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

Episode Date: October 18, 2018

In this five-part series, Thomas Dayspring, M.D., FACP, FNLA, a world-renowned expert in lipidology, and one of Peter's most important clinical mentors, shares his wealth of knowledge on the subject of lipids. In Part IV, Peter and Tom review the history and current use of drugs to prevent cardiovascular disease. They also discuss why some drugs appear to be more effective than others, an in-depth conversation about niacin, cholesterol and brain health, and the futility of using CKs (creatinine kinase) and liver function tests to identify adverse effects in statins, to name a few topics in this episode. We discuss: Bile acid sequestrants and statins [2:00]; Ezetimibe (Zetia) [15:00]; PCSK9 inhibitors [27:30]; Fibrates [41:00]; Fish oil, DHA, and EPA [1:01:00]; Niacin [1:05:15]; PCSK9 inhibitors [1:23:45]; Cholesterol, statins, and the brain [1:30:00]; Elevated creatine kinase (CK) and liver function tests (LFTs) on statins [1:50:30]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. 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 at peteratia-md.com.

Hi everyone, welcome to episode four of the week of day spring. In this episode, we cover a lot of drugs. We talk about statins, we talk about cholesterol regulation, we talk about ezzetomybe, also known as zedia, 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 niac span, which has fallen out

of favor. This came up a little bit on the discussion I had with Ron Krause several months ago, and we can revisit it 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 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, 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 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, NICE and has been used that in finitum 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 NICE and available back then was immediate release of 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 me a mice into those people. Neomysin, the antibiotic. Which interrupted the patobiliary circulation of cholesterol and lowered cholesterol anywhere, no outcome evidence with it. But along came the bile acid sequestrians, which we hinted on, will make you excrete biolacids, which therefore you have to use up your endogenous cholesterol to make new biolacids. So you will lower your cholesterol metrics that you're looking at.

Crazy long outcome trial. It did seem to work. They paged a lot of statistics, I think, in retrospect on and didn't have the type of this is the LRC. 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 will does reduce clinical events. To me, the tragedy 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 by the way, these questions do raise HDL cholesterol a milligram or two milligrams per cent, 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's got a property that lowers really potently cholesterol and that was the statin group Akiro Endo and my colleges 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 statinsins lower LDL cholesterol dramatically. Pretty low doses, they seemed to be safe. All the after LRC, the FDA need, it 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 the lovestatin, Mavicor being the Ferris 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

Lone behold farm and new ultimately are gonna have to do serious outcome trials and The first group of people they studied were Swedish guys who survived an M I and had an LDL cholesterol of 190. So these patients had FH patients? In retrospect, they're FH patients, you know, who's got an LDL cholesterol once? Definition, one of the definitions of FH. And giving them a dose of Symbastatin, got your 25, solo, percent reduction in clinical events. So outcome data, bingo, great drug. And right behind them was Bristol Meyer Squibb, who had the much weaker stat and pravastatin sold originally

as the branded provocol. Let's study Irishmen who have not had a clinical event, but also their LDL cholesterol is 18190. Some more FH Irish men. So you're going from secondary prevention FH, basically, to primary prevention FH. And low and behold, reduced virtually every afterstrum. 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 was down in the 20s. You know, it's very good for both of them.

They're just a little higher inS because they were sicker people. I'm surprised the NNT could be that low in primary prevention. No, and it was probably 40 to 50 in West Scotland, but it was good. But these are nightmare primary prevention. And 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 less, but five year trials, you know. And so in significant p-values, correlated with the LDL cholesterol levels, and retrospect 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, it's 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 it's 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 gonna 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. I'll give you five 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, we'll talk about the miracle drug, which is a PCS K9 inhibitor, which there's a few things I enjoyed debating with people.

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. Right. It's just so difficult. So it's meaningless what a lipid modulating drug does to mortality. Meaningless, unless you got a randomized blind to 30-year trial, then I might say what's wrong.

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. That's still a flat lip and 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 de-saturase.

That drug lowered cholesterol. Was there any of that drug again? Try Paranol. Try Paranol. So try Paranol, come on. It was that 24-carb and it didn't allow you to unsaturate the... It did not allow you to turn Desmastral into cholesterol. And so now that's at the very bottom of this pathway.

Penultimate less. Penultimate molecule into the ultimate step. And all of a sudden, you inhibited that with this drug. Cholesterol levels went down. FDA approved it. Well, one would go up. Desmastral went up. Desmastral.

And there was at least a congenital disease called Desmastral Losis. levels went down. FDA approved it. Well, it would go up. Does Mosterol went up? It was a Mosterol. And there was at least a congenital disease called Mosterolosis. Maybe that, I don't know if they even know about that, go back then. We know about it now. That maybe would have been a flag. But when you look at, so if I recall correctly, about three or four years after this 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.

Because after a scrosses was occurring cataracts, we're occurring red blood cell. And it turns out, this nostril turns out to have other roles in about it's a potent cell membrane signaling molecule involved with inflammatory pathway. So God knows what else you're doing by perturbing desmosterral levels and cells and stuff.

So you live and learn. So there's one endpoint that's getting better, another endpoint that you didn't know anything about or biomarkers 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. And you have been several other cholesterol-synch squalding 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 on the food chain, meaning it's higher on the synthetic pathway.

So if you are backing things up, they are less recovery time to their left-by-coil cholesterol. They'll be more acetyl-CoA, more acetyl-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 the liver. At least it's been theory wise, because the pharma kinetics of a stat, and let's face it, the real place you want in a 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 and 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 will ultimately make its way back to deliver. So as long as I can enhance LDL receptors, by the way, which is pretty 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, is that of my Bollacetcy questions, PCSK9 inhibitors. So it's 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 shown, some trials haven't worked out. And I'll make a case for it then, I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also

also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, and I also, 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? Sure. And did they understand that that was the primary? I think the, even the, 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, it's cause over expression of LDL receptor, it's probably going to be good. So there are hypothesis generating that are genetics studies even on the LDL receptor

led to any new the biology questions refers. That's how biology 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 fellow right into that pathway without seemingly disrupting anything else. Of course, PCSK 9 works on adhesetamib through a less potent pathway, but still expresses LDL receptors than do the statins. So they work. Though, is etymib's main mechanism of action is in the gut? I'll argue with you on that, because where I talked about these spednail, Peter talked about the Neiman-Pix C1 like protein which enhances the absorption of starols including cholesterol

in the gut and that's is that amybs 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 denovosynthesized 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, like which the liver requires 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 is screech 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 super saturated body fluid full of cholesterol in your body, your bile, super cholesterol rich. The liver can pull cholesterol back, he flux it so to speak from the bile back into the

liver. Why? Because what is also expressive to a paddle, billy area surface, the Neiman pixie one like protein. So, as that of my has two areas where it acts. It blocks the intestine from internalizing cholesterol, but it prevents the liver from internalizing cholesterol from a biliary source.

