#23 - Tom Dayspring, M.D., FACP, FNLA – Part IV of V: Statins, ezetimibe, PCSK9 inhibitors, niacin, cholesterol and the brain

Foreign. Hey everyone. Welcome to the Peter Attia Drive. I'm your host, Peter Attia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful, top performing individuals in the world. And this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics@peterattiamd.com. Hi everyone. Welcome to episode four of the Week of DaySpring. In this episode, we cover a lot of drugs. We talk about statins, we talk about cholesterol regulation, we talk about ezetimibe, also known as Zetia, and we talk about the most recent class of drugs introduced to this field, a drug, a class known as the PCSK9 inhibitors. There are two such drugs on the market today. We talk about fibrates and we also talk about the use of fish oil, niacin or niaspan, which has fallen out of favor. This came up a little bit on the discussion I had with Ron Kraus several months ago, and we get revisited here. Tom has a very different point of view on this from Ron. So you will be able to determine which of those views that you favor, which camp you're going to be in. On the niacin side, we talk about the role of cholesterol, statins, and brain health. And another, another thing that I learned was about the futility of using CKs and LFTs to address statin response or ill response. So again, another great example of how I'm doing these shows, but I'm learning along the way. And so I'm confident that any physician listening to this is going to learn something and that hopefully this becomes kind of a part of your ongoing medical education. So sit back and get ready for episode four. So while we're on that topic, like, let's go back and talk about the drug. So we just finished with kind of one very niche story. But when it became pretty clear that there was an association, a strong association, frankly, between cholesterol and heart disease, you now had another target. Because as you said, if, you know, if we went back in time, 50, 60 years, if you were astute enough, you would have your patient stop smoking, you would manage their blood pressure. What was the first drug that was specifically brought to market to target cholesterol?

Well, niacin has been used that infinitum forever without a lot of data. But they knew it changed certain metrics that you were measuring. Total cholesterol, HDL cholesterol. And the only form of niacin available back then was immediate release. A pretty much intolerable drug for most people. But you could find some people who could take the massive doses needed for that. So that was around, believe it or not, when I was coming up. And total cholesterol was the only measurable thing. And they knew that if it was 400 or something, you were probably in trouble. They gave neomycin to those people mice.

And the antibiotic.

Yeah. Which interrupted the hepatobiliary circulation of cholesterol and it lowered cholesterol anyway. No outcome evidence with it. But along came the bile acid sequestrations, which we hinted on will make you excrete bile acids, which therefore you have to use up your. Your endogenous cholesterol to make new bile acids. So you will lower your cholesterol metrics that you're looking at. And in a crazy long outcome trial, it did seem to work. They pudged a lot of statistics, I think in retrospect on and didn't have.

The type of this is the lrcc.

Yes. So there was a little proof that not only what Framingham said is true, cholesterol is a risk marker, risk factor, depending on how you want to label it. But lowering it does reduce clinical events. To me, the tragedy of that is for the next 20 to 30 years, the only thing that the pharmacological industry focused on was cholesterol as their metric of that's all we got to do. We got to find stuff that lowers cholesterol metrics or improves cholesterol metrics in one or the other direction. And biology questions do raise HDL cholesterol a milligram or 2 milligrams percent, which turns out to have some statistical significance.

So potentially without any physiologic significance.

Correct. And it's a minuscule thing. So who knows? So that led to just investigation of everything else. And all of a sudden this guy discovers a fungus that has got a property that lowers really potently cholesterol. And that was the statin group Akira Endo, a mycologist over there in Japan who unbelievably has not gotten a Nobel prize yet, and there'd be no statins without him bringing it to the table and stuff. We wound up statins lower LDL cholesterol dramatically. Pretty low doses. They seem to be safe all the after lrc the FDA needed was if you got a product that didn't harm anybody and it's lowering LDL cholesterol. Welcome aboard. So several statins got Approved starting in 1987, with Lovastatin, Mevacor being the first and came on the market. Guys like me who are well into believing, yes, lowering LDL cholesterol, the only metric we have now, and that's good people seem to do better, became very aggressive statin people. And that story told early, where we used to see mis like crazy in our heyday, we stopped seeing them anymore. So we had at least anecdotal belief that these things were working. And lo and behold, pharma knew ultimately they're going to have to do serious outcome trials. And the first group of people they studied were Swedish guys who survived in MI and had an LDL cholesterol of 190.

So these patients had F. In retrospect.

They'Re FH patients, you know, who's got an LDL cholesterol, what's definition? One of the definitions of FH. And giving them a dose of Simvastatin got you 25 so percent reduction in clinical events. So outcome data, Bingo. Great drug. And right behind them was Bristol Myers Squibb, who had the much weaker statin Pravastatin, sold originally as the branded Pravacol. Let's study Irish men who have not had a clinical event, but also their LDL cholesterol is 180, 190 some more FH. Irishman.

So you're going from secondary prevention FH basically to primary prevention FH and LO.

And behold, reduced virtually every athlete.

Do you remember what the NNT was for that group and what the duration of the trial?

You know, some of it had to do with the base, somebody who's down in the 20s, you know, it was very good for both of them. Just a little higher in the 4s because they were sicker people.

I'm surprised the NNT could be that low in primary prevention.

No, it was probably 40 to 50 in West Scotland, but it was good. But these are nightmare primary prevention. These were.

How long were these trials? Five years, six years?

Yeah, they were five years. Some of them went a little longer, some a little, little less. But five year trials, you know, and so. And significant P values correlated with the LDL cholesterol levels. In retrospect, they, you know, in sub cohorts they did measure apob, which shows.

But this is an important point to make and this is kind of. I've learned a lot from You. I've learned a lot from Ron, I've learned a lot from Alan, I've learned a lot from everybody in this space. But if there's one person who really got me to understand the limitations of clinical trials, it's Alan with his long view of this disease. You know, I've told this story before, but Alan's the guy who bought me my very first copy of Starry's pathology textbook and, you know, is really the guy that got me looking at these autopsy pictures of kids and realizing, hey buddy, this disease starts when you're born. So the thing that I think most people misunderstand when it comes to lipid lowering trials is they're always handicapped very much. They're behind a loaded gun which is pointing directly at them, which says, we're only going to give you five years to impact the course of a disease that has been going on for 50 years until now. You start, you take a bunch of 50 year olds and you put them in a trial where you're going to study them till they're 55. You have five years to try to move the direction of a ship that's been setting its course for 50 years.

Nowadays, because of the course, they would never give you five years to prove anything works. You'd have to prove it a lot sooner.

That's right.

So you better have a miracle drug.

So that's. And we'll talk about the miracle drug, which is a PCSK9 inhibitor, which there's few things I enjoy debating with you.

And last but not least, that's why you don't put mortality in this equation. It takes a long time to die to improve mortality.

Well, not only that, we're never powered to study mortality.

I mean, it's just so difficult, meaningless what a lipid modulating drug does to mortality. Meaningless. Unless you got a randomized blinded 30 year trial. Then I might say, what's wrong?

Yeah, yeah, I agree completely. So I guess I'm sort of humbled by blind luck sometimes, which is we look back with the benefit of knowledge. So it's not to disparage those that came before us, but they didn't have a clue what was going on. They didn't have a clue about the complexity. And if you think about it. So let's go back and talk about statins. So statins inhibit HMG CoA reductase, that is an enzyme that is prior to the bifurcation of the cholesterol synthetic pathway.

It's still a flat lipid molecule.

That's right. You inhibit that. And we're going to talk about a whole bunch of great things. But there was a drug you taught me about a few years ago, an esoteric drug that inhibited Delta 24 desaturase. That drug lowered cholesterol. What was the name of that drug again?

Triparinol.

Triparinol. So tripurinol comes on.

Wasn't that 24 carbon? It didn't allow you to unsaturate.

It did not allow you to turn desmosterol into cholesterol. And so now that's at the very bottom of this pathway.

Penultimate, last.

The penultimate molecule into the ultimate step. And all of a sudden you inhibited that with this drug. Cholesterol levels went down, FDA approved, would go up. Desmostral.

And there was at least a congenital disease called desmostrulosis maybe that. I don't know if they even knew about that though back then. We know about it now, that maybe would have been a flag that.

But when you look at. So if I recall correctly, about three or four years, drug was approved because this is an era when you could approve a drug just by showing it lowered cholesterol. The drug was pulled off the market in the late 60s.

Yeah. Because atherosclerosis was occurring, cataracts were occurring, red blood cell. And it turns out desmostral turns out to have other roles in the body. It's a potent cell membrane signaling molecule involved with inflammatory pathways. So God knows what else you're doing by perturbing desmosterol levels in cells and stuff, you know, so you live and learn. So there's one endpoint that's getting better, another endpoint that you didn't know anything about or biomarker is getting worse and it's probably doing some bad things.

And therein lies the sort of humility of drug development. Right. Which is you've got this synthetic pathway. You have. At first glance, you have two things that are similar. A statin which inhibits one enzyme in the pathway. This other drug that inhibits another enzyme in the pathway. And yet one seems to be okay and one seems to be not okay.

Several other cholesterol squalene synthase inhibitors that have failed for one reason or another. So it is a mega investment. And this is probably far worse where If I say 999 out of a thousand drugs don't come anywhere close to a commercial success, it's probably way smaller than that.

So it seems to me that there's a couple of things that the statin had going for it which maybe at the time weren't realized. The first is it's higher in the food chain, meaning it's higher on the synthetic pathway. So if you are backing things up.

Yeah, there is some recovery time.

Yeah, they're less likely cholesterol, there'll be more acetyl CoA, more acetoacetyl CoA or whatever the other thing. And I don't know if this is true, although I've heard it speculated on, but truthfully, I've never seen the data with my own eyes. Do statins have selectivity for the liver?

Sure.

So that would be another unintended benefit, right? If you deprive them.

At least it's been theorized. Because the pharmacokinetics of a statin, let's face it, the real place you want to inhibit cholesterol synthesis is not per se in cells, but in the liver, because that's the tissue that can upregulate the most LDL receptors to get rid of your LDL particles. So I'm not really interested in stopping cholesterol synthesis in other tissues in your body, because they can get rid of it.

In fact, in an ideal world, you wouldn't want to inhibit cholesterol synthesis in a single tissue outside of the liver.

I mean, I would if I knew that cell was producing other cholesterol. But even if it was, that cell can get rid of it through those other pathways and it would ultimately make its way back to the liver. So as long as I can enhance LDL receptors, by the way, which is primarily the only pathway that's ever worked with drugs to reduce clinical events safely, is expressing in one way or another more LDL receptors, statins, ezetimibe, bile acid sequestrations, PCSK9 inhibitors.

So a very important point to make, what you're basically saying is the only drugs that have ever shown to both reduce cholesterol, but more importantly reduce events, have either been in isolation or in compounds or in combination where they are enhancing clearance pretty much.

I mean, some of them do affect production of the APOB particles a bit, but it's mostly enhancing clearance that works. So if you can do that safely and only a clinical trial can prove you're not hurting anybody, as we show in some trials haven't worked out. And I'll make a case for the niacin trials also. And niacin does nothing to an LDL receptor that we know about. So if niacin's work in a lower apob, which it does, it's true other mechanisms not proven to reduce clinical events.

When they first put statins out there, it was known that they were inhibiting cholesterol synthesis. Did they also understand the effect they were having on the LDL receptors? And did they understand that that was the primary.

I think even why they went into that area was the Goldstein, the Nobel prize winning publication of the discovery of the Brown and Goldstein the LDL receptor. They knew that, wow, there's a pathway that if we can enhance cause overexpression of LDL receptor, it's probably going to be good. So their hypothesis generating their genetic studies even on the LDL receptor led to. And they knew the bio acid questions were first. That's how bile acid questions work. They upregulate LDL receptors to bring more cholesterol to the liver, so the liver can make more bile salts. So let's get better LDL receptor expression drugs and statin fell right into that pathway without seemingly disrupting anything else. Of course, PCSK9 works on at Ezetimibe through a less potent pathway, but still expresses LDL receptors than do the statins.

