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

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions along the way. I've spent the last several years working with

00:00:19.840 some of the most successful top performing individuals in the world. And this podcast

00:00:23.620 is my attempt to synthesize what I've learned along the way to help you live a higher quality,

00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

00:00:33.000 and other topics at peteratiyahmd.com.

00:00:41.380 Hi everyone, welcome to episode four of the week of Dayspring. In this episode,

00:00:46.560 we cover a lot of drugs. We talk about statins, we talk about cholesterol regulation, we talk about

00:00:52.500 ezetimibe, also known as Zetia, and we talk about the most recent class of drugs introduced to this

00:00:58.360 field, a drug, a class known as the PCSK9 inhibitors. There are two such drugs on the

00:01:04.680 market today. We talk about fibrates, and we also talk about the use of fish oil, niacin, or niospan,

00:01:11.320 which has fallen out of favor. This came up a little bit on the discussion I had with Ron Krauss

00:01:15.580 several months ago, and we get revisited here. Tom has a very different point of view on this from

00:01:20.520 Ron, so you will be able to determine which of those views that you favor, which camp you're going

00:01:25.300 to be in on the niacin side. We talk about the role of cholesterol, statins, and brain health,

00:01:29.840 and another thing that I learned was about the futility of using CKs and LFTs to address

00:01:38.440 statin response or ill response. So again, another great example of how I'm doing these shows,

00:01:44.940 but I'm learning along the way, and so I'm confident that any physician listening to this

00:01:50.000 is going to learn something, and that hopefully this becomes kind of a part of your

00:01:53.620 ongoing medical education. So sit back and get ready for episode four.

00:02:01.520 So while we're on that topic, let's go back and talk about the drugs. So we just finished with

00:02:06.240 kind of one very niche story, but when it became pretty clear that there was an association,

00:02:12.060 a strong association, frankly, between cholesterol and heart disease, you now had another target,

00:02:18.380 because as you said, if we went back in time, 50, 60 years, if you were astute enough, you would have

00:02:24.660 your patients stop smoking, you would manage their blood pressure. What was the first drug that was

00:02:31.000 specifically brought to market to target cholesterol?

00:02:36.280 Well, niacin has been used that infinitum forever without a lot of data, but they knew it changed certain

00:02:43.120 metrics that you were measuring total cholesterol, HDL cholesterol, and the only form of niacin available

00:02:50.660 back then was immediate release, a pretty much intolerable drug for most people, but you could

00:02:55.300 find some people who could take the massive doses needed for that. So that was around. Believe it or

00:03:00.940 not, when I was coming up, and total cholesterol was the only measurable thing, and they knew that

00:03:05.740 if it was 400 or something, you were probably in trouble. They gave niacin to those people.

00:03:11.060 Niacin, the antibiotic.

00:03:12.120 Yeah, which interrupted the hepatobiliary circulation of cholesterol, and it lowered cholesterol

00:03:19.720 anywhere, no outcome evidence with it, but along came the bile acid sequestrants, which we hinted on,

00:03:24.980 will make you excrete bile acids, which therefore you have to use up your endogenous cholesterol to

00:03:29.720 make new bile acids, so you will lower your cholesterol metrics that you're looking at,

00:03:35.460 and then in a crazy long outcome trial, it did seem to work. They pudged a lot of statistics,

00:03:42.320 I think, in retrospect on it, and didn't have the type of statistics.

00:03:44.840 This is the LRC.

00:03:45.840 Yes. So there was a little proof that not only what Framingham said is true, cholesterol is a risk

00:03:53.020 marker, a risk factor, depending on how you want to label it, but lowering it does reduce clinical

00:04:00.260 events. To me, the tragedy of that is for the next 20 to 30 years, the only thing that the

00:04:08.760 pharmacological industry focused on was cholesterol as their metric of, that's all we got to do. We

00:04:16.160 got to find stuff that lowers cholesterol metrics or improves cholesterol metrics in one or the other

00:04:23.000 direction. And biolasticity questions, do raise HDL cholesterol a milligram or two milligrams per cent,

00:04:28.700 which turns out to have some statistical significance.

00:04:32.640 Potentially without any physiologic significance.

00:04:35.100 Correct. And it's a minuscule thing, so who knows. So that led to just investigation of

00:04:40.780 everything else. And all of a sudden, this guy discovers a fungus that has got a property that

00:04:46.240 lowers really potently cholesterol. And that was the statin group, Akiro Endo, a mycologist over

00:04:53.480 there in Japan, who unbelievably has not gotten a Nobel Prize yet. And there'd be no statins without

00:05:00.080 him bringing it to the table and stuff. We wound it. Statins lower LDL cholesterol dramatically,

00:05:08.040 pretty low doses. They seem to be safe. All the, after LRC, the FDA needed was if you got a product

00:05:15.100 that didn't harm anybody and it's lowering LDL cholesterol, welcome aboard. So several statins got

00:05:20.580 approved starting in 1987 with lovastatin, Mevicor being the first and came on the market. Guys like

00:05:28.320 me who are well into believing, yes, lowering LDL cholesterol is the only metric we have now. And

00:05:35.240 that's good. People seem to do better, became very aggressive statin people. And that story told early

00:05:41.600 where we used to see MIs like crazy in our heyday, we stopped seeing them anymore. So we had at least 1.00

00:05:48.880 anecdotal belief that these things were working. And lo and behold, pharma knew ultimately they were

00:05:55.280 going to have to do serious outcome trials. And the first group of people they studied were

00:06:01.260 Swedish guys who survived an MI and had an LDL cholesterol of 190.

00:06:07.440 So these patients had FH.

00:06:08.740 Well, in retrospect, they're FH patients, you know, who's got an LDL cholesterol, one of the

00:06:13.920 definitions of FH. And giving them a dose of simvastatin, got your 25% reduction in clinical

00:06:21.760 events. So outcome data, bingo, great drug. And right behind them was Bristol-Myers Squibb who had

00:06:30.380 the much weaker statin, Pravastatin, sold originally as the branded Pravacol. Let's study Irish men who 1.00

00:06:39.080 have not had a clinical event, but also their LDL cholesterol is 180, 190, some more FH Irish men. 0.86

00:06:46.360 So you're going from secondary prevention FH basically to primary prevention FH.

00:06:50.420 Yeah. And lo and behold, reduced virtually every atherosclerone.

00:06:54.080 Do you remember what the NNT was for that group and what the duration of the trial?

00:06:58.020 You know, some of it had to do with the baseline, but it was down in the 20s. You know,

00:07:02.240 it was very good for both of them. It was just a little higher in the 4S because they were sicker

00:07:06.260 people. I'm surprised the NNT could be that low in primary prevention.

00:07:10.180 No, it was probably 40 to 50 in west of Scotland, but it was good. But these are nightmare primary

00:07:16.280 prevention. And these were, how long were these trials? Five years? Six years?

00:07:19.500 Yeah, they were five years. Some of them went a little longer, some a little less,

00:07:22.660 but five-year trials, you know. And so, and significant p-values correlated with the LDL

00:07:29.440 cholesterol levels. In retrospect, they did, you know, in sub-cohorts, they did measure APOB,

00:07:33.880 which shows. But this is an important point to make. And this is kind of, I've learned a lot from

00:07:38.420 you. I've learned a lot from Ron. I've learned a lot from Alan. I've learned a lot from everybody

00:07:42.180 in this space. But if there's one person who really got me to understand the limitations of

00:07:48.160 clinical trials, it's Alan, with his long view of this disease. You know, I've told this story

00:07:54.240 before, but Alan's the guy who bought me my very first copy of Starry's pathology textbook. And,

00:07:59.940 you know, is really the guy that got me looking at these autopsy pictures of kids and realizing,

00:08:05.100 hey, buddy, this disease starts when you're born. So, the thing that I think most people

00:08:10.180 misunderstand when it comes to lipid-lowering trials is they're always handicapped. 0.78

00:08:15.180 Very much.

00:08:16.160 They're behind a loaded gun, which it's pointing directly at them, which says,

00:08:20.260 we're only going to give you five years to impact the course of a disease that has been going on

00:08:26.160 for 50 years until now. You take a bunch of 50-year-olds and you put them in a trial where

00:08:31.480 you're going to study them until they're 55. You have five years to try to move the direction of

00:08:38.120 a ship that's been setting its course for 50 years.

00:08:41.260 And nowadays, because of the course, they would never give you five years to prove anything

00:08:46.200 works. You'd have to prove it a lot sooner.

00:08:47.900 That's right.

00:08:48.340 So, you better have a miracle drug.

00:08:49.740 So, that's, and we'll talk about the miracle drug, which is a PCSK9 inhibitor,

00:08:53.760 which there's a few things I enjoy debating with people more.

00:08:56.240 And last but not least, that's why you don't put mortality in this equation. It takes a long

00:09:00.080 time to die to improve mortality metrics.

00:09:03.340 Well, not only that, we're never powered to study mortality. I mean, it's just so difficult.

00:09:06.860 It's meaningless what a lipid modulating drug does to mortality. Meaningless, unless you've

00:09:12.360 got a randomized blind to 30-year trial, then I might say, what's wrong?

00:09:15.940 Yeah. Yeah. I agree completely. So, I guess I'm sort of humbled by blind luck sometimes,

00:09:21.840 which is we look back with the benefit of knowledge. So, it's not to disparage those

00:09:26.760 that came before us, but they didn't have a clue what was going on. They didn't have a

00:09:30.100 clue about the complexity. And if you think about it, so let's go back and talk about statins.

00:09:34.900 So, statins inhibit HMG-CoA reductase. That is an enzyme that is prior to the bifurcation

00:09:40.900 of the cholesterol synthetic pathway.

00:09:42.580 It's still a flat lipid molecule.

00:09:44.600 That's right. You inhibit that, and we're going to talk about a whole bunch of great things. But

00:09:48.860 there was a drug you taught me about a few years ago, an esoteric drug that inhibited delta-24

00:09:53.880 desaturase. That drug lowered cholesterol. Was the name of that drug again?

00:09:59.120 Triparanol.

00:09:59.980 Triparanol. So, triparanol comes one.

00:10:01.540 It was that 24-carbon. It didn't allow you to unsaturate the drug.

00:10:05.640 It did not allow you to turn desmosterol into cholesterol.

00:10:09.820 And so, now that's at the very bottom of this pathway.

00:10:12.240 Penultimate last step.

00:10:13.200 The penultimate molecule into the ultimate step. And all of a sudden,

00:10:17.060 you inhibited that with this drug. Cholesterol levels went down. FDA approved it.

00:10:22.040 But what would go up?

00:10:23.140 Desmosterol went up.

00:10:24.160 Desmosterol. And there was at least a congenital disease called desmosterolosis. Maybe that,

00:10:29.240 I don't know if they even knew about that, though, back then. We know about it now.

00:10:34.020 That maybe would have been a flag.

00:10:36.460 But when you look at, so if I recall correctly, about three or four years after this drug was

00:10:41.640 approved, because this is an era when you could approve a drug just by showing it lowered cholesterol,

00:10:46.840 the drug was pulled off the market in the late 60s.

00:10:48.720 Because atherosclerosis was occurring, cataracts were occurring, red blood cells.

00:10:53.280 And it turns out desmosterol turns out to have other roles in the body. It's a potent cell

00:10:58.780 membrane signaling molecule involved with inflammatory pathways. So, God knows what else

00:11:03.940 you're doing by perturbing desmosterol levels in cells and stuff, you know. So, you live and learn.

00:11:10.940 So, there's one endpoint that's getting better. Another endpoint that you didn't know anything

00:11:15.860 about or biomarker is getting worse, and it's probably doing some bad things.

00:11:20.240 And therein lies the sort of humility of drug development, right? Which is, you've got this

00:11:24.280 synthetic pathway. You have, at first glance, you have two things that are similar. A statin,

00:11:30.280 which inhibits one enzyme in the pathway. This other drug that inhibits another enzyme in the

00:11:35.220 pathway. And yet, one seems to be okay and one seems to be not okay.

00:11:39.160 There's several other cholesterol squalene synthase inhibitors that have failed for one

00:11:44.340 reason or another. So, it is a mega investment. And this is probably far worse, where if I say

00:11:50.520 999 out of 1,000 drugs don't come anywhere close to a commercial success, it's probably way smaller

00:11:57.180 than that.

00:11:57.740 So, it seems to me that there's a couple things that the statin had going for it, which maybe at

00:12:01.220 the time weren't realized. The first is it's higher on the food chain, meaning it's higher on the

00:12:06.100 synthetic pathway. So, if you are backing things up, they are less-

00:12:09.280 Yeah, there is some recovery time to other pathways to pick up.

00:12:11.280 Yeah, they're less like cholesterol. Oh, there'll be more acetyl-CoA, more acetoacetyl-CoA or

00:12:15.580 whatever. The other thing, and I don't know if this is true, although I've heard it speculated

00:12:19.380 on, but truthfully, I've never seen the data with my own eyes. Do statins have selectivity

00:12:24.280 for the liver?

00:12:25.600 Sure.

00:12:26.280 So, that would be another unintended benefit, right?

00:12:28.380 If you deprive the liver-

00:12:31.040 At least it's been theorized, because the pharmacokinetics of a statin, let's face it,

00:12:35.620 the real place you want to inhibit cholesterol synthesis is not per se in cells, but in the

00:12:40.780 liver, because that's the tissue that can upregulate the most LDL receptors to get rid of your

00:12:45.900 LDL particles. So, I'm not really interested in stopping cholesterol synthesis in other tissues

00:12:51.060 in your body, because they can get rid of it.

00:12:52.860 In fact, in an ideal world, you wouldn't want to inhibit cholesterol synthesis in a single

00:12:56.740 tissue outside of the liver.

