Lipids: Lightning Round with Dr. Dayspring (Episode 4)

So that's a lot of information, a lot of useful information. I almost want to transition to like a lightning round thing. And I'm actually the lightning round. Actually the first thing is going to have to do with the statins and the increase of lp. What are your thoughts about that?

I'm so glad you asked me that. Because atherosclerosis is an apob mediated disease. It's cholesterol in the artery wall. But if you got the genes that make apoprotein little a X percentage of your LDL population are going to be LP particles. You should be measuring LP in molar concentration. It's nanomoles per liter. If it crosses 50 nanomoles per liter, you enter the world of LP mediated risk. At a level of 125 nanomoles per liter, you entered a world of wow, you're in big trouble with LP. That's 125 nanomoles of LP particles. If I took that same personnel has an LP of 125 and I counted the number of LDL particles that don't have APO attached is an easy way of doing that. I would find it's 1800-2000. I don't want you to have an LP of 125 and I sure as hell don't want you to have a regular LDL particle count of 1200, 1500, 1800. So I'm going to give you a statin that may in X number of people increase the number of LP particles. We now know how it does it, but we can get to that if you want to. But if I give you a statin, probably a rare instance, I should actually repeat the LP to see are you one of the ones. So if you have an LP of 125I may increase it to 130 to 150. But your LDL particles without L apole attached, I've reduced from 1800 to 2000 to 1000, drastically lowered your cardiovascular risk. The trivial increase in LP particles is abrogated by the drastic reduction of non APO carrying LDL particles. That's why the few trials we have where they actually looked at LP and people on statins and Jupiter is the biggest trial that looked at that. They looked at their people with abnormal LP and they all were on statins, rosuvastatin or placebo. And in the people with lp, the rosuvastatin reduced mace. It didn't reduce it as much as it did in the people who didn't have lp. So what we say Is that statin reduced residual risk unfortunately not as bad as the people who weren't gifted with but it helped you. So the statins worked despite the fact in Jupiter it raised LP particle concentration. So if we're on the camera right now it increases LP that much it's and it drops normal LDL particles.

So it's an issue of just degree.

It's like the statins raising glucose at the end of the day they reduce heart attacks but yeah there's a little. You wish they didn't raise glucose. I wish the statins didn't raise LP in most people it's a trivial raise that is of zero concern. The Internet frauds use this as a way why you shouldn't use statins. It's ridiculous. Statins help people with it. Any guideline that you pull out now says if you have an LP that's in the at risk concentration after you've done whatever lifestyle if your LDL C is still high apob prescribe a statin to lower LDL cholesterol. That's the first guideline suggested treatment for lp. And look today you could add ezetimibe, you can add bempedoic acid but the little hey and you better be rich because your third party payer isn't going to pay for it because there's no FDA indication. The only drug we have nowadays that lowers LP by preventing the synthesis of LP particles in the liver is the PCSK9 inhibitors at 25% or so lowering. So should you take a PCSK9 inhibitor? Yes, if you need to get APO beta control but and if I had high LP linole personally I would be taking a PCSK9 inhibitor but maybe I can afford it. Whereas the run in it's $6,000 a year that you're going to have to pay for it.

So I'm asking actually educational question about patient and we actually talked about this before we went on the video today the concept of hyper absorbers we kind of briefly ran over it. I'm thinking about an individual in my head who cholesterol if I remember correctly 283 hundreds reacted poorly with statins, reacted poorly with the zetia, couldn't tolerate well call so went through the list of things um have not gone down the PSK9 rabbit hole with her did massive dietary changes. Um we actually did measure her um phytosterol um levels um and that was I think it was Boston Heart Labs I think was yeah they're pretty much doing, doing yeah it was a little bit of a hassle to get. She, she did herself went to the website and all that kind of stuff. Yeah, um, it's, it's a little different.

If you're not affiliated with that lab. It's just to get.

Yeah, yeah. So because we, we're over there is.

Empowerment dx, a company that uses direct to consumer. You can. They will mail you a lancet and a minuscule tube that you have to put like four drops of blood in. And they take that and they send it to Boston Heart and you'll get the exact same sterile pin and Power dx. Google them.

I'm familiar with it actually. So they, they'll do that.

They have a cholesterol panel that looks at the sterile mark.

Okay. Do you have any of the cost.

Of that is and 99.

Okay.

Yeah. So it's ways cheaper than the. And look, if you had to pay cash for it at Boston Heart Labs, it's probably more than 99.

Correct? Yeah. I'm not going, I'm not going to put the numbers in my head because I'm not 100% convinced about it. But anyways, this individual got it to like 17180 with an incredibly restrictive diet. Like just crazy, crazy restrictive diet. So I'm kind of thinking, okay, we've tried a lot of other things. You know, she has not done a PSK9 right now. But. But one of the things is now this individual is almost malnourished. And so I'm at the plague where it's like okay. And no. No diabetes, no blood pressure, no other risk factors risk treating numbers. And it's one of those things where it's like is this individual by restricting their diet so greatly is that remind.

Me how old this patient is.

She's in her 60s.

