies are done over a period of a couple of years and the heart disease is cooking for 30, 40 years. I mean, it can start super early. So, it’s pretty disingenuous to look at a trial that’s designed to approve a drug for better cardiovascular function, and then try to say, “Why is this not dropping all-cause mortality in the span of a year and a half or two years,” when that’s not even how heart disease develops? It takes decades. It’s really bad information for people to take that line of thinking.

Dr. Dayspring: It is.

John: And I think it’s…

Dr. Dayspring: Look, I wanna high-five you right now. And remember that when these drugs were discovered and they were willing to do studies, to do the type of study they’re looking for would cost hundreds of billions of dollars.

John: Right. It’s just not…

Dr. Dayspring: There’s no drug company that was gonna do that. You have to prove your product works in two, three, four years, that it reduces whatever input you think it does, and you didn’t hurt anybody in the process. And that’s what they do. Even those trials are ridiculously expensive, but you’re not gonna get the type of data other than post hoc follow-up of…like the Western Scotland study, which was done in the late 1980s and ’90s. We have 30-year data on it. And boy, over time, now, the critics are all, “Yeah, but you stopped randomizing it and binding it at four to five years.” So, they always come at you with that type of stuff. Now, it’s an endless debate. But I really suggest especially for the non-believers to pick up this week’s JAC. Even if you’re not a subscriber, maybe your library can get it for you. It’s the best 30 bucks you ever spent in your life to read the [inaudible 00:44:39] analysis and the editorial that goes with it. I think it could radically change the way we approach things.

John: We’re gonna link to that in the show notes. I think maybe the last big topic we’ll hit here and hopefully kick around a good bit is cholesterol absorption, Niemann-Pick C1-like 1 protein, ABCG5, ABCGA, Zebadiah, all that whole world, eggs. Are eggs good for you, bad for you? Let’s get into hyper-absorbers and whether you think that has value for people to know their status.

Dr. Dayspring: Okay. John, when I keep talking don’t shut up. Wave your hands or something else [inaudible 00:45:16] because it’s a topic, as you well know, that is extremely dear to me. It’s been a large part of my research life in this world. I was very much involved in the development of cholesterol absorption blockers in their heyday and got exposed to the world experts on this and everything. And it really became first working for laboratories, well involved with the methodologies that it takes to measure these different markers, you know, mass spec and chromatography and stuff. But it’s a fascinating world that tragically is understood by so few, even most lipidologists, to be truthful with you. So, of course, we measure cholesterol in the bloodstream. So, when I do a total cholesterol, HDL cholesterol, LDL cholesterol, all I’m doing is quantitating the mass of cholesterol molecules that is trafficked. And of all of those particles, that’s total cholesterol or LDL particles. That’s the LDL cholesterol in HDL particles. And that’s it. Now, the cool thing is that I’m actually measuring cholesterol in your blood. That’s not the only place in your body cholesterol can’t hurt you if it’s circulating in the blood. It might hurt you if it winds up in your arterial wall. Maybe or maybe it won’t hurt you if it gets cleared by the liver. But even sterol toxicity in the liver is a big part of fatty liver, so I wouldn’t say cholesterol is totally innocuous in excess in hepatocytes also.

So, if you told me today or shared with your audience what your total LDL cholesterol is, what if I then said to you, “Well, it’s pretty cool to know, John.” But of all the cholesterol that’s in your body, also recognized that whatever’s floating around your plasma has very little relationship to what your cellular cholesterol might be. No relationship to what your brain cholesterol might be, which is a totally different pool of cholesterol that doesn’t interact with the blood. That don’t tell me whether the intestine is that cholesterol came from your liver, your intestine, or where did it come. All I know is you got too much cholesterol. But for certain reasons, it might be important to know was that your excess cholesterol that’s circulating in the blood, is the reason for that that your cells, including your liver, but mostly your peripheral cells are producing too much cholesterol or is my intestinal…are my enter sites for whatever reason over-absorbing cholesterol, which would contribute to the cholesterol in the plasma?