00:12:58.140 I mean, I would if I knew that cell was producing other cholesterol, but even if it was, that

00:13:02.640 cell can get rid of it through those other pathways, and it would ultimately make its

00:13:06.560 way back to the liver. So, as long as I can enhance LDL receptors, by the way, which is

00:13:10.780 primarily the only pathway that's ever worked with drugs to reduce clinical events safely,

00:13:16.160 is expressing, in one way or another, more LDL receptors, statins, azetamide, biolacid

00:13:21.740 sequestions, PCSK9 inhibitors.

00:13:23.940 So, a very important point to make. What you're basically saying is,

00:13:26.740 the only drugs that have ever shown to both reduce cholesterol, but more importantly,

00:13:32.640 reduce events, have either been in isolation or in compounds or in combination, where they

00:13:38.080 are enhancing clearance.

00:13:39.720 Pretty much. I mean, some of them do affect production of the ApoB particles a bit, but

00:13:43.660 it's mostly enhancing clearance. That works. So, if you can do that safely, and only a clinical

00:13:49.220 trial can prove you're not hurting anybody, as we've shown some trials haven't worked out,

00:13:54.180 and I'll make a case for it, the niacin trials also. And niacin does nothing to an LDL receptor

00:14:00.020 that we know about. So, if niacin's working a lower ApoB, which it does, it's true other mechanisms

00:14:05.020 not proven to reduce clinical events.

00:14:08.800 When they first put statins out there, it was known that they were inhibiting cholesterol

00:14:13.200 synthesis. Did they also understand the effect they were having on the LDL receptors?

00:14:17.640 Oh, yeah. Sure.

00:14:18.020 And did they understand that that was the primary-

00:14:20.020 I think even why they went into that area was the Goldstein, the Nobel Prize winning

00:14:26.640 publication of the discovery of the Brown and Goldstein, the LDL receptor. They knew that,

00:14:32.440 wow, there's a pathway that if we can enhance cause overexpression of LDL receptor, it's probably

00:14:39.760 going to be good. So, their hypothesis generating their genetic studies even on the LDL receptor

00:14:46.020 led to, and they knew the bile acid sequestrons were first. That's how bile acid sequestrons work. 0.59

00:14:51.920 They upregulate LDL receptors to bring more cholesterol to the liver so the liver can make

00:14:55.760 more bile salts. So, let's get better LDL receptor expression drugs, and statin filler right into that

00:15:03.540 pathway without seemingly disrupting anything else. Of course, PCSK9 works on adazetamib through a less

00:15:13.800 potent pathway, but still expresses LDL receptors than do the statins. And so, they work.

00:15:20.140 Though, adazetamib's main mechanism of action is in the gut.

00:15:23.080 I'll argue with you on that, because where I talked about these, now, Peter talked about the

00:15:28.720 Neiman-Pick C1-like protein, which enhances the absorption of starols, including cholesterol in

00:15:33.960 the gut. And that's adazetamib's main area of action, inhibiting that from, so you do reduce

00:15:40.600 entry of cholesterol into the enterocyte. But remember, cholesterol gets into your liver, too.

00:15:47.680 And we think, oh, how does cholesterol get into your liver? Because the liver, de novo,

00:15:52.620 synthesized it, or you got all these particles bringing cholesterol back to the liver through

00:15:57.560 the direct and indirect cholesterol transport pathways. There's another pathway by which the

00:16:02.960 liver acquires cholesterol. The liver has an interface with the biliary system. And we've

00:16:09.160 always known, of course, that's how the liver pumps bile salts into the bile. That's how the liver

00:16:13.780 excretes free cholesterol. It pumps it into the bile, which brings it down to your gut.

00:16:17.700 But if the liver needs cholesterol in a pinch, what is a super-saturated body fluid full of

00:16:25.360 cholesterol in your body? Your bile. Super-cholesterol-rich. The liver can pull 0.76

00:16:30.520 cholesterol back, efflux it, so to speak, from the bile back into the liver. Why? Because what is

00:16:37.260 also expressive to hepatobiliary surface, the Neiman-Pick C1-like protein. So, azetamib has two

00:16:44.520 areas where it acts. It blocks the intestine from internalizing cholesterol, but it prevents the

00:16:50.560 liver from internalizing cholesterol from a biliary source. Put them both together, you're depleting the

00:16:57.360 liver of more cholesterol. And the liver needs cholesterol. There's a sterol sensor, the sterol

00:17:03.820 regulatory element binding protein, a nuclear transcription factor that turns on your genes

00:17:08.700 that make LDL receptors. So, this is interesting, Tom. I mean, the beauty of doing these podcasts

00:17:14.740 is I'm also learning as we're doing them, right? And this is an enormous insight to me that I now

00:17:20.600 remember you once telling me about this, but it was just one of those things where I was like drinking

00:17:24.460 from a fire hose and clearly this detail left me. I'm generally not a huge Zetia fan, Zetia or azetamib.

00:17:30.800 I just generally think it's kind of too impotent for real curiosity and sort of reserve it for

00:17:35.400 situations where patients can't really tolerate statins much and can't afford PCSK9 inhibitors

00:17:39.720 and all these things. Historically, the way I've decided on who's a great Zetia candidate or not

00:17:45.460 is looking at phytosterols or looking at other proxies of absorption. And I've argued, by the way,

00:17:52.680 that the trials that suggested Zetia were not that valuable. In monotherapy, it's never been shown to

00:17:59.760 reduce an event. No, they never did a monotherapy clinical trial. I think it would work if you

00:18:05.240 picked the right person. Well, that was always my argument, which was it might've been a mistake

00:18:09.000 in patient selection. You didn't select hyperabsorbers. But what you're saying would

00:18:14.920 suggest that that would dilute my argument, right? Because if it only worked at the Neiman-Pixy one

00:18:20.860 like one transporter, the argument would be target your hyperabsorbers. But if it also works at

00:18:27.040 biliary cholesterol, it shouldn't matter that much, should it? No, but yeah, no, that's part

00:18:31.160 of hyperabsorption. Because remember, if you're pulling it back into the liver, you're depleting

00:18:34.880 the cholesterol of a pool of cholesterol. But is the liver also then going to be a dominant source

00:18:40.220 of where we'll see cytosterol, campesterol, et cetera? The final body preservation way,

00:18:48.000 God forbid, phytosterols make it into your chalomicrons or your HDLs. And I can make the case that

00:18:54.380 if they ever get into a cell, they're going to injure that cell. But most of the chalomicrons are

00:19:00.020 going to deliver it to the liver first before it goes out in a VLDL. So the liver will, if you're

00:19:07.820 overabsorbing phytosterols, a lot of them do make their ways back to the liver. And the liver 0.93

00:19:13.240 recognizes them instantly as, using your analogy, that stupid bouncer in the intestine let you in. 1.00

00:19:21.160 That Neiman Peck and the ABC let you in. And you made it to, we're getting ready. We're the 0.99

00:19:27.900 backup police. So now you're the VIP lounge bouncer. Yeah, right. So boom, out you go again.

00:19:34.820 Now I realize those dopes may let you in again, but you're going to come right back here and I'm 1.00

00:19:38.860 getting you out again. So great analogy, Peter, the VIP bouncer. So who's to say,

00:19:46.740 Zetamib is taken out or reducing the functioning of the Neiman? And I think it's in both areas.

00:19:52.280 Merck knows this. Merck didn't want to, that's too much education to give. Let's just tell him it

00:19:57.620 blocks cholesterol absorption. The gut would make sense to most people. Most people,

00:20:01.820 including lipidologists, don't even know the liver's involved in the process.

00:20:05.400 So it was like advanced lipid study and stuff. We don't have to confuse people with that.

00:20:10.800 I've written a number of articles on Zetamib. Peter Toth and I, I think, did

00:20:13.940 one of our world-class articles on the mechanisms of it and stuff.

00:20:17.620 Yeah. What year was that? We've got to make sure we link to that one.

00:20:20.020 I'm bad with my years, but it's probably, I don't know, 2010, something like 2008.

00:20:27.200 But it's really with great diagrams, of course, showing you and explaining where Neiman Pick is

00:20:33.640 and everything.

00:20:34.200 And that's Toth, T-O-T-H. 0.98

00:20:35.380 Yeah, Peter is one of the genius and certainly mentors in my life. And of course, Peter and Mike

00:20:40.980 Davidson's had me write the chapter in the book, Therapeutic Lipidology on Phytosterolemia.

00:20:46.720 And Davidson's at Northwestern, right?

00:20:48.160 He's at University of Chicago.

00:20:49.400 University of Chicago.

00:20:50.000 Yeah. And look, very early on, probably because I was just such a good educator on lipids,

00:20:56.960 lipoproteins, and statin mechanisms of action, I was very early in Merck's investigation of

00:21:03.240 cholesterol absorption and became a very effective educator on that too. And, and therefore had

00:21:09.960 great contact with a lot of the Merck scientists, the Swedes who all invented all these absorption

00:21:16.180 markers and stuff and really became, you know, I had some specialties in lipidology and sterols

00:21:22.520 is one of them, you know?

00:21:23.940 Well, why do you think that the Zetia combination simvastatin trials, so the main trial with Zetia

00:21:29.360 was with and without simvastatin, correct? No. Or sorry, simvastatin with and without Zetia.

00:21:34.400 The reason why Zetia, Zetimib has taken so many damn hits is Merck's poor thinking of the type

00:21:41.840 of trials that let's bring to market to show that this is a great drug. And instead of just

00:21:46.700 doing the damn outcome data, even doing a select outcome trial in the right person, primary 0.96

00:21:52.940 prevention, as well as, of course, do your secondary prevention trials, even do that first if you want 0.98

00:21:57.500 to. And if that fails, you're not going to do anything with it. But let's, they wanted to just

00:22:02.800 get so much to market. What's the easiest thing to do? IMT. So let's take people with a lot of

00:22:10.280 lipid abnormalities, carotid intimal thickening, which is an ultrasound measurement of the thickness

00:22:15.440 of your carotid artery, which has some correlation with subclinical atherosclerosis and clinical events.

00:22:21.040 And that's unarguable. And therefore, they're at risk. They have lipid abnormalities. Let's give

00:22:27.440 them a, they're, you know, they're on a statin because we have to give them statins if their LDL

00:22:32.500 is out of, metric is out of whack. Let's give them one half of the group Zetimibe and the other half 1.00

00:22:38.340 placebo Zetimibe. And let's follow their IMTs. We only have to do that for a year or two and we'll see 0.94

00:22:44.120 IMT progression in one arm and no IMT progression in the other. Only did that. Virtually every lipid

00:22:52.160 parameter, including APOB got better. Every inflammatory markers got better. And the IMT

00:22:58.340 didn't change whatsoever. Meaning simvastatin had the same IMT as simvastatin plus azetimibe.

00:23:03.940 In a short time. And of course, we now know that what happens to IMT with any drug has

00:23:09.640 virtually no relationship to clinical outcomes. So that's not a tool you should be using to follow

00:23:15.420 up and saying, look at, it's like the coronary calcium score. It's not the tool you should be

00:23:20.020 using to demonstrate the efficacy. They should have looked at, but look at this APOB reduction

00:23:25.180 beyond what simvastatin can do. Look at the triglyceride reduction. Look at the CRP reduction

00:23:30.100 beyond what simvastatin can do. Or ox LDL or any of these things. At least say that doesn't mean

00:23:35.260 anything, but they had already polluted the minds that IMT was the best way to check the drugs.

00:23:40.800 In other words, obviously nothing trumps a hard outcome. If you can reduce mace,

00:23:44.060 that's the way to go. Sorry, major adverse cardiac event.

00:23:46.800 So they were taking a shortcut.

00:23:47.400 But they picked the wrong shortcut is basically what it comes down to.

00:23:50.280 There were better shortcuts you could take.

00:23:51.280 And who did that turn off big time? The images of the world, the cardiologists who instantly

00:23:57.480 dismissed the azetimibe as the world's most useless drug. Most cardiologists don't even know

00:24:02.680 what APOB is. And nevermind that. Hey, look at this. This is a potent thing.

00:24:07.280 I hinted to you last night. I was very much involved with the Riloxin, the first CERN that

00:24:11.140 came to the market of as good an APOB-lowering drug as azetimibe is, which might have portended

00:24:18.320 great cardiovascular benefit to the CERN Riloxin, which I believe it still has. In fact, we have some.

00:24:23.980 They did a big cardiovascular outcome trial where it was null. It didn't hurt anybody,

00:24:28.840 but it didn't reduce events. But if you looked at the primary prevention people

00:24:32.540 in that trial, it did lower events. Now, post hoc hypothesis generating data,

00:24:38.220 but an 8%, a 5% lowering of APOB mattered. And I think the right trial done with azetimibe

00:24:45.320 and outcomes, it would matter. But we're never going to know. And this

00:24:48.020 gets to a really interesting point when it comes to pharma's challenge of studying atherosclerosis

00:24:54.420 today. The industry is now going to always be a victim of the success of statins. It is

00:25:00.700 unethical to take high-risk patients and take them off statins, despite what the internet wants

00:25:05.400 to tell you that statins are evil and all that nonsense, which I don't want to get into.

00:25:08.980 But if you actually have any modest understanding of how these drugs work,

00:25:13.980 they absolutely save lives, especially when directed at the right patients at the right times.

00:25:19.880 What that means is you want to study another drug, you're adding it to a statin. You are not doing it

00:25:25.220 in mono, you know, you don't get to do the study of Zetia versus placebo. It's not ethical.

00:25:31.380 No, but-

00:25:32.000 If you've picked the right patient.

00:25:32.940 Could you think of a reason it would be ethical to do such a trial?

00:25:36.620 Yes, you take a bunch of highly, highly statin intolerant patients.