Put them both together. You're depleting the liver of molar cholesterol and the liver needs cholesterol. There's a sterile sensor, the sterile regulatory element, binding protein, a nuclear transcription fact that it 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 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. I'm generally not a huge Zedia fan.

Zedia or Zedia, am I? 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 stethens much and can't afford PCS, can't end inhibitors and all these things. Historically, the way I've decided on who's a great Zedia candidate or not is looking at phytosterols or looking at other proxies or of absorption.

And I've argued, by the way, that the trials that suggested Zedia were not that valuable in monotherapy, it's never been shown to reduce in a vet. They never did a monotherapy clinical trial. I think it 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 Neiman Pixie one like one transporter, the argument would be target your hyper absorbers. But if it also works at biliary cholesterol, that shouldn't matter that much. 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 soth. But is the liver also then going to be a dominant source of where we'll see cytosterol, compesterol, et cetera? The final body preservation way, God forbid phytosterols make it into your column microns

of your HDLs, and I can make the case if they ever get into a cell, they're gonna injure that cell. But most of the column microns are gonna deliver to the liver first before it goes out in a VLDL. So the liver will look, if you're over absorbing phytosterols, a lot of them do make their ways back to the liver. And the liver recognize them instantly is using your analogy. That stupid bouncer in the intestine let you in. That Neiman peck and the ABC let you in.

I think you may tell it, we're getting ready. We're the backup police. Listen, you're the VIP lounge manager. Right, so boom, out you go again. Now I realize those dobs may let you in again, but you're gonna come right back here and I'm getting you out again. You know, so the great analogy for you

is the VIP bouncer, Yeah, yeah, yeah. So who's to say, is that a mistake in out or reducing the functioning of the Neiman, and I think it's in both areas? Merc knows this, merc didn't want to, that's too much education. You give, let's just tell me blocks cholesterol absorption.

The gut would make sense to most people, most people in clearing 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 it. I'm Peter Tothen. I think did one of our class articles on the mechanisms of it and stuff. What year was that? We just got to make sure we linked that. I'm bad with my years, but it's probably, my 2008, but it's really with great diagrams of course showing you and explaining where Neiman Pick is and every.

And that's Tooth TO TA. Yeah, Peter is a whole one like we like to use and certainly mentism our life. And of course Peter and my devises had me write the chapter in the book, Therapeutic Lipidology on Phytosterolib. He knew it's in Northwestern, right? He's at University Chicago. Yeah, and look very early on, probably because I was just such a good educator on lipids, lipoproteins, and statin mechanisms 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, you know, especially in lipidology and starrows as one of them, you know. Why do you think that the Zedia combination, Sympastatin trials, so the main trial with Zedia was within without Sympastatin, correct? No, first of all, Sympastatin with the Zedia.

The reason why Zedia, Zedia, I'm not mistaken 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 It just doing the damn outcome daddy even Doing a select outcome trial in the right person primary prevention as well Of course do your second-year prevention trials even do that first if you want to and if that fails You're not gonna do anything with it But let's they wanted to just get so much to mark market. What's the easiest thing to do? I am T. So let's take people with a lot of people. What I am T is.

So what's the example people with I am T is? Carotted 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, there are at risk, they have lipid abnormalities. Let's give them a, they're, you know, they're on a statin because we have to give them statins if they're LDL. Is that a metric? Is that a whack? Let's give them one half of the group. Is that a mime? Any other half? Placebo is that a mime? 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.

Only did that. Virtually every lipid parameter, including APOB got better. Every inflammatory mark has got better. Any IMT didn't change whatsoever. Meaning, Simvastatin had the same IMT as Simvastatin, plus a set of my- 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 say, look, it's like the coronary calcium score. You know, it's not the tool you should be using to demonstrate the efficacy. They should have looked at, but look at the staple B reduction beyond what's in the statin can do. Look at the triglyceride reduction. Look at the CRP reduction beyond what's in the statin.

Or oxaldeal or any of these things. Or at least say that doesn't mean anything, but they had already polluted the minds that IMT was the best way to check the drugs. Obviously nothing trumps a hard outcome. If you can reduce mace, that's the way to go. Sorry, major adverse start. They're taking a shortcut.

But they picked the wrong shortcut. Is basically what it comes down to. There were better shortcuts you could take. And who did that turn off big time? The images of the world, the cardiologist, who instantly dismissed the ZMI, but the world's most useless drug. Most cardiologists don't even know what APOB is. And never mind that,

look at this as a potent thing. I hinted to you, I saw I was very much involved with the relax, then the first serum that came to the market up as good an APOB lowering drug as is that amide is, which might have portended great cardiovascular benefit to the serum relax, which I believe it still has. In fact, we have some, they did a big cardiovascular outcome trial, where it was no. 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, then, what is that amalgam now comes it would matter.

But we're never going to 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 even on all that nonsense, which I don't want to 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 don't get to do the study of Zedia versus placebo. It's not ethical. No, but if you've picked the right patient. But you think of a reason it 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 gonna do for a variety of reasons. But here's another, and Mark 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, this calcium and there's cholesterol in those aortic valves, that if we could lower cholesterol and people with aortic stenosis

re-reduce morbidity related to that. And we don't have to give mastatin, because statins failed to reduce outcomes in people with aortic stenosis. Those trials were already done. So they took the C-strial aortic stenosis as a atomite and lowered it. And guess what?

Did nothing to end points related because they're enrolling people who need surgery for that. I mean, that's just that kind of stuff. It breaks my heart. It doesn't anger me. It breaks my heart. But again, post-talk analysis, they did reduce the Schema events in that trial. What is that am I? So, am I's went down and Gaina went down, but that's post-talking Alice. They got lucky. They didn't power for that.

It may or may not be legit. Correct. So, you'd have to do another whole trial to do it again. But, they were hoping to speak by without doing, and the next thing they did was, statins had failed to reduce colonel prevents and people with chronic renal failure, statins didn't work.

So, let's give them a statin plus a zeta mime. 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 in a zeta mime and a statin in a zeta mime group reduced events. Where is it? So there was, but a statin in a zeta mime works. Yeah. So and then of course they really had a wait for the acute group reduced events, where is it so? And there were, but it's statinacetamide works.