Okay. So at an age group where somebody could have atherosclerosis, especially if it's gonna.

Be like, it's gonna be 58 to 68. 50.

Have you done a coronary calcium or any other imaging?

Yeah, we did CIMT as well. It was fine.

So zero cac?

Yes.

And even carotid? No carotid.

Yeah. We did a CMT in as well as ultrasound. The CMT showed her vascular age and her chronological age were within like one to two years.

So look to me right away that tells me in that 60 year old woman with a CAC of zero. And I put more weight on that than I do the imt but mostly because there's more data on it. You, you've got at least 10 years to worry about an acute coronary syndrome. So you got time to play. So what if whatever I was doing nutritionally was making her malnourished? I'd back off of the nutritional advice I'm giving her. Maybe you're restricting saturated fat or something too. Too damn low. Even cholesterol in a diet. If she's not a hyper absorber, restricting cholesterol in the diet is a total waste of time. So I wouldn't use that. That might be in somebody. If she's not a hyper absorber, where giving a phytosterol or better yet, a phytostanol supplement would help her. Lactobacilli, which reduced cholesterol absorption, would not malnourish her, but at least could. And even in a normal absorber, if you've measured sterols and she didn't have hyper absorption. Reducing absorption will make the liver grow more LDL receptors. That might help you lower apob if all of those drugs. You said she didn't respond. Now I want to know, is that because of side effects?

Side effects? Muscle aches, pains, fatigue.

I don't know what the hell to tell you, but if a patient comes back and says, I can't tolerate this drug or that drug, you pretty much have to leave them. You can't force a drug down there. They won't take it. So you fool yourself if you. So I don't know what you tell somebody like that, but I. I would back off on a diet to malnourish them, especially if I KNEW I had 10 years to play. If she had coronary plaque to that degree, I'd let her know.

And what would you.

Life is in your hands.

And what would you consider like your composite scores are 0 to 100, 100 to 400. Would you. Would you say a score less than.

There was a nice study probably two years ago that came out says you are in the same risk as somebody who's had an MI. MI if your coronary calcium enters the 300 range. So that's the nightmare range. But as a preventive lipidologist, and I'm not a cardiologist, but we have the American Society of Preventive Cardiology to which I belong. I do. Even those type of cardiologists look for primordial prevention, which is what she would be ugly cholesterol metrics, APOB metrics where we probably should lower it, but we have 10 years to lower it. But therefore any coronary calcium being positive would tell me I don't have 10 years. I don't know if I have eight years, five years, four years or two years, what I might do in that person is progress to a CTA with the clearly studies where they can see non calcified plaque. And regardless of whether you have calcified plaque or not, you can not only see non calcified plaque, but you get estimates on the vulnerability of that plaque. So it's a little bit more imaging costly. Your third party payer isn't going to pay for it. So you're talking a few thousand bucks, especially if you want the clearly your sight rather than a regular cta. So there are more advanced imaging things you can go to if possible that might twist your arm. I got to get a drug in there.

I think locally, I guess we lost power here. I think locally insurance will pay for the CTA aspect and clearly evaluations like 6 or $800 I think to get it. So you know that more than I do. Yeah, that's a good point. And I guess just, just for the audience because it clearly. I think, I think Dr. T mentions it in his stuff. I think it's part of his thing.

So I use it a lot. But we're actually experimenting a bit now to see what we are learning from it.

Why don't you tell us a little bit about that? That's something we have available here in the Richmond area that I've had a few patients ask me about can give.

You other parameters of blood flow through the arm. Any fractional BL through a true blockage or a dysfunctional blockage that is impeding blood flow. So if you have a little bit of a plaque and all X amount of blood should be flowing through that at a certain point where that fractional flow diminishes. And there are numbers that tell you, oh, that's no good, then you're into, you better do something about this. Now it doesn't mean you need a stent or anything if you're asymptomatic, but it does would call for more aggressive lipid management. So you would look at. That's pretty much the main parameter of.

The reporting and my understanding as well. It also gives you a little bit of. They'll tell you about the wall thickness. So you might have an opening, it's clear, but then you might have a thickening until you've got some degree of.

Yeah, and you know the one problem with that in my mind too, and Peter Libby gets into this in all his inflammatory discussions and everything is yes, we have plaque, we have plaque erosion and plaque rupture. But there is something called the plaque erosion, which is a plaque that doesn't extrude into the lumen and that may not even be associated with lipid abnormalities, but it's close to the endothelium and it causes erosion of the endothelium, which exposes the blood flow, mostly the coagulation system, to now the surface of that intracellular plaque. And it can induce a lot of hemodynamic changes, spasm, and also perhaps even clotting. And I don't know how you diagnose your ocean, and I don't think it clearly tells you much about that. Now, that's a minority of plaques. Most of the plaques are the. You're going to see them and their dysfunction are going to rupture and cause.

So back to the coronary calcium. Like, because I get people and unfortunately sometimes. And it's which cardiologists do your patients see? Right. So, yeah, so like they'll, the patient's like 65 and they have a calcium score of like 40 or 50. I'm kind of like, well, that's actually kind of low for your age. And then they see the cardiologist and they're like, oh my gosh, it's low.