00:25:40.180 So that would be one, which they're never going to do for a variety of reasons. But here's another,

00:25:45.960 and Merck did two big outcome trials where they could use, you didn't necessarily have to give a

00:25:51.280 patient a statin. They took people with significant aortic stenosis and of the belief, because hey,

00:25:59.100 there's calcium and there's cholesterol in those aortic valves, that if we could lower cholesterol

00:26:04.740 in people with aortic stenosis, we'd reduce morbidity related to that. And we don't have to

00:26:09.400 give them a statin because statins failed to reduce outcomes in people with aortic. Those trials were

00:26:13.880 already done. So they took the SEAS trial, aortic stenosis, azetimibe, and lowered it. And guess what?

00:26:24.360 Did nothing to endpoints related to, because they're enrolling people who need surgery for God's sake.

00:26:29.940 I mean, again, that just, I mean, that just, that kind of stuff just, it breaks my heart. It doesn't anger me.

00:26:35.340 It breaks my heart.

00:26:35.880 But again, post hoc analysis, they did reduce ischemic events in that trial with azetimibe.

00:26:41.740 So MIs went down, angina went down, but that's post hoc analysis.

00:26:45.920 And they got lucky. They didn't power for that. It may or may not be legit.

00:26:49.900 Correct. So you'd have to do another whole trial to do that again. But they were hoping to sneak

00:26:55.800 by without doing. And the next thing they did was statins had failed to reduce clinical events in

00:27:01.000 people with chronic renal failure. Statins didn't work. So let's give them a statin plus

00:27:06.360 azetimibe. So you had the SHARP trial, they had pretty bad GFRs. So everybody, two groups got a

00:27:16.200 statin, but the one group got a statin and azetimibe. And the statin and azetimibe group reduced

00:27:20.540 events. So there was, but it's statin, azetimibe works. And then of course, they really had to wait

00:27:27.840 for the acute carnage syndrome trial, improve it trial to really convince the cardiologist that

00:27:32.760 yes, a little bit of extra B lowering, at least in that type of horrendously risky people

00:27:38.860 matters. And we now have had that replicated with the PCSK9 in him. And a great point you made up

00:27:46.180 lately. I mean, cost them God knows how long the money to do that improve it trial. And they really

00:27:53.380 had extended a couple of extra years to reach statistical significance, which turns somebody's

00:27:59.440 loudmouths on the internet dismiss it because of that now. But it's a miracle in people that are

00:28:04.840 aggressively treated with statin that you've reduced their LDL-C to way, way down, that just by lowering

00:28:11.340 it a little bit more, you can get extra event reduction. And I would never downplay that. I think

00:28:16.900 it's miraculous that it worked. And I think it's why it's miraculous PCSK9 inhibitors work in trials

00:28:22.680 where they're enrolling you where your LDL-C is 70, for God's sakes, because you're on a statin or

00:28:27.220 statinazetamide. So that to me is one of the single most impressive things. And again, we don't know if

00:28:32.160 this is going to be true in 10 years. Again, all facts have a half-life. But from the moment we are

00:28:37.260 sitting here today having this discussion, the fact that the Fourier trial could take patients who

00:28:42.760 had an average LDL-C of 92 milligrams per deciliter on statins, that means they are at the 10th

00:28:49.900 percentile of the Framingham population on a statin. You are going to add either a placebo

00:28:55.260 or a PCSK9 inhibitor. In that case, it was Repatha. You're going to study them for less

00:28:59.840 than two and a half years. And you're going to even have the nerve to suggest that might reduce

00:29:06.400 an event. And oh, it did.

00:29:08.680 And if it doesn't, you've just wasted billions of dollars of our money. What bean counter allowed

00:29:13.440 that trial to proceed?

00:29:14.540 It is. I was, I mean, I had been following this story even before I became interested

00:29:18.920 in lipids, just out of interest in the sort of the novelty of you see a natural experiment,

00:29:24.740 which is PCSK9 hyperfunctionings, PCSK9 hypofunctionings, MR drug. It just became a

00:29:32.020 beautiful, elegant model. And then I remember-

00:29:35.140 Which in real life takes decades to express itself.

00:29:37.660 That's right. And this all took a decade. And I remember thinking, especially once I got interested

00:29:41.680 in lipids, on the one hand being excited, on the other hand thinking, there's no goddamn way this 0.98

00:29:46.300 trial can work. You could not reduce events in 2.2 years. And they did. And of course, 0.82

00:29:53.280 this is how naive I am. And this is why whenever people ask me for advice, friends will say,

00:29:57.500 hey, should I invest in this company or that company? My advice to them is don't listen to

00:30:01.600 a single thing I say, because you're asking a question, will the market value something,

00:30:06.140 which I have no input on. I can provide you plenty of input on whether it makes

00:30:11.500 scientific sense. But you have to talk to somebody with a different skill set to understand if that's

00:30:15.420 an investable thesis. And so I remember Amgen kind of got hammered when the trial came out because

00:30:21.360 people thought, eh, that wasn't enough of an improvement, at which I thought, it's amazing.

00:30:26.680 And in reality, in fairness to the market, I think what the market was basically saying is,

00:30:30.300 if you did the math based on that trial under those circumstances, it would be, you know,

00:30:34.600 a million dollars or more to save a life. Well, that's a fair question for the market to assess.

00:30:40.260 But if you look at it from a scientific standpoint, that you could take that patient population and

00:30:44.840 achieve that outcome, I think it's one of the most remarkable things in cardiovascular medicine.

00:30:49.400 And to your point, it doesn't even speak to the patients that I have on PCSK9 inhibitors.

00:30:55.280 My patients who take PCSK9 inhibitors are patients whom prior to this drug, we were flailing with

00:31:02.500 what? Maybe some niacin, maybe some monotherapy Zetia,

00:31:06.660 maybe the smallest dose of livalo that a human could tolerate and getting woefully inadequate

00:31:12.280 coverage. As you know, you're doing that off FDA label because they would want to try it.

00:31:17.420 And they're paying out of pocket for it.

00:31:18.980 So people who can afford it, but it's certainly the genetic model tells them you're doing smart

00:31:25.240 there. And what are your option is to, and I would say, as you know, there are certain

00:31:31.260 nutritional therapies that can send your LDL particle count off the roof. And people are

00:31:36.220 dismissing that as a meaningless biomarker now, because if you do this diet, biomarkers X, Y,

00:31:42.440 and Z, and maybe even your waistline looks better. But ApoB, LDLP, doesn't matter in them.

00:31:48.440 Every single thing that's ever been done genetically or properly done clinical trial shows,

00:31:53.520 it does matter. And an individual, can I say, yes, it matters in you, it does not? No.

00:31:59.780 But if I want to follow the bulk of the data, it matters over time. So maybe if I send your LDLP

00:32:07.260 off the chart for two years, it doesn't matter. But do I want to do this for the next 15 years?

00:32:12.520 If you're a young person on a type of nutritional program that sends that through the roof,

00:32:17.440 is that wise? How many of you going to be mad at me in 20 years or 15 years because I put you in

00:32:22.380 the CCU? I don't know. Yeah. How many Nobel prizes have been awarded within the field of

00:32:27.940 lipid science? At least three, right? Well, certainly you got the LDL receptor and you got

00:32:34.000 two for cholesterol and I'm guarantee on other lipid things there might be. I'm not a Nobel

00:32:40.740 historian. No, but it's interesting, right? I mean, I think this is one of the things that

00:32:45.000 I guess there are a handful of discussions I have with patients that I find frustrating. Some of them

00:32:49.980 are frustrating because I have the same discussion over and over again and I've written about the topic

00:32:54.560 and the patient just won't read what I've at least written or at least take the time to read or

00:32:59.440 listen to a lecture to then come back and ask a question. So that's sort of frustrating for a

00:33:04.160 different reason. But few things frustrate me more than having to discuss things where

00:33:09.320 the patient's baseline of knowledge is the internet, which obviously you have all the signal can be

00:33:16.860 found there. But the noise, of course, is so great that you just don't know. But it's these

00:33:22.320 discussions around cholesterol and statins that I find most disturbing because in some ways it's

00:33:29.380 partly the fault of the pharma industry, I think. They have to take some responsibility for this,

00:33:34.020 which is in an effort to get these drugs into the majority of people who need them, there's been a

00:33:40.400 need to simplify the message. And when you simplify things, especially things as complicated as this

00:33:46.360 field, you will undoubtedly make mistakes. You will undoubtedly create confusion. And so now we have

00:33:54.400 a system where most physicians don't understand enough to actually explain to their patients why

00:33:59.180 they are putting them on statins and which patients may or may not even be good statin candidates.

00:34:03.360 Something I want to come back to because you brought it up and I think it's worthy of its own

00:34:07.540 sort of thread that will go down, which is this whole brain issue. It's a totally separate issue,

00:34:12.940 but it's this idea of failing to educate patients and physicians has allowed basically a, I don't

00:34:20.600 know, call it a militia of internet noise that is just completely ungrounded in science. I mean,

00:34:27.460 it's just completely ungrounded. It's completely disconnected.

00:34:31.020 And you've already mentioned one example. There are several others where a drug has come to market

00:34:34.900 and then some harm develop it. So therefore you castigate every drug that's ever been invented as

00:34:40.740 aha. Even though we just, even though we just illustrated, right, you can take two drugs that

00:34:46.440 inhibit two enzymes and get completely different results. Same result, a biomarker, but different

00:34:53.760 outcomes. And so I always try to tell patients, although I don't know, that probably falls on

00:34:58.040 deaf ears, but you got to think of every drug like you think of a tool, right? You, you, if you had a

00:35:03.500 general contractor and he had a hammer, a screwdriver, a drill, a level, a nail, a screw, et cetera,

00:35:12.480 you would want to have the most tools in the tool belt. That's the first condition. And the second

00:35:16.640 condition is you'd want to know when to use each tool and what its limitation was. And in that sense,

00:35:24.080 the one view, which is statins should be in the drinking water. And then the other view, which is

00:35:29.640 statins cause everything from diabetes, Alzheimer's disease to global warming. Both of those views are

00:35:35.480 so idiotic that I just, it's very difficult for me to process that. And I've basically stopped 1.00

00:35:41.300 engaging on Twitter with any of that discussion. You can't either extreme, you got to get rid of

00:35:45.960 those people very quickly, or you just get annoyed all day long. And this is why it ultimately comes

00:35:53.580 down to, and it's the way you practice. So you got to individualize everything. So anybody who says

00:35:58.820 statins belong in the drinking water, that's no public health solution to anything, or nobody

00:36:04.340 should ever take, that's absurd. Statins have tons of proof that you got to pick and choose your

00:36:09.080 patients properly. And this is why in the latter part of my career, I've developed so much more into

00:36:14.480 biomarkers and other risk assessment tools, because the better we can define an individual's

00:36:21.580 risk to any disease that he might be prone to, we can attack that disease through many,

00:36:28.660 mechanisms. Part of an atherosclerosis, you got to attack ApoB. If you don't, good luck. But the

00:36:35.020 more you understand, and that's where biomarkers and really not understanding the only understanding

00:36:40.020 these pathways, you talk about a lot more clinical chemistry. The average clinician has no clue how a

00:36:46.000 laboratory reports a given concentration of anything to them. I'd like to go into triglycerides,

00:36:51.900 because everybody thinks the whole world, people have no clue how laboratories assay triglycerides,

00:36:56.960 and maybe later we can talk about that. Well, one of the things that I've been pleased with

00:36:59.860 is once I got back into medicine, I realized I didn't know that stuff. And I have been really

00:37:06.640 fortunate. Every lab I have reached out to, to come and actually come to the lab and see how it works,

00:37:12.900 including THD. They've all opened the doors and said, come on in, Peter.

00:37:17.320 Odor, what can happen? And they overdo it. I love it. They literally will walk me from every station to

00:37:23.340 every, this is where the specimen arrives. So you can see where the FedEx box dumps off the

00:37:27.960 specimen. This is how we take it out. This is how it's handled. This is boom, boom, boom, all the way

00:37:33.160 to here are the magnets where we're doing the NMR. And I've, and I've got precision analytics has also

00:37:37.280 been great. I went up and spent two days with them a few years ago. And I agree. I mean, again,

00:37:41.120 not every physician I think has the luxury of time because they're clinically so much busier than I am.

00:37:45.740 So I don't, I certainly don't fault physicians for not doing that, but I do wish there was a way to

00:37:50.440 make that sort of experience more available to physicians because the more you understand how

00:37:55.560 these tests are done, the more you understand what your blind spots can be. Yeah. And I was

00:37:59.740 doing it for a while when I had more of a net presence with full lectures, which I don't do

00:38:03.900 anymore or they're not available on the net anymore. But just one other thing, like I tell you, most people

00:38:09.600 are clueless that labs don't measure triglycerides. They measure glycerol in your blood and they

00:38:14.700 calculate that into triglycerides. But when you get an LDL cholesterol or a total, let's talk about

00:38:20.600 LDL cholesterol. The assay that's analyzing the sterol in that particle has no difference. Does it know

00:38:28.780 whether it's cytosterol, campesterol, desmostrol, cholesterol? No. All it knows is it's a sterol.

00:38:34.260 So it just knows it's not a stanol. When you get LDL, it's even, it'll measure a stanol too, but they would

00:38:40.500 likely be a small part of it. So LDL cholesterol is really LDL cholesterol plus LDL cytosterol plus

00:38:47.400 LDL desmostrol. And the other 48, then a little bit of whatever stanol's got to, may have made their 0.77

00:38:53.100 way into your body too. So they don't know that. So in a person with phytosterolemia, a large part of

00:38:58.900 that LDL cholesterol value is a- Is the phytosterol. Yeah. So, but they don't realize. So they don't even

00:39:05.220 know, could ezetimibe have a, if phytosterols are injurious and I can make that case, I would,

00:39:10.620 if I did a one hour lecture to you using proper slides, you would be pretty convinced. I want

00:39:16.440 phytosterols not in my body. Ezetimibe is the only way to keep them out there. And wherever you're going

00:39:23.420 next, my final word on ezetimibe would be, if you're a big believer in this reverse cholesterol

00:39:29.340 transport process, which I've certainly expounded on now, what is the number one pharmacologic agent

00:39:36.160 that increases the amount of cholesterol that's winding up in your toilet bowl because it's in

00:39:40.780 your stool? That would be the best reverse cholesterol transport because the final common 0.88

00:39:46.900 pathway to reverse cholesterol transport is it's out of the body. Ezetimibe by far. So I can make the

00:39:54.560 case that if I wanted a lipid lowering drug in the drinking water as first line, it would be a

00:40:00.060 ezetimibe, not a statin, you know? So very interesting. And very controversial. Yeah. And

00:40:07.700 look, the FDA would put me in a lunatic asylum. And so would these so-called evidence-based guys.

