Ep. 495 Are You At Risk for Dementia? – The Most Overlooked Cholesterol Marker You Need to Know with Dr. Thomas Dayspring

We have the second episode in a series of conversations with Dr. Thomas Dayspring today. 

The esteemed Dr. Dayspring is an expert on internal medicine and clinical lipidology. In this episode, we continue with our last conversation, diving into Lp(a) and the influences of gender, race, and menopause. We explain how estrogen is a PCSK9 inhibitor and explore the significance of brain health and risks for dementia. We tackle cholesterol synthesis and discuss the side effects of statins, clarifying who is most susceptible to their impact on the brain. We also examine the significance of the desmosterol biomarker, highlighting the level to aim for, especially when making decisions regarding cholesterol medications, and we answer one question from a listener. 

You may want to listen to this insightful conversation with the renowned Dr. Dayspring more than once. He has graciously agreed to return and film additional episodes, where we will dive into more questions from listeners. 

IN THIS EPISODE, YOU WILL LEARN:

• Why Lp(a) is like a wolf in sheep's clothing for many individuals

• How Lp(a) levels are higher in African Americans and women, especially after menopause 

• Dr. Dayspring highlights that Lp(a) particles are even more pro-inflammatory than LDL particles

• How PCSK9 inhibitors are the only drugs that significantly reduce Lp(a)

• Why do women have a higher risk of dementia than men?

• Dr. Dayspring explains ApoE as the key lipoprotein for brain cholesterol transport.

• How statins cross the blood-brain barrier to lower brain cholesterol

• Why desmosterol levels matter

• New therapies that can lower ApoB and Lp(a)

• Why imaging is essential for menopausal women with elevated ApoB and Lp(a)

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“Lp(a) is an LDL particle and is part of the superfamily of LDL particles.”

– Dr. Thomas Dayspring

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Connect with Dr. Thomas Dayspring

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Journal Article: Atherosclerosis: Non-genetic influences on lipoprotein(a) concentrations 

Journal of the American Heart Association: Trajectories of Blood Lipid Profiles in Midlife Women: Does Menopause Matter? 

Transcript:

Cynthia Thurlow: [00:00:02] Welcome to Everyday Wellness Podcast. I'm your host, Nurse Practitioner Cynthia Thurlow. This podcast is designed to educate, empower and inspire you to achieve your health and wellness goals. My goal and intent is to provide you with the best content and conversations from leaders in the health and wellness industry each week and impact over a million lives. 

[00:00:29] Today is the second in a series of conversations with Dr. Tom Dayspring. As many of you already know, he is an esteemed expert on not only internal medicine but also clinical lipidology and today we are continuing our conversation, speaking at length about Lp(a) and the influence of gender, race and menopause, how estrogen is a PCSK9 inhibitor, the importance of brain health as well as risk for dementia, statin side effects and who is most susceptible to the brain effects of statins, the physiology of cholesterol synthesis, the significance of the biomarker desmosterol and levels to aim for, especially if you are making decisions about cholesterol medications and we tied in one listener question. 

[00:01:22] Dr. Dayspring graciously will be coming back to film an entire episode or episodes on diving into listeners questions. Again, you'll probably want to listen to this conversation more than once. 

[00:01:38] Now, before we tie up ApoB, let's talk about goals. So, from your perspective, based on the data, based on your clinical experience, if someone does not have heart disease, does not have diabetes or any other diabetes adjacent diagnoses, where do you like to see their ApoB?

Dr. Thomas Dayspring: [00:01:55] Yeah, it's pretty easy. For years we've had the LDL cholesterol goals and a little bit lately something we didn't talk about non-HDL cholesterol which is really your ApoB cholesterol. Total cholesterol minus your HDL cholesterol is your ApoB cholesterol. It's actually a little bit-- [crosstalk] 

Cynthia Thurlow: [00:02:11] Poor man's. 

Dr. Thomas Dayspring: [00:02:12] Yeah, the poor man's ApoB. It's a better guesstimate of ApoB than is the LDL cholesterol. The NLA last year put out an exquisite treatise on this or so letting you know that. But if you read the fine print, they will tell you ApoB is even better than non-HDL cholesterol. But non-HDL cholesterol is free. If you had to pay cash for it's a $20 cash, that it's going to bankrupt too many people. But many doctors don't know what ApoB is, so patients have to get into an argument with their docs on what testing they want and that's never fun. 

[00:02:45] The goals for LDL cholesterol pretty much came down to in a primary prevention setting, if you could reduce the LDL cholesterol to what is called the 20th percentile population cut point, that would mean if your LDL-C is-- and nowadays that turns out to be around 70, that 80% of people are worse than you, but 20% of people actually have a better LDL-C. And obviously, the higher it is, the more likely the heart disease. So that would tell you if we could get you to the 20th percentile in a primary prevention setting, we're probably doing pretty good. 

[00:03:21] Unless you have a multitude of other risk factors which would be an indication to lower it even more as we would if you were a stent survivor or an MI survivor, where we probably want to bring it down. The current guidelines for that type of patient say make the LDL-C 55 mg. So that's you're approaching under the fifth percentile, closer to the second percentile. If I could just do some reverse engineering, why wouldn't I make your ApoB at the 20th percentile in a primary prevention setting and a second percentile in a secondary prevention setting. 

[00:03:57] So, with the ApoB, it's like about 60 for primary prevention and its 45 in a secondary prevention setting. Now, albeit known, there is zero harm in making an LDL-C 30 or an ApoB 30. But if you got it down to the 40 level or so ApoB in a secondary prevention setting, maybe to the 60, that's where you have to be. And there's very interesting Dan Sofer, a recent president in the NLA buddy of mine, we've done a couple of podcasts together recently. [crosstalk] into a study I didn't know or forgotten about it. It was one of the PCSK9 inhibitors, but it was one of these intravascular ultrasound tests where they're actually measuring plaque volume.

Cynthia Thurlow: [00:04:40] IBEX, yeah.

Dr. Thomas Dayspring: [00:04:41] And so they were putting people on the PCSK9 inhibitor, neuron statins with the PCSK9 inhibitor, at what level of lowering did they have to get to reduce MACE? And if you really were interested in regression of your plaque, what levels did they have to be? And to just summarize that very quickly, he's got an elegant graph that shows it. Once you started bringing the LDL cholesterol down below 70, you really started to do away with heart attacks and stents and things. But for those who just like we want cancers out of our body with those who would want the plaque to disappear. Not there's a lot of evidence showing you have to do that, but it sort of looks cool if you do a repeat image, “God, my plaque is gone. Thank you, doctor.” You really have to get it down to that under 40 mg/dL or so. So why not?