Yeah. And then of course they really had a wait for the acute car. And then syndrome, Italian, prove 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 PCSK-9 in it. And a great point you made up lately. I mean, question, 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 some of these loud mouths on the internet dismiss it because of that now. But it's a miracle and people that are aggressively treated with statinet, you've reduced our LDLC 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 LDLC is 70 for God's sakes because you're on a statin or statin is that a mind? 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 LDLC of 92 milligrams per

desk leader on statins. That means they are at the 10th percentile of the framing hand population 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 mean, I had been following this story even before I became interested in lipids just out of interest in the sort of the novelty of you see a natural experiment, which is PCSK9 hyperfunctioning, PCSK9 hypofunctioning's MR drug. It just became a beautiful elegant model. And then I remember, but it's... It should 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 investible thesis. And so I remember, Amgen kind of got hammered when the trial came out because people thought, 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, you know, 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 PCS K9 inhibitors

My patients who take PCS K9 inhibitors are patients whom prior to this drug we were flailing with What maybe some niacin maybe some monotherapy zedia Maybe the smallest dose of live-alow 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 And they're paying out a pocket for it. Yeah, so people who can know for 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 trials shows, it does matter. And in individual, can I say, yes, it matters in you, it does not know. 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 to Roof, is that wise? How are you 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 Pri 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 you on other lipid things or 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. I 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 candidate. It's something I wanna come back to

because you brought it up and I think it's worthy of its own sort of thread that will go down, which is this whole brain issue. It's 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 ungr- it's completely disconnected. And you've already mentioned one example, there are several others where a drug has come to market and then some harm will develop it. So therefore you castigate every drug that's ever been invented as a-ha. Even though we just- Yeah, even though we just illustrated, right? You can take two drugs that inhibit two enzymes and get completely different results.

Same result on an biomarker, but different outcomes. And so I always try to tell patients, although I don't that probably falls on deaf ears, but you got to 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, etc., you would want to have the most tools in the tool belt. That's the first condition.

The second condition is you'd want to know when to use each tool and what its limitation was. In that sense, the one of 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 either extreme. You gotta 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. So 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. That's absurd.

Stands 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 developed so much more into biomarkers and other risk assessment tools. Because the better we can define and individuals risk to any disease that he might be prone to, we can attack that disease through many mechanisms. Part of it, Athenosis, you gotta attack APOB. If you don't, good luck. But the more you understand,

and that's where biomarkers, and really not understanding the only understanding of these pathos, you can 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 as a triglycerides and maybe later we can look at that.

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. Oh, there we go.

I'm 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 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 it 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 tell 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 total, let's talk about LDL cholesterol. The assay that's analyzing the sterile in that particle has no difference. Does it know whether it's cytostral, canpestral, desmostral, cholesterol? No, all it knows is it's a sterile. So it just knows it's not a standoff? When you get LDL, it's even made, I'll measure a standoff too, but they would likely be a small part of it. So LDL cholesterol is really LDL cholesterol

plus LDL cytochromosol. LDL does mosterol. And the other 48, then a little bit of whatever stannels got to may have made their way into your body too. So they don't know that. So in a person with phytosterelemia, large part of that LDL cholesterol value is a... Is the phytosterem.

So, but they don't realize. So they don't even know, could in Zatomite have a bit, if phytostere. Yeah. But they don't realize. So, they don't even know, could an zetamide have a... If phytosterels are injurious, and I can make that case, if I did a one-hour lecture to using proper slides, you would be pretty convinced, I want phytosterels not in my body, zetamide is the only way to keep them out there. And wherever you go next, my final word on a Zedimide would be, if you're a big believer 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? It definitely is. It's the best reverse cholesterol transport, because the final common pathway to reverse cholesterol transport is, it's out of the body.

Zedia am I 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 a Zedia am I, not a statin. You know, so very interesting. And very controversial. 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 homostatic pathways, it's a great drug. Yeah, well, we'll come back to all drugs. I guess the next least. Most of the time we do have to lower APOB a lot more than is Adamine could ever do by itself. So the one that we've left out before we get... I want to come back to Niasin 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 Niasin through a clinical trial standpoint and then we'll get into the PCS-K9. 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 Zetamib, also known as Zedia. So we use this an opportunity to go into the next drug. So all right. So Tom, that was pretty, pretty insightful stuff on Zedia, also known as Zetamib. 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 phenophibrate 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 phenophibrate and you have gemphibrizol. And they're both out there. Both can be attained generically nowadays. So phenolfibrate still comes in branded forms. That's the tri-liplates. You don't have to,

that's one of them. There are other branded forms available out there. Gem fibrizol is a pro drug. It has to be converted into the active fibric acid, whereas phenolfibrate 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. Gemphibrozole has a monotherapy outcome trial given to veterans with coronary artery

disease who have low H shell cholesterol and high triglycerides, and it reduced events as much as a statin didn't any trial. So, there's outcome evidence. Was it independent of triglyceride levels? Yeah, it was independent, although they enrolled people. But some many of the men to triglyceride levels were certainly not at super high levels or so. But it was mostly low HDL cholesterol.

And virtually all of those people have some degree of trigolousrite 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 Trail. Yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah,

yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah I remember Jim Fibresol already had outcome data from the Helsinki heart trial too. So this would be the second trial. Now phenylfibrate 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 and wrong people,

heavy, concomit, use of statins. Nobody in any Jim Fibresol trial was ever polluted by people sneaking in statins with it at the same time. And clearly, whatever five rates do, they do it differently. And statins in the question is can it contribute to a 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

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 works, and in 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 docks as you take this, don't take it. Yeah, so that's the bigger problem scientifically, of course, the counterargument 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. No, no. Yes. So they were legitimate trials that were ethical. Whereas with the PCSK 9 trials, it was statin. You couldn't do it. 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 gemphibrizol work, and it's kind of interesting. You couldn't explain the benefit of gemphibrizol 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 over the other? Plyatrophic type of febrates or doing something that we weren't measuring with any biomarkers. So I mean, some of that is probably true. But then they didn't at least, in a cohort of it, they did a post-hocchanalysis using NMR. And this was Jim Mottfos, who did this.

And he found out that they benefit of the Jim Fibrizol 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 a causator, and it raised the HDL particles, which had a statistically significant tie-in to 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 a 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, it's 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 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, fibrate help delipidate HDL particles. So, if you're in the old school, hey, you're increasing reverse cholesterol transport because the fibrates are perigulate, the scavenger receptor B1, which we dilipidate your HDL. So, of course your HDLs would become smaller. And then the small HDLs could theoretically traverse back into the arterial wall, pull cholesterol out of your sterile leading foam cells, the histopathologic marker of the plaque, atherogenesis. And by the way, and 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, a sudden call and Dan Radarcoin, this term years ago, macrophosure versus cholesterol, transport. And he used to make the case, the only aspect of the RCT that matters as far as atherosclerotic clinical outcomes is dilipidating 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 that. There's a couple of them. There's ABCA1, which will lipidates small, lipid poor HDL particles, but there's ABCG1, 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, add it to the macrophage into a bigger or a small HDL,

which can then return to the plasma. The small one, a sterifies it, becomes immature 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 delipidating plaque in your artery wall, but I can have some confidence that if I'm using a fiberate,

that's one of the things I'm doing if you do have plaque in your artery wall and who doesn't. You know? Now, so why do you think the fiberates work best in patients with a higher triglyceride level? Because their main mechanism of that, look, so they modulate HL particles,

but triglycerides and has a lot to do with HL remodeling too. But fibrates mostly stop the synthesis of VLDL particles, triglyceride-rich LDL particles in the liver by depleting triglyceride pools in the liver. Remember what determines the lipidation of apobee in your liver? All humans make two tons more of apobee than they ever have a prayer of lipidation of apobee and your liver. All humans make two tons more of apobee than they ever have a prayer of lipidating and changing into an apobee particle.