00:40:14.560 But if you're analyzing this from cholesterol homeostatic pathways, it's a great drug.

00:40:20.920 Yeah. Well, we'll come back to all drugs. Most of the time, we do have to lower ApoB a lot more

00:40:27.040 than ezetimibe could ever do by itself. So the one that we've left out before we get,

00:40:32.540 I want to come back to niacin from a trials perspective, but let's take a break right now

00:40:37.180 and then we'll come back and we'll pick it up with, I want to talk about the fibrates.

00:40:41.900 And then obviously I want to talk about niacin through a clinical trial standpoint,

00:40:45.100 and then we'll get into the PCSK9. So we'll take a break right now and we will come back.

00:40:50.920 Okay, guys. So we are now back. We're going to slice this beginning into where we finished off.

00:41:01.220 So we had sort of more or less finished talking about ezetimibe, also known as Zetia. So we use

00:41:08.500 this as an opportunity to go into the next drug. So, all right. So Tom, that was pretty,

00:41:13.960 pretty insightful stuff on Zetia, also known as ezetimibe. Let's move to another class of drugs

00:41:20.080 that doesn't get a lot of use. I can probably count on two hands the number of times I've

00:41:26.040 prescribed it, which is phenofibrate or more broadly, it's class of fibrates. What the heck 0.68

00:41:31.560 are these drugs? How do they work and when should we use them? Well, if you practice in the United

00:41:36.520 States, you do have two choices. You have phenofibrate and you have gemfibrazole. And they're both out

00:41:43.080 there. They're both can be attained generically nowadays. So probably phenofibrate still comes

00:41:49.360 in branded forms. That's the trilipics. You don't have to. That's one of them. There are other

00:41:53.500 branded forms available out there. Gemfibrazole is a pro-drug. It has to be converted into the active

00:41:59.900 fibric acid, whereas phenofibrate is the active form right away. So it's a little bit more bioavailable

00:42:06.000 than it. It's kind of interesting for the purists of the world. Gemfibrazole has a monotherapy outcome

00:42:12.980 trial given to veterans with coronary artery disease who had low HDL cholesterol and high

00:42:18.860 triglycerides, and it reduced events as much as the statin did in any trial. So there's outcome

00:42:24.180 evidence. Was it independent of triglyceride level? Yeah, it was independent, although they enrolled

00:42:29.280 people. But many of the men, the triglyceride levels were certainly not at super high levels

00:42:36.760 or so. But it was mostly low HDL cholesterol, and virtually all of those people have some degree

00:42:43.500 of triglyceride elevation. But they tried to recruit people with what at the time was considered a normal

00:42:49.680 LDL cholesterol also. Which trial was this? It's called the Veterans Affairs High Density Lipoprotein

00:42:56.320 trial. Oh, VA HIT. Yeah, yeah, yeah. I didn't realize that was VA HIT. Yeah, and that was

00:42:59.560 gemfibrazole. And remember, gemfibrazole already had outcome data from the Helsinki heart trial too.

00:43:04.840 So this would be the second trial. Now, phenofibrate did come along with a couple of big trials, but it

00:43:11.120 missed the primary outcome, but hit some secondary outcomes for a whole lot of reasons. Enrolling

00:43:16.520 the wrong people, heavy concomitant use of statins. Nobody in any gemfibrazole trial was ever polluted by

00:43:23.560 people sneaking in statins with it at the same time. And clearly, whatever fibrates do, they do

00:43:29.440 it differently than statins. And the question is, can it contribute to a statin? But those trials

00:43:35.120 weren't designed to do that, but they were so polluted by statin use. And I just want to clarify

00:43:39.380 what you mean. I know what you mean, but I want the listener to understand. When you say polluted by,

00:43:43.080 what we're talking about is statins are so potent that when you include them in trials,

00:43:48.860 you are making it much harder for a new drug or compound that's being investigated to show its

00:43:54.940 effect because you've effectively raised the bar much higher for what needs to be done.

00:44:00.380 Sure. You've taken out one path. You're trying to prove with a certain class of drug that

00:44:04.200 via these mechanisms, very different, it works. And then all of a sudden you're getting rid of all

00:44:09.700 the ApoB particles via the statin. So yeah. And the statin is not given in a randomized fashion here.

00:44:15.720 Somebody takes it, somebody don't. Some docs says, you take this, don't take it.

00:44:19.320 Yeah. So that's the bigger problem scientifically. Of course, the counterargument is, look,

00:44:23.540 ethically, we don't want someone getting randomized to no medication. And then the second issue is if

00:44:29.420 the statin is the standard of care and therefore in the community, quote unquote, that's the way these

00:44:34.020 drugs are going to be used is with or without statins. That's the way they should be tested. So

00:44:37.920 it's all of these are fair points. But when you ask a true efficacy question versus an

00:44:44.080 effectiveness question, the cleaner you can ask that question, the better. And there's

00:44:49.420 no cleaner way to ask it than to not have another drug involved.

00:44:52.600 Sure. And by the way, when those trials were done, it was not standard of care that you had

00:44:56.160 to be on a stat.

00:44:56.900 No, no.

00:44:57.320 Yes. So they were legitimate trials that were ethical.

00:45:00.520 Whereas with the PCSK9 trials, it was statin care. You couldn't have a no statin arm in those

00:45:05.820 trials.

00:45:06.100 Right. That being said, these are all factors that go into the post hoc, at least interpretation

00:45:12.220 of some of these trials. But anyway, so gemfibrazole worked. And it's kind of interesting. You couldn't

00:45:17.960 explain the benefit of gemfibrazole in the VA HIT trial. But even though it did raise HDL cholesterol,

00:45:24.060 it was like a milligram and a half increase. And it lowered triglycerides, but not to a significant

00:45:30.620 extent. So why did it work? Or were there other pleiotropic type effects of fibrates or doing

00:45:38.720 something that we weren't measuring with any biomarkers or so? And I mean, some of that is

00:45:43.600 probably true. But then they didn't, at least in a cohort of it, they did a post hoc analysis

00:45:50.480 using NMR. And this was Jim Otfos who did this. And he found out that the benefit of the gemfibrazole

00:45:58.000 in the VA HIT trial could be easily explained by what it did to LDL particle count, which fibrates

00:46:04.800 do lower in certain patients, depending on the cause that are, and it raised the HDL particles,

00:46:11.680 which had a statistically significant tie-in to the clinical endpoint. And that was the first trial

00:46:18.020 showing anything that raising an HDL metric in a clinical trial, maybe if you want to do an HDL

00:46:24.560 metric, it's HDL particle count.

00:46:26.680 So can we make sense of that in light of what we spoke about, I don't know, 20, 30 minutes ago,

00:46:31.440 which was raising HDL cholesterol without paying any attention to particle number or particle size

00:46:37.440 is so noisy and at least as likely to be counterproductive as it is productive.

00:46:43.280 Here, you had two pieces of information of the three, at least, which is you had more particles,

00:46:48.920 you didn't change the cholesterol content in total. So you could make some inference. Again,

00:46:55.780 it's not necessarily correct, but you could at least have a better guess that you could make

00:46:59.780 about the clearance of cholesterol through HDL. But of course, then you have to make an assumption

00:47:04.900 about the size of the particle, correct?

00:47:07.220 Yeah, but very interesting in that NMR analysis, whereas HDL particle went up, it was almost all

00:47:13.400 small HDL particles. And for years, people have been running around saying the small HDLs are bad

00:47:18.940 and the big HDLs are good. And there was serious evidence that, boy, what BS that is. So fibrates

00:47:25.840 help delipidate HDL particles. So if you're in the old school of, hey, you're increasing reverse

00:47:32.120 cholesterol transport because the fibrates upregulate the scavenger receptor B1, which would

00:47:36.740 delipidate your HDL. So of course, your HDLs would become smaller. And then the small HDLs could

00:47:42.160 theoretically traverse back into the arterial wall, pull cholesterol out of your sterile laden foam

00:47:48.240 cells, the histopathologic marker of the plaque atherogenesis. And by the way, and aside for that,

00:47:54.880 when we talked about the complexities of the reverse cholesterol transport process,

00:48:00.440 one pathway I didn't mention, it's a sub-sub-pathway, something called, and Dan Rader coined this term

00:48:06.760 years ago, macrophage reverse cholesterol transport. And he used to make the case, the only aspect of

00:48:13.020 the RCT that matters as far as atherosclerotic clinical outcomes is delipidating the foam cells

00:48:19.480 in your artery wall of cholesterol. And that's really the job of an HDL. It can get into the

00:48:24.800 artery wall very easy. There's another ABC that facilitates that. There's a couple of them. There's

00:48:29.720 ABCA1, which will lipidate small, lipid-poor HDL particles, but there's ABCG1, which will lipidate

00:48:37.940 big mature HDL particles. So you have two ABC sterile efflux transporters in the surface of

00:48:43.800 macrophages that can pull cholesterol, efflux cholesterol out of the macrophage into a big

00:48:49.740 or a small HDL, which can then return to the plasma. And the small one esterifies it, becomes a mature

00:48:56.120 one and gives it to LDL, which returns it to the liver. So macrophage RCT, which is certainly

00:49:03.780 an incredibly functional aspect of what HDL does, has absolutely no relationships to the serum HDL

00:49:11.940 cholesterol level. So again, how do I know? I can't use HDL-C as a metric to tell me I'm

00:49:19.180 delipidating plaque in your artery wall, but I can have some confidence that if I'm using a fibrate,

00:49:25.600 that's one of the things I'm doing if you do have plaque in your artery wall, and who doesn't?

00:49:30.260 You know. Now, so why do you think the fibrates work best in patients with a higher triglyceride

00:49:36.000 level? Because their main mechanism of that, look, so they modulate HDL particles, but triglycerides,

00:49:42.660 and it has a lot to do with HDL remodeling too, but fibrates mostly stop the synthesis of VLDL

00:49:51.260 particles, triglyceride-rich LDL particles in the liver by depleting triglyceride pools in the liver.

00:49:58.160 Remember, what determines the lipidation of ApoB in your liver? All humans make two tons more of 0.68

00:50:05.780 ApoB than they ever have a prayer of lipidating and changing into an ApoB particle. The vast majority

00:50:11.440 of your ApoB gets catabolized because it's unused. So people always say, oh, what produces increase

00:50:16.900 ApoB? Nothing. Your liver makes way more ApoB than any human can ever use.

00:50:22.000 Why do we think that is?

00:50:23.020 I don't know. People just assume, hey, if you're making too much of something, you got to be

00:50:27.640 increasing the components. Except that one component we make too much of and never use is ApoB.

00:50:33.180 Yeah. I just, I wonder why that teleologically would be the case that we would make orders of

00:50:38.460 magnitude more ApoB than we could ever want to export.

00:50:42.700 Well, remember, A-beta-lipoproteinemia is death. So you have to make ApoB particles.

00:50:47.380 They transport energy. They transport phospholipids. They transport fat-soluble

00:50:52.260 vitamins, the big particles. So you can't not have ApoB particles in your plasma.

00:50:57.700 So you think it's just a margin of safety that is so big it's not even...

00:51:00.860 Well, yeah. They just make far more than we ever use. So it's very easily catabolized.

00:51:06.360 So you have a lot of it. But what determines the creation of the VLDL particle in the liver?

00:51:13.020 It's the lipid pools. How much lipid is available to attach to ApoB and create a

00:51:18.960 circular spherical particle that's going to be ejected by the liver? And that comes down to

00:51:25.220 the cholesterol pool and the triglyceride pool that's in that triglyceride is the stored energy

00:51:31.220 in your liver. And cholesterol ester is the stored cholesterol in your liver. Cholesterol,

00:51:37.440 I think I mentioned before, binds to the cholesterol ester binds to the... Or free cholesterol binds to

00:51:44.000 the ApoB first. Some of the cholesterol will be esterified even in the circulation, some in the

00:51:49.320 liver via that ACAD enzyme. And so then once you get the little primordial spherical VLDL,

00:51:57.160 then triglycerides are transferred in using MTTP, microsomal triglyceride transfer protein.

00:52:03.140 And now you got a real VLDL ready to be shipped out. Other, as it passes through something called

00:52:10.720 the space of this, which is a little space between hepatocytes and the plasma, other apoproteins

00:52:17.580 join there. But believe it or not, many of them, as soon as that nascent VLDL or whatever you want

00:52:24.220 to call it enters plasma, a ton of the apoproteins just leave your HDL particles. One of the functions

00:52:30.040 of HDLs, remember I told you to transport proteins, they transport a ton of these proteins that are

00:52:36.100 involved with lipoprotein catabolism. So C2 jumps off of HDLs, E jumps off of HDLs and goes right on to

00:52:45.360 the surface of a VLDL if it was not put there as it passed through the space of this. And they all

00:52:51.400 determine the catabolic fate of that VLDL particle. So fibrates through several mechanisms,

00:52:58.820 one, DGAD is an enzyme involved with the synthesis of triglycerides. It's adding fatty acids to

00:53:04.960 glycerol. Fibrates are a potent inhibitor of that. So you just stop triglyceride production with

00:53:11.280 fibrates. Omega-3 fatty acids work in a similar way. So they deplete the hepatic pool of triglycerides

00:53:18.380 and you're going to make less VLDL particles. And remember, a fibrator is not going to blow away

00:53:23.480 your LDL-P like a statin does, but it's going to blow, hey, 10, 15% reduction in part, depending

00:53:30.940 on the triglyceride richness, not the serum triglyceride level, but the triglyceride

00:53:36.080 richness of the core. So that's one of the reasons.