[00:05:32] Since there's no adverse side effects, dropping something down to 60 to 40 to 20. Why not? So, those are the goals that I would suggest for those therapies quickly. The last thing if we're going to digress from lipoproteins. Lipoproteins traffic cholesterol, the ApoB particles, the VLDLs and chylomicrons bring energy triglycerides to your muscles or for storage of your adipocytes. Any cholesterol that's in a Chylo absorbed cholesterol or any cholesterol in a VLDL put there by the liver is immediately returned to the liver. They do not deliver cholesterol to any cell in your body. LDLs, some of which come from as a VLDL loses trigs, it shrinks and becomes an LDL. But about 40% of your LDLs deliver just made de novo and secrete it then. But people are shocked to hear because we've been taught erroneously that LDLs are delivering that cholesterol. No, they're not. 

[00:06:30] LDLs are in plasma for one reason and here's why they float around for several days and they don't get cleared in minutes, like the VLDLs and chylos. HDLs pull unwanted cholesterol out of any cell. It wants to get rid of it so the cholesterol doesn't get toxic and crystallize and kill the cell. Cells can pump out unwanted cholesterol, but the only place they can pump it to is a little baby HDL that accepts it. And before you know it, the HDL fills up and gets big. Now, the HDL could bring it back to the liver, bring it back to your gut, transintestinal cholesterol efflux. It could actually deliver it to your steroidogenic tissue. So that is one of the lipoproteins that can bring cholesterol to those gonads and adrenal cortex. But 50% of the cholesterol end in HDL using a lipid transfer protein, CETP, cholesteryl ester transfer protein goes from the HDL to the LDL.

[00:07:25] So, the LDL that the liver sent out is all of a sudden carrying more cholesterol, but it's returning it to the liver. It's like the HDL says, “Yo, LDL, take my cholesterol, please. Save me the trip back to the liver. If you take my cholesterol, I'll get smaller and I can go back and gather more cholesterol.” So that's some interesting physiology there. So, LDLs are an integrate part of the reverse cholesterol transport system. Then HDL brings it back. That's direct RCT. If an ApoB and most of them or LDLs bring it back that's indirect reverse cholesterol transport. Total RCT is the sum of direct and indirect. I hate to call it a modern concept because I've known about it for about 15-20 years, but most people are still totally- they all think HDLs are the only purveyors of reverse cholesterol transport. They work in tandem. They like each other, these particles and the other.

Cynthia Thurlow: [00:08:19] I love it. It's all about balance in our bodies. 

Dr. Thomas Dayspring: [00:08:22] Totally is. So, this is why again, when you're lowering LDL cholesterol, you are enhancing reverse cholesterol transport through the mechanisms we've described. And that's good because then the liver can put it in your bowel, send it out, make it a bile salt, which you can excrete fecally if you don't want it, or the liver can use itself, or the liver can just put a little bit more in the next VLDL and LDL going out. And the reason cholesterol are in those particles is they provide some structural-- It makes the particles spherical. And a spherical particle can gather a lot more lipids than a little flatbed particle. So, cholesterol is doing structural purposes in the ApoB particles. It's serving no purpose other than that. 

Cynthia Thurlow: [00:09:04] It's so fascinating. I would love to touch on Lp(a) because I think this is such an important conversation. We know it is seven to eight times more atherogenic than an LDL. And yet what is everyone, I say everyone-- A lot of people that are not in the know choose to focus on the LDL, but yet Lp(a) is what I like to think of, it's like the wolf in sheep’s clothing for a lot of individuals.

Dr. Thomas Dayspring: [00:09:28] That's an adequate explanation. So Lp(a) is an LDL particle. So, it's part of the super family of LDL particles. But it's the black cousin in certain cases because it can do, as Cynthia just said, it could be a bad news player, far worse than an LDL particle for particle. So, an Lp(a) is an LDL particle that your liver made and was going to shoot out as it does. Remember, 40% of your LDLs came right out of the liver. But if you inherited the wrong genes, your protein making apparatus, the gene tells them to make a protein you should not be manufacturing apoprotein (a). And that little a, once it's produced has a high affinity. It jumps right onto the primordial LDL particle in the liver, converting an LDL into what's called an Lp(a) particle and then that gets secreted.

[00:10:23] Now, most of us who don't inherit those genes make a trivial amount of apoprotein (a). So, you may have a few LDL particles, but they don't raise any level of cardiovascular risk. When you are making too much apo(a), you're generating too many of these Lp(a) particles and then bad new stuff can start to happen. So that's what Lp(a) particle is. So, why is it worse than an LDL? Well, that apo(a) protein, it's sort of an interesting protein like ApoB, it's quite big. It comes in different sizes, small and big. But the bigger ApoA can even exceed ApoB in molecular weight. And it's a bunch of little curlicues, protein loops that are called kringles. So, if you read about Lp(a), you hear kringles, those are the segments of what all of the kringles together make up the entire apoprotein (a). 

[00:11:12] But a couple of those kringles have a high affinity to trap and bind to what we call oxidized lipids, specifically oxidized phospholipids. Firemen listening, no, oxidation is what creates fires. So, you have a lipoprotein that's on fire. Oxidized lipids are particularly destructive to any tissue. Oxidized or other molecules are bad news too. But we're talking lipids today. So, you never want an oxidized lipid moiety to enter your artery wall, which is going to have inflammation going on, once the ApoB particle crashes now it's going to be worse inflammation. So, they're incredibly proinflammatory particles. Previously, we used to think it had homology to plasminogen, antifibrinolytic thing, but that's a lot of belief nowadays. But they do know it is a platelet aggravator. It causes dysfunctional platelets. So, you have hypercoagulability due to platelet dysfunction. 

Cynthia Thurlow: [00:12:07] Like, it's sticky. 

Dr. Thomas Dayspring: [00:12:07] Yeah. So, not only do you have this particle that's carrying the wrong type of lipids, it's screwing up your coagulation system, specifically your platelets, also may be adversely affecting tissue factor which is part of the coagulation cascade also. So, do you think of a worse whammy for atherosclerosis, which is not only in part cholesterol plaque, but it's plaque rupture with thromboses. So, now you got something generating highly inflamed plaque that is prone to rupture. And now once you do rupture, your platelets are going to really cause the thrombus you don't want in the lumen of your artery. 