The vast majority of your apobee gets catabolized because it's unused. So people always, oh, what produces increased apobee? Nothing, your liver makes way more apobee than any human can ever use. Why do we think that is? I don't know, people just assume, hey, if you're making too much a sudden,

you've got to be increasing the components. Except the one component we make too much of and never use is APOB. Yeah, I just wonder why that teleologically would be the case that we would make orders of magnitude more APOB than we could ever want to export. A betalipoprotonemia is death. So you have to make A-pope particles. They transport energy, they transport phospholipids,

they transport fat soluble vitamins, the big particles. So you can't not have A-pope particles in your eyes. So you 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 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, it's the stored energy in your liver. And cholesterol esters, the stored cholesterol in your liver. Cholesterol, I think I mentioned before, binds to the cholesterol ester, binds to the, or a free cholesterol binds to the APOB first. Some of the cholesterol will be a starifide, even in the circulation, some in the liver,

via that 8-cat ends on. And so, then, and once you get the little primordial spherical VLDL, then triglycerides are transferred in using MTTTP, microthermalal Tricholids, right, transfer protein. And now you got a real VLDL ready to be shipped out. As it passes through something called the space of this, 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 an interest plasma, a ton of the apoproteins just leave your HDL particles, one of the functions of

HL. As you remember, as all these 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 on to the surface of a VLDL. If it was not put there as it passed through the space of this, so a nail determined the catabolic fate of that VLDL particle. So fibrates through several mechanisms, one, de-gadders an enzyme involved with the synthesis of triglycerides.

It's adding fatty acids to glycerol. Fibrates are a potent inhibitor of that. So 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 gonna make less VLDL particles. I remember a fiber is not gonna blow away your LDL P like a statin does,

but it's going to blow at 10, 15% reduction in part depending on the triglyceride richness, not the theorem triglyceride level, but the triglyceride richness of the core. So that's one of the where's the backup of free fatty acids? Because at some point if you're not synthesizing as much triglyceride, but you still have... Well, you still have enough fatty acids. You're absorbing fatty acids. You're at a Pocytus storm. But is there a hepatic backup of fatty acids?

Well, de novo synthesis. So in other words, this would not decrease Nafoldi if you had a patient. Because at first blush, you'd think, well, a fibrate should be able to reduce fatty acid to reduce fatty liver. It was thought that for years, but it's just never been proven in a trial that that alone would do it. Whereas actually, a Zedomype has more data on reducing fatty liver than a fibrate still. And most people all blame fatty liver on triglycerides. It's a starroles 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 is that am I 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 it's a toxic disease to the 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 it 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, it doesn't matter about, it 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 or synthesis of triglyceride. So triglyceride, but 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

hepatocelular toxicity is cholesterol. It's just not all fatty acids. And I'm not implying there are no role of fatty acids or fatty acid synthesis triglycerides. Since this is related to fructose, but it's not all just somehow ignore cholesterol and you're gonna get rid of fatty liver. And you can't even separate it too,

because if you have a lot of triglycerides, you're gonna have a lot of apobiparicose that are part of the cause that's sterile, so you think. That's probably the bigger issue. It's very difficult to disaggregate them when triglycerides are elevated. So really, the ideal candidate for phenophibrate is going to be someone with an elevated apobene

and an elevated triglyceride. So if you look at, even if you take the two positive gem fibres, all trials, and the failure of phenophibrate in a couple of trials, easily explained if you look at things, but if you do look in the, and basically they enroll people that didn't have insulin resistance, or triglyceride rich lipoproethanes, and gave them a vibrate. So they designed a clinical trial

where nobody in their right mind would ever give that person a vibrate for a bunch of reasons. Hey, but they were diabetic. But, and that was there. Where they were diabetic? Yeah, field trial is 100% diabetics. And so they figure it's a no brain or 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 and appropriate 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'm not happy with your LDL cholesterol take a stat.

So it contaminates, you know, we can always guess if we could have kept it as a pure trial of fiber, it had worked in diabetics, but you know, that's just the opinion that didn't work. But it did work in everybody who had an increase in triglycerides and low HL cholesterol. It worked. and that's where the outcome reduction was. Very interesting, which no little lipid drug has ever done, it reduced several microvascular endpoints in those trials to retina, but the amputations peripheral neuropathy, renal disease, even though phenophibrate can raise creatinine a little bit, GFR improved

and renal outcomes improved. So what other drug you can give a person that relicens this chance of a diabetic retinopathy if he's a diabetic, nothing. Now it's post-hoc, it's secondary, well that was a secondary outcome. So the trials weren't designed to prove that. So they were hypotheses, you'd have to theoretically go back and do that before the FDA would ever be approval, but kind of interesting data. So I always made the case, what? Fibrates reduce amputations, neuropathic ulcers, improve renal disease, save your eyes. improve renal disease, save your eyes. Why do you not on a fibrate if you're a diabetic?

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 an analysis of those secondary endpoints in everything. What are the main side effects of phenophybrate? Not a heck of a lot. It's a pretty well tolerated drug.

Anybody can get any number of any side effects with it or so. People used to be afraid of the increasing creatinine until in the field. A large number of patients were doing creatinine clearance and that didn't go. So there was a muscular buildup of creatinine. I had nothing to do with GFR or renal clearance of it. But there's nothing much to it. There are some drug drug interactions.

I mean, the phenophiberate is that in my, I mean, they're both very well tolerated. It's certainly more tolerated than statins. They really are and you can make the case that I said, at least in a diabetic, which is probably gonna be, especially with what we know now, the patient was gonna wind up on a fiber. Now, most lipidolids wouldn't use it into you statinize, somebody or statinize them,

and zedimize them, got their APOBs good as you can get it, 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 person's that were helped, at least in post-hoc analysis of every single fiberate trial, including a VA hit there and all the phenofibrate trials. So that's pretty much where it's reserved to people with these identifiable by hyper-traglisteredemia patients or so. I want to talk about people with triglycerides of 400 or