00:53:39.640 Now, where's the backup of free fatty acids? Because at some point, if you're not synthesizing

00:53:45.160 as much triglyceride, but you still have-

00:53:48.200 Well, you still have enough fatty acids. You're absorbing fatty acids. You're adipocyte

00:53:51.960 storm.

00:53:53.700 But is there a hepatic backup of fatty acids?

00:53:57.680 Well, de novo synthesis.

00:53:59.120 So in other words, this would not decrease NAFLD if you had a patient, because at first blush,

00:54:04.720 you'd think, well, a fibrate should be able to reduce fatty acid, to reduce fatty liver.

00:54:08.760 I just thought that for years, but it's just never been proven in a trial that that alone

00:54:14.640 would do it. Whereas actually ezetimibe has more data on reducing fatty liver than a fibrate

00:54:20.100 still. And most people all blame fatty liver on triglycerides. It's a sterols that really

00:54:26.820 cause a large part of the lipotoxicity that results in injury to the cells in your liver.

00:54:33.820 And there's a lot of animal data on ezetimibe eradicating fatty liver because they deplete

00:54:39.740 the cholesterol pool in the liver. So it's not all fatty acids and triglycerides that are causing

00:54:45.960 fatty liver. Sounds like it is, but that's a toxic disease. It's a lipotoxic disease and it's not all

00:54:52.960 fatty acids.

00:54:54.120 Although the fatty acids must play a significant role when you look at, I shouldn't say must,

00:54:59.140 but would suggest it because when you look at some of the preliminary data now that's coming out

00:55:03.440 with fructose elimination, meaning without restricting any other macro or micro, you know,

00:55:10.360 not, it doesn't matter about, it seems that glucose is not that relevant, even fatty acid

00:55:14.220 composition, not that relevant. If you completely restrict fructose.

00:55:18.400 Well, fructose is a major stimulus for synthesis of the triglyceride.

00:55:23.460 The triglyceride, but not, not to my knowledge, I don't know where it would fit into the cholesterol

00:55:27.860 synthetic pathway, right?

00:55:29.080 But look, it's a lipotoxic disease, but one of the major lipids that's causing

00:55:34.520 hepatocellular toxicity is cholesterol. It's just not all fatty acids. And I'm not implying

00:55:39.960 there no role of fatty acids or fatty acid synthesis, triglyceride synthesis related to

00:55:45.280 fructose, you know, but it's not all just somehow ignore cholesterol and you're going to get rid of

00:55:52.120 fatty liver. And you can't even separate the two because if you have a lot of triglyceride,

00:55:56.480 you're going to have a lot of ApoB particles that are part of the cause of that sterile toxicity.

00:56:00.980 Yeah, that's probably the bigger issue. It's very difficult to disaggregate them once

00:56:04.240 triglycerides are elevated. So really the ideal candidate for phenofibrate is going to be someone

00:56:10.140 with an elevated ApoB and an elevated triglyceride.

00:56:12.380 So if you look at, even if you take the two positive gemfibrozole trials and the failure of

00:56:19.080 phenofibrate in a couple of trials, easily explained if you look at things, but if you do look in the

00:56:25.940 and basically they enroll people that didn't have insulin resistance or triglyceride rich

00:56:30.520 lipoproteins and gave them a fibrate. So they designed a clinical trial where nobody in their

00:56:34.820 right mind would ever give that person a fibrate for a bunch of reasons. Hey, but they were diabetic,

00:56:41.580 but, and that was, they were diabetic. Yeah. Field trial is a hundred percent diabetics. And

00:56:46.440 so they figure it's a no brainer. Fibrates because of so many things that they do will improve

00:56:52.860 outcomes. And then maybe they would have, but the field trial was so polluted by statin,

00:56:58.680 unauthorized use of statins, inappropriate use of statins. Remember you're in a clinical trial,

00:57:03.000 you got the trialist watching you, but you're going to your own private doctor. He can,

00:57:07.020 and they were nervous at the time because the statin data was coming in and it was almost,

00:57:11.300 it was getting to the point where you're a bad doctor if you don't give a statin to somebody

00:57:16.320 with a lipid disorder. So they said, I know you're in a trial. We don't know what you're getting,

00:57:19.920 but I'm sorry. I'm not happy with your LDL cholesterol, take a statin. So it contaminate,

00:57:27.120 you know, we can always guess if we could have kept it as a pure trial of fiber, it had worked

00:57:33.540 in diabetics, but you know, that's just opinion. It didn't work, but it did work in everybody who had

00:57:40.800 an increase in triglycerides and low HDL cholesterol. It worked in, that's where the outcome reduction

00:57:47.860 was. Very interesting, which no other lipid drug has ever done. It reduced several microvascular

00:57:54.620 endpoints in those trials to retinopathy, amputations, peripheral neuropathy, renal disease,

00:58:02.040 even though phenylfibrate can raise creatinine a little bit, GFR improved and renal outcomes improved.

00:58:09.660 So what other drug you got, you can give a person that lessens this chance of a diabetic retinopathy

00:58:15.960 if he's a diabetic, nothing. Now it's post hoc, it's secondary. Well, that wasn't, that was

00:58:22.040 secondary outcomes. So the trials weren't designed to prove that. So they were a hypothesis. You'd have

00:58:27.620 to theoretically go back and do that before the FDA would ever give you approval, but kind of

00:58:31.800 interesting data. So, you know, I always made the case, what? Fibrates reduce amputations,

00:58:38.920 neuropathic ulcers, improve renal disease, save your eyes. Why the hell are you not on a fibrate

00:58:46.660 if you're a diabetic, you know? So again, using that type of data and people use drugs for far less

00:58:52.640 data than that. These are big, huge trials. And all of those endpoints have published their

00:58:58.160 analysis of those secondary endpoints and everything.

00:59:02.160 What are the main side effects of phenofibrate?

00:59:05.040 Not a heck of a lot. You know, it's a pretty well tolerated drug. Anybody can get any number

00:59:10.480 of any side effects with it or so. People used to be afraid of the increasing creatinine until

00:59:15.760 in the field trial there, and a large number of patients were doing creatinine clearance and

00:59:20.160 that didn't go. So there was a muscular buildup of creatinine that had nothing to do with GFR or

00:59:25.620 renal clearance of it. But there's nothing much to do. There are some drug-drug interactions.

00:59:30.640 I mean, the phenofibrate, azetamide, I mean, they're both very well tolerated,

00:59:34.700 certainly more tolerated than statins.

00:59:36.720 They really are. And you can make the case, at least in a diabetic, which is probably going to be,

00:59:41.480 especially with what we know now, the patient who's going to wind up on a fibrate. Now,

00:59:45.060 most lepidolish wouldn't use it until you statinize somebody or statinize them, azetamize them,

00:59:52.060 got their ApoB as good as you can get. It's still not there. Or triglycerides,

00:59:57.420 which is what they're looking at. Too bad in my mind. But they look at that and it's still high.

01:00:02.500 That is the persons that were helped, at least in post-hoc analysis of every single fibrate trial,

01:00:09.100 including the VA hit there and all the phenofibrate trials. So that's pretty much where

01:00:13.960 it's reserved to people with these identifiable by hypertriglyceridemia patients or so.

01:00:19.800 And we're not talking about people with triglycerides of 400 or 4,000 where pancreatitis

01:00:25.860 comes into play. We don't probably all use a fibrate and a lot of other stuff there like omega-3s

01:00:31.380 there on hopefulness that it would reduce the incidence of pancreatitis. Not proven yet,

01:00:37.600 but you would attack that degree of hypertriglyceridemia. But the real world is

01:00:44.160 people with triglycerides between 130 and 300, that insulin resistant world, which we've already

01:00:51.840 clearly defined as an ApoB disorder. So that's why your statinazetamide is your first line drugs there.

01:00:58.900 But if you didn't normalize that with your statin or statinazetamide, or indeed triglycerides

01:01:04.220 were still high. So you're presuming there still are triglyceride rich lipoproteins,

01:01:09.200 whatever they may be. They might be remnants. They could be LDLs that are triglyceride rich.

01:01:14.160 Especially in the lipidology community who are way more familiar with fibrates, although

01:01:18.600 it's sadly a disappearing drug that even younger lipidologists come on board have never been

01:01:24.840 taught anything about. And they don't go back and root these. So it's the older guys like me who grew

01:01:29.280 up through all those trials, have lectured on them, have written on them, really have a better

01:01:34.340 understanding of it than a younger lipidologist. And that's unfortunate because we're going to have

01:01:38.540 a potentially effective drug for a certain amount of people is just not going to be used anymore.

01:01:44.680 They're apt to use a fish oil instead, which because it lowers triglycerides. And it's so easy

01:01:49.960 to tell somebody to take a fish oil. They're not going to go home and read potentially scary stuff on

01:01:55.100 the internet where they might with a fibrator.

01:01:57.300 Oh no, they're going to still read it.

01:01:58.580 Yeah. I guess on everything, you're going to read some crazy stuff on the internet. So

01:02:03.040 tragically to me, because I don't believe there's-

01:02:05.900 And when you say fish oil, is it more the EPA that's having the effect on triglyceride or DHA?

01:02:09.920 EPA would have more an effect on ApoB, but DHA is the triglyceride. There's some recent new data

01:02:17.240 published on that. Because DHA is just more potent on C3 than is EPA. So I personally think you ought to

01:02:25.180 give both. If the primary reason you're going to throw a fish oil, a prescription fish oil product at

01:02:31.580 somebody is, I need extra ApoB lowering. Yeah. Then I would give high dose EPA, but I monitor

01:02:38.400 omega-3 levels in every body. So not everybody can convert EPA to DHA. DHA is just as crucial for a lot of

01:02:46.400 reasons. Your brain sure wants it. So I will measure, oh my God, I'm giving you a lot of EPA,

01:02:51.980 but you're one of the people who can't convert it to DHA. So then I would-

01:02:55.580 Give you a DHA. Give you some DHA. Or you take the high strength EPA and you throw in a lesser

01:03:01.160 strength EPA, DHA combo tablet, which is how you get it. As far as I know, there's no DHA only tablet.

01:03:08.680 Where is EPA only tablets? Certainly in the prescription realm. So, you know, fine. If you

01:03:15.040 want to lower ApoB, you can stick with your ApoB. But I don't have, where is my evidence that if I use

01:03:21.480 whatever fish oil therapy you want to use, I'm improving microvascular disease. I have

01:03:26.720 pretty serious evidence that I'm doing that, at least with phenofibrate. And the other thing,

01:03:32.500 although they're both available generically, sometimes these little drug companies, they'll

01:03:36.260 force gemfibrozole on you. The real reason, when you ask me, are there any side effects about

01:03:41.920 fibrates? And I did say the word drug interactions. Phenofibrate has a serious drug interaction with

01:03:48.960 coumadin. So you have to lessen the coumadin dose there. We're using a lot less coumadin.

01:03:53.040 We're using much more eloquence these days.

01:03:54.320 Yeah. So that's becoming less of a big worry. But God forbid somebody's on coumadin. You didn't

01:03:59.260 know that. You threw big dose phenofibrate out of them. They may be calling you up with a lot of

01:04:03.200 bruises because, you know, you potentiate the anticoagulant effect. Gemfibrozole raises statin

01:04:11.260 levels through the roof. So there's much more incidence of myositis and rhabdomyolysis when you use

01:04:18.460 gemfibrozole with a statin. And there's none of it with phenofibrate. So if you want to use a

01:04:24.920 fibrate, I strongly encourage it because it is generic nowadays to use phenofibrate because you're

01:04:31.520 going to be using it with a statin in the vast majority of cases. So you don't have that worry,

01:04:36.400 the muscular worry or so. So those are the two big things you better know about fibrates.

01:04:41.800 So most of the lipidologists, or at least were somewhat schooled on fibrates, are going to use

01:04:48.840 it in people where the triglyceride parameter is still high because they're assuming. I think if

01:04:54.580 we had better metrics of triglyceride-rich lipoproteins, maybe VLDL remnants or people who

01:05:00.940 have high LDL triglyceride levels, and they would likely be people who have APOC3 on their LDLs.

01:05:08.500 We have some other evidence that I want to fibrate on board you or so. So that's where that's going

01:05:15.680 to get used. But that's not your average person who walks into, and if he walks into the average

01:05:20.320 doc, the doc's going to be chasing LDL cholesterol or non-HGL cholesterol if they're a little more

01:05:25.140 astute and they're going to stop there.

01:05:27.500 I want to come back to, I made a note here to come back to VLDL remnants. So I got another question

01:05:33.880 on that. But I do want to finish our tour of drugs. So the next drug to then get into, we've already

01:05:39.360 kind of talked about a little bit, but I want to come back to it because I know you have a strong

01:05:43.000 point of view on it. And I got to be honest, I'm a little bit ambivalent. I don't know the last time

01:05:47.340 I prescribed this drug, but just from an intellectual standpoint, I'm always interested in these drugs

01:05:53.680 for people who can't go down a mainstream route. And that drug, of course, is niacin. So I don't think

01:06:00.000 there's anybody out there that says, hey, niacin is first line. I don't think anybody would argue

01:06:03.520 that. I think the question is, you take a statin intolerant patient who's got normal triglycerides,

01:06:10.740 who maybe doesn't respond particularly well to monotherapy Zetia, who can't afford a PCSK9

01:06:17.220 inhibitor and doesn't meet the regs for approval. Are these patients who should be on niacin? So

01:06:23.080 I'll go back to where we were earlier. Niacin exists in an immediate release and in a time release form.