And so they work, though Ezetimibe's main mechanism of action is in the gut.

I'll argue with you on that because where I talked about these now Peter talked about The Niemann Pick C1 like protein which enhances the absorption of sterols, including cholesterol in the gut. And that's Ezetimibe's main area of action, inhibiting that from. So you do reduce entry of cholesterol into the enterocyte. But remember, cholesterol gets into your liver too. And we think, oh, how does cholesterol get into your liver? Because the liver de novo synthesized it. Or you got all these particles bringing cholesterol back to the liver through the direct and indirect cholesterol transport pathways. There's another pathway by which the liver acquires cholesterol. The liver has an interface with the biliary system. And we've always known, of course, that's how the liver pumps bile salts into the bile. That's how the liver excretes free cholesterol. It pumps it into the bile, which brings it down to your gut. But if the liver needs cholesterol in a pinch, what is a supersaturated body fluid full of cholesterol in your body, your bile, super cholesterol rich, the liver can pull cholesterol back, efflux it, so to speak, from the bile back into the liver. Why? Because what is also expressive to hepatobiliary surface, the Niemann pick C1 like protein. So ezetimibe has two areas where it acts. It blocks the intestine from internalizing cholesterol, but it prevents the lungs, liver from internalizing cholesterol from a biliary source. Put them both together, you're depleting the liver of more cholesterol. And the liver needs cholesterol. There's a sterile sensor, the sterile regulatory element binding protein, a lot nuclear transcription factor that turns on your genes that make LDL receptors.

And so this is interesting, Tom. I mean, the beauty of doing these podcasts is I'm also learning as we're doing them. Right. So, and this is an enormous insight to me that I, I now remember you once telling me about this, but it was just one of those things where I was like drinking from a fire hose and clearly this detail left me my. I'm generally not a huge zetia fan. Zetia or zetimibe, I just generally think it's kind of too impotent for real curiosity and sort of reserve it for situations where patients can't really tolerate statins much and can't afford PCSK9 inhibitors and all these things. Historically, the way I've decided on who's a great Zetia candidate or not is looking at phytosterols or looking at other proxies of absorption. And I've argued, by the way, that the trials that suggested zetia were not that valuable in monotherapy. It's never been shown to reduce.

No, they never did a monotherapy clinical trial.

They didn't even do a monotherapy would.

Work if you picked the right person.

Well, that was always my argument, which was it might have been a mistake in patient selection. You didn't select hyperabsorbers. But what you're saying would suggest that that would dilute my argument. Right? Because if it only worked at The Niemann pick C1 like one transporter, the argument would be target your hyperabsorbers. But if it also works at biliary cholesterol, it shouldn't matter that much, should it?

No, but, yeah, no, that's part of hyperabsorption because remember, if you're pulling it back into the liver, you're depleting the cholesterol of a pool of cholesterol. So it's.

But is the liver also then going to be a dominant source of where we'll see cytosterol, composterol, etc.

The final body preservation way. God forbid phytosterols make it into your chylomicrons or your HDLs and I can make the case that if they ever get into a cell, they're going to injure that cell. But most of the chylomicrons are going to deliver it to the liver first before it goes out in a vldl. So the liver will. If you're over absorbing phytosterols, a lot of them do make their ways back to the liver and the liver recognized them instantly as using your analogy, that stupid bouncer in the intestine let you in. That Niemann peck and the ABC let you in. We're getting ready. We're the backup police.

So now you're the VIP lounge bouncer.

Yeah. Right. So boom, out you go again. Now I realize those dopes may let you in again, but you're gonna come right back here and I'm getting you out again, you know, so. Great analogy, Peter. The VIP bouncer. Yes. So who's to say xetomibes taken out or reducing the functioning of the Nieman And I think it's in both areas. Merck knows this. Merck didn't want to. That's too much education to give. Let's just tell them it blocks cholesterol absorption. The gut would make sense to most people. Most people, including lipidologists, don't even know the liver's involved in the process. So it was like advanced lipid study and stuff. We don't have to confuse people with that. I've written a number of articles on. Is that a. Peter Totena, I think did one of the world class articles on the mechanisms of it and stuff. Yeah.

What year was that? We got to make sure we link.

To that with my years. But it's probably, I don't know, 2010, something like 2008. But it's really with great diagrams of course, showing you and explaining where Niemann Pick is and everything.

And that's Toth T O T H. Yeah, Peter is. We'll make sure we link to that.

And certainly mentors in my life. And of course Peter and Mike Davidson has had me write the chapter in the book Therapeutic Lipidology on phytosterol.

Davidson's at Northwestern, right.

He's at University of Chicago. And look, very early on, probably because I was just such a good educator on lipids, lipoproteins and statin mechanism action. I was in very early in Merck's investigation of cholesterol absorption and became a very effective educator on that too and therefore had great contact with a lot of the Merck scientists, the Swedes who all invented all these absorption markers and stuff and really became subspecialties in lipidology and sterols is one of them.

Why do you think that the Zetia combination Simvastatin trials. So the main trial with Zetia was with and without Simvastatin. Correct?

No.

Or sorry, Simvastatin with and without.

The reason why Zetimibe has taken so many damn hits is Merck's poor thinking of the type of trials that let's bring to market to show that this is a great drug. And instead of just doing the damn outcome data, even doing a select outcome trial in the right person, primary prevention as well as of course do your secondary prevention trials even can do that first if you want to. And if that fails, you're not going to do anything with it. But let's. They wanted to just get so much to market. What's the easiest thing to do? Imt. So let's take people with a lot of lipid abnormalities, carotid intimal thickening, which is an ultrasound measurement of the thickness of your carotid artery, which has some correlation with subclinical atherosclerosis and clinical events. And that's unarguable and therefore they're at risk. They have lipid abnormalities. Let's give them. They're on a statin because we have to give them statins if their LDL is out of metric, is out of whack. Let's give them one half of the group ezetimibe and the other half placebo Ezetimibe and Let's follow their IMTs. We only have to do that for a year or two and we'll see IMT progression in one arm and no IMT progression in the other. Well, we did that. Virtually every lipid parameter, including apob, got better, Every inflammatory markers got better and the IMT didn't change whatsoever.

Meaning Simvastatin had the same IMT as Simvastatin plus Ezetimibe in a short time.

And of course we now know that what happens to IMT with any drug has virtually no relationship to clinical outcomes. So that's not a tool you should be using to follow up and saying, look at it's like the coronary calcium calcium score. You it's not the tool you should be using to demonstrate the efficacy they should have looked at. But look at this APOB reduction beyond what Simvastatin can do. Look at the triglyceride reduction. Look at the CRP reduction beyond what.

Simvastatin or OXLDO or any of these things.

At least say that doesn't mean anything. But they had already polluted the minds that IMT was the best way to check drugs.

Obviously nothing trumps a hard outcome. If you can reduce mace, that's the way to go. Sorry, major adverse cardio.

Taking a shortcut.

But they picked the wrong shortcut is basically what it comes down to. There are better shortcuts you could take.

Who did that? Turn off big time the images of the world, the cardiologists who instantly dismissed Ezetimibe as the world's most useless drug. Most cardiologists don't even know what APOB is. And never mind that, hey, look at this is a potent thing. I hinted to you I was very much involved with the Relox, the first serum that came to the market of as good an APOB lowering drug as Ezetimibe is, which might have portended great cardiovascular benefit to the serum naloxone, which I believe it still has. In fact we have some. They did a big cardiovascular outcome trial where it was null, didn't hurt anybody, but it didn't reduce events. But if you looked at the primary prevention people in that trial, it did lower events. Now post hoc hypothesis generating data, but an 8%, a 5% lowering of APOB mattered. And I think the right trial done with ezetimibe and alcohol, it would matter.

But we're never gonna know. And this gets to a really interesting point when it comes to pharma's challenge of studying atherosclerosis today, the industry is now going to always be a victim of the success of statins. It is unethical to take high risk patients and take them off statins, despite what the Internet wants to tell you that statins are evil and all that nonsense, which I don't wanna get into. But if you actually have any modest understanding of how these drugs work, they absolutely save lives, especially when directed at the right patients at the right times. What that means is you want to study another drug, you're adding it to a statin, you are not doing it in mono. You know, you don't get to do the study of zetia versus placebo. It's not ethical.

No.

But if you've picked the right patient.

Could you think of a reason it was would be ethical to do such a trial?

Yes, you take a bunch of highly, highly statin intolerant patients.

So that would be one which they're never going to do for a variety of reasons. But here's another. And Merck did two big outcome trials where they could use you didn't necessarily have to give a patient a statin. They took people with significant aortic stenosis and of the belief because hey, there's calcium and there's cholesterol in those aortic valves that if we could lower lower cholesterol in people with aortic stenosis, reduced morbidity related to that. And we don't have to give them a statin because statins failed to reduce outcomes in people with aortics. Those trials were already done. So they took the siege trial aortic stenosis ezetimibe and lowered it and guess what did nothing to endpoints related because they're enrolling people who need surgery for.

I mean again, that just, I mean that just that kind of stuff just. It breaks my heart. It doesn't anger me. It breaks.

But again, post hoc analysis, they did reduce ischemic events in that trial with ezetimibe. So MIS went down, angina went down. But that's post hocus.

And they got lucky. They didn't power for that.

No.

It may or may not be legit.

Correct. So you'd have to do another whole trial to do that again. And so but they were hoping to sneak by without doing and the next thing they did was statins had failed to reduce clinical events in people with chronic renal failure. Statins didn't work. So let's give them a statin plus azetimibe. So you had the sharp trial renal. They had pretty bad gfrs. So everybody two groups got a statin, but the one group got a statin and ezetimibe and the statinized AMIBE group reduced events so there. But it's statin ezetimibe works.

Yeah.

So and then of course they really had to wait for the acute coronary syndrome Tylee improve it trial to really convince the cardiologist that yes, a little bit of extra B lowering at least in that type of horrendously risky people matters. And we now have had that replicated with the PCSK9 in him. And a great point you made up lately. I mean cost them God knows how long the money to do that improve it trial. And they really had extended a couple of extra years to reach statistical significance which turns somebody's loud mouse on the Internet dismiss it because of that now. But it's a miracle in people that are aggressively treated with statin that you've reduced their LDL C to way Way down, that just by lowering it a little bit more, you can get extra event reduction. And I would never downplay that. I think it's miraculous that it worked, and I think it's why it's miraculous. PCSK9 inhibitors work in trials where they're enrolling you, where your LDL C is 70, for God's sakes, because you're on a statin or statinized.

So that, to me is one of the single most impressive things. And again, we don't know if this is going to be true in 10 years. Again, all facts have a half life. But from the moment we are sitting here today having this discussion, the fact that the Fourier trial could take patients who had an average LDL C of 92 milligrams per deciliter on statins. That means they are at the 10th percentile of the Framingham population of. On a statin, you are going to add either a placebo or a PCSK9 inhibitor. In that case, it was repatha. You're going to study them for less than two and a half years and you're going to even have the nerve to suggest that might reduce an event. And, oh, it did.

And if it doesn't, you've just wasted billions of dollars of our money. What bean counter allowed that trial to proceed? It is.

I was. I mean, I had been following this story even before I became interested in lipids. And just out of interest in the sort of, the novelty of, you see, a natural experiment which is PCSK9 hyper functionings, PCSK9 hypofunctionings, Mr. Drug. It just became a beautiful, elegant model. And then I remember in real life.

Takes decades to express itself.