4,000 where pancreatitis comes into play. We will probably all use a five-brain and a lot of other stuff there like omega-3s there. On hopefulness that it would reduce the incidence of pancreatitis, not proven yet, but you would attack that degree of hyper-traglisteridemia. But the real world is people with triglycerides between 130 and 300 that insulin resistant world, which we've already clearly defined as an apobedis order. So that's why your statin azetamide is your first line drugs there. But if you didn't normalize that with your statin azetamideib 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 triglyceride rich. 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 toward anything about middle, go back and root these. So it's the older guys like me who grew up through all those trials have lectured on 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 cause it lowers triglycerides and it's so easy to tell somebody to take a fish oil. They're not gonna go home and read potentially scary stuff on the internet where they might with a five-rate or so. Or they're gonna still read it. I guess on everything, you're gonna read

some crazy stuff on the internet. So tragically, to me, because I don't believe this... And when you say fish oil, is it more the EPA that's having the effect on triglyceride or DHA? No, EPA would have more effect on APOB, but DHA is the triglyceride. There's some recent new data published 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, we'll make it three 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 some DHA, or you take the high strength EPA, and you show in a lesser strength EPA, DHA combo tablet, which is how you get it. So as I know, there EPA, DHA combo tablet, which is how you get a... So as I know, there's no DHA only tablet. Where is EPA only tablet? Certainly in the prescription realm. So, you know, fine. If you want a lower APOB, you can stick with your APOE, but I don't have... Where is my evidence that if I used whatever phisiot therapy, I want to use some happy, I'm improving

microvascular disease. I have pretty serious evidence that I'm doing that at least with phenylfibrate. And the other thing, although they're both available generically, sometimes these drug comes to force gem fibrozole on you, the real reason when you ask me are there any side effects about fibrates, and I did say the word drug interactions. Fino vibrates has a serious drug interaction with cumidant, so you have to lessen the cumidant dose there. We're using a lot less cumidant.

You're using much more eloquisties. Yeah, so that's becoming less of a big worry. But God forbid somebody's on cumidant. You didn't know that. You threw big dose fino vibrate out. I mean, you put a lot of bruises because you know, you potentially ate the anticoagulant. In fact, gem fibrizololo has her raises statin levels through the roof. So there's much more incidents of myocides and rabdo myolysis when you

use gem fibrizol with a statin. And there's none of it with phenylfibrate. So if you want to use a fibrate, I strongly encourage you, because it is generic nowadays, to use phenylfibrate, because you're going to be using it with a statin and 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 fibrate. You don't, and so most of the lipidologists, or at least were somewhat schooled on fire rates, 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 LDLs. We have some other evidence that I want to vibrate on board you or so. That's where that's going to get used, but that's not your average person who walks into if he walks into the average doctor, that's going to be chasing LDL cholesterol. They're non-HL cholesterol, if they're a a little more stew 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 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, but I want to come back to it because I know you have a strong point of you 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's eti-a, who can't afford a PCS-K9 inhibitor and doesn't meet the regs for approval. Are these patients who should be on nice? And so, I'll go back to where we were earlier. NIS in exists in an immediate release

in a time release form. Two types of time release forms. Oh, I didn't even realize that. Intermediate release and sustained release. So NIS span the Abbott version. That's intermediate release. And that's a prescription only product which you're not gonna get covered by an agent.

No, no, no, 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 it. I don't know what you had. I know. And if you want to, you somehow believe in NICE,

and I 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 a case, you're not flushing, Nyson isn't working in you. So let's talk about what? The sustained release is cheap. You can get sustained release, but the biggest problem was in clinical trials,

Nyson being a toxic drug it is, there's way more hepatotoxicity with sustained release Nyson than there is with the short release or the extended release where there's no hepatotuxicity. 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 at lower cholesterol. Lower LDL cholesterol. Yeah, and better yet, raise HL cholesterol. That's what everybody always focus on on. Everybody, and since low HL cholesterol is a risk factor, we now know APOB related, but whatever. Therefore, if low HL cholesterol is a risk factor. We now know APOB related, but whatever, therefore, if low HL cholesterol is bad, raising HL cholesterol has to be good.

And nice and is the best product you had at the time. And then, so trials were done with nice and, and it was kind of funny because I listened to the podcast, you and Ron Kraus did, and it was kind of cool because you made the case a little bit for nice and 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 it was kind of cool because you made the case a little bit for NICE in Ron Ditt. But at the end, as you just said, you're ambivalent to an environment 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 has failed. 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 course. All right. But I think at the end of your, go back and listen to your boss and met him. 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 point of view on that, right? No, because there was never, they weren't statinized in. Now, you kind of had a different point of view on that, right? No, because there was never, they weren't statinized in any, it's certainly the big, nice and has one trial designed to use nice and it's 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 car near disease, you give them thyroid hormone.

They're not... You make a hyper thyroid? You make a hyper thyroid. Not exactly good if you have car near your eye. So that drug failed. They used a primitive, fiberate, clofibrate,

and there was some question of a mortality adversity there. So that was hit number one on the whole foot. Nobody in America uses clofibrate anymore. It's probably still available in Europe. I don't think anybody uses it. So vibrate, 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 and 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 about getting it anyway. So yes. And then they had a nice and immediate release, nice and 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, you better be empowered or better not have been much toxicity

and you better come in and have hit your primary endpoint, because what will the FDA never, ever allow you to discuss a secondary endpoint? If you fail the primary endpoint, you've failed drug. All you've done by improving some secondary endpoint is generated in 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 that's what Niesin did to mortality. It worsened it, not statistically, but 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? But wait a minute, myocardial infarctions were down. It was like me telling you in that aortic stenosis trial, but hey, is that any of those

myocardial infarctions, but it didn't reduce aortic... But in fairness, was the trial powered for mortality or was it powered for... For look, the 16th done and no, it was powered mortality mortality was the only endpoint and all the odds that are 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 if fail. That's kind of amazing because I mean that's very unusual.

What are you talking about a trial in the 1960s, early trials, how they picked endpoints and stuff there, but Nias and so don't come and preach to me that it hit secondary endpoints. Wait a second, why is it that Niesin failed this trial in the 60s and it was only three or four years ago that 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 Niesin in probably better design 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 pay for it at least.

The FDA would never give it an indication without primary endpoint data. 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 earn the original trial, small number, and low and behold mortality was improved in that group of people, coronary mortality. So there we have evidence that Niasin improves coronary mortality. So there we have evidence that Niasin improves coronary mortality.

It put a problem into this election by the way. 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 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 them in the end, but get published and thank God it did. So we learned a lot about a lot of drugs in that trial. So there was no evidence in the trial designed to prove nice and reduce coronary heart disease, at least the level one evidence. Then of course, guys said, well, angiography got introduced and it could start doing regular angiograms. It's not 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 looming of arteries in people with coronary arteries, who took niacin. That's the hatch trial. It's a small, well under 100 people, given niacin, no statins or anything. 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, and it trial absolutely not empowered to look at

clinical outcomes, there were less coronary events in this trial. And I 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 nice and 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 presumably,

50 in each arm, it was a one-to-one randomization. No, I think they just did danger grams of people, and they put them on knives, and then they did a routine of them. Oh, so 100 people with a cross, so basically you were your own control. Yeah, your baseline arteriogram was and then you follow up with.