01:06:28.600 There are two types of time release forms. Oh, I didn't even realize that.

01:06:32.140 Intermediate release and sustained release. So NIA SPAN, the Abbott version, is intermediate

01:06:37.140 release. And that's a prescription only product, which you're not going to get covered by any

01:06:41.540 third party payer. No, no, no. I learned that the hard way because I had a patient that was on it a

01:06:44.700 few years ago and he got a bill for like, they wanted $3,000 for it. I didn't know it was that high.

01:06:51.840 It's ridiculous. But if you want to, you somehow believe in niacin and don't want to give it a trial, 0.83

01:06:57.020 immediate release. And you got to give it three, four times a day at massive doses. You'll flush

01:07:02.800 your brains out. Most people, you're going to make it because you're not flushing. Niacin isn't 0.92

01:07:06.800 working in you. So let's talk about what the sustained release is cheap. You can get sustained

01:07:11.540 release. But the biggest problem was in clinical trials, niacin being a toxic drug it is. There's

01:07:17.420 way more hepatotoxicity with sustained release niacin than there is with the short release or the

01:07:22.400 extended release where there's no hepatotoxicity. So first of all, niacin became interesting as you

01:07:28.040 talked about because it's known, it's been known for a long period of time. It lowers cholesterol,

01:07:32.360 lowered LDL cholesterol. Yeah. And better yet raised HDL cholesterol. That's what everybody

01:07:37.940 always focused on. Everybody. And since low HDL cholesterol is a risk factor, we now know APOB

01:07:44.160 related, but whatever. Therefore, if low HDL cholesterol is bad, raising HDL cholesterol has

01:07:49.300 to be good. And niacin is the best product you had at the time. And then, so trials were done with

01:07:55.560 niacin. And it was kind of funny because I listened to the podcast, you and Ron Krause did. And it was

01:08:00.840 kind of cool because you made the case a little bit for niacin, Ron did. But at the end, as you just

01:08:06.520 said, you're ambivalent to it. And even Ron says, I don't use it much anymore. And then you maybe wind

01:08:11.100 up, okay, it's a fourth line drug if everything else has failed. All right, I'm not going to smack you

01:08:15.360 around too much if you say that. And you can't prescribe a PCSK9 inhibitor because of cost.

01:08:21.220 All right. But I think at the end of the year, go back and listen to you. You both admit it. You

01:08:24.840 don't use the darn drug anymore. I think the difference is, and this is where I'd love to 0.96

01:08:29.540 hear your take. I think Ron's point of view was the niacin trials may have failed for the same

01:08:36.840 reason that we would see the discussions we talked about earlier, which was overly statinized

01:08:41.220 patients. Now, you kind of had a different point of view on that, right?

01:08:44.780 No, because there was never, they weren't statinized in any, certainly the big, niacin has 0.87

01:08:50.380 one trial designed to use niacin as a monotherapy. It was that big coronary drug project, which

01:08:57.160 was a multi-pronged therapeutic trial where they randomized people to a bunch of drugs.

01:09:02.980 One group was given solely thyroid hormone. Thyroid hormone lowers LDL cholesterol. And all

01:09:08.160 they did was kill people by, with coronary disease, you give them thyroid hormone. They're

01:09:12.120 not-

01:09:12.560 You make them hyperthyroid. 1.00

01:09:13.440 You make them hyperthyroid. Not exactly good if you have coronary. So that drug failed.

01:09:18.540 They used a primitive fibrate, clofibrate, and there was some question of a mortality adversity

01:09:25.500 there. So that was hit number one on the whole, nobody in America uses clofibrate anymore. It's

01:09:32.100 probably still available in Europe. I don't think anybody uses it. So fibrate arm of that trial

01:09:37.560 failed. And they used estrogen given to men because, hey, women don't get heart disease

01:09:44.500 because they have high estrogen levels. If we just gave estrogen to men, they wouldn't get heart

01:09:50.020 attacks. And they had immediately stopped the trial by precipitating heart attacks in men by

01:09:54.460 prescribing estrogen. The only thing that would make that funnier was, please tell me they gave

01:09:59.780 it orally.

01:10:00.680 They did.

01:10:01.280 Oh, God.

01:10:04.600 That was about the only form they had back then. Anyway, so yes. And then they had a niacin, 0.98

01:10:10.200 immediate release niacin arm. And now, you know, in a clinical trial world, if you go down to the

01:10:17.700 FDA and you just put a drug through a clinical trial, it better be empowered or better not have

01:10:22.780 been much toxicity. And you better come in and have hit your primary endpoint. Because what will the

01:10:27.940 FDA never, ever allow you to discuss a secondary endpoint? If you fail the primary endpoint, you've

01:10:33.720 failed drug. All you've done by improving some secondary endpoint is generated a new hypothesis. Let's

01:10:40.060 go back and do a trial on those people. So what was the primary endpoint in the coronary drug project?

01:10:46.440 The favorite endpoint that people today love, mortality. And guess what niacin did to mortality?

01:10:52.540 It worsened it. Not statistically, but you could say it was no, but it was certainly going in the

01:10:59.120 wrong direction. So did I care when they did the secondary analysis that, but wait a minute,

01:11:05.380 myocardial infarctions were down. It was like me telling you in that aortic stenosis trial,

01:11:10.540 but hey, Zeddy, it reduced myocardial infarctions, but it didn't reduce the aortic.

01:11:13.980 But in fairness, was the trial powered for mortality or was it powered for?

01:11:19.740 Look, no, it was powered. Mortality was the only endpoint in all the arms of those trials. That's

01:11:26.700 what they were looking back at then. All-cause mortality or coronary mortality?

01:11:30.040 No, it was all-cause mortality. I don't know. It failed.

01:11:32.900 That's kind of amazing because, I mean, that's very unusual.

01:11:35.220 You're talking about a trial in the 1960s, you know, early trials, you know, what, how they

01:11:39.680 picked endpoints and stuff? But niacin, so don't come and preach to me that it hits secondary end

01:11:45.640 points. But wait a second, wait a second. Why is it that niacin failed this trial in the 60s and it

01:11:49.720 was only three or four years ago that the, basically the payers said we're no longer paying for it?

01:11:54.440 Well, because we've had a lot of other trial data that's come down since then where other types of

01:12:00.200 niacin and probably better designed trials also failed to reduce any endpoints. So the evidence

01:12:06.000 became overwhelming. Show me a damn trial where it works and then maybe we'll give you, 0.99

01:12:11.760 we'll pay for it at least. The FDA would never give it an indication without primary endpoint data or so. 0.97

01:12:18.600 Then the other thing they did with that coronary drug project is they published like 10, 12 years

01:12:24.600 later, the most ridiculous post hoc analysis done on questionnaires, sent to people who they could

01:12:30.240 round up who they discovered. You were in the original trial, small number, and lo and behold,

01:12:37.460 mortality was improved in that group of people, coronary mortality. So there we have evidence that

01:12:43.940 niacin improves coronary mortality.

01:12:47.360 The problem is that this election, by it.

01:12:48.900 It's the worst. It wouldn't even be published today. It would be laughed at if you ever submitted it

01:12:54.680 to a journal. The coronary drug project might, I don't think a drug company would even send the

01:13:00.280 coronary drug project to a journal nowadays. I mean, they almost have to nowadays. In all trials,

01:13:05.380 they tried to hide them in the end, but the population, thank God it did. So we learned a lot

01:13:10.980 about a lot of drugs in that trial. So there was no evidence in a trial designed to prove nice and

01:13:15.900 reduce coronary heart disease, at least the level one evidence. Then of course, guys said, well,

01:13:21.740 angiography got introduced and they could start doing regular angiograms. There's something called

01:13:27.080 quantitative angiogram where you're basically looking at the lumen of an artery and seeing

01:13:31.820 how much plaque may be extruding into the lumen. You're doing nothing to what plaque may be existing

01:13:37.840 in the coronary artery walls. And in that trial, using quantitative angiography, they did see a

01:13:44.020 statistically significant improvement in the lumen of arteries in people with coronary arteries.

01:13:51.720 who took niacin. That's the HATS trial. It's a small, well under a hundred people given niacin,

01:13:59.560 no statins or anything. And they come to this inclusion was a 90% event reduction.

01:14:06.240 Not only did we see a fraction of a millimeter increase in the lumen, and by the way, at that rate,

01:14:12.980 it would have taken you 200 years to open up the artery seriously to hemodynamic blood flow.

01:14:18.560 But in this small cohort, in a trial, absolutely not empowered to look at clinical outcomes,

01:14:24.200 there were less coronary events in this trial. And that got extrapolated through a lot of

01:14:28.860 disingenuous marketing of people saying, oh, look at this. Nothing ever gives you that type

01:14:34.660 of outcome reduction. It's a 90% event reduction. And there are a bunch of-

01:14:39.820 I'm sorry. Just make sure I understand that. I'm actually not even familiar with the HATS trial. So

01:14:43.080 this had a hundred subjects in it?

01:14:45.620 Yeah.

01:14:46.080 So presumably-

01:14:46.820 98, something like that.

01:14:47.160 So 50 in each arm? It was a one-to-one randomization?

01:14:50.360 No. And I think they just did the angiograms of people and they put them on niacin and they

01:14:54.000 did a repeat angiogram.

01:14:54.820 Oh, so a hundred people with a crossover. Basically, you were your own control.

01:14:57.680 Yeah. Your baseline arteriogram was in your follow-up.

01:15:00.940 Right. So the- I mean, I don't want to get into a lecture on shitty science, 0.72

01:15:04.720 but I can't help myself. To be clear, there's no placebo group here. 0.62

01:15:09.000 Right.

01:15:09.760 In other words, you've completely eliminated the- 0.58

01:15:14.280 You're looking at angiographic changes from a drug.

01:15:16.460 No, understood. But there's a performance bias here.

01:15:19.320 Every patient in that trial knows that they are being given a compound that is supposed to make

01:15:23.980 them better.

01:15:24.720 Yeah. And they're given other advice too, but-

01:15:26.880 But the point is you have no idea of knowing if they've changed any other behavior that may or may

01:15:31.400 not contribute to an improvement, notwithstanding the bigger issue I would have with that trial,

01:15:35.560 which is that the millimeter change of an angiogram doesn't actually tell us anything-

01:15:41.720 Oh, we now know it's meaningless, yeah.

01:15:43.280 About the vulnerability of plaque or true events.

01:15:45.820 No. And you certainly can't use that type of numbers of people to generate outcome data. They

01:15:52.000 did it. It was disingenuous for them to do it. It's absurd for anybody to ever talk about it,

01:15:56.920 but they did it. Because look, we're in our infancy on these drugs. We're learning as we go along.

01:16:03.720 It's easy for us to say that now and everything. And there were three or four other nice and

01:16:08.900 angiographic trials that sort of indicate, boy, the images look better when we follow up on these

01:16:14.680 people. And HDL cholesterol is going up, so what else could it be? And that HDL, that HATS trial,

01:16:21.900 was so impressive to people that they said, the only way we really can prove this is to do a giant,

01:16:29.120 randomized, prospective, blinded trial where we give niacin, add it to whatever else,

01:16:37.980 get this HDL raising on top of, we're already given drugs that lower LDL cholesterol.

01:16:44.100 Was this Aim High? So Aim High was the first. So there'd been no Aim High if there wasn't this

01:16:49.300 HATS angiographic trial first. That was the whole premise to let's spend money on the

01:16:54.260 Aim High trial because now we are in the statin era where you do have to give everybody a statin.

01:17:00.920 So we'll make everybody's LDL cholesterol perfect. And by the way, if a statin doesn't do it,

01:17:05.620 we'll add azetamide to it also. So we will get LDL-C perfect, but HDL-C is still going to be low.

01:17:12.080 So we're now going to add niacin. And this, I think, is Ron's real point,

01:17:16.240 which is when you look at that trial, which was really then using niacin to increase HDL-C in an

01:17:24.040 already optimized LDL patient, you missed an opportunity to actually ask.

01:17:29.440 You didn't miss it because here's what happened. In that trial, niacin made the ApoB go lower than

01:17:35.840 statin and azetamide did by themselves. So you got additional serious ApoB lowering and no outcome

01:17:42.060 reduction. So how much, how much lower did it get? Another 10, 15%. So here is a drug that is

01:17:49.160 drastically further lowering ApoB, atherogenic particles. It's raising that, as I now call it,

01:17:55.180 stupid metric HDL cholesterol, but it's not working. Well, I just told you Reloxfin, I believe, 0.97

01:18:01.200 works because it lowers ApoB. Why didn't niacin? Because it's got to be doing something bad

01:18:06.160 that's aggravating your arteries. And you give me a drug that causes acanthosis nigricans in human

01:18:13.340 beings, pathognomonic of insulin resistance. Why would I ever give that drug to a human being?

01:18:19.380 So niacin causes worsens. And the only person who you're probably going to wind up giving niacin to

01:18:25.320 is probably insulin resistant, identified by triglyceride HDL abnormalities. You're giving niacin.

01:18:31.120 And it makes them worse. And I could read off 15 other well-known side effects with niacin.

01:18:36.460 I don't think anybody would dispute that. And so why did it fail, even though it lowered ApoB,

01:18:42.640 beyond what a statin is at a market? And that's a very interesting point, right? And I guess the

01:18:45.960 only, if I could wave a magic wand, the only other question I'd have, which is purely intellectual,

01:18:49.900 again, I don't really think niacin has a place anymore, is could the wash on mortality,

01:18:55.180 despite the reduction in ApoB, be explained by the worsening of insulin resistance?