And this all took a decade. And I remember thinking, especially once I got interested in lipids, on the one hand being excited, on the other hand, thinking, there's no goddamn way this trial can work. You could not reduce events in 2.2 years, and they did. And of course, this is how naive I am. And this is why whenever people ask me for advice, friends will say, hey, should I invest in this company or that company? My advice to them is, don't listen to a single thing I say because you're asking a question. Will the market value something which I have no input on? I can provide you plenty of input on whether it makes scientific sense, but you have to talk to somebody with a different skill set to understand if that's an investable thesis. And so I remember Amgen kind of got hammered when the trial came out because people thought, eh, that wasn't enough of an improvement, at which I thought it's amazing. And in reality, in fairness to the market, I think what the market was basically saying is if you did the math based on that trial, under those circumstances, it would be a million dollars or more to save a life. Well, that's a fair question for the market to assess. But if you look at it from a scientific standpoint, that you could take that patient population and achieve that outcome, I think it's one of the most remarkable things in cardiovascular medicine. And to your point, it doesn't even speak to the patients that I have on PCSK9 inhibitors. My patients who take PCSK9 inhibitors are patients whom, prior to this drug, we were flailing with what, maybe some niacin, maybe some monotherapy, Zetia, maybe the smallest dose of Livalo that a human could tolerate and getting woefully inadequate coverage.

As you know, you're doing that off FDA label because they would want to.

Try and they're paying out of pocket for that.

So people who can afford it, but it's certainly the genetic model tells them you're doing smart there and what are your option is to. And I would say, as you know, there are certain nutritional therapies that can send your LDL particle count off the roof. And people are dismissing that as a meaningless biomarker now, because if you do this, diet biomarkers X, Y and Z, and maybe even your waistline looks better, but apob LDLP doesn't matter in them. Every single thing that's ever been done, genetically or properly done clinical trial shows it does matter in an individual. Can I say yes, it matters. In you it does not. No. But if I want to follow the bulk of the data, it matters over time. So maybe if I send your LDLP off the chart for two years, it doesn't matter. But do I want to do this for the next 15 years? If you're a young person on a type of nutritional program that sends that through the roof, is that wise?

How many?

You're going to be mad at me in 20 years or 15 years because I put you in the CCU? I don't know.

Yeah. How many Nobel Prizes have been awarded within the field of lipid science? At least three. Right.

Well, certainly you got the LDL receptor and you got two for cholesterol. And I'm guarantee on other lipid things there might be. I'm not a Nobel historian.

No, but it's interesting, right? I mean, I think this is one of the things that I guess There are a handful of discussions I have with patients that I find frustrating. Some of them are frustrating because I have the same discussion over and over again, and I've written about the topic, and the patient just won't read what I've at least written or at least take the time to read or listen to a lecture, to then come back and ask a question. So that's sort of frustrating for a different reason. But few things frustrate me more than having to discuss things where the patient's baseline of knowledge is the Internet, which obviously you have all the signal can be found there. But the noise, of course, is so great that, you know, you just don't know. But it's these discussions around cholesterol and statins that I find most disturbing because. And in some ways, it's partly the fault of the pharma industry. I think they have to take some responsibility for this, which is in an effort to get these drugs into the majority of people who need them, there's been a need to simplify the message. And when you simplify things, especially things as complicated as this field, you will undoubtedly make mistakes, you will undoubtedly create confusion. And so now we have a system where most physicians don't understand enough to actually explain to their patients why they are putting them on statins and which patients may or may not even be good statin candidates. Something I want to come back to, because you brought it up, and I think it's worthy of its own sort of thread that it will go down, which is this whole brain issue. It's a totally separate issue. But it's this idea of failing to educate patients and physicians has allowed basically a. I don't know, call it a militia of Internet noise that is just completely ungrounded in science. I mean, it's just completely un gra. It's completely disconnected.

And you've already mentioned one example, there's several others, where a drug has come to market and then some harm would develop it. So therefore, you castigate every drug that's ever been invented as, aha.

Even though we're all poison. Even though we just illustrated, right? You can take two drugs that inhibit two enzymes and get different results and get completely different results.

Same result on the biomarker, but different outcomes.

And so I always try to tell patients, although, I don't know, it probably falls on deaf ears, but you gotta think of every drug like you think of a tool, right? If you had a general contractor and he had a hammer, a screwdriver, a drill, a level, a nail, a Screw, et cetera. You would want to have the most tools in the tool belt. That's the first condition. And the second condition is you'd want to know when to use each tool and what its limitation was. And in that sense, the one view, which is statins should be in the drinking water, and then the other view, which is statins cause everything from diabetes, Alzheimer's disease, to global warming. Both of those views are so idiotic that I just. It's very difficult for me to process that. And I've basically stopped engaging on Twitter with any of that discussion. You can't either extreme, you got to.

Get rid of those people very quickly, or you just get annoyed all day long. And this is why it ultimately comes down to. And it's the way you practice. You got to individualize everything. So anybody who says statins belong in the drinking water, that's no public health solution to anything or nobody should ever take. That's absurd. Statins have tons of proof that you got to pick and choose your patients properly. And this is why in the latter part of my career, I've done developed so much more into biomarkers and other risk assessment tools, because the better we can define an individual's risk to any disease that he might be prone to, we can attack that disease through many mechanisms. Part of an atherosis, you got to attack apob. If you don't, good luck. But the more you understand, and that's where biomarkers and really not understanding only understand these pathways, you talk about a lot more clinical chemistry. The average clinician has no clue how a laboratory reports a given concentration of anything to them. I'd like to go into triglycerides, because everybody thinks the whole world. People have no clue how laboratories assay triglycerides. And maybe later we can.

Well, one of the things that I've been pleased with is once I got back into medicine, I realized I didn't know that stuff. And I have been really fortunate. Every lab I have reached out to to come and actually come to the lab and see how it works, including thd. They've all opened the doors and said, come on in, Peter Oder, we're gonna have you. And they overdo it. I love it. They literally will walk me from every station to every. This is where the specimen arrives. So you can see where the FedEx box dumps off the specimen. This is how we take it out. This is how it's handled. This is boom, boom, boom, all the way to. Here are the magnets where we're Doing the NMR and I've got precision. Analytics has also been great. I went up and spent two days with them a few years ago. And I agree. I mean, again, not every physician, I think, has the luxury of time because they're clinically so much busier than I am. So I certainly don't fault physicians for not doing that. But I do wish there was a way to make that sort of experience more available to physicians because the more you understand how these tests are done, the more you understand what your blind spots can be.

Yeah, and I was doing that for a while when I had more of a net presence with full lectures, which I don't do anymore, or they're not available on the net anymore. But just one other thing. Like I told you, most people are clueless that labs don't measure triglycerides. They measure glycerol in your blood and they calculate that into triglycerides. But when you get an LDL cholesterol or a total. Let's talk about LDL cholesterol. The assay that's analyzing the sterol in that particle has no difference. Does it know whether it's cytosterol, campestrel, desmostral cholesterol? No, all it knows is it's a sterile.

So it just knows it's not a stanol.

When you get ldl, it's even metal measure a stanol too. But they would likely be a small part of it. So LDL cholesterol is really LDL cholesterol + LDL, sitosterol + LDL and the other 48. And a little bit of whatever stanol's got may have made their way into your body too. So they don't know that. So in a person with phytosterolemia, a large part of that LDL cholesterol value.

Is a, is the phytosterone.

Yeah, so. But they don't realize, so they don't even know. Could ezetimibe have a. If phytosterols are injurious and I can make that case, I would If I did a one hour lecture to you using proper slides, you would be pretty convinced. I want phytosterols not in my body. Ezetimibe is the only way to keep them out there and wherever you go next. My final word on ezetimibe would be, if you're a big believer in. In this reverse cholesterol transport process, which I've certainly expounded on now, what is the number one pharmacologic agent that increases the amount of cholesterol that's winding up in your toilet bowl because it's in your stool. That best reverse cholesterol transport because the final common pathway to reverse cholesterol transport is it's out of the body Ezetimibe by far. So I can make the case that if I wanted a lipid lowering drug and the drinking water is first line, it would be Ezetimibe, not a statin.

You know, so very interesting and very controversial. Yeah.

And look, the FDA would put me in a lunatic asylum and so would these so called evidence based guys. But if you're analyzing this from cholesterol homeostatic pathways, it's a great drug.

Yeah. Well, we'll come back to all drugs, I guess the next.

Most of the time we do have to lower apob a lot more than ezetimibe could ever do by itself.

So the one that we've left out before we get. I want to come back to niacin from a trials perspective. But let's take a break right now and then we'll come back and we'll pick it up with I want to talk about the fibrates and then obviously I want to talk about niacin through a clinical trial standpoint. And then we'll get into the PCSK9. So we'll take a break right now and we will come back. Okay guys, so we are now back. We're going to slice this beginning into where we finished off. So we had sort of more or less finished talking about Ezetimibe, also known as Zetia. So we'll use this an opportunity to go into the next drug. So. All right, so Tom, that was pretty insightful stuff on Zetia, also known as Ezetimibe. Let's move to another class of drugs that doesn't get a lot of use. I can probably count on two hands the number of times I've prescribed it, which is fenofibrate or more broadly, it's class of fibrates. What the heck are these drugs? How do they work and when should we use them?

Well, if you practice in the United States, you do have two choices. You have phenofibrated and you have gemfibrazole and they're both out there. Both can be attained generically nowadays. So probably phenofibrate still comes in branded form.

That's the triliptics.

You don't have to. That's one of them. There are other branded forms available out there. Gemfibrazole is A pro drug, it has to be converted into the active fibric acid, whereas phenofibrate is the active form right away. So it's a little bit more bioavailable than it. It's kind of interesting for the purists of the world. Gem fibrizole has a monotherapy outcome trial given to veterans with coronary artery disease who had low HDL cholesterol and high triglycerides. And it reduced events as much as a statin did in any trial. So there's outcome evidence.

Was this independent of triglyceride level?

Yeah, it was independent, although they enrolled people, but some, many of the men, the triglyceride levels were certainly not at super, super high levels or so, but it was mostly low HDL cholesterol. And virtually all of those people have some degree of triglyceride elevation. But they tried to recruit people with what at the time was considered a normal LDL cholesterol also.

Which trial was this?

It's called the Veterans Affairs High Density Lipoprotein Trial. VA hit.

Yeah, I didn't realize that was via hit.

Yeah, and that was gemfibrizole. And remember, gemfibrizole already had outcome data from the Helsinki heart trial too, so this would be the second trial. Now, phenofibrate did come along with a couple of big trials, but it missed the primary outcome, but hit some secondary outcomes for a whole lot of reasons. Enrolling the wrong people, heavy concomitant use of statins. Nobody in any GEM fibrizole trial was ever posted polluted by people sneaking in statins with it at the same time. And clearly whatever fibrates do, they do it differently than statins. And the question is, can it contribute to statin? But those trials weren't designed to do that. But they were so polluted by statin use.

And I just want to clarify what you mean. I know what you mean. But I want the listener to understand when you say polluted by. What we're talking about is statins are so potent that when you include them in trials, you are making it more, much harder for a new drug or compound that's being investigated to show its effect, because you've effectively raised the bar much higher for what needs to be done.

Sure, you've taken out one path, you're trying to prove with a certain class of drug that via these mechanisms very different, it works. And then all of a sudden you're getting rid of all the apob particles via the statin. So, yeah, and the statin is not Given in a randomized fashion here, somebody takes it, somebody don't. Some doc says, you take this, don't take it.

Yeah. So that's the bigger problem scientifically, of course, the counter argument is, look, ethically, we don't want someone getting randomized to no medication. And then the second issue is if the statin is the standard of care and therefore in the community, quote, unquote, that's the way these drugs are going to be used, is with or without statins, that's the way they should be tested. So it's. All of these are fair points. But when you ask a true efficacy question versus an effectiveness question, the cleaner you can ask that question the better. And there's no cleaner way to ask it than to not have another drug involved.

Sure. And by the way, when those trials were done, it was not standard of care that you had to be on a statin. Yes. So they were legitimate trials that were ethical.