And that might be important for me to know because if I didn’t wanna lower apoB or its cholesterol metrics, might I, therefore, alter lifestyle, which we’re always gonna try? Might I use a cholesterol synthesis inhibitor, the statin family of drugs? Bempedoic acid is a new one. Or might I give you a drug that reduces the absorption of cholesterol in your gut? And that would be the ezetimibe. There are others in the pipeline that are coming. The good news is… The reason we have these PCSK9 inhibitors, which can clear some of our existing apoB particles, is somebody 10 years ago or a little more than that did genetic studies and said, “Oh, my God. PCSK9 affects your LDL receptor expression. And if we inhibit PCSK9, your LDL receptors live a lot longer and they clear all your LDL particles.” So, the people who have genetic loss of function of PCSK9 don’t get much coronary disease. So there’s the genetic example of, wow, that’s a good therapeutic avenue.

Well, there’s also that in the early 2000s that genetics studies were produced that, my God, if for some reason you’re born with genetic hypo-absorption of cholesterol, you don’t get a lot of heart disease. So, that would say, “God, if we could ever invent a pharmacologic therapy that reduces absorption of cholesterol it almost certainly will reduce cardiovascular disease,” and we see the HMG-CoA reductase gene. The Mendelian Association study show is tied in with atherogenesis. So, we had genetic studies that would suggest, geez, if we could inhibit cholesterol synthesis, we would reduce cardiovascular disease. I mean, I dare would be. What if I could inhibit resorption and inhibit synthesis and enhance clearance? You wanna give me to triple therapy statins that are my PCSK9 inhibitors, but you would have newborn baby apoB levels for the most part.

But anyway, back to, therefore, looking at your total LDL cholesterol doesn’t help me in that manner. So, will there be blood tests, biomarkers, that I can order that would in you or anybody else say, “Tom, this person is likely his cells are making way too much cholesterol,” or, “Tom, this person is over-absorbing too much cholesterol from the gut,” or maybe they’re doing both, or maybe they’re doing neither and it’s just an LDL receptor defect where it’s not clearing the apoB particles. So, these type of biomarkers can help you make those type of decisions. So, here we go. What are… I can’t measure cholesterol and say, “Are you over-synthesizing or not,” because you might be over-absorbing it. You might not be clearing it. So, that can’t tell me. Cholesterol synthesis is a very complex synthetic chain of 37 steps, but, you know, A changes into B, changes into C, changes into D. Do that 37 times right through the alphabetic order. And let’s get to the, what is the sterol molecule that is penultimate, meaning it’s the last step before it gets transformed into cholesterol? If I could measure that in your blood, and it’s high, I know, wow, you’re over-synthesizing a lot of sterols and it only takes one more step to make cholesterol.

So, with respect to cholesterol synthesis markers, the penultimate sterols, meaning the sterols that can get converted to cholesterol, and the synthetic chain are either desmosterol, D-E-S-M-O sterol, or lathosterol, L-A-T-H-O sterol. There are plenty of laboratories that can measure that for you. And you wanna get the absolute concentration. You don’t wanna look at their ratio to total cholesterol. So, if either of those are both irrelevant, if we realize we’re dealing with a hyper synthesizer of cholesterol and if nutritional advice doesn’t improve that, one of which might be reduce saturated fats, not in everybody, but it might help some. If you see… If you impact on either of them you’re probably gonna reduce cholesterol in apoB metrics. So, that’s how we can evaluate synthesis. How about absorption? Absorption is a little more complicated because it’s multi-step. Of course, everybody’s intestine has a pool of cholesterol in it, which is subject to absorption from the gut movement into the cells that line your small intestine. They’re called enterocytes.

Now, of the cholesterol pool that is available for absorption, maybe 15% to 20% of it comes from cholesterol you’re eating, but the overwhelming majority of cholesterol in your gut came out of your liver, came out of your biliary system, your bile ducts, and got deposited in your liver. So, the overwhelming majority of cholesterol that is available for absorption is endogenously-produced cholesterol that made its way back to the intestine. And this is why, in most people, the amount of cholesterol in the diet is pretty irrelevant as far as is it gonna wind up in your artery wall because it’s gotta compete with absorption from biliary cholesterol, which is the vast majority of it. The other thing with cholesterol that we eat, much of that cholesterol is cholesterol ester. And that cannot be absorbed. It’s a big molecule. So, the only way you can separate cholesterol from the fatty acid is a pancreatic lipase as the esterified. And that can have variable occurrence in given individuals also. So, anyway, the sterol will be polled from your gut pool into the enterocytes by a membrane receptor that recognizes sterols and pulls them in. That’s called the Niemann-Pick C1-Like 1 protein. And if you have that protein in proper amounts and it’s functioning properly, you will absorb 50% to 60% of the cholesterol that’s in your gut lumen.