01:18:58.780 It's explained by something. Yeah. No, but I'm saying like that would actually be an interesting

01:19:03.300 thing to try to quantify. Could be explained by GI bleeding above an acute niacin, well-known to do

01:19:10.060 that. It could be explained by all sorts of hematologic parameters, disruption, platelet reactivity

01:19:16.020 with niacin, well-known, and a bunch of other things that niacin has been implicated in. So to me,

01:19:22.660 every time you use a drug, you're using trial data benefits versus risk. And I see some benefits

01:19:29.460 to niacin. I don't think the HCL is a benefit, but lowering ApoB, I'm going to always consider

01:19:35.100 that a good benefit. But if nothing is happening, there's something adverse going on, which I don't

01:19:40.180 understand. Look, they took that extended release product off the market in Europe based on this

01:19:45.260 trial. In the United States, it's still here, but they just made it unaffordable. So they don't want

01:19:50.140 you use in it. Immediate release niacin is you're basically prescribing a vitamin at a mega dose.

01:19:56.920 One other little aside, because I know there's people who take niacin. Remember,

01:20:01.600 these trials were done with massive pharmacological doses of niacin. They didn't take a multivitamin

01:20:07.400 with niacin in it, which has nothing to lipids or lipoproteins. So if you want to be a niacin

01:20:13.520 player, in the coronary drug project, immediate release niacin was four grams a day. Try that.

01:20:19.260 That sustained release niacin. Wait, wait. So those patients took one gram four times a day?

01:20:24.080 Yeah. They worked their way up to it. Because many could just, hey, if this is as much you can

01:20:30.600 take, that's what you, but they got them on pretty high doses, I will say in those days. Kudos

01:20:35.000 to the docs in those trials and everything. So X number of people could tolerate. Kudos to the

01:20:39.280 patients for tolerating it. Yeah. Listen, if you get not only flushing, but massive

01:20:46.120 pruritus can occur when you use immediate release. It's a scary phenomenon to a layman who experiences

01:20:52.020 that, who hasn't been warned. I remember a call I got early in my practice, like at two in the morning,

01:20:57.940 the guy thought he was going to die. He had dialed 911 because he just had an extensive

01:21:02.660 pruritic reaction and he felt his whole body was on fire. If he'd had a swimming pool,

01:21:08.040 he would have jumped into it because he just thought his body was burning up. And I just said,

01:21:12.780 you're going to think I'm crazy. Chew two aspirins and just call me back in an hour. It'll be gone.

01:21:19.820 I forget whether he did wind up in the ER or not. Now that's an extreme reaction, but it occurs.

01:21:25.880 So, and look, I've taken an eye on a couple of years on myself on some of the beliefs before we

01:21:30.160 knew a lot of this that, because I could not tolerate a statin or statinizetamib and I had an

01:21:35.300 APOB issue and I hadn't learned about intermittent fasting or follow the low carb diet at that time.

01:21:42.120 So, unfortunately, niacin didn't even lower the APOB in me, did nothing, but I tolerated it for

01:21:48.060 whatever reason, but did nothing. And who knows what it did to my insulin resistance, you know?

01:21:53.840 For me, niacin sort of grew out of favor with patients even before the final trial. I think

01:22:00.020 just the exacerbation of insulin resistance became sort of problematic.

01:22:04.980 And by the way, the last trial, they did another trial because it was a branded product. They took

01:22:09.060 that extended release niacin, but they combined it with an anti-itch compound and aha. So,

01:22:15.820 everybody's can tolerate niacin now, and they added it to a statin. That was the heart protection study

01:22:21.220 thrive. And it was basically a duplication of the AIM-HI trial. Nice increase in HDL cholesterol,

01:22:28.380 further reduction in APOB, and zero outcome change, and a lot of toxicity. Much of the toxicity is

01:22:36.100 just glucose exturbations. You're going to aggravate glucose. Anyway, so Europe decided that's it. So,

01:22:42.240 they took that combo pill off the market. I'm sure you can still get immediate release niacin in Europe

01:22:46.960 if you want it. You know, it's a vitamin, for God's sakes, a mega dose. So, I just don't like

01:22:52.420 people out there who want to extol niacin. Fine, but don't start telling them niacin has a lot of

01:22:58.460 data. It's got zero data. And these are the same people who bash fibrates who do have two large

01:23:05.260 randomized perspective trials, Helsinki and VA HIT with fibrates, and yet they never consider a

01:23:11.900 fibrate. They always tell you, oh, niacin's the better drug. And at least in the field trial,

01:23:17.320 niacin or phenylfibrate had all these microvascular. There's no prayer niacin reduces

01:23:22.160 diabetic retinopathy, amputations, kidney disease. But yet, there was that battle. People bashed

01:23:28.360 fibrates, hold them to the high standard of you got to hit your primary endpoint, and they never

01:23:33.440 held niacin. And to be honest with you, the same, that's what Ron Krause did in that study. So,

01:23:38.360 I understand what he's talking about. There is some data if you want to extol it,

01:23:41.400 but it's not the type of data you and I use anymore.

01:23:44.340 So, we'll go from the stepchild to the poster child, which we've already kind of alluded to,

01:23:50.360 which are Repatha and Proluent, these two PCSK9 inhibitors. And I'll just give a little bit of

01:23:56.980 background, obviously. What's the name of the fellow up in Toronto who actually discovered this?

01:24:01.540 Oh, I thought it was in Texas. Hobbs, Helen Hobbs was the first person who discovered the

01:24:07.940 Oh, no, no. Sorry. I mean, the PCSK9 expression.

01:24:11.020 No, sorry. No, I mean, the actual family of PCS, the PCS family. Yeah, I believe-

01:24:15.540 Oh, PCS, look, there's at least 10 members in the family.

01:24:18.280 There are.

01:24:18.540 They've been around forever.

01:24:19.420 Yeah, yeah.

01:24:19.900 I think it's-

01:24:20.960 I don't know who discovered number nine.

01:24:22.480 I don't know. I think because I grew up in Toronto, I have a fondness for remembering

01:24:25.560 anything that anyone from Toronto did, but we'll figure it out in the show notes. I could be

01:24:29.180 making all this up, but I do think there was, there's a guy in Toronto who actually discovered

01:24:32.840 this family of proteins, but you're right. Then the ninth one to come along-

01:24:37.140 Yeah, Helen Hobbs did the genetic evaluation, genetics, gain of function, loss of function, 1.00

01:24:41.060 explains outcomes.

01:24:41.900 And the gain of functions were discovered first, correct?

01:24:44.440 Yeah.

01:24:45.560 So I'll explain this really quickly and briefly. You can expand upon it. PCSK9 degrades LDL receptors.

01:24:53.960 So if you have a gain of function, you are more rapidly degrading LDL receptors on the

01:25:00.460 liver. You're going to have a decrease in your clearance of LDL. You will have a higher

01:25:05.300 LDL. These patients had very high events. In fact, these patients make up, what, 5% to

01:25:10.160 10% of what we would diffusely refer to as familial hypercholesterolemic.

01:25:13.780 That's correct. It's one of the many, and I think in one of your podcasts, people don't

01:25:18.260 understand. FH could be a thousand different disorders.

01:25:20.860 Yeah, FH is a phenotype, not a genotype.

01:25:22.620 And they're not all autosomal dominant. Some are heterozygote disorders of various genes,

01:25:27.560 but the phenotype is an LDL cholesterol above 190.

01:25:31.280 And then you fast forward to about 2004, 2005, maybe it was 2006, but even I remember this. And

01:25:37.320 again, this was before I became kind of a lipid wannabe, but I would still read the New

01:25:42.320 England Journal of Medicine just because it's sort of interesting. And there was the discovery

01:25:46.280 of the hypo-functioning PCSK9 folks. And I really do remember this, and I'm surprised I

01:25:52.200 remember it given that it wasn't from-

01:25:53.560 I actually discovered in African-Americans first, I believe in a Jackson trial down there.

01:25:57.100 That's exactly right, yeah. And these were folks that were walking around with an LDL cholesterol

01:26:01.660 between 10 and 30 milligrams per deciliter, and they were completely event-free. And of course,

01:26:09.400 the first-

01:26:09.780 Not 100%, but significant reduction.

01:26:12.000 Dramatic reduction. And the reductions, I believe we actually went back and did a calculation to

01:26:17.600 see if their reductions, how congruent they were with some of the more recent Mendelian

01:26:23.020 randomizations. And they're very similar, and it's not surprising because that's effectively how

01:26:27.280 you would model a reduction, a lifetime exposure reduction. The thing that interested me, because

01:26:33.780 I remember at the time, like many people, I'm sure, I sort of had this concern, which is,

01:26:38.800 well, God, if cholesterol levels- I mean, I now realize I was being naive, but my concern was,

01:26:43.740 God, if your LDL is low, that must mean you can't make hormones. It must mean that you're going to

01:26:48.820 get some other awful disease. And so the interesting thing to me was those people didn't have any of

01:26:54.240 these other phenotypes. They didn't seem to have deficiencies or deficits as a result of that.

01:26:58.960 And of course, I think that trial is what was the catalyst for Amgen, Sanofi, and these other

01:27:05.620 companies to start working on these drugs. Yes. And by the way, they've since studied in these

01:27:10.000 people where they've blown away LDL cholesterol at 10 and 15, there's been zero effect on

01:27:15.300 reproductive hormones or adrenocortical hormones. It goes back to what I just told you. Those glands

01:27:20.600 synthesize all the cholesterol they need, and they get it from HDL. So none of them are waiting for an

01:27:25.880 LDL to show up with cholesterol to keep them functioning. So it's all the nonsense you get when

01:27:31.740 you go to a health food store or a gym where the guy tells you, you got to raise your atrial

01:27:36.620 cholesterol or something because you're helping your testosterone level in the blood. It has nothing

01:27:42.400 to do with it. Or if you deplete testosterone because God forbid you're actually taking a statin,

01:27:47.120 you're screwing up your testicular function. You're not having nothing to do with it.

01:27:51.340 Yeah. Yeah. There doesn't seem to be any evidence of that.

01:27:53.560 Uh, so that put into perspective, yes. But so the genetic model is if you got an LDL cholesterol

01:28:01.060 of 10 and 20, nothing's going to be wrong with you. And you're certainly going to have far less

01:28:06.980 heart disease. And when we use talk about loss of function, that means your LDL receptor half-life

01:28:13.420 is much longer. We didn't get into it before. We told you the liver makes LDL receptors.

01:28:18.640 There's theoretically any cell could. If your liver expresses an LDL receptor, how long does

01:28:23.420 it stay there for? Two, three days. And it grabs your ApoB particle. It brings it into an endosome,

01:28:31.300 but then the LDL receptor travels back to the surface, grabs another one. I used to, those of

01:28:36.800 you old enough to use to watch the Adams family on TV, it's like things hand coming out of a box.

01:28:42.180 It's the LDL receptor, grabs something, pulls it in, but things arm comes right back out again.

01:28:46.440 But if in some people that LDL receptor might be catabolized in the lysosome endosome, then it

01:28:53.180 can't go back to the surface. And PCSK9 is a major determinant of how quickly you recycle your

01:28:59.840 LDL receptor or you do not recycle it. So by putzing with the expression of that enzyme,

01:29:07.220 we can give you much further expression of your LDL receptor. And as you said,

01:29:11.700 enhance clearance of your ApoB particles, including not only your LDLs, which are 90 to 95%, but you're

01:29:19.380 clearing remnants also. So for those who believe, oh, remnants are the bad guys, that's not a reason

01:29:25.800 not to use a PCSK9 in here, but I'll get rid of them also. Now, we're going to come back to this

01:29:31.800 because I want to talk a little bit about the brain and you alluded to it earlier, but I don't

01:29:35.320 want to derail us now. So I'm saying this just as much to remind me as to remind you. You can come

01:29:42.320 up with multiple ways to lower LDL. And I say LDL, I'm talking the actual particle number.

01:29:49.220 You can inhibit the synthesis of cholesterol, which in turn also activates the clearance,

01:29:55.060 or you can just go directly after the clearance. So the former would be how a statin works. The latter

01:29:59.880 would be how a PCSK9 inhibitor works.

01:30:01.500 And you can also make the evidence that if you're depleting the cholesterol pool in the liver,

01:30:05.500 you'll make a few less either LDL particles or VLDL precursors, which would contribute to a lowering

01:30:12.340 of ApoB. And that is a small part of both the zetamides and the statins. In fact, most of it is

01:30:16.840 clearance, but you are producing less particles too. So, but this is an area where I do probably have a

01:30:23.480 slightly different view from the mainstream lipid world, which is certainly there's a, there's a

01:30:31.080 favorable hypothesis that's the zero LDL hypothesis. This idea that-

01:30:35.080 Well, you can't make LDL.

01:30:36.120 Well, not only do you. I think, I think, let me rephrase that. What they're basically arguing is

01:30:40.480 the lower you drive LDL, the better. And I do take a little bit of issue with that because I think it

01:30:46.800 depends how you lower it. And it also defends, depends on what you define as better or worse.

01:30:52.200 If you're talking about lowering LDL reduces the risk of atherosclerosis,

01:30:57.240 I think that's pretty clear. But at some point, my concern has always been if you lower LDL

01:31:04.360 through cholesterol synthesis inhibition a lot, do you impact other organs, namely the brain?