Whereas with the PCSK9 trials, it was statin of care. You couldn't have a no statin arm in those trials.

Right. That being said, these are all factors that go into the postdoc, at least interpretation of some of these trials. But anyway, so GEM fibrizole worked. And it's kind of interesting. You couldn't explain the benefit of gemfibrazole in the VA HIT trial, but even though it did raise HDL cholesterol, it was like a milligram and a half increase. And it lowered triglycerides, but not to a significant extent. So why did it work? Or were there other pleiotropic type effects of fibrates or doing something that we weren't measuring with any biomarker? So, and I mean, some of that is probably true, but then they didn't, at least in a cohort of it, they did a post hoc analysis using nmr, and this was Jim Mapfos who did this, and he found out that the benefit of the gemfibrizole in the VA HIT trial could be easily explained by what it did to LDL particle count, which fibrates do lower in certain patients depending on the causative. And it raised the HDL particles, which had a statistically significant tie into the clinical endpoint. And that was the first trial showing anything that raising an HDL metric in a clinical trial, maybe if you want to do an HDL metric, it's HDL particle count.

So can we make sense of that in light of what we spoke about, I don't know, 20, 30 minutes ago, which was raising HDL cholesterol without paying any attention to particle number or particle size is so noisy and at least as likely to be counterproductive as it is productive. Here you had two pieces of information of the three, at least, which is you had more particles, you didn't change the cholesterol content in total. So you could make some inference. Again, not necessarily correct, but you could at least have a better guess that you could make about the clearance of cholesterol through hdl. But of course then you have to make an assumption about the size of the particle. Correct.

Yeah, but very interesting in that NMR analysis, whereas HDL particle went up, it was almost all small HDL particles. And for years people have been running around saying the small HDLs are bad and the big HDLs are good. And there was serious evidence that, boy, what bs that is. So fibrates help delipidate HDL particles. So if you're in the old school of hey, you're increasing reverse cholesterol transport because the fibrates upregulate the scavenger receptor B1, which would delipidate your HDL. So of course your HDLs would become smaller and then the small HDLs could theoretically go back, traverse back into the river arterial wall, pull cholesterol out of your sterile laden foam cells, the histopathologic marker, the plaque atherogenesis. And by the way, an aside from when we talked about the complexities of the reverse cholesterol transport process, one pathway I didn't mention, it's a sub sub pathway, something called. Dan Rader coined this term years ago, macrophage reverse cholesterol transportation. And he used to make the case. The only aspect of the RCT that matters as far as atherosclerotic clinical outcomes is delipidating the foam cells in your artery wall of cholesterol. And that's really the job of an hdl, it can get into the artery wall very easily.

There's another ABC that facilitates.

There's a couple of them. There's ABCA1, which will lipidate small lipid poor HDL particles. But there's ABC G1, which will lipidate big mature HDL particles. So you have two ABC sterile efflux transporters in the surface of macrophages that can pull cholesterol efflux cholesterol out of the macrophage into a big or a small hdl, which can then return to the plasma. And the small one esterifies it, becomes a mature one and gives it to ldl, which returns it to the liver. So macrophage rct, which is certainly an incredibly functional aspect of what HDL does, has absolutely no relationships to the serum HDL cholesterol level. So again, how do I know I can't use HDL C as a metric to tell me I'm the lipidating plaque in your artery wall, But I can have some confidence that if I'm using a fibrate, that's one of the things I'm doing. If you do have plaque in your arterial wall and who doesn't, you know now?

So why do you think the fibrates work best in patients with a higher triglyceride level?

Because their main mechanism of that look. So they modulate HDL particles, but triglycerides and has a lot to do with HDL remodeling too. But fibrates mostly stop the synthesis of VLDL particles. Triglyceride rich LDL particles in the lips liver by depleting triglyceride pools in the liver. Remember what determines the lipidation of apob in your liver? All humans make 2 tons more of apob than they ever have a prayer of lipidating and changing into an apob particle. The vast majority of your apob gets catabolized because it's unused. So people always oh, what produces increase apob? Nothing. Your liver makes way more apob than anything human can ever use.

Why do we think that is?

I don't know. People just assume, hey, if you're making too much of something, you got to be increasing the components. Except one component we make too much of and never use is apob.

Yeah, I just I wonder why that teleologically would be the case that we would make orders of magnitude more apob than we could ever want to export.

Abeta lipoproteinmia is death. So you have to make APOB particles. They transport energy, they transport phospholipids, they transport fat soluble vitamins, the big particles. So you can't not have apob particles.

In your think it's just a margin of safety that is so big it's not even.

Well, yeah, they just make far more than we ever use. So. And it's very easily catabolized, so you have a lot of it. But what determines the creation of the VLDL particle in the liver? It's the lipid pools. How much lipid is available to attach to apob and create a circular spherical particle that's going to be ejected by the liver and that comes down to the cholesterol pool and the Triglyceride pool that's in that triglyceride is the stored energy in your liver, and cholesterol ester is the stored cholesterol in your liver. Cholesterol, I think I mentioned before, binds to the cholesterol ester binds to the, or free cholesterol binds to the apob first, some of the cholesterol will be esterified even in the circulation, some in the liver via that ACAD enzyme. And so, and then once you get the little primordial spherical vldl, then triglycerides are transferred in using mttp, Microsomal triglyceride transfer protein. And now you got a real VLDL ready to be shipped out. Other as it passes through something called the space of dis, which is a little space between hepatocytes and the plasma, other apoproteins join there, but believe it or not, many of them, as soon as that nascent vldl, or whatever you want to call it, enters plasma, a ton of the apoproteins just leave your HDL particles. One of the functions of HDLs, remember I told you, transport proteins. They transport a ton of these proteins that are involved with lipoprotein catabolism. So C2 jumps off of HDLs, E jumps off of HDLs and goes right onto the surface of a VLDL if it was not put there as it passed through the space of disk. And they all determine the catabolic fate of that VLDL particle. So fibrates through several mechanisms. One, DGAT is an enzyme involved with the synthesis, synthesis of triglycerides. You know, it's adding fatty acids to glycerol. Fibrates are a potent inhibitor of that. So you just, you just stop triglyceride production with fibrates. Omega 3 fatty acids work in a similar way, so they deplete the hepatic pool of triglycerides, and you're going to make less VLDL particles. Remember, a fibrate is not going to blow away your LDLP like a statin does, but it's going to blob 10, 15% reduction in part depending on the triglyceride richness, not the serum triglyceride level, but the triglyceride richness of the core. So that's one of the.

Now where's the backup of free fatty acids? Because at some point, if you're not synthesizing as much triglyceride, but you still.

Have, you still have enough fatty acid, you're absorbing fatty acids, your adipocytes, thorium.

But is there a hepatic backup of.

Fatty acids or de novo synthesis?

So in other words this would not decrease NAFLD if you had a patient. Because. Because at first blush you'd think well a fibrate should be able to reduce fatty acid to reduce fatty liver.

It's thought that for years, but it's just never been proven in a trial that that alone would do it. Whereas actually ezetimibe has more data on reducing fatty liver than a fibrates do. And most people all blame fatty liver on triglycerides. It's a sterols that really cause a large part of the lipotoxicity that results in injury to the cells in your liver. And there's a lot of animal data on Ezetimibe eradicating fatty liver because they deplete the cholesterol pool in the liver. So it's not all fatty acids and triglycerides that are causing fatty liver. Sounds like it is, but that's a toxic disease to the. It's a lipotoxic disease and it's not all fatty acids.

Although the fatty acids must play a significant role. When you look at. I shouldn't say must, but would suggest it because when you look at some of the preliminary data now that's coming out with fructose elimination, meaning without restricting any other macro or micro, you know, not. It doesn't matter about. Seems that glucose is not that relevant. Even fatty acid composition not that relevant if you completely restrict fructose.

Well, fructose is a major stimulus for synthesis of the triglycerides.

Of the triglyceride. But not, not to my knowledge. I don't know where it would fit into the cholesterol synthetic pathway. Right.

But look, it's a lipotoxic disease but one of the major lipids that's causing hepatocellular toxicity is cholesterol. It's just not all fatty acids. And I'm not implying or no role of fatty acids or fatty acid synthesis. Triglyceride synthesis related to fructose. Yeah, but it's not all just somehow ignore cholesterol and you're going to get rid of fatty liver. And you, you can't even separate the two because if you have a lot of triglyceride you're going to have a lot of the apob particles that are part of the cause of that sterile dose.

Yeah, that's probably the bigger issue is very, very difficult to disaggregate them once triglycerides are elevated. So really the ideal Candidate for phenofibrate is going to be someone with an elevated apob and an elevated triglyceride.

So if you look at, even if you take the two positive GEM fibrizole trials and the failure of phenofibrate in a couple of trials, easily explained if you look at things. But if you do look in the. And basically they enroll people who didn't have insulin, insulin resistance or triglyceride rich lipoproteins and gave them a fibrate. So they designed a clinical trial where nobody in their right mind would ever give that person a fibrate for a bunch of reasons. Hey, but they were diabetic. But they were diabetic. Yeah. Field trial is 100% diabetics. And so they figure it's a no brainer fibrates because of so many things that they do will improve outcomes. And then maybe they would have. But the field trial was so polluted by statin. Unauthorized use of statins, inappropriate use of statins. Remember, you're in a clinical trial, you got, the trial is watching you, but you're going to your own private doctor, he can. And they were nervous at the time because the statin data was coming in and it was almost, it was getting to the point where you're a bad doctor if you don't give a statin to somebody with a lipid disorder. So they said, I know you're in a trial, we don't know what you're getting. But I'm sorry, I, I'm not happy with your LDL cholesterol. Take a statin. So it contaminate. You know, we can always guess if we could have kept it as a pure trial of fiber. But it worked in diabetics. But you know, that's just opinion. It didn't work. But it did work in everybody who had an increase in triglycerides and low HDL cholesterol. It worked. And that's where the outcome reduction was very interesting. Which no other lipid drug has ever done. It reduced several microvascular endpoints in those trials too. Retinopathy, amputations, peripheral neuropathy, renal disease. Even though phenofibrate can raise creatinine a little bit, GFR improved and renal outcomes improved. So what other drug you got you can give a person that lessens his chance of a diabetic retinopathy if he's diabetic? Nothing. Now it's post hoc, it's secondary. Well that wasn't, that was secondary outcomes. So the trials weren't designed to prove that. So they were a hypothesis. You'd have to theoretically go back and do that before the FDA would ever give you approval. But kind of interesting data. So I always made the case what fibrates reduce amputations, Neuropathic ulcers Improve renal disease. Save your eyes. Why the hell are you not on a fibroid if you're a diabetic? You know. So again using that type of data and people use drugs for far less data than that. These are big, huge trials and all of those endpoints have published their analysis of those secondary endpoints in everything.

What are the main side effects of you know of fibrate?

Not a heck of a lot. You know it's a pretty well tolerated drug. Anybody can get any number of any side effects with it or sell. People used to be afraid of the increasing creatinine until in the field trial there and a large number of patients were doing creatinine clearance and that didn't go so there was a muscular buildup of creatinine had nothing to do with GFR or renal clearance of it. Yeah but there's nothing much.

There are some drug drugs, drug the phenofibrate ezetimibe. I mean they're both very well tolerated. Certainly more tolerated than statins.