Right, so 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 groupup. 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... You're looking at anti-agographic changes from a drug. No, I understand, 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 are given other advice too, 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 the vulnerability of plaque or true events. No. And you know, and you certainly can't 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 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, so to indicate, boy, the images look better when we follow up on these people and HL cholesterol's going up, so what else could it be? And that HDO, 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 NICE and add it to whatever else, get this HDL raising on top of we're already given drugs that lower LDL cholesterol is. Is this aim high? So So aim high was the first. So there'd been no aim high if there wasn't this hats in geographic trial. First, that was the whole premise to let's spend money on the aim high trial because now we are in the statin or 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 a zedamide to it also. So we will get LDLC perfect but HLC is still gonna be low so we're now gonna 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 HDLLC and an already optimized LDL patient. You missed an opportunity to actually ask. You didn't miss it because here's what happened. In that trial niacin may be able to be lower than statin and is edamide did by themselves. So you got additional serious APOB lowering and no outcome reduction.

So how much lower do I get? Another 10, 15%. So here is a drug that is drastically further lowering ApoB, atherogenic particles. It's raising that, as I know, called stupid metric HL cholesterol, but it's not working. Well, I just thought your relax fan, I believe works, because it lowers ApoB.

Why didn't I send, because it's gottaoby. Why did niacin? Because it's got to be doing something bad that's aggravating your arteries. And you give me a drug that causes acanthosis, migricans, and human beings, pathoglomonic of insulin resistance. Why would I ever give that drug to a human being? So niacin causes worse since, and the only person who you're probably going to wind up giving niacin to is probably insulin insulin resistant identified by triglyceride HDL abnormalities. You're giving nice and I could read off 15 other well known side effects with nice and probably. I don't think anybody would dispute that.

I think it's I think it's I think it's fail. Even though at lower depot be beyond what is very important. It'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 Niesin has a place anymore is, could the wash on mortality,

despite the reduction in APO B be explained by the worsening of insulin resistance? Could you explain 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 acute, you know, nice and well known to do that. It could be explained by all sorts of hemologic parameters, disruption, platelet reactivity

with nice and well known and a bunch of other things that nice and has been implicated. And so to me, every time you use a benefit, but lowering APOB, I'm going to always consider that a good benefit, but if it's nothing that's happening, there's something that's going on, which I don't understand. Look, they took that extended release product off the marketing. You're 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 it. Immediate release in I assume is you're basically

describing 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 nothing to lipids or lipoproteins. So if you want to be a niacin player, will you pick? In the coronary drug project, a community release of niacin was four grams a day. Try that.

Sustain release niacin. So those patients took one gram four times a day. Yeah. They worked their way up to it. stain release, and I see. Well, it's so those patients took one gram four times a day. Yeah. Oh, they worked their way up to it. Yeah, you know, so because many just, hey, if this is as much a intake, that's what you, but they got them in pretty high doses,

I will say, you know, this is kudos to the docs and those trials and everything. So extra number of people, kudos to the patients for tolerating. Yeah. Listen, if you get not only flushing, but massive paritis can occur when you use the meaty 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 a two in the morning, the guy thought he was

gonna die. He had dial 911 because he just had an extensive, puritic reaction and he felt his whole body was on fire if he'd had a swim in pulley would have jumped into it but he just thought his body was burning up and I just said you're gonna think I'm crazy. Choo-to-ass friends and just call me back in an hour it'll be gone. I forget whether he did wind up in the ER or not. Now that's an extreme reaction, but it occurs.

So, look, I took a nice couple of years on myself on some of the beliefs before we knew a lot of this because I could not tolerate a stat and a statin is at a moment. I had an APOB issue and I hadn't learned about intermittent fasting or followed a low carb diet at that time. So, unfortunately, not even I didn't even lower the APO B and made it 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, Nyson 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 and I said, but they combined it with an anti-itch compound and, uh-huh. So everybody's can tolerate nice. And now, and they added it to a stat, and that was the heart protection study thrive. And it was basically a duplication of the aim high trial, nice increase in HL cholesterol,

further reduction in HLB, in zero outcome change, and a lot of toxicity. And much of the toxicity is glucose, exturbations, you're gonna have your fake glucose. Anyone so, Europe decided that's it, so they took that combo pill off the market. I'm sure you can still get immediate release in ISE in Europe if you want it, you know, it's a vitamin for that's it. So they took that combo pill off the market. I'm sure you can still get immediate release in the US if you want it.

You know, it's a vitamin for God's sakes, but I'm mega dose. So I just don't like people out there who want to extol nice and fine, but don't start telling them nice and has a lot of data. It's got zero data. And these are the same people who bash vibrates

who do have too large randomized post-stractive trials, Helsinki and VA hit, with fibrates, and yet they never consider a fibrate. They always tell you, no, nice, since the better drug. And at least in the field trial, nice phenylfibrate had all these microvascular. There's no prayer, nice, and reduces diabetic and retinopathy, amputations, kidney disease. But yet there was that battle. People bashed fibrates, hold them to the high standard of you gotta hit your primary endpoint

and they never held nice. And to be honest, we have the same, that's what RunCrowst did in that study. So I understand what he's talking about. There is some dad, if you want to extol it, but it's not to type a dad of you and I use it more. So we'll go from the stepchild to the poster child which we've already kind of alluded to which are Repata and Praljuent, these two PCS K9 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 Hobbes. Helen Hobbes was the first person who discovered the... Oh, I know, sorry. I mean this thing. PCS cannot express it. Yeah, sorry. No, I mean the actual family of PCS, the PCS family. Oh, PCS?

Look, there's at least 10 members in the family. There are. I've been around forever. Yeah, and I don't know who discovered that. 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 nine-footer would come along. Yeah, how did you get genetic evaluation? Genetics, gain a function, loss a function, explain how it comes. And the gain of functions were discovered first, correct? Yeah. So I'll explain this really quickly and briefly.

You can expand upon it. PCS, K9, 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 makeup what, five to 10% of what we would. That's infusely, which are a duest familial hyperclestrolia. It's one of the many, and

there's like a few thousand. Yeah. The podcast people don't understand FH could be a thousand different disorders. Yeah, FH is a phenotype. And they're not all autosomal dominant, some are heterozygate disorders of various genes, but the phenotype is an LDL cholesterol above 190. 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 want to be, 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 hypofunctioning PCSK9 folks. And I really do remember this, and I'm surprised I remember it. Actually discovered in African-Americans first, I believe, a Jackson trial, then. That's exactly right, yeah. And these were folks that were walking around with an LDL cholesterol between 10 and 30 milligrams per desoleter, and they were completely event free.

And of course, the first- Not 100 percent, but just significant reduction. Dramatic reduction, right? 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. 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 Sonofi 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 adrenocortical 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 it,

or if you deplete testosterone, because God forbid you're actually taking a stat and you're screwing up your testicular function, you're not having nothing to do with it. 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 car

hard disease. And when we use talked about loss of function, that means your LDL receptor half life is much longer. We didn't get into it before. We told you to live or mix 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 end to the zone, but then the LDL receptor travels back to the surface, grabs another one. I used to, those of you old enough to use the watch, the Adam's family on TV. It's like, things hand coming out of a box.