[00:12:44] So, bad news player, you did mention before, like 20% of people having it, but there's some very interesting data that came out in the last year from something called the Horizon trial, which is places that do a lot of screening for Lp(a) and just so they could warn people, you have high yield, go see your doctor please. But they have a big database now, so 20% is a generalization. In African-Americans it's upwards of 50% and in women, it's 30%. It's worse than men, just like heart disease seems to be worse and it has nothing to do with Lp(a). But there's just one of these gender things that, and I should have mentioned it with the menopause, when you lose estrogen, your apoprotein(a) concentration goes up. So, whatever your Lp(a) was, it's going to be higher after menopause. 

[00:13:33] Now, if it was low, it's going to be a little higher, but not terrible. If you're in the intermediate risk range, some of the women are going to bump to the high-risk range. If you're already in the high-risk range now you're in a worse high-risk range. So, another thing, in general, we're told you don't have to ever repeat Lp(a) again once you get it once per lifetime. But there are certain situations that maybe you should. I think most would agree at menopause, it's time to reevaluate Lp(a), no matter what it was to begin with itself. So, back to menopause a little bit. So, Lp(a)-- Cynthia mentioned it's many, many times more atherogenic particle for particle than an LDL particle. But this is counterbalanced by another thing because you have infinitely more regular LDL particles who had L apo(a) attached to it then you do have Lp(a) particles. 

[00:14:26] For example, a normal Lp(a) particle count is under 50 nmol/L). Most have 10 or 15 nmol/L. So, a normal physiologic 20th percentile LDL particle is about 1000 nmol/L. So, but let's look at the people with high Lp(a). High Lp(a) is 150 nmol/L. That's a high risk Lp(a). So, if you had an Lp(a) of 150, 200, 250, it's still an extreme minority particle compared to the LDLs that are floating around. So, they both could kill you. So, never ignore LDL particles at the expense of Lp(a). But right now, with a little bit of exception, which we can get into if you want to, we cannot reduce Lp(a) concentrations. We don't even have Level 1 evidence that reducing it will save lives. 

[00:15:21] We all believe it will, but we're waiting for the randomized control trial to prove that just yet. And you can't debate that lowering ApoB, the regular LDL particles will save lives or so. So, right now the guideline recommended treatment is for the high Lp(a) patients to get ApoB is LDL cholesterol, non-HDL cholesterol to go. Tom Dayspring says get ApoB to go, the better marker. And the practices I advise, if you have very high Lp(a), we would be shooting for that ApoB well under 40. There's a little evidence from the ODYSSEY trial, which is a PCSK9, that the best outcomes were in the ACS survivors who also had high Lp(a) and they were put on in that case, alirocumab. But they're all the same is what they do. Once you hit an ApoB about 30, that's where you got the best results. 

[00:16:16] Since there's no harm lowering ApoB to 30 with a PCSK9 inhibitor, if I could, why wouldn't I get to that? You might not get that without a PCSK9 inhibitor, but it's something for anybody with very high risk Lp(a) to think about. And if you cannot get a third-party payer to cover a PCSK9, now if you don't already have heart disease, they say, “No, go have a heart attack, then we'll cry risk.” So, please, and this is an individual decision, I bet, if I told somebody you had a terminal cancer, but here's a drug that would cure for you, but it's going to cost you $6,000 a year, everybody would pay for it. It's your choice whether you can afford $6,000 a year. Some can, some can't and I understand that, but I think a patient has to be told about that. 

[00:17:02] If we can't get coverage for it. Is there any chance you could generate that sort of money or maybe use some of these accessory drug plans that might help you out with it a little bit? So, whatever it's lowering, never think-- always look at Lp(a) in conjunction with the regular LDL particles. And the last part on that little thing, because you Google it, you're going to find, “Oh, my God. If your doctor puts you on a statin, it can in some cases, not everyone raise Lp(a) a little bit.” So, yeah, so going back to the study I just mentioned, if your Lp(a) is 200, all right, it goes up anywhere from 5 to 20%, it goes to 250, but your regular LDL particle count drops by the thousands. 

[00:17:49] So, yeah, you're giving yourself a few more of the really bad guys, but you're totally eradicating the other contributors. And this is why every guideline, they recommend statins as the first line therapy. And if you didn't get the goal, then they'd be telling you to add whatever to it. So, ignore the nonsense that you can't use a statin because it might increase Lp(a). First of all, most people who don't have Lp(a), who cares? You're normal. You're going to still be normal. It's not like it's sending you into this stratospheric range, 

Cynthia Thurlow: [00:18:21] Right? It's like not statistically significant. So, two things. Number one, I was reading a study which is sitting on my lap that was looking at reduction of Lp(a) with transdermal oral estrogen or Estradiol, actually. And what was interesting was when it was looking at this cohort group, estrogen does lower Lp(a) used in HRT. It appears that oral, not surprising, is a little bit superior to transdermal. But, you know, looking at--[crosstalk] 

Dr. Thomas Dayspring: [00:18:47] [crosstalk] best effect getting into the liver where these lipoproteins are made with transdermal, not so readily.

Cynthia Thurlow: [00:18:54] And it's very clear it's estradiol. So, it's the bioidentical. We're not talking about conjugated equine estrogen. 

Dr. Thomas Dayspring: [00:19:00] [crosstalk] using horse urine-- [crosstalk] 

Cynthia Thurlow: [00:19:02] Do you know?

Dr. Thomas Dayspring: [00:19:03] Anymore, probably still the number one prescribed. I don't know. 

Cynthia Thurlow: [00:19:05] No, no, it's interesting. I met someone socially and she, for whatever reason, decided to share her HRT regimen with me. And I was like, Premarin? They will put you on Premarin. I was like, “Why?” 

Dr. Thomas Dayspring: [00:19:16] 40 types of different estrogen, right? 

Cynthia Thurlow: [00:19:18] And it's equine estrogen. It's not bioidentical. So, I just mentioned that because I think that's important. But that is one of the limiting issues that these PCSK9 inhibitors because people will come into programs and they'll share with me. “Oh, well, I didn't want to take a statin, so the only other option I had to get my lipids to goal was Repatha. But Repatha costs X number X thousands of dollars a year and like trying to make decisions and I know that isn't per se.” So, my hope is at some point it's going to come off patent just like ezetimibe did, then that was very expensive years ago. 

Dr. Thomas Dayspring: [00:19:51] It’s a [unintelligible [00:19:53] tide. So, they're difficult to make.

Cynthia Thurlow: [00:19:58] Yeah. 