They really are. And you can make the case as at least in a diabetic, which is probably going to be especially with what we know now the patient who's going to wind up on a fibroid. Now most lepidologists wouldn't use it until you statinize somebody or statinize them and zetimize them. Got their apob as good as you can get. It's still not there. Or triglycerides which is what they're looking at too bad in my mind. But they look at that and it's still high. That is the persons that were helped as at least in post hoc analysis of every single fibrate trial including the VA hit there and all the phenofibrate trials. So that's pretty much where it's reserved to people with these identifiable bihypertriglyceridemia patients or so. And we're not talking about people with triglycerides of 400 or 4000 where pancreatitis comes into play. We'll probably all use a fibrate and a lot of other stuff there like Omega 3 is there on hopefulness that it would reduce the incidence of pancreatitis. Not proven yet. But you would attack that degree of hypertriglyceridemia. But the real world is people with triglycerides between 130 and 300 it that insulin resistant world which we've already clearly defined as an APOB disorder. So that's why your statinib is your first line drugs there. But if you didn't normalize that with your statin or statinized or indeed triglycerides were still high. So you're presuming there still are triglyceride rich lipoproteins, whatever they may be. They might be remnants. They could be LDLs that are triglycerides, especially in the lipidology community who are way more familiar with fibrates. Although it's sadly a disappearing drug that even younger lipidologists come on board have never been taught anything about. Middle go back and Rudy. So it's the older guys like me who grew up through all those trials, have lectured on them, have written on them, really have a better understanding of it than a younger lipidologist. And that's unfortunate because we're going to have a potentially effective drug for a certain amount of people is just not going to be used anymore. They're apt to use a fish oil instead which because it lowers triglycerides and it's so easy to tell somebody to take a fish oil they're not going to go home and read potentially scary stuff on the Internet where they might with a fiber.

Oh no, they're going to still read it.

Yeah, I guess on everything you're going to read some crazy stuff on the Internet. So tragically to me because I don't believe there's.

And when you say fish oil, is it more the EPA that's having the effect on triglyceride or dha?

EPA would have more an effect on apob. But DHA is the triglyceride. These are some recent new data publish on that because DHA is just more potent on C3 than is EPA. So I personally think you ought to give both. If the primary reason you're going to throw a fish oil, a prescription fish oil product at somebody is I need extra APOB lowering. Yeah. Then I would give high dose EPA. But I monitor Omega 3 levels in everybody. So not everybody can convert EPA to dha. DHA is just as crucial for a lot of reasons. Your brain sure wants it. So I will measure. Oh my God. I'm giving you a lot of epa but you're one of the people who can't convert it to dha. So then I would give you dha. Give you some DHA or you take the high strength EPA and you throw in a lesser strength EPA DHA combo tablet, which is how you get it. As far as I know, there's no DHA only tablet. Where is EPA only tablets? Certainly in the prescription realm. So, you know, fine, if you want to lower apob, you can stick with your apob. But I don't have where is my evidence that if I used whatever fish oil therapy you want to use, I, I'm happy I'm improving microvascular disease. I have pretty serious evidence that I'm doing that at least with phenofibrate. And the other thing, although they're both available generically sometimes these old drug companies, they'll force gemfibrazole on you. The real reason, when you ask me, are there any side effects about fibrates and I did say the word drug interactions. Phenofibrate has a serious drug interaction with, with Coumadin. So you have to lessen the Coumadin dose there.

We're using a lot less eliquis these days.

Yeah. So that's becoming less of a big worry. But God forbid somebody's on coumin and you didn't know that you threw big dose phenofibrate out on me, they'd be calling you up with a lot of bruises because, you know, you potentiate the anticoagulant effect. Gemfibrazole, though has her raises statin levels through the roof. So there's much more in incidence of myositis and rhabdomyolysis when you use gemfibrazole with a statin and there's none of it with phenofibrate. So if you want to use a fibrate, I strongly encourage you because it is generic nowadays too to use phenofibrate because you're going to be using it with a statin in the vast majority of cases. So you don't have that worry, the muscular worry or so. So those are two big things you better know about fibrates you don't get. So most of the lipidologists at least were somewhat schooled on fibrates, are going to use it in people where the triglyceride parameter is still high because they're assuming. I think if we had better metrics of triglyceride rich lipoproteins, maybe VLDL remnants or people who have high LDL triglyceride levels and they would likely be people who have Apoc3 on their LD LDLs. We have some other evidence that I want to fibrate on board you or so. So that's where that's going to get used. But that's not your average person who walks into. And if he walks into the average doctor, doc's going to be chasing LDL cholesterol or non H.L. cholesterol if they're a little more astute and they're going to stop there.

I want to come back to I made a note here to come back to VLDL remnants. So I want to I got another question on that. But I do want to finish our tour of drugs. So the next drug to then get into we've already kind of talked about a little bit. But I want to come back to it because I know you have a strong point of view on it. And I got to be honest, I'm a little bit ambivalent. I don't know the last time I prescribed this drug. But just from an intellectual standpoint, I'm always interested in these drugs for people who can't go down a mainstream route. And that drug, of course is niacin. So I don't think there's anybody out there that says, hey, niacin is first line. I don't think anybody would argue that. I think the question is you take a statin intolerant patient who's got normal triglycerides, who maybe doesn't respond particularly well to monotherapy zetia, who can't afford a PCSK9 inhibitor and doesn't meet the regs for approval, are these patients who should be on niacin? So I'll go back to where we were earlier. Niacin exists in an immediate release and in a time release form.

Two types of, of time release forms.

Oh, I didn't even realize that.

Intermediate release and sustained.

So Nia span, the Abbott version, intermediate.

And that's a prescription only product which you're not going to get covered by any.

I learned that the hard way because I had a patient that was on it a few years ago and he got a bill for like they wanted $3,000 for no B vitamins. It's ridiculous.

But if you want to, you somehow believe in niacin or want to give it a trial immediate release and you got to give it three, four times a day at massive doses. You'll flush your brains out. Most people you're going to make the case you're not flushing. Niacin isn't working and you get. So let's talk about the sustained release is cheap. You can get sustained release. But the biggest problem was in clinical trials, niacin being the toxic drug. It is. There's Way more hepatotoxicity with sustained release niacin than there is with the short release or the extended release ended release where there's no hepatotoxicity.

So first of all, niacin became interesting as you talked about, because it's known, it's been known for a long period of time. It lowers cholesterol. Lowered LDL cholesterol.

Yeah. And better yet, raised HDL cholesterol. That's what everybody always focus on everybody. And since low HL cholesterol is a risk factor, we now know apob related. But whatever. Therefore, if low HDL cholesterol is bad, raise HL cholesterol has to be good. And niacin is the best product you had at the time. And then so trials were done with niacin. And it was kind of funny because I listened to the podcast you and Ron Krause did, and it was kind of cool because you made the case a little bit for niacin. Ron did. But at the end, as you just said, you're ambivalent to it. And even Ron says, I don't use it much anymore. And then you maybe wind up, okay, it's a fourth line drug. If everything else is fair. Oh, all right. I'm not going to smack you around too much if you say that. And you can't prescribe a PCSK9 inhibitor because of cost. All right. But I think at the end of your. Go back and listen to you, you both submitted, you don't use the darn drug anymore.

I think the difference is, and this is where I'd love to hear your take. I think Ron's point of view was the niacin trials may have failed for the same reason that we would see the discussions we talked about earlier, which was overly statinized patients. Now you kind of had a different, different point of view on that, right?

No, because there was never. They weren't statinized in any. As certainly the big niacin has one trial designed to use niacin as a monotherapy. It was that big coronary drug project, which was a multi pronged therapeutic trial where they randomized people to a bunch of drugs. One group was given solely thyroid hormone. Thyroid hormone lowers LDL cholesterol. And all they did was kill people by with coronary disease, you give them thyroid hormone. They're not.

You make them hyperthyroid.

You make them hyperthyroid. Not exactly good if you have coronary art. So that drug failed. They used a primitive fibrate clofibrate and there Was some question of a mortality adversity there. So that was hit number one on the whole. Nobody in America uses Cofibrate anymore. It's probably still available in Europe. I don't think anybody uses it. So fibrate arm of that trial failed. And they used estrogen given to men because, hey, women don't get heart disease because they have high estrogen levels. If we just gave estrogen to men, they wouldn't get heart attacks. And they had immediately stopped the trial by precipitating heart attacks in men by prescribing estrogen.

So the only thing that would make that funnier was, please tell me they gave it orally.

They did.

Oh, yeah.

That's about the only form they had back then anyway.

So.

Yes, and then they had a niacin immediate release niacin arm. And now, you know, in a clinical trial world, if you go down to the FDA and you just put a drug through a clinical trial, better be empowered or better not have been much toxicity. And you better come in and have hit your primary end endpoint because what will the FDA never, ever allow you to discuss? A secondary endpoint. If you fail the primary endpoint, you have a failed drug. All you've done by improving some secondary endpoint is generated a new hypothesis. Let's go back and do a trial on those people. So what was the primary endpoint in the coronary drug project, the favorite endpoint that people today love? Mortality. And guess what niacin did to mortality? It worsened it. Not statistically, but it. You could say it was null, but it was certainly going in the wrong direction. So did I care when they did the secondary analysis that. But wait a minute. Myocardial infarctions were down. It was like me telling you in that aortic stenosis trial. But hey, Zetti, it reduced myocardial infarctions, but it didn't reduce aortic.

But in fairness, was the trial powered for mortality or was it powered for.

Look, this statistics done it. No, it was powered or mortality was the end. The only endpoint in all the arms of those trials. That's what they were looking back at then.

All cause mortality or coronary mortality?

No, it was all cause mortality. I don't know, it failed.

It's kind of amazing because, I mean, that's very unusual.

Talking about a trial in the 1960s, you know, early trials, you know, what, how they picked endpoints and stuff. But niacin. So don't come and preach to me that it hits secondary endpoints.

Wait a second, wait a second. Why is it that niacin failed this trial in the 60s and it was only three or four years ago that the basically the payers said we're no longer paying for it?

Well, because we've had a lot of other trial data that's come down since then where other types of niacin and probably better designed trials also failed to reduce any endpoints. So the evidence became overwhelming. Show me a damn trial where it works and then maybe we'll give you. We'll pay for it at least the FBI, FDA would never give it an indication without primary endpoint data or. So then the other thing they did with that coronary drug project is they published like 10, 12 years later the most ridiculous post hoc analysis done on questionnaires sent to people who they could round up who they discovered you were in the original trial, small number. And lo and behold, mortality was improved in that group of people. Coronary mortality. So there we have evidence that niacin improves coronary mortality.

The problem is of this selection, but it's still worse.

It wouldn't even be published today. It would be laughed at if you ever submitted it to a journal. The. The coronary drug project might. I don't think a drug company would even send the coronary drug project to a journal nowadays. I mean, they almost have to nowadays. No trials. They tried to hide that in the end, but you know, it get population. Thank God it did. So we learned a lot about a lot of drugs in that trial. So there was no evidence in a trial designed to prove niacin reduce coronary heart disease, at least the level one evidence. Then of course, guys said, well, angiography got introduced and they could start doing regular angiograms called quantitative angiogram, where you're basically looking at the lumen of an artery and seeing how much plaque may be extruding into the lumen. You're doing nothing to what plaque may be existing in the coronary artery walls. And in that trial using quantitative angiography, they did see a statistically significant improvement in the lumen of arteries in people with coronary artery disease who took niacin. That's the Hatch trial. It's a small well under 100 people given niacin, no statins or anything, and they come to this inclusion was a 90% event reduction. Not only did we see a fraction of a millimeter increase in the lumen, and by the way, at that rate, it would have taken you 200 years to open up the artery seriously to hemodynamic blood flow, but in this Small cohort in a trial. Absolutely not empowered to look at clinical outcomes. There were less coronary events in this trial and that got extrapolated through a lot of disingenuous marketing of people saying, oh, look at this, nothing ever gives you that type of outcome. Reduction in Niacin, 90% event reduction. And there are a bunch of.

I'm sorry, just make sure I understand that. I'm actually not even familiar with the Hatch trial. So this had 100 subjects in it.

Yeah.

So 50 in each arm. It was a one to one randomization.

No, I think they just did angiograms of people and they put them on niacin and they did a repeat 100.

People with a crossover. Basically you were your own control.

Yeah. Your baseline arteriogram was. And your follow up.

Right. So the. I mean, I don't want to get into a lecture on shitty science, but I can't help myself. To be clear, there's no placebo group here.