For a 60 year old. But if that was a 35 year old, that's a 99th percentile, correct?

Well, it's all. That's. That's devil's in the details, right? Totally, yeah. And so do you have a particular paradigm because you mentioned with this one individual, I'm thinking about score of zero. You're like, you got 10 years. So let's say you're in your 50, let's say 55 to 65 range. What calcium score would you think of? Like, okay, we've got eight years, you know, is it less than 40, 30? Is it going to be in the.

Real world that we have to make any decisions you make what. And it's age dependent. So rather than the absolute, you look at what percentile they fall and what Z score sort of is there a particular parameter? And the higher the percentage, the more likely I'm going to. I don't know if I got 10 years with you in it, I'm going to treat it.

So you go and tell you off the report proper because it gives you those numbers on the report.

And then, look, this comes down to what we've always called the practice of medicine. Sooner or later, as a doctor, you've got a lot of information, but you're going to have to make a darn Decision, for God's sakes, based on your wisdom, your years of experience. It might just be an educated guess in some instances, but it's better you have an educated guest than their neighbor has an educated guest. So we have to do that sometimes. So we use numbers like that. If you're in a practice that is 100% devoted to longevity, and not only longevity, but when you reach old age, you have health span. So you have none of the chronic diseases and you can enjoy longevity, you pretty much. I know Peter has said it on podcasts. If you listen to some of his Instagram nightly 32nd, I don't know what they're called on his posts on Instagram. He gives some good stuff there. Peter looks at it like if you had somebody that had a bacterial infection, you eradicate that pathological bacteria. He thinks APOB is causal at a rather low concentration. The Mendelian study showed if you have hypobatalipoproteinemia, you don't get atherosclerosis. If you already had it, you regress it and have a far decreasing mace. So he's of the belief you eradicate apob. So if longevity and health span is what is in your binoculars, you're treating APOB if it's a little bit high, and that would be if you have LP above 60, maybe if you don't have LP or terrific other risk markers of F, you can live with an APOB between 80 and 60, but it's likely to be a lot closer to 60 than 80. So that's what a longevity practice might do. Longevity practice that's written in New York Times bestseller book on how to achieve longevity. But for run of the world physicians where you do have limitations on what you can prescribe and course on what you can prescribe, maybe your apob you live with a little higher apob or do you use different levels of apob? But if I have any calcium score, I want your APOB at least a bit lower than what it is. And that's presuming you don't have lp, because if you have lp, I don't care what your calcium score is. And there are studies showing that lp, although it's a terrible calcifier of your aortic valve, it doesn't correlate that much with arterial wall calcification. So be careful not respecting LP despite a pretty good coronary calcium score.

So the lp, the primary risk is with aortic valve calcification, not coronary artery calcification.

Yes, you can get calcified Arteries, obviously, but you can also have non calcified arteries with high lp. So just be careful saying, oh, your tag score is zero. I'm not worried about your lp.

Okay, I got you in that context. Not in the context of overall cardiovascular disease. In the context of a norm of a zero calcium score. Okay, fair enough.

So look, I think you're going to live with certain amounts of calcium score. You're not throwing a kitchen sink of therapeutics at somebody, but you're going to watch it. The danger gets into repeating coronary calcium. I don't think we know what that means, especially if you're on a drug. We know statins can increase coronary calcification, but reduce me. So should you even be doing cats again? And there are articles written that, yeah, but you don't mind a little bit of an escalation. But if it's really going high and the worry is if you see calcified plaque, you're missing the vulnerable plaque that goes along with the calcified. So I wish we had definitive answers on any of these. We don't. This is why it comes down to the beauty of practicing medicine in an intelligent way and making decisions through other.

Information and looking at other labs and other stuff. It's not just simply treating numbers.

As you mentioned, part of my career was women's health big time. That gets even more complicated as a woman approaches perimenopause or post menopause. It even gets problematic nowadays if a woman decides I want to have children, you better be doing serious metabolic and lipid evaluations before she decides to. Let's create a little embryo, you know, let's know what my cardiovascular, where the embryo is going to live for nine months. It's better to live in a cardiovascular metabolic, healthy woman. So you want to check a lot of things ideally before pregnancy occurs, if not asap. As soon as pregnancy occurs, you look.

At a lot of stuff. I conclude we actually do that when patients come in for pre pregnancy preparation and we'll do a bunch of metabolic stuff and nutritional.

To be honest with you, when somebody becomes an adult now in a woman, of course they can conceive long before they turn 21. I think guys late teens, 20, 21, by then they need their initial lipid panel and an lp and that's a good start. Of course with a blood pressure measurement and a waist size measurement, then you're off to the races.

I tend to like do those things, to be honest with you, when I see kids before we go to college because my thing is like the average five. And you went with your approach for the average American. Unfortunately, this is as good as it gets. You literally and your senior in high school. It's only going downhill from here, unfortunately. I tell them that. So let's check your cholesterol now and I'll see you in four years. Check your numbers, check your A1C, check your A bunch of things and we'll see how college did for you. I was the best health of my life at the end of college, which is not normal. And so it's.