Dr. Thomas Dayspring: [00:19:58] So, will anybody ever want to make a generic. It has a niched indication. So, it'll be a long while. And I believe the first drug that's under investigation, which if we're lucky we'll get that on next year, it should have been this year. It's been postponed. They're only studying the nightmare. So, it only may get a secondary prevention indication, not primary. And if you think PCSK9 inhibitors were expensive when they first came out, 15 grand a year. This is for even more niched. 

Cynthia Thurlow: [00:20:26] Wow. 

Dr. Thomas Dayspring: [00:20:26] I don't know what it might cost, other than for the billionaires, it might be off label use, isn't going to happen. 

Cynthia Thurlow: [00:20:34] Yeah. I mean, I think that's-- [crosstalk]

Dr. Thomas Dayspring: [00:20:35] I don't know that. 

Cynthia Thurlow: [00:20:36] Yeah, I mean those are the concerns that I have just from a perspective of as a clinician, the affordability is an issue like if people can't pay their mortgage because they are-- [crosstalk].

Dr. Thomas Dayspring: [00:20:46] Say anything bad, if you can't afford it, you can't afford it. I can't afford a yacht. I'm going to sail on this.

Cynthia Thurlow: [00:20:51] [laughs] Not in my budget. 

Dr. Thomas Dayspring: [00:20:53] Not going to happen. 

Cynthia Thurlow: [00:20:54] Yeah, absolutely. 

Dr. Thomas Dayspring: [00:20:56] The last thing, but again, there's just so much to mention about menopause but we did say the Lp(a) goes up and if estrogen is a PCSK9 inhibitor, we do know PCSK9 inhibitor is the only on the market drug that can lower Lp(a). And we do know estrogen lowers Lp(a) a little bit. In fact, in that first trial that put the scare of, God, into us that hormonal therapy Prempro was causing heart attacks was in the Hirsch trial where they rounded up women with severe coronary disease, Prempro versus placebo. And it looks like “Oh, my God, they had a year to get worse.” Except for the people who had high Lp(a), they had a less event. So, there was a little hypothesis generating data back then there. And last but not least, how does PCSK9 inhibitors reduce apoprotein(a)?

[00:21:48] It hasn't been totally worked out, but it looks like it either inhibits the synthesis of apoprotein(a) or it prevents the marriage of Apo(a) that got produced to the LDL particle. It may be a chaperone protein that it gets inhibited. So, at the end of the day you'll have less Lp(a). So, I'm not sure what the estrogen story is. So, estrogen inhibits PCSK9. Does it inhibit Apo(a) synthesis or the marriage of apo(a) to the LDL primordial LDL particle. But it lowers it a bit. Now, not with the same potency as a PCSK9 inhibitor, but again, in general, a lot of menopausal women need to be on hormonal therapies. [laughs] [crosstalk] And if you have Lp(a) and you can wind up on a PCSK9, I would imagine they're synergistic. Nobody's done studies that I'm aware of. Let's combine both of them.

Cynthia Thurlow: [00:22:42] Yeah, I tried looking. I couldn't find anything. 

Dr. Thomas Dayspring: [00:22:44] Maybe in some rats someplace-- [crosstalk] 

Cynthia Thurlow: [00:22:47] But not in humans.

Dr. Thomas Dayspring: [00:22:47] Not every menopausal woman is a rat. 

Cynthia Thurlow: [00:22:50] No, no, no. But it's interesting to me is the other side of that is, you know, if we're looking at estrogen as being potent but not as potent as these drug therapies, where do we need our serum estradiol levels to be? that's where my brain automatically goes. Because everyone thinks about-- we know based on research that we want estrogen between 60 to 100 for bone protection. And so that's where my brain goes. Like, I'm sure we probably need them to be high enough for it to really be effective because sometimes people get put on the lowest dose estrogen patch as an example. And you know, their estrogen levels are like 25 pg/mL. It's like a whiff, like hoo.

Dr. Thomas Dayspring: [00:23:33] I can't answer that question using the concentration to predict. It's tough to know that or so, I mean, the old days you would judge estrogen theory by FSH and LH because maybe I've restored, premenopausal balance or so, but I don't know how to answer that question. You would know far more about these hormone levels and so would be extrapolating it to the efficacy of a given drug or not.

Cynthia Thurlow: [00:23:57] No, no, it's just it was one of those things that popped into my head while we were talking. 

Dr. Thomas Dayspring: [00:24:01] No, I don't know that there's any official guideline even telling you to follow up with estrogen levels. But there are people who do it out there. 

Cynthia Thurlow: [00:24:10] Absolutely. There's a lot of opinions about different things. 

Dr. Thomas Dayspring: [00:24:13] So, again, no Level 1 evidence, but we don't need Level 1 evidence on everything. A trusted practitioner who's been well experienced in doing it. Yeah, I'd listen to them. 

Cynthia Thurlow: [00:24:25] Absolutely. I'd love to pivot and talk about the brain. 

Dr. Thomas Dayspring: [00:24:30] Pretty important. 

Cynthia Thurlow: [00:24:30] Very important. And largely because the more I learn, the more I'm just humbled that we function at all given the fact that, women go through menopause, men go through andropause. But there's such dynamic shifts and changes in what's going on at a cellular level in the brains as we're getting older.

Dr. Thomas Dayspring: [00:24:48] Number one, dementia is much higher incidence in women than it is in men. So, again, we have gender differences with so many of our organs, including the darn brain. So, I think you have to be particularly worrisome about future cognitive impairment and dementia in women. And so, there are a lot of issues that go into that. Many people who follow me online know I've had the privilege the last three-four years of working with what she calls herself the first preventive neurologist fellowship trained out of the Dementia Clinic at Weill Cornell in Manhattan. My dear friend Kellyann Niotis, we've done many shared podcasts together, including a couple of great ones on lipids and brain health. Well worth listening for any of your listener who want more info than what we're just going to get into. 

[00:25:40] And we work together. We still work together. We are cojoined on a lot of projects together. But one of the reasons she wanted to associate with me is she knows everything that anybody can know on how to prevent it. But she knew lipids were such an integral part of forestalling many chronic brain diseases, Parkinson's, Lewy body, many, many other types of dementia other than Alzheimer's or so. And she knew she had to know a lot more about lipids than is taught in neurology residencies, which is zero, maybe how to spell cholesterol-

Cynthia Thurlow: [00:26:13] Siloed.

Dr. Thomas Dayspring: [00:26:14] -go beyond that. Yeah. So, she did a lot of self-study herself and then we became so tight and she taught me as much about the brain as I taught her about lipids. And I always joke with her. “Oh, Tom, you're my mentor. Prior to meeting you, I even forgot what type of cells make up the brain, for God's sakes.” And what did I know about brain, nothing. But she's really taught me to the next level and I brought her up. And here's what we now know. One Alzheimer's disease, part of its big instigating factor is there's too much cholesterol in the brain. And cholesterol precipitating in neurons does the same thing. Cholesterol precipitating in your liver or any other cell, it crystallizes and kills it. 