Now, if you don’t express that receptor very well, you will be a hypo-absorber of cholesterol. And people who have those snips who are genetic hypo-absorbers have significantly lower incidence of coronary heart disease as they go throughout life. Very interesting. Hyper-absorbers, by the way, tend to have high apoB, so you wouldn’t want to be a hyper-absorber of cholesterol. But if you’re not doing genotypes or measuring markers of cholesterol absorption, you’d have no way of knowing that. So, what can I measure that would tell me your enterocytes are pulling too much cholesterol out of your gut lumen? Again, I can’t measure cholesterol because you might be synthesizing it elsewhere. So, we do certainly, to variable degrees, but all of us get some vegetables into us. And vegetables, for the most part, plants don’t contain much cholesterol, if at all.

They carry in their cell membranes other sterols that look very much like cholesterol, but they’re not exactly the same structure. And they’re called phytosterols. Now, human cells have zero use for phytosterols because we’re not plants. We need zoosterols. We need animal-produced sterols, cholesterol. So, that Niemann-Pick C1-Like 1 protein is really a good bouncer. It has a much higher affinity for cholesterol than it does for any phytosterol. So, even if you have phytosterols in your gut, very few of them are being internalized by the Niemann-Pick C1-Like 1 protein whereas a lot of cholesterol might be. But if they do get internalized into the enterocyte, they will wind up in your chylomicrons or your enterocyte shoots them down into some of your HDL particles. So, they will appear in your plasma. So, if we measure plasma phytosterols and the two most commonly that are measured are sitosterol, S-I-T-O-sterol, or campesterol, C-A-M-P-E-sterol. They’re in plants. They shouldn’t be in your body to any appreciable degree. So, if I measured either of those biomarkers, preferably both, and they’re elevated in you, and we have normal reference ranges. We know what is low, normal or high absorption. I can classify you as a hypo-normal or a hyper-absorber of cholesterol.

Now, in our world, this tells you nothing about fatty acid absorption or absorption of anything else. This is strictly sterol absorption. So, we can measure those in the blood. And it doesn’t take… If you have an apoB problem, and I’ve got to lower your apoB, if you have excess phytosterols in your body, a same therapeutic avenue would be to reduce absorption. You really can’t do that very well by, “Oh, I just won’t eat cholesterol in a diet,” because most of the cholesterol in your gut is coming through your liver and your biome, so it’s still gonna be there and you’ll still absorb it. But ezetimibe interferes with the activity, the function of that Niemann-Pick C1-Like 1 protein. So, ezetimibe is an incredible blocker of cholesterol absorption. Now, what happens to cholesterol if it’s not absorbed into your enterocytes? Where does it go? It goes right out of your rear end into the toilet bowl. It becomes a fecal sterol. You excrete it. If you want… You’ve probably all heard of the concept of reverse cholesterol transport. The final step of RCT is increased fecal sterol excretion. The number one therapy we have in our armamentarium to improve reverse cholesterol transport is ezetimibe right now. So, excess sterols are harmful in your arterial wall. One way to get them out of the body is stop their absorption.

A little side caveat. We always think of absorption as gut movement, enterocyte, chylomicron, or HDL and into your plasma. Well, there’s another big pool of cholesterol that can make its way back into the body. One of the pools in your body that has the most cholesterol is your bile system, your biliary system. You’ve got tons of bile ducts. You’ve got a gall bladder storing it. It’s super enriched in cholesterol because when the liver wants to get rid of cholesterol, it excretes it into the bile with the hope that it’ll go to your intestine and it’ll get excreted out as a fecal sterol. But your liver, if for some reason it needed cholesterol, can reabsorb cholesterol from your bile system back into the liver. How does it do that? That same Niemann-Pick C1-Like 1 protein that’s expressed in your intersites is expressed in the hepatobiliary surface.

So, the good news is ezetimibe not only would reduce intestinal reabsorption of cholesterol, it prevents the liver from re-absorbing any cholesterol that you’ve already excreted. So, it’s a dual mechanism of action for ezetimibe. And if you, therefore, deplete the amount of cholesterol that’s gonna be delivered to the liver either through back flux or through chylomicrons, your liver’s cholesterol pool will be diminished. And liver makes cholesterol to make a lot of stuff including bile acids. So, where would the liver get cholesterol if your absorption avenues are blocked? The liver expresses LDL receptors, which enhance the clearance of your cholesterol carrying apoB particles. And that’s at the end of the day how ezetimibe works. Actually, at the end of the day how the statin works. Statins decrease the hepatic cholesterol pool by inhibiting synthesis. Ezetimibe inhibits sterol absorption. If you do both, you’re gonna express more LDL receptors and clear your apoB particles to a much higher magnitude.