It's the LDL receptor, grab 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 putsing 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 98.95% 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, bro. 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 I'm saying this just as much to remind me is 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, and you have it all work. Yeah, and you can also make the evidence that if you're depleting the cholesterol pool and the liver, you'll make a few less Eter LDL particles or VLDL precursors, which would contribute to a lowering of apobay.

And that is a small part of both the zedomides and the statins, in fact, 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 the... Well, you can't make LDL. Well, not only can you. I think, 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 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 on our talk today, look at his 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 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,

but how much because that brain really needs it, and the brain has no other source of cholesterol only. 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, they're really only a handful we're really looking at today, right? Lipitor and Crestor are doing the lion's share of the work. For some patients who are very sensitive, we'll use live-alow or will use preva statin. But we're not really doing much in a way of sympathastatin or any of these older drugs,

correct? No, no. If you're following guidelines, what you're doing is prescribing hypotency statins or at least moderate intensity statins. So if you want to follow the guidelines, the only choices you have are Resuwa statin or a torvostatin lipitoracrestor at a 40 milligram or above dose for a torv or a 20 milligram or above dose for a Resuwa. If you're stuck, they would allow you to sneak

Simba 40 milligrams in today, but that's at best a moderate dose, Dan. 80 milligrams of Simba's been taken off the market. That used to be- Yeah, to be quite high with some. Well, because of a variety of pharmaconec reasons, has a ton of drug-drug interactions. And we're in a polypharmacy world, whereas there's far less with a torvian and infinitely less with Rizuba statin and the Patavistatin, you mentioned, live a lower cell. 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 Pravistatin. In Pravistatin, very cheap. It's almost free if you go to a drug store 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 25% reduction as any a Torva or Res a trial ever did. So again, Bristol used to explain that to magical mystery,

pleiotropic effects of preabstant. But I would make the case that, all right, if APOB, LDL, if you're going. I would also argue though, patients are sicker today. I think patients are more metabolically ill today than they were. That meaning, I think the Crestor trials have a higher bar to cross than the Prevast trials. But that again, that's just my bullshit speculation.

Oh, I think the lipid level enrollments with the West of Scotland were twice as horrific as any reserve statinja. Yeah, they were, but they had FH. So these are patients who weren't necessarily metamoleically ill. Yeah, I have to say what you're saying. So the end of this discussion comes

where I got a lower APO B. Yeah. So yeah, you'll, unless somebody's incredibly statin' sensitive and there are ways of predicting statin' the responsiveness or hyporevance of this, if you wanna just routinely pick for a reserve stat and go down that path, I'm all free. So what do we know about CNS penetration of these statin'

? Well, I get to that and look, I jumped on reserve statin' bandwagon, being a giant, private statin guy, because it's one of the, what I would call, herpato selective statins. It's hydrophilic. It goes right into the liver. It doesn't need transporters. So you don't need much in a drug to get in the liver and hipocletral synthesis and up-regulate

LDL receptors. So Resube Staten of five milligrams is a lot of people. They 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, tapo B reduction, use whatever it takes to get your HAPO B 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 minds. 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 liver is various receptors, polimin. 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 pharmaconetics like you do with pravastatin or rezoovastatin. That being said, you're talking, 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, 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 a torvastatin, symbastatin, get into the brain more easily than do lovastatin, symbastatin, and a torvastatin. Well, wait, say that again.

The most lipophilic statin is easier to cross the blood that and cymbastatin to the tube. And the lovestatin will probably be the worst. Whereas prevastatin it'd be less. Provastatin would be far less, edwood would resourced. And you have that fluvastatin, sort of a water-soluvestatin, is probably more in the class of resuven. And what about liver loaves?

Also liver loaves would be the same, it's a 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 read those cholesterol synthesis and a liver I'm gonna upgrade LDL receptors. I don't know that I want to do it in every cell in the body, but I'm probably not, I know I'm gonna upgrade LDL receptors. I don't know that I wanna do it every cell in the body,

but I'm probably not, I know I'm not what 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 need to be depleted of cholesterol to variable degrees. Now Tom, I'm just gonna 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 desolate or their LDL particle number is 500 nanomole per liter. These are people in primary prevention, but 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, gosh, they're desmosteral 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 bio marker of brain cholesterol synthesis. Now, very interesting. We talked about two pathways of cholesterol synthesis. It wants to desmosmosterola block pathway and the other is the Lafosterola, Candaceousal pathway. Well it turns out the block pathway predominates in the brain. So

would but I should I do spinal taps and measure CSF Desmosterol in these people? I'm gonna go with no. Yeah, it'd be a tough, uh, uh, uh, uh, by the way, don't leave. I'm gonna come back and just do a quick silent half on you today. Hey, I just, we're just waiting there in the waiting room. I imagine even trying to do a clinical trial, what that was, what you're trying to prove and enrolling people into that, you know, so, and gonna happen. But so people know we can measure Desmastrol in the blood, and there's lots of articles correlating that

with cholesterol synthesis, as there is with the lethosterol. And you can make the case in peripheral cells, maybe even lethosterol is a more dominant pathway. They're probably both at play, but also the Desmastrol pathway is much more important in younger newborns and, rather than older people. I didn't know that. Yeah.

Maybe that's a critical patient. For whatever reason, want to give a stat into a really young FH, a home, as I guess, FH patient. Well, I've been involved in one of those cases. Yeah. So, might as monstral be money. So here's what we know. So when people with these cognitive and mild cognitive impairment or various dimensions

have low cholesterol when you wind up autopsy in their brains, they do have low-dose monstral in their cerebral spinal fluid, suggesting that they do part of their impairment or cholesterol depletion in the brain is their brains aren't synthesizing as much cholesterol. And nice trial where they done this, 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 RBI is very high in there. So now all of a sudden, a serum desemostral level becomes a biomarker of brain synthesis of cholesterol. And there are what is by far, it's not even close. The biggest reason that a brain has suppressed desemostral cholesterol synthesis, it's stannous.

Yeah. So I would make the case. So I'm gonna pause here because I know what you're gonna say and I agree, but I'm gonna 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, suggest 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 statin. There are many different factors of disease. A lot of things that contribute to dementia. So in general, the vast majority of people take statins wind up to mention, no, absolutely not. There's not any evidence that is shown at least from the cumulative statin trials The vast majority of people take statins wind up to men to know absolutely not. There's not any evidence that is shown at least from the cumulative statin trials or so,

but are there certain individuals where that is? By the way, in these trials where they measured low both serum and CSF-desmosterol, guess what there was a significantly increase 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 stat and I'm going to push it to, I would for a variety of reasons much rather give you a baby statin plus a zedomybe. And by the way, baby statin plus a zedomybe gives you the exact same APOB reduction as does the gorilla statin, the megadosa of it. But I think with a lot of other additional benefits a zedomybe 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 carnalist statin per guidelines, and I simply measured serum desmonstral on your next visit, and it was low, that tells me 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 were 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, oh my God, it causes diabetes, does it? Well, yeah, and a small, small subset of the population, we're gonna see a slight uptick in the risk of diabetes, especially with a torvus statin. Does that mean statins cause diabetes? And it needs to be avoided as a result of that? No. Does it, you know, do a certain subset of patients end up getting, you know, muscular pain, of course, it's probably five to 10 percent. 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 my hypothesis.