[00:26:57] You don't want to be killing too many neurons over time. So, obviously there is a cholesterol threshold in the brain at which it becomes dangerous. And just to quickly why when the neuron cell membranes are overloaded with cholesterol, they start producing beta-amyloid and tau proteins and stuff, amyloid precursor proteins get involved. So, you want to have healthy neuronal cell membrane cholesterol balance. You never want to have excess. So, and we know Alzheimer's on autopsy, they got too much cholesterol in their brain. So, there would be a hypothesis that if I could lower in the people at risk for Alzheimer's disease their brain cholesterol, would that be an AD preventive strategy? It's certainly plausible. 

[00:27:43] And if you look at all the statin trials that have ever been done and none have ever been designed prospectively to statins prevent AD or not. But there's been a lot of post hoc analysis and no drug has been tested as often in randomized clinical trials as statins. So, we have a lot of data and there's observational data too. So, it looks like if you want to be fair, statins do not harm, they do not cause Alzheimer's disease under any circumstances. But they're null, they probably don't cure. But there have been some trials that suggest, they maybe do so maybe they do, maybe they don't. They certainly don't harm anybody. So, nobody should be if I'm going on a statin because my brain will shrink or whatever, I get Alzheimer's is disease not true. 

[00:28:30] Not to say an extreme minority of people can't get brain fog when they first initiate their statin. You've written a zillion statin, so have I and we've had X number of people, “Hey, since you started me on that drug, I'm not adding right, I'm not remembering, I'm not thinking right. And I stopped it by myself and my brain came right back.” So, in some people, through whatever mechanism, it does cause brain fog. And I'll give you my opinion on that in a little bit. So, cholesterol is so crucial to the brain because I think the brain has more cells than any other organ per se. It actually makes more cholesterol than does the liver. Everybody thinks the liver makes the most cholesterol. 

[00:29:11] So, when does the brain start making cholesterol and like the second trimester in pregnancy. Now, the first trimester, it's all mom's cholesterol. But the brain is not that big in the first trimester. But it does start to develop pretty quickly. So, it's not only mom's cholesterol, but junior or junior miss starts developing, synthesizing cholesterol big time. And in the second and third trimester, there's a lot of cholesterol synthesis going on in the fetal brain, still some from mom, day of delivery, no more mom's cholesterol. It's your brain has to generate it by itself. The cells that make up the brain are neurons. I don't want to say most brain cells were important. But the neurons generate the action potentials that make everything else in your body work. 

[00:29:57] And they got to have a perfect amount of cholesterol in their membranes. But listen, oligodendrocytes make myelin sheaths that coat every axon and dendrite in your body. You have to have all of your nerve endings coated by myelin, which comes from cholesterol. So, oligodendrocytes are the major cholesterol producing cell in the brain. But there's another cell called astrocytes, and astrocytes, oligodendrocytes and microglia are a different type of glial cell. They're not neuronal cells, so they're collectively called glial cells. So, up until about the age of 10, plus or minus a few years, every cell in your brain is making cholesterol like there's no tomorrow because the brain growth pretty much stops at age 10. You're pretty much your skull is your adult size by then, you're not getting-- your brain isn't getting much bigger. 

[00:30:50] So, by the age of 10, it has all the cholesterol it needs. Now all of a sudden, and I joke with my little ways of anecdotes, the neuron finally says, “I've got all the cholesterol I need now. I don't want to make it anymore, because here's why, and this is not taught.” Cholesterol synthesis is exceedingly complex. It's over 30 steps. It takes over 30 ATP molecules to generate one cholesterol molecule. And that is a terrible waste of energy. Which is why even in the periphery, cholesterol gets recycled so much. Even if you put it into the gut, it gets reabsorbed so you don't have to synthesize more cholesterol- [crosstalk] 

Cynthia Thurlow: [00:31:31] [crosstalk]

Dr. Thomas Dayspring: [00:31:31] -ATP, which your cells could use. And the neuron needs all the ATP it can get. So, it says to its buddies there, I'm going to not make cholesterol because I need my ATP for all my synapses. The kid's getting smarter, I need more synapses or whatever. He's an athlete now. I need more synapses. So, would you guys make the cholesterol and send it over to me? Well, the oligodendrocytes said “No. I need it all for the myelin.” But the astrocytes said, “I'll do it.” The myocytes are an immune cell. They can make cholesterol, but that's not the biggest generator of it. So, the astrocyte makes all the cholesterol, but how does it get to the neuron? It has to jump from the astrocyte, they don't jump these particles. 

[00:32:14] So, the astrocyte actually makes a brain lipoprotein. Brain can't make ApoB, so there are no ApoB particles to traffic cholesterol in the brain. The brain can't make ApoA-1 either. So, what type of lipoproteins did the brain make? What is the one peptide the brain makes? ApoE. Okay, and we'll get into the isoforms in a minute, but we're talking ApoE generality here. So, if the astrocyte synthesizes ApoB, it sticks cholesterol on it and you form a brain lipoprotein. Now, they're very small. It actually has the density of a plasma HDL particle. So, you'll hear people calling them brain HDL particles, but they have nothing to do with the plasma HDL particles, which are ApoA-1 particles and in the brain are ApoE particles. And when the astrocyte makes it, it secretes the ApoE, HDL density particle and it swims through the brain interstitial tissue, which is called the matrisome.

[00:33:15] And hey, there's a neuron. And the neuron, guess what can make LDL receptors, LDL receptor-related protein or something called the scavenger receptor B1. All of those except ApoE is a ligand. So, the LDL receptor in the LRP grabs the astrocyte, creating HDL and pulls it into the neuron. Cholesterol delivery, the scavenger receptor just delipidates the cholesterol from the particle and pulls the cholesterol in, cholesterol delivery. So, that is the brain transportation system of cholesterol. So, and the neuron's not making it, but the astrocyte is doing it for them. So, here's where this gets a little interesting. So, since cholesterol is so important in the brain, if there's too much cholesterol, maybe we do want to suppress cholesterol synthesis a little bit. How would I do that? Well, there's only one drug that crosses the blood-brain barrier and would inhibit cholesterol synthesis in the brain. It's our statins. They inhibit cholesterol synthesis in any organ that they can get into, which is virtually every organ in the body. 

Cynthia Thurlow: [00:34:21] Even though we're told there are ones that are less likely to cross the blood-brain barrier. 