And you know that we have done enough autopsy studies on young soldiers and even non military people who've croaked early and on autopsy, my God, look what's in their arteries. They weren't going to have a heart attack next week, but within the next 10 years they. So that's where it takes decades to build up. But if you got the risk factors and you're 20, they've had two decades to screw up your arteries. So yeah, the sooner you look, the pediatric societies want a lipid panel by around the age 8 or 9 to rule out FH. I would say if you're doing a lipid panel, doing lp, you're not going to act on it in a pediatric range group, but somewhere in your teenage years.

So this is a question I know someone in my community is going to ask me, so I'm going to ask you this question like that. That recommendation only was in the last couple years when PSK9s came to market.

Say about 10 years. What age? You should start lipid screening now. Lipid treatment is gonna just pretty much apply to homozygous FH or maybe severe heterozygous fh. And if God forbid, your kid has that, you belong in a specialized lipid clinic that deals with children.

That's a different story.

Yeah, we're talking very different therapeutic approach to that.

I don't personally think I've actually seen.

Yeah, most people in their lifetime would never see that. And in fact, if you're doing good family history, if mom has fh, you know, heterozygous and dad has it, they should both be going to a lymphedologist and a geneticist before they get pregnant to genotype them. What are you gonna pass on here? What are you not. Sometimes they only discover their own FHS when the kid gets a heart attack at age 8, but it's rare.

And to jog my memory, like for homozygous and heterozygous and this real is the general question with the cholesterol numbers. If someone has a cholesterol of over 400, like what are the numbers? I have some gray stuff in my head where that you can think, oh my gosh, this person probably is homo versus heterozygous.

Again, it's a really poor marker because you really have to do more advanced testing. And look, if the LDL cholesterol is above 190, you at least might be familiar. Hypercholesterolemic. Step one is to rule out secondary hypercholesterolemia, severe hypothyroidism, kidney disease, certain liver diseases which should be obvious. Then the kidney disease, you'd be nephrotic with swelling. The liver disease, you'd probably be jaundiced by that stage. But hypothyroidism, we don't usually see hypothyroidism to that degree. To dry building they did in the old days. That's when they had myxedema and quarters that you could see from two miles away. We don't see that anymore that degree of hypothyroidism. But there are other causes. There are certain drugs that can send your cholesterol through the roof. Sometimes mostly prescribed by either psychiatrists for some of the psychotic disorder dermatologists, some of the dermatologic drugs. But the most common cause nowadays are these ketogenic diets that in X number of people can give you what we call the FH phenotype. Your LDL cholesterol is from 240 to 400 which normally we're even thinking homozygous.

I've seen multiple patients do that and see their cholesterols go to 350s.

They're the people. My belief is they have to re examine the saturated fat in their diet. There is a little bit of evidence that if you love ketogenic diet, just do it without get ketogenic by not using saturated fat, using the monogenic, the monounsaturated fatty acids and the polyunsaturated fatty acids that can help you. Otherwise you want to eliminate the saturated fat and see if your LDL cholesterol apob disappear. If they do not but you believe I got to go back to the saturated fat, then either you play Russian roulette and say it's not going to bother me or you take a lipid modulating drug. But I'm going to tell you if you're on one of those diets and your LDL C IS 400 oh, we could throw the kitchen sink at you and might not get your LDL cholesterol back to normal when you make your LDL particles humongous. And anybody that has an LDL cholesterol above 200 has gigantic fluffy Buffy LDL particles. Don't assume they're innocent because they're killing FH patients right and left. When your APOB is at or your LDL particle is that big, the apob that it's on the surface totally changes its confirmation and it's no longer compliant with the LDL receptor. So LDL receptors is just as poor as clearing Fluffy Buffy LDLs as it is small LDLs. And that's why people with FH or diabetes have such high LDL particle counts. One it's too many fluffy buffies, and the other ones it's too many smalls. So even that can't help you. So that's very high. But there aren't people out there who just say, I'm taking my chances. They do a coronary calcium. If it comes back zero, they say, oh, I got 10 years to play with almost all. And you probably notice better than I. But even on the little experience I've had or other. Nobody stays on a ketogenic diet for 10 years.

They can't.

It's not the world's easiest diet.

I mean, a lot of the literature and data on longevity is actually with three to five day water fast. And so. So everything else is trying to intermittent little fast. So we're trying to replicate.

I'm a guy who lost 70 pounds with an intermittent fasting five days a month and the rest of the month sort of a hypocaloric diet, low carbs. And I lost 70 pounds that and it turns out it was probably just the hypocaloric. For a guy like me who was eating tons of calories, I don't know, the intermittent fasting, did that contribute? I mean, the debate is still on in that, you know, so I don't know. But I do know this. I was religious with that for four years. But even me, who knew the consequences after four years you just start slipping and slipping and before you know it, you're on that road to where you were again. So that's the problem with that type of diet. Nobody wants to stay teachotic. And if you're truly ketonic, you're sticking your finger all the time to prove you're ketonic.

Yeah, I kind of did some. There's a breath device you can use and other things and you kind of get the feel for it. But personally, it takes me like 18 hours before I start creating ketones. And so it's like day one.