Right.

In other words, you've completely eliminated.

You're looking at angiographic changes from a drug.

No, I understood, but there's a performance bias here. Every patient in that trial knows that they are being given a compound that is supposed to make them better.

Yeah. And they're given other advice too. But.

But the point is you have no idea of knowing if they've changed any other behavior that may or may not contribute to an improvement. Notwithstanding the bigger issue I would have with that trial, which is that the millimeter change of an angiogram doesn't actually tell us anything about.

We now know it's meaningless. Yeah.

The vulnerability of plaque or true events.

No. And you know, and you certainly can use that type of numbers of people to generate outcome data. They did it. It was disingenuous for them to do it. It's absurd for anybody to ever talk about it, but they did it. And because, look, we're in our infancy on these drugs. We didn't, you know, we're learning as we go along. It's easy for us to say that now and everything. And there were three or four other nice. And angiographic trials that sort of indicate body images look better when we follow up on these people. And HDL cholesterol is going up, so what else could it be? And that hdl, that Hatch trial was so impressive to people that they said the only way we really can prove this is to do a giant randomized prospective blinded trial where we give niacin, add it to whatever else, get this HDL raising on top of we're already given drugs that lower LDL cholesterol aim high. So aim high was the first. So there'd been no aim high if there wasn't this hat's angiographic trial first. That was the whole premise to let's spend money on the aim high trial. Because now we are in the statin error where you do have to give everybody a statin. So we'll make everybody's LDL cholesterol perfect. And by the way, if a statin doesn't do it, we'll add ezetimibe to it also. So we will get LDL C per perfect. But HCLC is still going to be low. So we're now going to add niacin.

And this I think is Ron's real point, which is when you look at that trial, which was really then using niacin to increase HDL C in an already optimized LDL patient, you missed an opportunity to actually miss it.

Because here's what happened in that trial. Niacin made the apob go lower than statin and ezetimibe did by themselves. So you got additional serious apob lowering and no outcome reduction.

So how much lower did you get?

Another 10, 15%. So here is a drug that is drastically further lowering apob atherogenic particles. It's raising that as I now call it stupid metric, HDL cholesterol. But it's not working. Well, I just told you. Raloxifen, I believe works because it lowers apob. Why did niacin. Because it's gotta be doing something bad that's aggravating your arteries. And you give me a drug that causes acanthosis nigricans in human beings, pathognomonic of insulin resistance. Why would I ever give that drug to a human being? So niacin causes worsens and the only person who you're probably going to wind up giving niacin to is probably insulin resistant, identified by triglyceride HDL I abnormalities. You're giving niacin and it makes them worse. I could read off 15 other well known side effects with niacin.

I don't think anybody would dispute that. I think, I think it's.

Why did it fail even though it lowered apob beyond what?

And that's very interesting. That's a very interesting point. Right. And I guess the only. If I could wave a magic wand, the only other question I'd have, which is purely intellectual, again, I don't really think niacin has a place anymore is could the Wash on mortality despite the reduction in apob. Be explained by the worsening of insulin resistance.

Explained by something.

Yeah, no, but I'm saying like that would actually be an interesting thing to try to quantify.

Could be explained by GI bleeding above an occult in acute niacin well known to do that. It could be explained by all sorts of hematologic parameters. Disruption, platelet reactivity with niacin well known and a bunch of other things that niacin has been implicated in. So to me, every time you use a drug you're using trial data benefits versus risk. And I, I see some benefits to niacin. I don't think the HCL is a benefit. But lowering apob I'm going to always consider that a good benefit. But if it's nothing is happening. There's something adverse going on which I don't understand. Look, they took that extended release product off the market in Europe based on this trial in the United States. It's still here, but you just made it unaffordable. So they don't want you using any immediate release. Niacin is. You're basically prescribing a vitamin at a mega dose. One other little aside because I notice people who take niacin, remember these trials were done with massive pharmacological doses of niacin. They didn't tell take a multivitamin with niacin in it which has does nothing to lipids or lipoproteins. So if you want to be a niacin player will you in the coronary drug project immediate release and ice was 4 grams a day. Try that sustain release niacin.

Wait, so those patients took one gram four times a day?

Yeah. They'll work their way up to it. Yeah. You know so because many just hey, if this is as much it can take, that's what you. But they got them on pretty high doses. I will say in those days. Kudos to the docs in those trials and everything.

So extra number of people for tolerating.

Yeah, listen, if you get not only flushing, but massive pruritus can occur when you use immediate release. It's a scary phenomenon to a layman who experiences that who hasn't been worn. I remember a call I got early in my practice like at 2 in the morning. The guy thought he was gonna die. He had dialed 911 because he just had an extensive pruritic reaction and he felt his whole body was on fire. If he'd had a swimming pool, he would have jumped into it. But he go because he Just thought his body was burning up and I just said you're going to think I'm crazy. Chew two aspirins and just call me back in an hour, it'll be gone. And I forget whether he did wind up in the ER Noff. Now that's an extreme reaction but it occurs so and look, I took nice in a couple of years on myself on some of the beliefs before we knew a lot of this that because I could not tolerate a statin or statin ezetimibe and I had an APOB issue and I hadn't learned about intermittent fasting or followed a low carb diet at that time. So unfortunately niacin didn't even lower the apob in me. Did nothing but I tolerated it for whatever reason but did nothing. And who knows what it did to my insulin resistance.

You know for me niacin sort of grew out of favor with patients even before the final trial. I think just the exacerbation of insulin resistance became sort of problematic.

And by the way the last trial they did another trial because it was a branded product. They took that extended release niacin but they combined it with an anti itch compound and aha. So everybody's can tolerate niacin now and they added it to a statin that was the heart protection study thrive and it was basically a duplication of the aim high trial. Nice increase in HDL cholesterol, further reduction in apob and zero outcome change. And a lot of toxicity include much of the toxicity is just glucose extirpations. You're going to aggravate glucose anyway. So Europe decided that's it. So they took that combo pill off the market. I'm sure you can still get immediate release niacin in Europe if you want it. You know it's a vitamin for God's sakes, a mega dose. So I just don't like people out there who want to experience stole niacin. Fine, but don't start telling niacin has a lot of data, it's got zero data. And these are the same people who bash fibrates who do have two large randomized prospective trials, Helsinki and VA hit with fibrates and yet they never consider a fibrate. They always tell you niacin is the better drug. And at least in the field trial niacin or phenofibrate had all these micro neurovascular. There's no prayer. Niacin reduces diabetic and retinopathy, amputations, kidney disease. But yet there was that battle people bashed fibrates hold them to the high standard of you got to hit your primary endpoint. And they never held niacin. And to be honest with you, the same. That's what Ron Kraus did in that study. So I understand what he's talking about. There is some data, if you want to extol it, but it's not the type of data you and I use anymore.

So we'll go from the. The stepchild to the poster child, which we've already kind of alluded to, which are repatha and praluent, these two PCSK9 inhibitors. And I'll just give a little bit of background, obviously. What's the name of the fellow up in Toronto who actually discovered this?

Oh, I thought it was in Texas. Hobbs. Helen Hobbs was the first person who discovered the PCSK9 expression.

The actual family of PCs. The PCs family, yeah.

PCs. Look, there's at least 10 members in the family. They've been around forever.

Yeah. And I think.

I don't know who discovered.

I don't know. I think because I grew up in Toronto, I have a fondness for remembering anything that anyone from Toronto did. But we'll figure it out in the show notes. I could be making all this up, but I do think there was. There's a guy in Toronto who actually discovered this family of proteins. But you're right, then the Helen Hodgs.

Did the genetic evaluation at gain of function. Loss of function explains how the gain.

Of functions were discovered first. Correct?

Yeah.

So I'll explain this really quickly and briefly. You can expand upon it. PCSK9 degrades LDL receptors. So if you have a gain of function, you are more rapidly degrading LDL receptors on the liver. You're going to have a decrease in your clearance of ldl. You will have a higher ldl. These patients had very high events. In fact, these patients are make up what, 5 to 10% of what we would diffusely refer to as familial hypercholesterolemia.

Correct. It's one of the many. And I was like one of the podcasts people don't understand. FH could be a thousand different disorders.

FH is a phenotype.

They're not all autosomal dominant. Some are heterozygous disorders of various genes. But the phenotype is an LDL. Cholesterol above 100.

And then you fast forward to about 2004, 2005, maybe it was 2006, but even I remember this. And again, this is before I became kind of a Lipid wannabe. But I would still read the New England Journal of Medicine just because it's sort of interesting. And there was the discovery of the hypo functioning PCSK9 folks. And I really do remember this and I'm surprised I remember it given that.

It was discovered in African Americans first, I believe in the Jackson trial.

That's exactly right.

Yeah.

And these were folks that were walking around with an LDL cholesterol between 10 and 30 milligrams per deciliter. And they were completely event free. And of course the first 100% but significant reduction, dramatic reduction, and the reductions, I believe we actually went back and did a calculation to see if their reductions, how congruent they were with some of the more recent Mendelian randomizations. And they're very similar. And it's not surprising because that's effectively how you would model a reduction, a lifetime exposure reduction. The thing that interested me because I remember at the time, like many people I'm sure I sort of had this concern which is, well, God, if cholesterol levels, I mean, I now realize I was being naive, but my concern was, God, if your LDL is low, that must mean you can't make hormones. It must mean that you're going to get some other awful disease. And so the interesting thing to me was those people didn't have any of these other phenotypes. They didn't seem to have deficiencies or deficits as a result of that. And of course I think that trial is what was the catalyst for Amgen Sanofi and these other companies to start working on these drugs.

Yes. And by the way, they since studied in these people where They've blown away LDL cholesterol at 10 and 15. There's been zero effect on reproductive hormones or adrenal cortical hormones. Goes back to what I just told you. Those glands synthesize all the cholesterol they need. They get it from hdl. So none of them are waiting for an LDL to show up with cholesterol to keep them functioning. So it's all the nonsense you get when you go to a health food store or a gym where the guy tells you you gotta raise your HDL cholesterol or something because you're helping your testosterone level in the blood has nothing to do with. Or if you deplete testosterone because God forbid you, you actually taking a statin, you're screwing up your testicular function, you're not having nothing to do with it.

Yeah, yeah. There doesn't seem to be any evidence of that.

So that put into perspective. Yes, but. So the genetic model is if you got an LDL cholesterol of 10 and 20, nothing's going to be wrong with you and you're certainly going to have far less coronary heart disease. And when we talk about loss of function, that means your LDL receptor half life, life is much longer. We didn't get into it before we told you the liver makes LDL receptors. Theoretically any cell could. If your liver expresses an LDL receptor, how long does it stay there? For two, three days. And it grabs your apob particle, it brings it into an endosome, but then the LDL receptor travels back to the surface, grabs another one. I used to, those of you old enough who used to watch the Adams famous on tv, it's like thing's hand coming out of a box. It's the LDL receptor. Grabs something, pulls it in, but things arm comes right back out again. But if in some people that LDL receptor might be catabolized in the lysosome endosome, then it can't go back to the surface. And PCSK9 is a major determinant of how quickly you recycle your LDL receptor. You do not recycle it. So by putzing with the expression of that enzyme, we can give you much further expression of your LDL receptor and as you said, enhance clearance of your apob particles, including not only your LDLs, which are 90 to 95%, but you're clearing remnants also. So for those who believe oh, remnants are the bad guys, that's not a reason not to use a PCSK9 in here, but get rid of them also.

Now we're going to come back to this because I want to talk a little bit about the brain and you alluded to it earlier, but I don't want to derail us now. So going to, I'm saying this just as much to remind me as to remind you you can come up with multiple ways to lower ldl. And I say ldl, I'm talking the actual particle number. You can inhibit the synthesis of cholesterol, which in turn also activates the clearance. Or you can just go directly after the clearance. So the former would be how a statin works, the latter would be how a PCSK9 inhibitor works.