What I think is really going on here, this is my hypothesis. Alzheimer's disease, as you said a second ago, is multiple diseases. It is not a disease. Right. I don't have any cognitive. Yeah, yeah, yeah. But even if you talk about Alzheimer's disease, even if there is a final common pathway or a set of pathonomonic 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 increase incidents 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 Delator 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 stat and 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, sure, 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, 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 treat. And for anybody who throws it in your face, there's no evidence of that in any stat. And shall say, my God, I've read the FDA package in sort of every single stat and

it's on the market. And cognitive impairment is listed as a potential side effect of every single stat. Did the FDA just make that up? No, it's been seen in clinical trials. 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 Desmastral 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 is 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 Desmastral as a continuous variable and using a statistical technique called Receiver Operating Characteristic Curve Production, they show that once Desmastral 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 detailed than people want, but the higher that number, which varies basically between 0.5 and 1, 1 is a perfect study. One, there's nothing as a diagnostic test with a 1. One 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 possibility, 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've written as much statins as anybody. If you tell me you've never seen cognitive impairment in a patient you've started on a stat and 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, there are a lot of reasons that could occur, and look, who doesn't have a day where you wake up thinking I'm a little foggy today for son, and it's not gonna 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 is APOB reductions. I got a lot of ways of getting your APOB to go without maximizing a statin. So in my mind, if there's monstrel 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 further by stopping cholesterol absorption back into the liver and intestine with a zetamide that does nothing to cholesterol synthesis, a PCSK9 inhibitor. So with and in most people, baby statin and zetamide will give you the exact same

apob reduction of your gorilla stat stat and we have outcome evidence in the improved trial. That is that I've been statin for the guys, I got to 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 know, I will bet as much money as I have in my bank account days could never, they couldn't even tell you what does Marshall is, they've never read anything about the cholesterol 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, and 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, and the statin, you know, the statin conspiracy theorists, a great ammo,

which is, aha, if they spring in a teah 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, but of course any reasonable doctor, if a patient can mean complaining of statin or cognitive impairment, they pretty much stop all drugs. It's 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.

I mean, if the listener is sort of saying, what the hell is the takeaway from this? I think it's a couple of things. One is statins are not bad. Statins are still the mainstay backbone of anti-lippid therapy. Be thoughtful about which ones you use. 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 to I'm actually going back and using prevastatin much more than

I used to. I'm surprised that how much I find myself reaching for prevastatin, 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 their CK goes from a baseline of 50 to 300, even if they're asymptomatic, I don't like it.

So I'm gonna switch that. That way I would ship in a CK elevation as nothing to do with statin toxicity or statin So it's a silly biomarker. You think so totally and evidence with totally well. I know it doesn't correlate that well with my First of all before you ever do that make sure you have a baseline Yes, of course a lot of people working now Americans not even working out. They just have high CK like those African American so so but I didn't realize that And you know when you should stop a stat when to see when there's like a 10,000 full elevation of CK

Then you might start to worry so CK there's any number of guidelines issued on set It's not a bio market 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 I did not realize that I'll get some info to you on that 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 stack. Yeah, well, those are those are the easy cases. But don't you see case to dictate your stat and the therapy? I think the point here is I can't imagine giving any lipid lowering therapy without being able to measure phytosterols, stannols, and does most of them. Some with you there, most lipidolors 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 azetamide, or if they could afford it? You can make the case if it was free, is preva statin lets just use PCSK9 and it better for God's sake, because you know, whatever other minor side effects of statin's maybe, I don't think we've seen much with PCSK9. I mean, of course, more time the guy would just be here.

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

and start injecting everybody with a PCS K9 inhibitor or not, because there's handcuffs on them. But there's no handcuffs on you using generic azetamib to a baby statin, is you have to buy on to LDLC is not your best surrogate of atherogenic lipoproteins, APOB or LDL particle count is, and if that's your real goal at therapy, then you got a lot of options available to you. Now, the one thing I used to use the combo lowest dose stat and possible coupled with is that in my, if there was some evidence of even mild elevation of phytostarol and

stano. One thing I've noticed, and I, 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 show you'd have to look back at C's where Improves it should show that. And prove it to use the Symbastatin and his edimib improve it. Yeah, and there was nothing more than.

I don't know what it is. I don't know what it is. I keep seeing these allergies. 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 or anything going on in a liver as a result of a statin. There's no correlation whatsoever. So I'm repeating them in all the time because maybe as a 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 amnesty, your measuring level on a stat, not related to anything. You've 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 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, I want to see it. I have other use. I don't know 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 open and panic.

That's not in your differential diagnosis of why the M&A says they're changing. Yeah, I don't know, Tom, I saw. It's been looked at extensively, Peter. I'm gonna go back and look at this. I'll show you the entire document where they've analyzed all the data in the world on M&A since that therapy, it's in consequential. 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 Zedia. And then their next blood test, their transaminase, has have doubled. And then the only thing you do is stop the Zedia and it returns to baseline. All right, so something is happening, but is it 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 is that? Am I going to use in a patient? Okay. Figure out how else the lower people be. So, fine, I understand there are things that will come into play in an individual patient with a data that doesn't support it by your making an individual decision. That's my point. Of course. That's my point. Of course.

You've got to be able to make an individual decision, which is what we're saying with the, with the Dismaster all 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. And a suppress cellular synthesis, which has nothing to do with the amount of cholesterol you measure in the blood. Great point.

And has not, cholesterol synthesis is not affected per se by PCSK9 inhibitors. Is that am I, is interesting? If you go with is that am I monotherapy, or actually get a little reflex increase in cholesterol synthesis? Yes. And vice versa, people with that. Monotherapy, a hyperbsorb stat. therapy, I actually get a little reflex increase in cholesterol synthesis and vice-versus. First of all, with the statin, monotherapy, hyperabsorb statin. There's a little bit of physiologic homeostasis going on there. And that's not changing levels to these talks.

No, no. And that, believe it or not, has become one of the times when I like using Zadia, 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 Zedia, and you'll sometimes get that reflex. And I argue with clinicians too, they are doing sterile testing, so I had time to identify my hyperabsorbers, and I surely make sure Zed amives on my APOB lowering therapy and 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 hypoabsorber, the genetic model is they live longer if they have genetic loss of function of anemone pixie when they're protein. So even in a patient who's not hyperabsorbing cholesterol, you do get additional apobelowering, maybe not of the same magnitude, but you get it. And you're changing them into the genetic model of longevity, maybe.

You're certainly keeping phytosteros out of them. You can find all of this information and more at pterotiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at pterotiamd.com. What's a Nerd Safari you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity,

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