Yes.

Yeah. And so you really need to be at least doing a 24 hour.

So I don't know that that's the answer. But I, as a lipidologist, I worry, yeah, APOB is proven to be causal. I don't know. There obviously there are some people, as with almost any other risk factor for any disease, go through life and somehow escape the dangers of high income beef through whatever other protective genes they may have. But I don't think you know that till you're 90 years old and you.

Make it, you make it.

So that's why I say, well, that's sort of Russian roulette.

Last thing I want to ask you. And this I know some people that I'll see in the next couple months will ask me, why didn't you ask this question apoe4. So obviously people who get their gene stuff done, they see that and all of a sudden they're like, oh my gosh, it's the end of the world, right? Kind of thing. Like, what are you, what are some brief thoughts about that? Not APOE3 or I'm calling them E3E3 or E3 like APOE4 4. You know, I'm a believer.

Just like everybody going to have an ill people a once in their life. In the future you may need it more if we ever get successful therapies to attest the efficacy. But that's in the future. Right now you need one lp, so.

You wouldn't necessarily recommend repeating it and doing things and repeating the LP two times.

Now where we repeat it. If you're one of these statin worried people you want to see, does your LP go up? I'm fine. Repeat it, but also make sure you're repeating APOB and I'll tell you how to calculate non apo little a APOB. And it's very easy. You have to know one number to convert APOB2 molar concentrations. So then I think people who go on PCSK9 inhibitors like to know you're telling me it lowers LP. So fine, we'll repeat it if you're on a PCSK9 inhibitor, but I know of no other reason to repeat it. People are now saying, hey, as you go into menopause, Apolitol A can go up. Estrogen is a factor that can keep apolitical A reduced. So it can go up as you lose estrogen. Usually it's a 5mg per deciliter variant. So it's in Irrelevant. There is some variability in how it changes. Also some people go up a little higher. But I will tell you this. It almost never takes somebody who's in a low risk LP zone and puts them in the high. You may go into the lower parts of the intermediate LP zone for which there's nothing we're doing about it now, but lowering APOB anyway. And if you're a nightmare LP and you go on estrogen and it goes up a little bit, you're still a nightmare lp. So you haven't worsened anything. So there's that little thing. Never ever check LP why a patient is sick. APO little A is produced in excess in acute situations. So. And a really inflammatory disease or any. I got a sore throat. Don't be chill can help you. Little A. Yeah. Have you.

Have you seen. Gone up with people post Covid or with COVID or is that something.

I don't have that much experience. There's a lot of leather showing that which I have not taken the time to read. So there are interactions there and the earth immune system and a lot of interest into the research on LP in that situation.

So briefly, like the APOE 4. Like what?

So I believe everybody ought to genotype themselves for E4. And there's two reasons. One, whether you have one or two E4s, you are at increased risk for cognitive impairment and not only Alzheimer's disease, but Lewy Body dementia, frontotemporal dementia, believe it or not. E4, if you're the kid who's going to play football, if you're going into the military and you get concussed more than once, way more neurologic impairment down the road. We're almost at the point where if you carry an E4 gene, your kids should not play ice hockey or football or some other rugby or even soccer where the ball is hitting, go into some other sport, take up golf or something. There's information emerging on that if you have a stroke and you're in E4, the recovery can be a lot worse than if you're not E4. So there are good reasons to know that. So now you're not going to absolutely get dementia even if you have E44. About 80% of them will be going down, but some won't. And just because you have E3, E3 doesn't mean you can't get cognitive impairment and you're at less rest. For sure, E2 seems to be protective against the standard types of Alzheimer's disease, but there is a type of dementia, even E2 is rarely associated with such angioate deposits in the wall of your artery. Kind of rare angioid arteriopathy, it's called. So. But most people are not going to have that.

Is that like. Because I've had a patient with the beta amyloid. They actually had a vasculop with a beta amyloid. And they actually.

Yeah, that's what it is.

Okay. Yeah. Actually, I've had one patient with that. Yeah.

Yeah. So that's something you have to watch for. E2 might be a little more. So if you have the preventive neurologist I work with, V2, they're going to scan your MRI looking for certain deposits that we tell them, oh my God, you're getting that type of amyloid angiopathy. So it would be rare. But if you're a preventive neurologist is the type of stuff you watch for very carefully when you're counseling people on the results. Now, listen, E4 also puts you at high risk for hypercholesterolemia, hyper beta lipoprotein emia. So they're at increased risk for heart disease. And one of the reasons is, and I'm the lead author of the article that brought this to light, while at HDL Labs, we had 600,000 sterile specimens that we could look at absorption of sterols in the blood and everything. And we showed that the major causes of hyperabsorption of cholesterol that you can predict ahead of time is carrying an E4 gene or being a menopausal women. So again, loss of estrogen is involved, going from a normal absorptive state to a hyper absorptive absorption of cholesterol. I'm not talking fatty acids or other lipids, specifically steroids. So kind of interesting. So APOE gives you a lot of stuff. Now the people say, oh my God, you don't want to know you're going to dementia because there's nothing you can do about it. That was true about 15, 20 years ago. But I can tell you there have been Alzheimer's disease clinics that for 20 years have been measuring the APOE 4 Genesis because they believe there's a lot of stuff you can do if you get the E4s early in life with lifestyle and even certain supplemental, even prescription medicine nowadays that would prevent the development of Alzheimer's disease. One of the things thought to be causal for Alzheimer's too is APOB. So preventive neurologists treat APOB with an aggressive passion in their E4 carriers. There's other machinations you have to watch There, but you do. So if you knew you had an E4 if you either should really assume they're a hyper absorber of cholesterol. And maybe just start with zeti if you need a drug to lower apob. In the past we were all told well E4s don't respond to statins. Of course not, because there's so many are hyper absorbers of cholesterol which identifies a group of statin hyporesponders. So if you know ahead of time you're a hyper responder the statin should not be your first APOB lowering drug ezetimibe should be.