Dr. Thomas Dayspring: [00:34:26] Well, that's what we were once told, but said not to be so true. [Cynthia laughs] Used to be lipophilic hydrophilic. But if you're in a steady state with a statin that may be true on day one, the lipophilic get in easier. But if you're in a steady state where the statin levels, they all get in over time, so they all have the potential to inhibit the synthesis of cholesterol in the brain a little bit. Now in many people that's probably good. So, it'll be one of the ways to ward off Alzheimer's disease. And trust me, there's many more. Don't think “Hey, statins are going to cure everybody of Alzheimer's disease.” But they are the only lipid drug currently available that can interfere with cholesterol synthesis in the brain. Bempedoic acid only works in the liver. 

[00:35:06] The PCSK9 monoclonal antibodies can't cross the blood-brain barrier. And ezetimibe works in the gut, not going up and attaching to Niemann-Pick in the brain. So, the statins could do that. But you could also hypothesize, might there be the oddball patient who is just a hyper responder to a statin and the statin goes into the brain and it suppresses cholesterol synthesis. Not just an average good amount, but it over suppresses cholesterol, plausible. And I would say maybe that explains in some people this brain fog than we all know and is in the FDA package insert as a rare possibility. So, could it just be in that person? It just was too much. Maybe they need a lesser dose of the statin. Another reason to use a baby dose to start with or so. But that'd be one thing. 

[00:36:01] But might there be a way of monitoring it? So, here we go. So, the neuron, I told you how toxic cholesterol is to a neuron. So, if for whatever reason there's too much cholesterol in the cell membranes of neurons, evolution is given the neuron and no other cell in the brain a way to get rid of cholesterol. Neuron was given an enzyme that changes cholesterol into what's called an oxysterol. The big name is 24S-hydroxycholesterol. It's an oxysterol, believe it or not is a bile acid. When your liver changes cholesterol, bile acid is an oxysterol. And it's the same enzyme in the liver that is in the neuron there. So, why would the neuron be creating a bile acid? Well, in the brain we call it an oxysterol, but it is a bile acid. 

Cynthia Thurlow: [00:36:53] Fascinating. 

Dr. Thomas Dayspring: [00:36:53] And you're going to see it's going to wind up in the liver. So, 24S-hydroxycholesterol, that means a normal cholesterol molecule has one hydroxy group on one side. 24S has at the 3-position, like [unintelligible [00:37:07] at the 24. So, it's got a hydroxy, a water-soluble molecule at both ends of the molecule. It's a water-soluble lipid. It's a hydrophilic lipid. It can slip right out of the neuron membrane, can easily cross the blood-brain barrier, go in plasma where it rapidly binds either to albumin or more likely to a passing lipoprotein and they return it to the liver. The liver goes where did you get this bile salt? I'll just make it into a real bile salt. So that's the brain actually can excrete cholesterol through the liver into the bile. So, 24S-hydroxycholesterol, now that would be an interesting biomarker. 

[00:37:46] I wish we could measure it in the plasma because if you have Alzheimer's disease, your neurons try and get rid of cholesterol and 24S-hydroxycholesterol level in the plasma is high. It's not an available test outside of a research lab. It's a mass spec test that they just don't offer. But we have another. So, a little bit about cholesterol synthesis in cells and especially the brain. Cholesterol synthesis, very complex over 30 steps. Starts with a 3 carbon-acetate, 5 carbon citrate, goes through numerous elongations and becomes a 30-molecule, linear molecule, a cholesterol precursor called squalene, that is so long it starts to bend upon itself. It becomes cyclic. So, this flat linear cholesterol precursor becomes a cyclic molecule. And most people know cholesterol has four rings, three have six and one has five components and that's cholesterol. 

[00:38:46] So, the first sterol precursor, the cyclic precursor, squalene becomes something called lanosterol. Lanosterol goes through about a dozen more modifications through one of two pathways and it becomes cholesterol. So, one pathway and it's another, like I said, a dozen steps. And this is the pathway that is used by virtually everything in the peripheral cell that's not in the brain. It goes through something called the Kandutsch–Russell pathway. All you have to know is the penultimate, the next, the last sterol that changes into cholesterol is called lathosterol. Okay, so if I was measuring lathosterol in the blood and you and it was high, I would know your peripheral cells are over synthesizing cholesterol. No wonder you have high ApoB. The brain evolution has decided, first of all, we're going to give everybody two pathways just in case one is faulty without cholesterol, you're dead. So, we want to have a backup pathway. And this is called the block pathway. The man who discovered it got the Nobel prize for discovering this pathway. And although it's a minor pathway in the peripheral cells, it's the major pathway in the brain cells.

[00:39:40] And so, the astrocytes use the block pathway through desmosterol. So, could we measure desmosterol in the bloodstream? Well, wait a minute, you're not doing a brain biopsy measuring desmosterol. We're not doing spinal taps measuring-- Does it really correlate? Turns out it does. An eloquent study published probably a decade ago where these people went in and they figured out this by themselves. So, they did spinal taps on a whole bunch, over 100 people. And they did plasma levels. 

[00:40:30] And in the CSF they checked desmosterol in the plasma, they checked desmosterol, measured by the same LC mass spec test, high correlation between the two. In other words, your plasma desmosterol tells you what's going on with the brain. It's only a minor pathway in the periphery, so it's not going to be contaminated by all the peripheral cellular synthesis. And in that same study, here comes the earth-shattering data. The people with low desmosterol were the ones who got cognitive impairment and Alzheimer's disease, which makes desmosterol a proven biomarker to who in your patient makeup is going to get Alzheimer's disease. You might want to just check desmosterol on that. 

[00:41:14] Right now, about the only thing you're doing of it in family history is maybe you're looking at really obtuse genes or maybe you're doing the ApoE genotype because we know the E4 carriers are the ones most prone to dementia. And why you're not doing ApoE4 genotype and a desmosterol level. Now you got 2, you got E4 and a low desmosterol. Whoa. So, that is pretty much proven right now. So, everything else I'm going to tell you now is a hypothesis. So, there are other things that affect desmosterol. First of all, if you were not on any drugs and you came to me, you had low desmosterol, I'd be worried there's Alzheimer's in your future.

[00:41:57] So, I'd call my buddy Kellyann, what are all the other lifestyle modifications you make early in life to put this person on the road to good brain health? And there are many. Nobody should ever think there's nothing you can do to prevent Alzheimer's disease nowadays. 

Cynthia Thurlow: [00:42:10] Very important. 