So, I think if we measured those biomarkers, we’d understand that the last thing, you know, these people into functional foods, one of the long-term therapeutic avenues that have been advocated are, “Oh, you can buy these supplemental phytosterols, psychosterol [SP], campesterol, and all these sterols that are in here. And if you swallow them, they compete at the intersite interface with your biliary micelles with cholesterol. So, you will absorb less cholesterol. That’s true. And you will reduce LDL cholesterol, but the price you might be paying for that is you’re over absorbing sitosterol, campesterol. And there are any number of studies is showing that is not healthy. There’s a particular brand new genetic study just published showing the last thing you wanna do is introduce phytosterols to any significance to your plasma. So, by the way, how would I know to scream at a patient, “Under no circumstances supplement phytosterols,” and measure phytosterols in their blood? If they’re already elevated, I’m sure as heck I’m not gonna advise them to take more. I got other ways to lower apoB.

John: Yeah. I mean, well, there’s a few things there, one of which is for the desmosterol test you’re looking to see whether somebody is a synthesizer and that will presumably determine whether they would go on a statin. And once they’re on a statin, don’t you need to continue to measure desmosterol to make sure that your cholesterol synthesis has not gone to zero?

Dr. Dayspring: Well, if you’re me, you would. That’s certainly not recommended by any guidelines or many experts don’t even know what desmosterol is tragically or so. So, yes. I believe… Absorbing… Nobody’s gonna… You don’t absorb the sterols. You’re always gonna reabsorb a little bit. But when does inhibition of cholesterol synthesis necessary to further express LDL receptors to reduce apoB become…? You’ve saturated that pathway. Don’t keep over-suppressing cholesterol synthesis because might there be a reason not to do that? Now, although no cell in the body needs cholesterol delivered to it, and that’s why the amount of cholesterol in your lipoproteins are so useless, people are, “Oh, my LDL is 20. My cells will die.” No, they won’t. All the cells in your body have all the genetic material to de novo synthesize all the cholesterol they need. But if you take away the ability to at least generate physiologic amounts to cellular cholesterol, would that be good? Nobody’s ever gonna do that trial. So, at the present time, I’d rather not do that. I’d rather inhibit cholesterol synthesis to my normalized lathosterol or desmosterol. I don’t wanna over-suppress it unless somebody’s on their third bypass or something like that where I don’t care what I’m doing, and I got to get rid of all the apoB particles. And thank God we have PCSK9 inhibitors in our therapies now that we can achieve that without over-prescribing very high doses of statins.

This is one of the reasons, by the way, I disagree with the guidelines that say, “If you’re gonna start the statin and start the maximum dose and see where it gets.” Well, I much prefer to start lower doses of statin and very often combine them with ezetimibe or on other nutritional therapies, and see. Can you get to a physiologic apoB? Then why in the world would I wanna give you a gorilla statin? I know I gotta quote all the studies that prove that they all use gorilla statins. That’s a Dayspring-ism for maximum dose of a statin, by the way. But I don’t buy it. People who followed me for years know I prefer to optimize the statin or apoB-lowering therapy by using smaller doses of whatever I gotta use very often in combination. And if I can achieve a safe apoB, that’s how I would rather do it. So, when I tell you don’t maximize the statin, just realize I’m going against guidelines, in most cases, not all. Now, a lot depends on what type of cardiovascular nightmare you are. But so I agree with you. And the biggest worry is, yeah, so, you have to produce cholesterol, but… Although plasma cholesterol doesn’t get into the brain, your brain is very good at synthesizing cholesterol, certain statins do get into the brain. So, my biggest worry is do I… If I don’t wanna over-suppress cholesterol synthesis, and it’s near impossible to do that in peripheral cells, but it’s possible, I sure as hell don’t wanna do it in your brain cells.

John: Right. Yeah.