So maybe an E4 with high cholesterol.

I'm telling you, E4 and high HDL cholesterol just starts adrenaline if you need.

A drug to lower apob because HDL and LDL absorb together like you said previously, they're probably enter a site when.

It hyper absorbs cholesterol, it has to get rid of it. So it's two, three options. The intestine overloader when absorbed cholesterol can stick it in a column micron, ship it out, lipidate an HDL particle, take it out of here. HDL or resecreted to the gut via ABCG5 G8 transporter. But you have to have functional G5G. Most hyper absorbers that escape mechanism is broken genetically. So once cholesterol gets in, they can't get rid of it. And that's why there's hyper absorption of cholesterol to begin with. If you were doing genetic analysis on people, if you're doing it day one and you see a loss of function of ABC G5 or G8 those are the sterile exporter membrane transporters. You know you're going to be a hybrid. It's by the way if you have just heterozygous fhe and you now have hyperabsorption, you check G5 G8, you've identified another G, you're a compound heterozygote. You got two genes driving your LDL cholesterol and one of the therapies better be ezetimibe in such a patient. So there are interesting. That's why I believe sterile testing for everybody can really help you. Especially a practice like yourselves where you're looking at things to do precision medicine day one knowing hypersynthesizer hyperabsorber. If you get to the point that I need pharmacological treatment, you know, really smartly. Ezetimibe or statin benadoic acid another Interesting caveat to all of that. If I went with a statin monotherapy in everybody, God forbid a hyper absorber statins can worsen the absorption of cholesterol because by inhibiting synthesis the body genes say oh my God, we're not synthesizing cholesterol. They turn on the absorption genes more. So that kind of information can tell. In such a case if you're going to especially use a potent statin, you might day one go with baby statin and ezetimibe and you'll get way more apob lowering. So and many lipidologists. Now granted most lipidologists people walking into their office with scary apobs they don't start monotherapy anymore. It's almost all statinized by day one. And I'll tell you, even most lipidologists are not measuring the sterile markers because of the complexity of being associated with Boston Heart Lab. Most of them don't know about even a direct to consumer. Your patient has to do that now it takes a month to get their for them to do that and you get the results back, you know.

Understood. Yeah.

Roadblocks. So but you can see as you get into even better understanding absorption you might make a little better therapeutic decisions. Hyper absorbers, that's where you should avoid the phytosterol supplements like they're the plague because not only will you absorb cholesterol, you'll start absorbing campestrel cytosterol and above a certain threshold in the plasma they are toxic to your tissues, you know. So that's why I think even post therapy of measuring of sterols provides information but only if you understand that information. And luckily all you have to do is read my two chapters in therapeutic lipidology. Just totally deal with the intestine.

There you go. Sounds great. So I really appreciate your time dropping out here. You've had a great conversation if people want to know more about you. What are you doing? What are you know, I know you said you're like in the, you know, in a great situation, you're not really retired. Like where can people find more about you? Another question is what are you doing? What's your next thing? Are you like, like just in cruise mode, you know.

No, there's never a cruise mode methodology because I have to keep relearning what I used to think because it keeps changing and we're not. So I had to rethink the whole HDL hypothesis. We got into a little bit of that today so I had to re rethink the whole reverse Cholesterol transport process. I didn't know anything about cholesterol absorption until ezetimibe came around and I was introduced to the world experts who were studying that because I was in on the ground four with the AT too. So there's always much to learn and relearn. But for people who the best way to see what I'm thinking and keep on top of what I'm reading is follow me on Twitter @doctor lipid. It's not at Tom base Spring. Maybe you could put in a search thing. What's tab springs, rlippi, Twitter, whatever they call them you'd find at Dr. Lippy. If you're a healthcare professional, that doesn't necessarily mean MD or doctor, but it could be you're a PhD researching lipids, you're a nurse practitioner, an RN and LPN, a nutritionist, a lipid scientist, or you know, you can ask to connect with me through LinkedIn. I try and keep it to healthcare professionals then because I think there's a little better understanding, I can get a little deeper. And LinkedIn allows me to use a lot more words than Twitter.

This is true.