You can also make the evidence that, that if you're depleting the cholesterol pool in the liver, you'll make a few less either LDL particles or vldl precursors, which would contribute to A lowering of apob. And that is a small part of both ezetimibes and a statins effect. Most of it is clearance, but you are producing less particles too.

But this is an area where I do probably have a slightly different view from the mainstream lipid world, which is certainly there's a favorable hypothesis that's the zero LDL hypothesis.

This idea that, well, you can't make ldl.

Let me rephrase that. What they're basically arguing is the lower you drive ldl, the better. And I do take a little bit of issue with that because I think it depends how you lower it and it also depends on what you define as better or worse. If you're talking about lowering LDL reduces the risk of atherosclerosis, I think that's pretty clear. But at some point, my concern has always been if you lower LDL through cholesterol synthesis inhibition a lot, do you impact other organs, namely the brain?

Well, you don't know. Remember, when you're measuring whatever LDL metric, it's what's in floating around your plasma. The only place I'll make that's irrelevant, you know, you're not measuring cellular cholesterol based on an LDL cholesterol. So you tell me what your LDL cholesterol level is. I have really no clue. Are your cells synthesizing or not synthesizing, exporting, effluxing or whatever to particles that carry cholesterol. But as I think we indicated earlier in our talk today, look, it is integral cells do have to make cholesterol. So you certainly wouldn't want to stop cholesterol synthesis in probably any cell in your body because the cell membranes of nothing else requires it. And we talked about the brain. Certainly the only way it has cholesterol is it makes it. So if we did know we were inhibiting cholesterol synthesis in the brain, would you be really that comfortable with that? And if you were, is there certain limits where I wouldn't mind reducing it a little bit bit, but how much? Because that brain really needs it and the brain has no other source of cholesterol.

Now, nowadays, with the exception of patients who have been on a statin for a long, long period of time, when it comes to patients that are relatively new to statins, there are really only a handful we're really looking at today, right. Lipitor and Crestor are doing the lion's share of the work. You know, for some patients who are very sensitive, we'll use Livalo or we'll use Use Prevastatin. But we're not really doing much in the way of Simvastatin or any of these older drugs, correct?

No, no. If you're following guidelines, what you're doing is prescribing high potency statins or at least moderate intensity statins. So if you want to follow the guidelines, the only choices you have are Rosuvastatin or Atorvastatin, Lipitora crestor at a 40 milligram or above dose for Atorva or a 20 milligram or above dose for Resuva. If you're stuck, they would allow you to sneak Simba 40mg into there, but that's at best a moderate dose stat. And 80mg of Simba has been taken.

Off the market quite high with Simba.

Well, Simba, because of a variety of pharmacokinetic reasons, has a ton of drug. Drug interactions and we're in a polypharmacy world. Whereas there's far less with Atorva and infinitely less with Rosuvastatin and the Pitavistatin. You mentioned liver lower. So. But I would make the case that if you want the statin has the most data that you're going to do good, it would be Pravastatin and Pravastatin very cheap. It's almost free. If you go to a drugstore for.

It, it's just not that potent. Right. Even at 80 milligrams, you know, but.

If you use the outcome trials, they got the exact same 20, 25% reduction as any ETORVA or ROSUVA trial ever did. So again, Bristol used to explain that to magical mystery Pleiotropic effects of pravastatin. But I would make the case that. All right, if APOB LDLP is your problem.

I would also argue, though, patients are sicker today. I think patients are more metabolically ill today than they were. Meaning I think the Crestor trials have a higher bar to cross than the Previs trials. But then again, that's just my speculation.

Oh. I think the lipid level enrollments with the west of Scotland were twice as horrific as any residual statin.

Yeah, they were, but they had fh. So these are patients who weren't necessarily.

Metabolically ill. Yeah, I understand what you're saying. So the end of this discussion comes. I got a lower apob.

Yeah.

So, yeah, you'll in unless somebody's incredibly statin sensitive in our ways of predicting statin responsiveness or hyporesponsiveness of this. If you Want to just routinely pick for Rezuvastatin and go down that path. I'm all for you.

So what do we know about CNS penetration of these statins?

Well, we'll get to that. And look, I jumped on Rosuvastatin bandwagon being a giant Pravastatin guy because it's one of the what I would call hepatoselective statins. It's hydrophilic, it goes right into the liver. It doesn't need transporters. So you don't need much of the drug to get in the liver, inhibit cholesterol synthesis and upregulate LDL receptors. So resume a statin, 5mg is all a lot of people need. You don't need 40, they want you to 40 because in a trial that's the dose they use where they got heart attack reduction. But since it all comes back to apob reduction, use whatever it takes to get your apob down. In my mind, you know, that's not how the guidelines exactly figure out how to do it. They like to give level one star rated evidence or so mine be a lesser degree of evidence. So you pick. So they get in. The other drugs are not as hydrophilic. So the only way they get into the liver is various receptors pull them in. There's a whole variety of transporters that pull molecules into the liver, but they're subject to interference with a ton of other drugs that may be in your system or other molecules. So you don't have the clean pharmacokinetics like you do with Pravastat or Rosuvastatin. That being said, you want to introduce the brain into the discussion. Now all statins can get into the brain. They can cross the blood brain barrier, but the statins that cross it much easily are the lipophilic statins because they have to pass a lipid membrane, the blood brain barrier. So atorvastatin, simvastatin get into the brain more easily than then do lovastatin, Simvastatin and atorvastatin.

Wait, say that again.

The most lipophilic, the lipophilic statin's easier.

To cross the blood and Simvastatin are the two.

Lovastatin would probably be the worst, you.

Know, whereas prevastatin it'd be Pravastatin would be far less.

Edward, with resource statin you have that Fluvastatin, sort of a water soluble statin is probably more in the class of Razuvin. And what about little so Livalo would be the same. So you non lipophilic statin. So if you're worried about statins getting into the brain, you might want to choose the hydrophilic ones or so. But the only concern I might have is, well, if those statins are getting into the brain, it's great to reduce cholesterol synthesis in a liver. I'm going to upregulate LDL receptors. I don't know that I want to do in every cell in the body, but I'm probably not. I know I'm not with any of them. Totally inhibiting cellular synthesis, cholesterol. But the brain, it's way more dependent on cholesterol. And then we have studies of people with Alzheimer's disease and other cognitive. Their brains seem to be depleted of cholesterol to variable degrees.

Now, Tom, I'm just going to stop you right here because if I had a dollar for every time I had a brutal argument with a cardiologist about this point. Because up until this point in the discussion, if you're a card carrying lipidologist or a cardiologist who really understands lipids, you're kind of on board. You're in the camp of let's lower ldl. But I do get patients from time to time who are more than at their LDL goal, meaning their LDL cholesterol is 40 milligrams per deciliter. Their LDL particle number is 500 nanomole per liter. These are people in primary prevention. But, you know, let's assume they have a calcium score of 800 or something. I mean, they're very high risk. But I look at that and I say, well, God, their desmosterol levels unmeasurable.

Well, you're advancing the discussion here. So let me continue down this pathway. So if cholesterol synthesis is so crucial for the brain, man, I need a biomarker of brain cholesterol synthesis. Now, very interesting. We talked about two pathways of cholesterol synthesis. One is the desmosterol, a block pathway, and the other is the lefosterol, the cancer Dutch Russell pathway. Well, it turns out the block pathway predominates in the brain. So would. But should I do spinal taps and measure CSF desmosterol in these people, I'm.

Gonna go with no.

Yeah, it'd be a tough. Oh, by the way, don't leave. I'm gonna come back and just do a quick spinal tap on you today.

Hang on, just, just wait there in the waiting room or imagine even trying.

To, trying to do A clinical trial where that was what you're trying to prove and enrolling people into that, you know, so isn't going to happen. But so people know we can measure desmosterol in the blood and there's lots of articles correlating that with cholesterol synthesis as there is with lithosterol. And you can make the case in peripheral cells, maybe even lithosterol is a more dominant pathway. They're probably both at play. But also the desmostral pathway is much more important in younger newborns and youth rather than older people. So I didn't know that. Yeah. So maybe that's a critical patient. If you for whatever reason want to give a statin to a really young fh, a homozygous FH patient.

I've been involved in one of those cases.

So my desmostral be mining. So here's what we know. So when people with these cognitive, mild cognitive impairment or various dementias have low cholesterol, when you wind up autopsy in their brain, they do have low desmostral in their cerebral spinal fluid suggesting that they do part of their impairment or cholesterol depletion in the brain is their, their brains aren't synthesizing as much cholesterol. And nice trial where they done this. They car. They did do spinal taps on the people in the trial measured CSF desmostral and they measured serum desmostral.

What was the correlation?

Identical. The RVA is very high in there. So now all of a sudden a serum desmostral level becomes a biomarker of brain synthesis. Synthesis of cholesterol. And there are what is by far, it's not even close the biggest reason that a brain has suppressed desmostral cholesterol synthesis. It's statinus. Yeah. So I would make the case and.

I'm going to pause here because I know what you're going to say and I agree, but I'm going to give you the counterpoint before you even start so you can color your commentary. The heterogeneous population based data say statins reduce Alzheimer's disease.

Nothing serious suggests that. I mean, yeah, you want to start looking at crazy.

Which is not to say that the trials are using that as an outcome. It's just that we're not seeing an increase in Alzheimer's disease in the statins.

Dementia is a multifactorial disease. A lot of things that contribute to dementia. So. So in general, do the vast majority of people take statins, wind up dementin? No, absolutely not. There's not any evidence that has shown that, at least from the cumulative statin trials or so. But are there certain individuals where that is. And by the way, in these trials where they measured low bottom both serum and CSF desmosterol, guess what? There was a significantly increased incidence of Alzheimer's disease and mild cognitive impairment. So yes, this is all at the hypothesis level. It's looking at a biomarker, not clinical endpoint trials. But that's enough evidence to me to say if I'm going to give you a statin, I'm going to push it to. I would, for a variety of reasons, much rather give you a baby statin plus ezetimibe. And by the way, baby statin plus ezetImibe gives you the exact same apob reduction as does the gorilla statin, the mega dose of it. But I think with a lot of other additional benefits ezetimibe brings and certainly less potential side effects and certainly less cholesterol synthesis suppression, including the brain. So if I were giving you massive doses of your favorite gorilla statin per guidelines, and I simply measured serum desmostral on your next visit and it was low, that tells me I've over. I've stopped the synthesis of cholesterol too much.

So, Tom, you are the only other person in this space who will entertain this discussion with me. I mean, I just can't tell you how many times I get into debates with other lipid folks who say that is complete and utter nonsense. And they point to the absence of a huge upsurge in Alzheimer's disease in the statin trials. Now, to which I say the following. One, I am sympathetic to what you are saying because I realize that all of the anti statin rhetoric out there is so illogical and they throw everything in the sink, right? Like, you know, oh my God, it causes diabetes. Does it?

Well, yeah.

In a small, small subset of the population, we're going to see a slight uptick in the risk of diabetes, especially with atorvastatin. Does that mean statins cause diabetes and it needs to be avoided as a result of that? No, of course not. Does it, you know, do a subset of patients end up getting, you know, muscular pain? Of course, it's probably 5 to 10%. It might be even a bit higher depending on the nature of the trial. But what I think is really going on here, this is, this is my hypothesis. Alzheimer's disease, as you said a second ago, is multiple diseases. It is not a disease.

Right. Cognitive impairment.