Dr. Dayspring: And there’s nice studies that show that cerebral spinal fluid desmosterol correlates extremely well with plasma desmosterol, serum desmosterol. So, if it’s low in serum, the odds are good it’s lower in your brain too. And they’ve also linked a low CSF desmosterol to cognitive impairment and Alzheimer’s disease. So, I think desmosterol… And by the way, desmosterol is a better mark of synthesis in the brain than lathosterol. So, I do use desmosterol and say, “Tom, you’ve done enough with your statin. Figure out what else you got to use to get apoB down.” So, I’m on board with what you said there, but you’d get many other opinions on that.

John: Yeah. And then it touches on the next piece, which you got into, which is this whole absorption pathway. It sounds like you’re saying not necessarily a big need to limit nuts and seeds and eggs if you’re a hyper-absorber because most of this stuff is coming from the biliary tract anyway, and so the dietary interventions for hyper-absorbers are fairly limited.

Dr. Dayspring: Yes. But as you know, there are other molecules in those plants, nuts, and seeds that may be beneficial to you. So, I don’t want you to necessarily not do it. So, the real people who get into danger with the phytosterols are these people taking the supplements or they’re getting 2,000, 3000 milligrams it is. The average vegan who is eating nothing but vegetables may ingest 400 to 500 milligrams of phytosterols a day. But for these people who are drowning themselves with these totally unproven in clinical trials of phytosterols supplements, yes, I’m lowering LDL cholesterol. None of them are measuring what they’re doing to LDL phytosterol and HDL sitosterol. I just think that’s… Until somebody does a blanket randomized trial showing that can’t harm you and that will help, which nobody is ever gonna do because you’re talking a billion-dollar trial and the supplement industry sure as hell isn’t gonna do it. So, I avoid those things like the plague if… If I’ve measured your phytosterols and you’re not absorbing them, go drown yourself in supplements if you want to, but I then would do a two-month follow up to just be sure you’re not over-absorbing them because you’re overwhelming your gut with them.

John: I gotcha. Okay. Yeah. This has been a great overview of the whole world of LDL particles, cholesterol, heart health. If there’s one message you’d like to close out with that you want our audience listening to this show to know, what would it be?

Dr. Dayspring: It’s always with me, is understand as much of the pathology as you can. Certainly, understand in the lipid lipoprotein world, it’s apoB. Everything else you’re doing other than that is like a sub-metric of apoB. So, make your risk assessment, your therapeutic things, on apoB. But atherosclerosis is a multifactorial disease. You gotta examine a lot of things. And last but not least, and I think this is where your mindset comes in, individualize your recommendations based on what is going on in the person you’re staring in the eyes. It’s nice to know what he did in 10,000 people in this trail or that trail, but I don’t know, does this person even fit in that trial? Are they on the left side of the curve, the right side of the bell-shaped curve? Are they in the middle? You don’t know because virtually none of our patients meet the exact criteria that all these trials use for enrollment. So, individualize. And whatever therapeutic risk assessment or therapeutic advice you can come up with, please, in two months repeat your biomarkers, put them on the scale again, recheck their blood pressure, and that will give you good guidance that I think what I’m doing is probably right.

John: Yeah. Test don’t guess, apoB is the primary marker, and personalize everything.

Dr. Dayspring: [inaudible 01:07:51] Yep.

John: Yeah, absolutely.

Dr. Dayspring: You get another high-five.

John: Yeah. Dr. Dayspring, we really appreciate you coming on. We love your work. This is so much good information. Thank you for sharing your knowledge and your wisdom with our audience and we wish you a happy fall. And I see you got the Rutgers’ shirt on. I think you’re in for a rough football season, but…

Dr. Dayspring: Oh, yeah. [inaudible 01:08:10] support all the way.

John: …other than that.

Dr. Dayspring: And for your listeners. I have a lot of followers. Please join me at Dr. Lipid on Twitter.

John: Yes, absolutely. Thank you, Dr. Dayspring. Have a great day.

Dr. Dayspring: All right. Take care.

John: Yep. Bye.

Dr. Dayspring: Bye.

John: The “GeneFood” podcast is our attempt to synthesize the latest developments in the fields of genetics, nutrition, and medicine, and offer you practical tips and stories you can use in your own unique health journey. If you enjoy this podcast you can find more information online at mygenefood.com.

John O'Connor

John O'Connor is the founder of Gene Food, a nutrigenomic startup helping people all over the world personalize nutrition. John is the host of the Gene Food Podcast and a health coach trained at Duke's Integrative Medicine Program. Read his full bio here.

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