Dr. Thomas Dayspring: [00:42:11] It's malpractice to ever say that to anybody. There's tons of things, much of them are going to be lifestyle. But there's a bunch of credible supplements one can use right now. Hormonal therapy, we might just allude to a little bit would be certainly of high consideration in a woman, who is heading down that road. But what about, hey, a lot of women need statins and stuff. And guess what is the number one cause of low desmosterol in the plasma? It's people who run statins. 

Cynthia Thurlow: [00:42:38] Yeah.

Dr. Thomas Dayspring: [00:42:41] Way more people are on statins than are going to get Alzheimer's disease. So, statins inhibit the cholesterol synthesis pathway. It's step number three. So, they reduce both lathosterol and desmosterol. If you're measuring that one way to, I mean, you check statin efficacy by ApoB. But if you were measuring markers of cholesterol synthesis ahead of time and you saw high synthesis, lathosterol and desmosterol would probably be high. And if you put them on a statin, they're both going to go down a little bit as is your ApoB because when you inhibit synthesis, more LDL receptors. So, if you called me up today and said, “Tom, I just for the heck of it did what you said. It's a desmosterol, mine’s low.” What does that mean? So, the first question I'm going to ask you what is your family history of Alzheimer's disease? Do you know your ApoE4 genotype? And number two, are you on a statin? And I would need to know both of those to give you a coherent answer as to what it might mean, a low desmosterol. I can't measure 24S-hydroxycholesterol. 

[00:43:37] Desmosterol is available in labs in the United States so that I can get if I want it. And even if you ordered it direct to consumer. It's a $99 test. EmpowerRx, Google it and you will find out how to get that test yourself. And you get all the markers. It's not only desmosterol. So, this is a plausible theory now that if I am going to prescribe a statin. Absolutely, if there's a family history of Alzheimer's disease, maybe the patient already has some cognitive impairment or they're an ApoE4 single or double allele carrier. Does it hurt me to monitor desmosterol in that person? No. And if I saw and because I measure before starting drugs and afterwards, I would know. “Aha. Is it the statin?” Because I would like to know desmosterol is low to begin with because then if I had a lower ApoB, I'm probably not even going near a statin. 

[00:44:32] Now, this is all Tom Dayspring's opinion. I don't have a randomized [unintelligible 00:44:34] trial showing you this, so don't send Cynthia emails, “Where's this evidence?” [Cynthia laughs] I don't know how many people have read as much about sterols-- I am a lead author on a study analyzing 600,000 sterol metrics at the big laboratory in Richmond. I used to work in here and I've studied it to no end. I am one of the few lipidologists who can also call themselves a sterologist. So, I've done my homework and I've already told you this is just plausible. 

[00:45:04] And since I have many other ways to lower ApoB and somebody who might be at risk for that, why wouldn't I try to get ApoB to control without using a statin? If I started a statin and it started lowering it and it below the 20th percentile cut point is what I use is telling me you've suppressed your synthesis too much. Why wouldn't I either back off on the statin lesser dose if I were using a bigger dose. Another reason not to use the big dose day 1 or I would say no, let's just try ezetimibe, bempedoic acid, PCSK9 inhibitor. I believe by the end of the year we're going to have another incredible drug called obicetrapib, a CETP inhibitor which is a big ApoB fantastically lowers apoprotein(a) more than the PCSK9 inhibitor. It's an oral drug at 10 mg.

[00:45:59] And I believe next week it's the Annual Alzheimer's Disease Association up there in Canada. All I know is they've let it out. We're going to present what obicetrapib does to Alzheimer's disease biomarkers. I don't know what that's going to show. I doubt they're going up there to show it does nothing or-- [laughs] I think they'd be obligated to tell you if it harmed it. So yes, they would. But fingers crossed that it may actually be whatever they're measuring. Might it be any of the biomarkers I just mentioned the amyloid, the tau, 24S-hydroxy-- I don't know. But we're all anxiously awaiting that data for sure. So, we will have many options to get your lipids under control if we didn't have to use a statin or so. This is great news. So, everybody stay tuned for this. 

[00:46:48] By the way, since it just published in the New England Journal, it's a big study that in FH patients, severe ApoB, LDL cholesterol on top of high dose statin obicetrapib further lowers LDL cholesterol because most FH patients, you can't get the goal. So, there's need for combination therapy. And that's by the way, how bempedoic acid was given in FDA approval ezetimibe and a PCSK9 inhibitor before their trials were ever completed. And since obicetrapib has completed this trial, I'm guessing, and I had no idea, I have no affiliations with that company, New Amsterdam Pharma, that the FDA might let them come on the market for FH patients. Maybe I could use it off label if I wanted to. That's me saying that, doctors can make their own decisions, but it'd be on the market anyway, people to use. 

[00:47:41] So, I think it's a viable thing to monitor. And people look at the desmosterol if you have to prescribe a statin and for sure in the people who are really at risk. Last thing, I'll say is okay, they are at terrible risk. I really don't want to use it in them if I can. But since you know longevity, if we put you on a statin and you don't have a heart attack, you might start making age 80-90, because you're not in the CCU or the graveyard. Do we all want to be 80 and 90 without a brain? 

Cynthia Thurlow: [00:48:12] No. 

Dr. Thomas Dayspring: [00:48:13] So, wow. If I could negotiate this Alzheimer's prevention. So if you at your age, Cynthia, I don't want to over suppress desmosterol. Even if you're not an E4 carrier or anything else for the next 30-40 years. Why would I when I can get your ApoB perfectly with everything else? Again, it's just Tom Dayspring's opinion that's not evidence-based medicine. 

Cynthia Thurlow: [00:48:39] Well but it also you're a clinician for over 50 years of experience and very well versed in the literature. So, of course the question that will come in is what is the level of desmosterol that you are comfortable maintaining? Like this is your threshold of where you think it's most important to maintain above X. 

Dr. Thomas Dayspring: [00:48:56] And it goes right back to how I told you what the goals for ApoB and LDL cholesterol is. We use population percentile cut points. So that means we do not want a desmosterol to below the 20th percentile with lathasterol and desmosterol between the 20th and 80th percentile is basically normal. You know, you might be at one extreme or getting to the other, but we would just say okay, above the 80th percentile you're a hyper synthesizer. And if your ApoB is high, you'd want to lower it. If your ApoB is okay. All right, your body's getting rid of cholesterol via ways that it knows that you don't know. But trust your body if the blood tests are coming out okay. So, the interesting thing, there's two labs that I'm aware of, you can get these sterol metrics nowadays. The one most commonly uses the Boston Heart. 