Twitter is all graphics, which is why people really love me. Because even if you you read the long paragraphs, seeing a picture sometimes makes it a lot more than this. So now look on Twitter, my tweets, you can comment on my tweets and if it's a positive tweet, I'm either going to like it or I may even answer what you say to hey, I want you to think a little bit. You can direct message me at Twitter, but it better be good, better be a serious question. Don't message me and tell me I'm an idiot. That'll get you nowhere blocked, right? You won't be getting much more data. And of course LinkedIn. Any professional who messages me there, I will absolutely answer. If not call. So that's a good way. And look, I don't give out my email address. If you message me, I might. There are patients who are detectives and they somehow find out my email somewhere on the dark Internet. It's out there and they even only a few of them. Thank God I found my cell phone number. Normally my cell phone, if I don't recognize it, I don't answer it. You would then have to leave a voicemail and if it's intelligent then I might respond. But if I don't see it's Aaron Hartman calling me because he's in my yeah list now, I'm probably not going to answer the cell phone but they get it and if they leave an intelligent voicemail and too often it's somebody who it's a lipid nightmare who I know needs desperate help. I know they this is help they can't get from their local doctor. Maybe they've been in trouble. I may interface a little bit. I'm not going to become their doctor. I don't have to send but I can point them and direction. So that's the best way. You know I I still publish the Oddball article but if I did it would be tweeted. I actually get around through podcasts nowadays. This is why I jumped at this opportunity and really so because it was an in person which is way more fun than a zoom call where you still see me but it's sort of nar and or it's a phone thing where you only have to listen to me and God forbid even Peter in the initial eight podcasts we did slide notes with a lot of graphics so that helps. So this has been great fun. So that's the way. And even if you google me or want any of the search engines, I've done so many podcasts now, some are a lot better than others. I think this is going to be a real good one. There have been others. I just did with Simon Hill. It was two hours alone on LP Middle A. So that's like an ATEA podcast. Down and dirty. The last thing. Where am I going? Apart from still trying to help any doctor I can better understand run of the mill or even rare lipid disorders. Peter 2 years ago did a podcast with one of lipidologies. Superb world experts on everything but especially high density lipoproteins. Dan Raider. I've known Dan for 30 years for God's sakes. One of my first mentors, he was Philly. I was North Jersey. We weren't that far before we met at a lot of meetings and stuff. So Peter finishes podcast by Dan where are you going in lipids? What's left? I mean we pretty much therapeutically have what we need for the vast majority of non genetic nightmares nowadays. So where else are we going? Dan was very perceptive, as he always is. He goes, it's the brain. With this emerging incidence of cognitive and degenerative brain diseases, virtually every one of them has lipids and part of the etiology of them. We better start discovering how lipids are manufactured and transported in the brain. And if there are lipoproteins in the brain, what are they? What do they do in the brain? Do lipoproteins have anything to do with amyloid or tau. And the more we understand, if we understood that we might understand pharmacological approaches to correcting pathological brain alterations in lipoproteins.

That would be interesting.

So that's where I'm going now. I'm fortunate enough to work with a world class preventive neurologists in the practice I am who was trained at the Cornell Cognitive Impairment center where now I understand takes three years to get an appointment to trained under Richard Isaacson, the forefather of preventive neurology who now has left Cornell, runs his own Alzheimer's clinic down in Florida. Google him. CNN did a couple of nice interviews with him over the last few weeks and she trained under him. I've known Richard Isaacson. Peter introduced me to him I would say at least 10 years ago. And we started discovering lipidology in the brain together on a lot of things. So some of the things I now believe about the brain and Kellyanne or prevent neotis or preventive neurologist and he recognizes there are markers you can actually measure in the blood nowadays that give you some insight to the brain. And they sure as hell want to know if you have APOE 4 because they want to know when you're 20 years old. And believe me, if you see the interview he did with Dr. Gupta on CNN you will see some of their therapeutic approaches. And even when they take people with Alzheimer's now disease they actually improve it a little bit without using the big new drugs that you can prescribe that people like him will use here and there. But there are simpler things you can use. Biotelliacal beam lowering is one of those. And we'll wrap this up and invite me back another time when you prescribe a statin. Statins not only inhibit cholesterol synthesis in the liver but also in the brain. Cholesterol. The brain has one supply of cholesterol. It makes it, it cannot get it from the plasma. That's why you can have an HDL cholesterol of 5 or an LDL cholesterol of 10 in your plasma and have no brain manifestations in that because no brain lipoprotein enters the blood brain barrier shares cholesterol with the brain. So the brain has to de novo synthesize all its cholesterol.

Would that be the reason? Would that be the reason why certain like the water soluble versus the fat soluble statins while certain ones might have more of a cognitive effect thought at.