But even if you talk about Alzheimer's disease, even if there is a final common pathway or a set of pathognomonic features that define the disease, I think there are several ways to get there. There is a metabolic way that people get there that is probably explained by the increased incidence we see in cognitive impairment and Alzheimer's disease in patients with diabetes and insulin resistance. But there's also a vascular component that I don't think gets nearly enough attention. There's a guy named Jack de la Tour who I. You know, it's funny, I reached out to him recently to interview him for my book, and he's on a research sabbatical in Spain for two years, so I'll probably interview him by telephone. But I would like to eventually have him on the podcast. But he's done some of the most impressive work on looking at this sort of vascular hypothesis of Alzheimer's disease. My hypothesis is this, on average, you take a group of patients with terrible dyslipidemia, you give them a statin, you improve their vascular complications, which include atherosclerosis, and you're probably actually reducing Alzheimer's disease in those patients. In other words, all things coming. Are you better at being at the 90th percentile or the 10th percentile of APOB with respect to Alzheimer's disease? You're better off being at the 10th percentile. However, I think to your point, there's going to be a subset of patients in which you go too far. These are patients who don't synthesize a boatload of cholesterol. They're probably hyposynthesizers to begin with with. And you statinize the hell out of them and you are increasing their susceptibility. Now, again, that's the problem with everything I just said, is it takes more than a tweet.

And for anybody who throws it in your face, there's no evidence of that in any statin trial. Say, oh, my God, I've read the FDA package insert of every single statin that's on the market. And cognitive impairment is listed as a potential side effect of every single statin. Did the FDA just make that up up? No, it's been seen in.

Now, did the FDA make this link? Because I, you know, I'm talking about paper. There are actually papers that show. And we will absolutely link to this because I think this is one of the better papers. It's about six years old, but it looks at Desmosterol as a continuous variable. So in the same way that you might look at PSA as a continuous variable, it can be anything and try to decide the question at what cutoff does having a high PSA suggest that you have a high enough risk of prostate cancer? But using Desmosterol as a continuous variable and using a statistical technique called receiver operating characteristic curve production, they showed that once desmosterol fell below 0.5, the AUC, the area under the curve of the receiver operating characteristic was somewhere between 0.8 and 0.87, depending on the study and depending on gender. And again, maybe it's more detail than people want, but the higher that number, which varies basically between 0.5 and 1, 1 is a perfect study. One, there's no such thing as a diagnostic test with a 1, 5 is a coin toss when you get into the 0.8 territory, that's a very powerful predictor.

Correct. So I think it's careless to dismiss that as a potential player. We've given you a lot of the plausibility and there's even more. If you tell me you are a doctor who has prescribed a lot of statins and look, I was in practice 37 years, 20 of which I was writing as much statins as anybody. If you tell me you've never seen cognitive impairment in a patient you've started on a statin, you're a liar or you're a fool or you're not questioning your patients when they come back because it does occur. I don't know what a lot of reasons it could occur. And look, who doesn't have a day where you wake up thinking, I'm a little foggy today for some and it's nothing to do, but it happens. So we've now got a plausible explanation why it happens. If the real reason you're prescribing a statin is apob reductions, I got a lot of ways of getting your APOB to go without maximizing a statin. So in my mind, if Desmosterol is below a certain population percentile cut point, I've inhibited cholesterol synthesis probably. I probably get no bang for the buck on further LDL or particle lowering. APOB lowering. By having you continue to take that, I can clear APOB furthers by stopping cholesterol absorption back into the liver and the intestine. With Ezetimibe, that does nothing to cholesterol synthesis, a PCSK9 inhibitor. So. And in most people, baby statin and ezetimibe will give you the exact same APOB reduction of your gorilla statin. And we have outcome evidence in the improve it trial that Ezetimibe and statin for the guys I gotta see outcome data. You got it. So therefore, I use it as a tool to monitor statin therapy. Most people, and they also. These people would argue you, I will bet as much money as I have in my bank account, they never, they couldn't even tell you what Desmosterol is. They've never read anything about the cholesterol astral synthetic pathway and they don't know what they're talking about.

Yeah, I mean, look, in the end, I think this is such a contentious topic because we're getting so nuanced on something now and the world has lost its appetite for nuance. People want to know statins are good or statins are bad. And everything we've just said says it depends. Right? It depends on how you use them. You can give too much of these things. That doesn't mean they're bad. Because what we've also done, I realize, and I've been very deliberate about this because I think it's important to show both sides of this. We've also given the statin deniers in the statin, you know, the statin conspiracy theorists, a great ammo, which is, aha. If Dayspring and Atiya are sitting there bashing statins and talking about mild cognitive impairment and they take that discussion out of context, they're going to say, well, statins should be outlawed.

Yeah. And of course, any reasonable doctor, if a patient came in complaining of statin or a cognitive impairment impairment, they pretty much stop all drugs because that's the first explanation a drug is causing it. So it's not like I'd continue to force you to take a statin if you were cognitively impaired.

I mean, if the listener is sort of saying, what the hell is the takeaway from this? I think it's a couple things. One is statins are not bad. Statins are still the mainstay backbone of anti lipid therapy. Be thoughtful about which ones you use. You know, Tom, I have moved more to Crestor over Lipitor, though I still use Lipitor quite a bit. And in many ways, I'm sort of slowly migrating patients who seem to have no difficulty from Lipitor to Crestor. Two, I'm actually going back and using Pravastatin much more than I used to. I'm surprised at how much I find myself reaching for Prevastatin in a patient who doesn't tolerate, who has a slight CK bump. Even if they're not complaining of pain, if they're getting a CK Bump that you know their CK goes from a baseline of 50 to 300 even if they're asymptomatic. I don't like it, so I'm going to switch that.

By the way, I would chip in. That CK elevation has nothing to do with statin toxicity or statin. So it's a silly biomarker to follow.

You think so?

Totally. And the evidence would totally.

Well, I know it doesn't correlate that well with myositis at all.

First of all, before you ever do that, make sure you have a baseline ck. Because a lot of people, especially African Americans, not even working out, they just have high CK levels. African Americans. So.

So, but I didn't realize that you.

Know when you should stop a statin with a C. When is like a 10,000 fold elevation of CK, then you might start to worry. So CK, there's any number of guidelines issued on. It's not a biomarker that is of any use to you. And all you do by doing CK is when somebody goes from 50 to 300, they get the bejesus scared out of them and they stop their statin when there's no reason. The reason you should stop a statin is if they're having myopathic symptoms, aches or weakness, then I don't care what their CK level is.

I did not realize that.

I'll get some information info to you on that. So stop monitoring ck. And if they come in and tell you hey Peter, I'm feeling pain, or you somehow are doing some muscular strength testing or they tell you I don't get out of the chair as much proximal muscle weakness, stop the darn stat.

Yeah, well those are, those are the easy cases.

But don't use CK's to dictate your statin therapy.

I think the point here is I can't imagine giving any lipid lowering therapy without being able to measure phytosterols, stanols and desmosterol.

So I'm with you there. Most lipidologists would not be, but they just have not studied the data like they should. And even if what we're just talking about is pure hypothesis, what harm would you be doing by lessening the dose of a statin and substituting a little ezetimibe? Or if they could afford it, you can make the case if it was free as pravastatin. Let's just use PCSK9 inhibitors for God's sakes. Because you know, whatever other minor side effects of statins may be. I don't Think we've seen much with PCSK9?

No.

I mean, of course, granted, more time to go.

I was just about to say the skeptic will counter that, Tom. And say but we only have three and a half years of data with these drugs.

We're not going to use that except for people who can afford it or our nightmare patients where a third party will finally pay for it or so. So it's not like docs are going to run out tomorrow and start injecting Everybody with a PCSK9 inhibitor. They're not. Because there's handcuffs on them. But there's no handcuffs on you. Using generic ezetimibe to a baby statin is. You have to buy onto ldl. C is not your best surrogate of atherogenic lipoproteins. APOB or LDL particle count is. And if that's your real goal of therapy, then you got a lot of options available to you.

Now, the one thing I used to use the combo lowest dose statin possible coupled with ezetimibe. If there was some evidence of even mild elevation of phytosterol and Stanol. One thing I've noticed and again, I've just been a little delinquent. I don't think I've gone back and looked at the trials. Did the trials show an increase in transaminases with that combo?

No. And I think the only trial that would. You'd have to look back at sees where improve where they use the Simba statin and ezetimibe. Improve it. Yeah. And there was nothing more than.

I don't know what it is.

Not at all.

I don't know what it is. I keep seeing these.

And again, I will tell you, there's not a package insert in the world that tells you you should even be following aminase to judge statin. Anything going on in the liver as a result of a statin. There's no correlation whatsoever. So I'm repeating them and all the time because maybe as a bio. Biomarker of fatty liver or something else, but not a statin toxicity. It's not, you know. So don't ever let a patient stop because they've doubled their ast. Whatever amination measuring level on a statin not related to anything. You got great medical legal safety because that's what the guidelines are telling you to do. There's not a statin in the world that they're all out of the package insert that you should be following doing liver function tests.

Yeah. Again, I think part of the Problem is, like you, I'm going to follow liver function tests regardless. I have a very different view of how these things should be. I mean, yeah, so they have other.

Use and who's not going to do. It's part of your chemistry profile that you're probably doing on every patient every time. So you're going to see them, but you don't necessarily have. But be prepared when the patient calls you up in a panic. That's not in your differential diagnosis of why the aminases are changing.

Yeah, I don't know, Tom. I still have.

It's been looked at extensively.

I'm gonna go back and look at.

This entire documents where they've analyzed all the data in the world on aminase and statin therapy. It's inconsequential.

But I mean, I'll give you a silly example, which is I have seen the following at least four times. You take a patient, you make, they're on a statin, there's no other change. And the only thing you do is you add zetia and then their next blood test, their transaminases have doubled. And then the only thing you do is stop the zetia and it returns to baseline.

All right, so something is happening, but as a doubling of a transaminase of that etiology of any concern to you. So fine, if you want to stop it and see, go ahead. And if that's going to occasionally limit how much ezetimibe you're going to use in a patient. Okay. Figure out how else to lower apob. So fine, I understand there are things that will come into play in an individual, individual patient where the data doesn't support it, but you're making an individual decision.

That's my point. That's my point. You've got to be able to make an individual decision. Which is what.

Generalize.

Yeah, yeah. Which is what we're saying with the, with the desmosterol level. Again, I think most patients. Again, if someone's listening to this and they're freaking out because they're like, what the hell are these guys talking about? We are not saying that statins are causing dementia. What we're saying is. At least what I'm saying. I'll let Tom clarify for himself. There are going to be a subset of patients whose risk of dementia does go up with a statin. And it's our job, if we're prescribing those drugs, to know exactly who those patients are. And to the best of my reading of the literature, plus understanding the nature of the Biology. It's probably the patients in whom we overly suppress synthesis, for whom they don't make that much to begin with.

A suppressed cellular synthesis which has nothing to do with the amount of cholesterol you measure in the blood.

Great point.

Has not not cholesterol synthesis is not affected per SE by PCSK9 inhibitors. Ezetimibe is interesting. If you go with ezetimibe monotherapy you actually get a little reflex increase in cholesterol synthesis and vice versa. If you go with statin monotherapy, a hyper absorbed statin. So there's a little bit of physiologic homeostasis going on here. And this is like that's not changing levels to these toxins.

No, no, but. And that, believe it not, or, or not has become. One of the times when I like using zetia is if I've got a patient who really needs a statin because when you just look at their numbers, you get the sense that this is an LDL clearance deficiency, but you want to boost their synthesis a little bit, you do it concomitant with the zetia and you'll sometimes get that reflex.

And I argue with clinicians too who they are doing sterile testing. So I identify my hyperabsorbers and I surely make sure ezetimibe on board my apob lowering therapy in that patient. But I will make the case for you. Even if you do those markers and you're a normal absorber of cholesterol, but you have an apob problem. Even by taking a normal absorber of cholesterol and making them a hypo absorber, the genetic model is they live longer if they have genetic loss of function of Niemann pixi1 protein. So even in a patient who's not hyper absorbing cholesterol, you do get additional APOB lowering. Maybe not of the same magnitude, but you get it and you're changing them into the genetic model of longevity, maybe you know, you're certainly keeping phytosterols out of them.

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