Cynthia Thurlow: [00:49:43] Yep.

Dr. Thomas Dayspring: [00:49:44] And they have something called the cholesterol balance test. But here's where I'll defer with them. And listen, their lab director, Ernst Schaefer is the world's all time sterologist. Much of what I've learned has come from Ernie. I've known him a long time. He's taught me a lot. And I what I'm about to say came from one of his publications. Anyway, so they report all of the sterol concentrations via two ways and one, they call it the normalized value. And you will see red, green and yellow in her pretty little bar graphs there. But those colors correlate to this normalized value. Now that is a calculated value where they convert your cholesterol to molar concentration, your total cholesterol. Not every doc knows how to do that or wants to do it. 

[00:50:32] The sterols are measured in molar concentration, but you have to convert nanomoles to nanomoles or nanomoles to moles. So, it gets a little complicated. But then you would divide the sterol concentration by the total cholesterol concentration and you get a number and they figured out what is hyper-synthesis, hypo-synthesis or normal. Technically, they don't report hypo-synthesis, they just report hyper-synthesis. And I think that's a shortcoming of their report. But if you look closely at that report on the right-hand side, there's a column called Absolute Concentrations. That's what your eyes have to zero in on. That's in an individual patient, what you make decisions on. The normalized ratio is an epidemiologic tool. It's a way to compare populations of one another. I treat people one at a time, but the bad news is they don't tell you what's the 20th, 30th, 50th percentile. I have that. I've tweeted it any number of times and put it on LinkedIn. So, it's a little table you must have if you're going to interpret it. 

Cynthia Thurlow: [00:51:39] We'll have to make sure we grab it for the show notes. 

Dr. Thomas Dayspring: [00:51:41] So look at that and you will see what is the 20th percentile. And don't go below. The other lab, doing it gets complicated. You have to go through LabCorp. They send it out to the Mayo Clinic which does it, comes back to LabCorp. LabCorp will just send you a bunch of numbers and they're measuring about the 10 other sterols, which you absolutely don't have to confuse your brain about. They're with other rare lipid disorders, but they don't give you the percentile cut points. Now I have those too. If anybody wants the Mayo Clinic voice, message me on LinkedIn or something. If I haven't shared it with you, Cynthia, I will make-- finding you and I've posted them also on my social media things, so that's how you'll know where you are. 

[00:52:21] But if you call LabCorp and say I want plasma sterols, which is what the person answering the phone won't know what you're talking about, even if they go to their supervisor, they may not know. So, it takes a little bit of wringing necks to get that test done through LabCorp, but they can do it. 

Cynthia Thurlow: [00:52:40] What do you think at this point for a menopausal female that has elevated ApoB, elevated Lp(a) diagnostically to assess for cardiovascular risk if we're looking at a coronary artery calcification scan versus a CT Angio in a patient that is not symptomatic and is otherwise insulin sensitive and metabolically healthy.

Dr. Thomas Dayspring: [00:53:07] Well, for that type of woman, for sure, she needs a very thorough investigation. And we're always going to be interested in other aspects of her menopausal body that we would want to factor in. But realizing that she would be at extremely high cardiovascular risk. Imaging is important for a couple of reasons. Number one, you could say if we discern atherosclerotic heart disease, whatever ApoB I'm shooting for, the goal gets even a little more aggressive. Although, I could make the case that if you have very high Lp(a), I'm really trying to push a low ApoB anyway, but I might be a little more aggressive. And I think it also when you're talking aggressiveness with lowering ApoB, you're probably talking about combination therapies. 

[00:53:54] I think most people would be more readily agreeable to that if you could show them, picture their arteries, that you've got a lot of disease in your arteries already. You're not early in the game. We have far less-- [crosstalk]

Cynthia Thurlow: [00:54:06] It's not just lifestyle. 

Dr. Thomas Dayspring: [00:54:07] Yeah, well, lifestyle, yes, but lifestyle doesn't modulate Lp(a), it will help ApoB a lot. So, we never want to not advise lifestyle, but we can't solve Lp(a) by lifestyle alone. So, showing an artery that's involved, should it be a CAC, which is cheap coronary artery calcium or CTA, which is a little more expensive and most third-party payers won't pay for it unless you're having chest pain or some other indication. So, you can afford the cost. And the modern CTA is extremely low radiation. So, you're not really exposing yourself too much there. You want to make sure you're going to a center that does have the new lower [unintelligible [00:54:46] machines and everything because there are certain plaque characteristics and I'm involved with a lot of stuff. 

[00:54:54] I think you're going to see some CTA data soon, it will tell you exactly the type of plaques that are being seen in people with Lp(a). So, if you saw that type of plaque that would be a real indication for you to take your Lp(a) even more serious or so. So, I think within the next year you'll have answer on why CTA is probably a better test. But again, it's a cost thing just as some of the drugs we've talked about and so. But then right now it comes to blowing away ApoB. And we've already discussed how to do that but again it enters can I afford a PCSK9 inhibitor into the thing. I think if there's no contraindication to using it in a menopausal women, estrogen probably is a big part of that discussion also not by itself. 

[00:55:42] If you really have high Lp(a) it's probably cojoining with the PCSK9, but you could try. There's always crazy outliers to responses of everything so you never know and then decide. And I've told you in the future we may have another big player coming down. It's not here yet. So, I'll be back one day when that drug's around because that's the whole podcast that obicetrapib as to what it may or may not do. 

Cynthia Thurlow: [00:56:06] I can't wait. 

Dr. Thomas Dayspring: [00:56:06] So it's complex, but it's really not that complex. I rattle it off. And if you listen to me twice, you can jot down my talking points. The real trouble with most women and I've told you why I went into menopausal health because I thought women were getting the short shift. It's still in the real world that is very tough for a woman to find a practitioner who's well-schooled in both menopausal health and in cardiovascular care. I don't even want to call it advanced cardiovascular care anymore. It's basic. You have a clinician who's not measuring Lp(a) and is adverse to measuring ApoB. You need another opinion. You really do. Never mind measuring desmosterol that's later on down the road. Most physicians wouldn't know what that is, but they should know what ApoB and Lp(a) is. And if they don't, I think you need better advice. 

Cynthia Thurlow: [00:56:58] Well, I can't think of a better way to end the first of two podcasts that we will be doing together in person. Thank you again, Dr. Dayspring. I can't thank you enough. This has been a joy to spend afternoon with you. 

Dr. Thomas Dayspring: [00:57:11] And it's so much more fun in person than zooming you in. 

Cynthia Thurlow: [00:57:14] Yes, absolutely.

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