One time now known to be irrelevant. We now know if you're going to prescribe a statin once it's in steady state, all statins get into the brain and have the ability to inhibit cholesterol synthesis. Now, for Alzheimer's disease, some degree of lowering cholesterol synthesis is very desirable. What is not probably desirable is over suppression of cholesterol synthesis in the brain at a certain point. If you're suppressing cholesterol synthesis with a steroid statin. And look, if, even if you look at the statin data, they're neutral on cognition, they never worsen it. And a few people, they might even improve it. But it's not randomized controlled trials where we have that data. But you can't hurt anybody with a statin. But we think maybe there's a minority of patients you can. How about the few people who get brain fog when you do prescribe? They don't know the statistics. Could they be the ones that day one you're over suppressing cholesterol synthesis to show you how much cholesterol synthesis is desired and preserved in the brain. Cholesterol molecule half life in the plasma is three to five days gone. Either become a bile acid or out through fecal cholesterol in the brain, the half life is five years. That means that sub cholesterol molecules last 35 years. Rule of sevens with half lives. So that means once a brain synthesizes cholesterol molecule, it reuses it. Reuses it, reuses it. It doesn't excrete it and get rid of it like we do in the periphery of what the liver intestine can do. So that's why it doesn't need cholesterol from the plasma, because it makes its own, but now artificially, there's probably a certain point at which you don't want to stop synthesis. No other lipid drug affects lipid synthesis in the brain. So you don't have that worry with any other classes.

Do you know if you were to suppress the lipid synthesis for like 10 years and then you stop the medication, does that like.

No, we don't know. All we know now is there have been people who have studied biomarkers of cholesterol synthesis and the primary one is desmosterol.

Okay.

There are two pathways that cells synthesize cholesterol. One goes through desmostral, one goes through methosterol. If you're doing the Boston Heart, you get the concentrations of both of those methosterol pretty much tells you about synthesis in the peripheral cells. Desmostral is brain or steroidogenic tissue. They Use the desmostral path, the nice study that you can measure desmosterone in the cerebral spinal fluid. It correlates extremely well with plasma desmosterone. Ergo measuring plasma desmostral tells you what's going on in the brain because where does the CSF get desmostral from the brain interstitial tissue. So desmosterol when it's low in the cerebral spinal fluid or the plasma associated with people who develop cognitive impairment and Alzheimer's disease. So that is pretty serious provocative hypothesis generating information that maybe we ought to look at desmostral and people were prescribing statins to it. If we suppress it too much, maybe that's where you back up the stanol and lower apob with drugs that do nothing in the brain, which is every other lipid modulation.

That's actually intriguing. That could almost be another conversation.

It is and I told you we just did a two hour conversation on the Proof with Simon Hill in August. He is so zoom. He's going to interview me and Kellyanne Otis, the world's second best, maybe as good as Richard Isaacson, preventive neurologist who know and me and we're going to discuss lipids in the brain and degenerative brain. And there will be a lot in.

This mastero that's in August.

There's one other sterile metabolite that if the brain has to get rid of cholesterol because extra cholesterol in the brain is associated with Alzheimer's disease, you might want to know is there over synthesis of cholesterol in the brain. Now if neurons over synthesize cholesterol they have to get rid of it. Otherwise the cholesterol will crystallize and kill the neurons. Not advisable to kill neurons. The neuron is the only brain cell that carries an enzyme that the liver carries. The only two tissues that carry an enzyme that converts cholesterol into a hydrophilic oxysterol. Now what are the oxy sterols that the liver produces? Bile acids which go right to the bile duct and you get rid of them. So changing cholesterol to a bile acid really a hydroxy sterol gets excreted. The brain can convert cholesterol, which is a kind of hydrophobic molecule that cannot pass through the blood brain barrier and escape to a hydrophilic lipid called 24S hydroxycholesterol. It's a bile acid that the brain produces and the brain only changes cholesterol to that bile acid when it wants to get rid of it. Because it has a hydroxy group on both ends ends, it's sort of. It can pass right through the blood brain barrier, right into plasma where it jumps on the first light bulb protein, be it an HDL or an LDL or a vle, it comes by, they return it to the liver, which converts it to a bile acid and you get rid of it. So that is mother nature's way of brain getting rid of cholesterol, change it to an oxysterol, which will make its way back to the liver. So if we could measure 24s hydroxycholesterol and it's up in the plasma, you know, there's too much cholesterol in my brain and that might suggest a therapy. If it's down, you don't find it in the blood. And by the way, almost all 24S hydroxycholesterol in the plasma has a brain origin. Then you might say, wow, if I'm not finding it, is there hyposynthesis of cholesterol in the brain? And by the way, when you do autopsy brain Alzheimer's diseases, there is the low cholesterol.

Interesting.

Well, thank you. There's so much.

Yeah, thanks for the answer. That's super cool. Again, thanks for coming out to our office today. Thanks for your time. Really super appreciate it. Rlippid at Twitter, you sound like you're super approachable. That's actually how I got. Actually I got introduced to you from a local colleague, but I actually got a hold of you through just reaching out via LinkedIn. So again, thank you for your time. Thank you for your wisdom and your insight. It's been really super helpful.

I've had so much fun chatting with you and maybe we can do it again on one of these subsections.

Yeah, I know. It's like, it's almost like because we, we're starting another conversation which I think is going to take us another two, two to three hours, so.

Oh, yeah, no, you look, I have to get way more into the HDLs. You want to get into the triglyceride pathology. So another day.

Fair enough. Great. Well, thanks a lot for your time. I really super appreciate it.