01:31:12.680 Well, you don't know. Remember when you're measuring whatever LDL metric, it's what's

01:31:18.400 in floating around your plasma. The only place I'll make that's irrelevant, you know, you're not

01:31:23.480 measuring cellular cholesterol based on an LDL cholesterol. So you tell me what your LDL cholesterol

01:31:29.720 level is. I have really no clue. Are your cells synthesizing or not synthesizing, exporting,

01:31:35.760 effluxing, or whatever to particles that carry cholesterol. But as I think we indicated earlier

01:31:44.440 in our talk today, look, it is integral. Cells do have to make cholesterol. So you certainly wouldn't

01:31:50.380 want to stop cholesterol synthesis in probably any cell in your body because the cell membranes,

01:31:56.020 if nothing else, requires it. And we talked about the brain certainly, it's the only way it has

01:32:01.380 cholesterol as it makes it. So if we did know we were inhibiting cholesterol synthesis in the brain,

01:32:08.960 would you be really that comfortable with that? And if you were, is there certain limits where,

01:32:14.260 oh, I wouldn't mind reducing it a little bit, but how much? Because that brain really needs it. And the

01:32:19.620 brain has no other source of cholesterol. Now, nowadays, with the exception of patients who have been on

01:32:26.020 a statin for a long, long period of time, when it comes to patients that are relatively new to

01:32:31.180 statins, there are really only a handful we're really looking at today, right? Lipitor and Crestor

01:32:36.580 are doing the lion's share of the work. For some patients who are very sensitive, we'll use

01:32:42.020 Livolo or we'll use Prevastatin. But we're not really doing much in the way of Simvastatin or any

01:32:48.140 of these older drugs, correct? No, no. If you're following guidelines, what you're doing is prescribing

01:32:53.900 high potency statins or at least moderate intensity statins. So if you want to follow the guidelines,

01:33:00.120 the only choices you have are Resuva statin or Atorvastatin, Lipitor or Crestor at a 40 milligram

01:33:08.580 or above dose for Atorva or a 20 milligram or above dose for Resuva. If you're stuck, they would allow

01:33:15.860 you to sneak Simva 40 milligrams into there, but that's at best a moderate dose statin. 80 milligrams

01:33:22.720 of Simva has been taken off the market. Yeah, the side effects are quite high with Simva.

01:33:27.180 Well, Simva, because of a variety of pharmacokinetic reasons, has a ton of drug-drug interactions.

01:33:34.160 And we're in a polypharmacy world, whereas there's far less with Atorva and infinitely less

01:33:40.000 with Resuva statin and the Patavastatin you mentioned, Livolo or so. But I would make the

01:33:45.860 case that if you want the statin has the most data that you're going to do good, it would be

01:33:50.040 Pravastatin. And Pravastatin, very cheap. It's almost free if you go to a drugstore for it.

01:33:55.860 It's just not that potent, right? Even at 80 milligrams.

01:33:58.820 You know, but if you use the outcome trials, they got the exact same 25% reduction as any

01:34:03.120 Atorva or Resuva trial ever did. So again, Bristol used to explain that to magical mystery,

01:34:10.760 pleiotropic effects of Pravastatin. But I would make the case that, all right, if ApoB, LDLP is your goal.

01:34:16.460 I would also argue, though, patients are sicker today. I think patients are more metabolically ill today

01:34:20.960 than they were. Meaning, I think the Crestor trials have a higher bar to cross than the

01:34:25.940 Pravast trials. But then again, that's just my bullshit speculation. 0.97

01:34:28.220 Oh, I think the lipid level enrollments with the west of Scotland were twice as horrific as 0.97

01:34:33.480 any Resuva statin trial ever.

01:34:34.560 Yeah, they were, but they had FH. So these are patients who weren't necessarily metabolically ill.

01:34:39.000 Yeah, I understand what you're saying. So the end of this discussion comes, I got a lower ApoB.

01:34:43.300 Yeah. So yeah, you'll, unless somebody's incredibly statin sensitive, and there are ways of predicting

01:34:50.260 statin responsiveness or hyporesponsiveness. If you want to just routinely pick for Resuva statin

01:34:56.880 and go down that path, I'm all free.

01:34:58.480 So what do we know about CNS penetration of these statins?

01:35:00.880 Well, we get to that. And look, I jumped on Resuva statin bandwagon because of being a giant

01:35:05.120 Pravastatin guy, because it's one of the, what I would call hepatoselective statins. It's

01:35:12.380 hydrophilic. It goes right into the liver. It doesn't need transporters. So you don't need

01:35:16.940 much of the drug to get in the liver, inhibit cholesterol synthesis, and upregulate LDL receptors.

01:35:22.100 So Resuva statin, five milligrams is what a lot of people need. You don't need 40. They want you

01:35:26.580 just 40 because in a trial, that's the dose they use where they got heart attack reduction. But

01:35:30.760 since it all comes back to ApoB reduction, use whatever it takes to get your ApoB down. In my mind,

01:35:37.260 you know, that's not how the guidelines exactly figure out how to do it. They like to give level one

01:35:42.200 star rated evidence or so. Mine would be a lesser degree of evidence. So you pick, so they get in.

01:35:49.920 The other drugs are not as hydrophilic. So the only way they get into the liver is various receptors

01:35:56.400 pull them in. There's a whole variety of transporters that pull molecules into the liver,

01:36:00.620 but they're subject to interference with a ton of other drugs that may be in your system or other

01:36:05.120 molecules. So you don't have the clean pharmacokinetics like you do with Pravastatin or

01:36:10.100 resuvastatin. That being said, you're talking, you want to introduce the brain into the discussion.

01:36:17.780 Now all statins can get into the brain. They can cross the blood-brain barrier,

01:36:21.920 but the statins that cross it much easily are the lipophilic statins because they have to pass a

01:36:27.740 lipid membrane, the blood-brain barrier. So atorvastatin, simvastatin get into the brain

01:36:34.320 more easily than do lovastatin, simvastatin, and atorvastatin.

01:36:39.980 Wait, wait, say that again. The most lipophilic one.

01:36:42.180 The lipophilic statin is easier to cross the blood-brain barrier.

01:36:44.940 Yeah, which is atorvastatin and simvastatin are the two biggest.

01:36:47.320 And lovastatin would probably be the worst, you know.

01:36:50.180 Whereas prevastatin would be less.

01:36:52.080 Prevastatin would be far less. Ed Wood would resuvastatin. You have that fluvastatin,

01:36:56.280 sort of a water-cellulostatin is probably more in the class of resuvin.

01:37:00.220 And what about livalo?

01:37:01.720 Livalo would be the same. It's a non-lipophilic statin. So if you're worried about statins getting

01:37:09.100 into the brain, you might want to choose the hydrophilic ones or so. But the only concern

01:37:14.080 I might have is, well, if those statins are getting into the brain, it's great to reduce

01:37:19.040 cholesterol synthesis in the liver. I'm going to upregulate LDL receptors. I don't know that I

01:37:24.100 want to do it every cell in the body, but I'm probably not. I know I'm not with any of them

01:37:29.180 totally inhibiting cellular synthesis cholesterol. But the brain, it's way more dependent on

01:37:35.420 cholesterol. And then we have studies of people with Alzheimer's disease and other cognitive,

01:37:40.300 their brains seem to be depleted of cholesterol to variable degrees.

01:37:44.700 Now, Tom, I'm just going to stop you right here because if I had a dollar for every time I had a

01:37:48.980 brutal argument with a cardiologist about this point, because up until this point in the discussion,

01:37:55.340 if you're a card carrying lipidologist or a cardiologist who really understands lipids,

01:38:00.520 you're kind of on board. You're in the camp of let's lower LDL. But I do get patients from time

01:38:06.020 to time who are more than at their LDL goal, meaning their LDL cholesterol is 40 milligrams per

01:38:11.940 deciliter. Their LDL particle number is 500 nanomole per liter. These are people in primary prevention,

01:38:17.900 but let's assume they have a calcium score of 800 or something. I mean, they're very high risk.

01:38:21.680 But I look at that and I say, well, gosh, their desmosterol level is unmeasurable.

01:38:26.400 Well, you're advancing the discussion here. So let me continue down this pathway.

01:38:30.220 So if cholesterol synthesis is so crucial for the brain, man, I need a biomarker of brain

01:38:36.780 cholesterol synthesis. Now, very interesting. We talked about two pathways of cholesterol synthesis.

01:38:44.980 One is the desmosterol, a block pathway, and the other is the lithosterol,

01:38:48.960 Lacan-Dutch-Russell pathway. Well, it turns out the block pathway predominates in the brain.

01:38:55.540 So would, but should I do spinal taps and measure CSF desmosterol in these people?

01:39:02.720 I'm going to go with no.

01:39:04.240 Yeah. It'd be a tough, oh, by the way, don't leave. I'm going to come back and just do a quick

01:39:09.180 spinal tap on you today.

01:39:11.840 Hang on, hang on. Just wait there in the waiting room.

01:39:13.800 Or imagine even trying to do a clinical trial where that was what you're trying to prove

01:39:17.920 and enrolling people into that, you know? So it isn't going to happen. But, so people know we

01:39:23.860 can measure desmosterol in the blood and there's lots of articles correlating that with cholesterol

01:39:28.300 synthesis as there is with lithosterol. And you can make the case in peripheral cells,

01:39:34.840 maybe even lithosterol is a more dominant pathway. They're probably both at play, but also the

01:39:39.880 desmosterol pathway is much more important in younger newborns and youth rather than older

01:39:44.780 people. So-

01:39:46.340 I didn't know that.

01:39:46.940 Yeah. So maybe that's a critical patient if you, for whatever reason, want to give a statin to

01:39:52.720 a really young FH, a homozygous FH patient.

01:39:56.660 Well, I've been involved in one of those cases.

01:39:58.480 So might desmosterol be monine? So here's what we know. So when people with these cognitive,

01:40:06.620 mild cognitive impairment or various dementias have low cholesterol, when you wind up autopsy

01:40:11.840 in their brains, they do have low desmosterol in their cerebral spinal fluid, suggesting that

01:40:17.860 they do part of their impairment or cholesterol depletion in the brain is their, their brains

01:40:22.980 aren't synthesizing as much cholesterol. And nice trial where they done this, they car,

01:40:29.960 they did do spinal taps on the people in the trial measured CSF desmosterol and they measured

01:40:35.940 serum desmosterol.

01:40:37.480 What was the correlation?

01:40:39.440 Identical. The R is very high in there. So now all of a sudden a serum desmosterol level

01:40:46.680 becomes a biomarker of-

01:40:49.540 Brain synthesis.

01:40:50.160 Brain synthesis of cholesterol. And there are, what is by far, it's not even close, the biggest

01:40:58.100 reason that a brain has suppressed desmosterol cholesterol synthesis, it's statin use.

01:41:04.040 Yeah. So I would make the case-

01:41:06.780 So hang on, I'm going to pause here because I know what you're going to say and I agree,

01:41:10.960 but I'm going to give you the counterpoint before you even start so you can color your

01:41:14.840 commentary. The heterogeneous population-based data say statins reduce Alzheimer's disease.

01:41:22.840 Nothing serious suggests that. I mean, you want to start looking at crazy-

01:41:27.360 Which is not to say that the trials are using that as an outcome. It's just that we're not

01:41:31.420 seeing an increase in Alzheimer's disease in the statin trial.

01:41:34.160 Dementia is a multifactorial disease. A lot of things that contribute to dementia. So in general,

01:41:39.440 do the vast majority of people take statins, wind up dementin? No, absolutely not. There's not any

01:41:46.100 evidence that is shown that at least from the cumulative statin trials or so. But are there

01:41:51.060 certain individuals where that is? And by the way, in these trials where they measured low,

01:41:55.980 both serum and CSF desmostrol, guess what? There was a significantly increased incidence of

01:42:02.840 Alzheimer's disease and mild cognitive impairment. So yes, this is all at the hypothesis level. It's

01:42:10.240 looking at a biomarker, not clinical endpoint trials. But that's enough evidence to me to say,

01:42:17.360 if I'm going to give you a statin, I'm going to push it to, I would, for a variety of reasons,

01:42:23.500 much rather give you a baby statin plus ezetimibe. And by the way, baby statin plus ezetimibe gives you

01:42:29.980 the exact same Apo B reduction as does the gorilla statin, the mega dose of it. But I think with a lot

01:42:35.980 of other additional benefits, ezetimibe brings in certainly less potential side effects and certainly

01:42:40.760 less cholesterol synthesis suppression, including the brain. So if I were giving you massive doses

01:42:48.420 of your favorite gorilla statin per guidelines, and I simply measured serum desmostrol on your next

01:42:55.120 visit, and it was low, that tells me I've over, I've stopped the synthesis of cholesterol too much.

01:43:03.300 So Tom, you are the only other person in this space who will entertain this discussion with me.

01:43:09.000 I mean, I just can't tell you how many times I get into debates with other lipid folks who say

01:43:15.100 that is complete and utter nonsense, and they point to the absence of a huge upsurge in Alzheimer's

01:43:21.660 disease in the statin trials. Now, to which I say the following. One, I am sympathetic to what you are

01:43:27.360 saying, because I realize that all of the anti-statin rhetoric out there is so illogical, and they throw

01:43:33.780 everything in the sink, right? Like, you know, oh my god, it causes, you know, diabetes. Does it?

01:43:39.000 Well, yeah, in a small, small subset of the population, we're going to see a slight uptick in the risk of

01:43:43.120 diabetes, especially with a torvastatin. Does that mean statins cause diabetes, and it needs to be avoided

01:43:48.880 as a result of that? No.

01:43:49.980 Of course not.

01:43:50.720 Does it, you know, do a subset of patients end up getting, you know, muscular pain? Of course. It's probably

01:43:56.040 five to ten percent. It might be even a bit higher, depending on the nature of the trial. But what I think

01:44:00.720 is really going on here, this is, this is my hypothesis. Alzheimer's disease, as you said a

01:44:06.880 second ago, is multiple diseases. It is not a disease, right? I'm talking cognitive impairment.

01:44:12.140 Yeah, yeah, yeah. But even if you talk about Alzheimer's disease, even if there is a final

01:44:14.740 common pathway, or a set of pathognomonic features that define the disease, I think there are several

01:44:20.020 ways to get there. There is a metabolic way that people get there that is probably explained by the

01:44:26.580 increase incidence we see in cognitive impairment and Alzheimer's disease in patients with diabetes

01:44:31.380 and insulin resistance. But there's also a vascular component that I don't think gets nearly

01:44:35.720 enough attention. There's a guy named Jack De La Torre who I, you know, it's funny, I reached out to him

01:44:40.420 recently to interview him for my book, and he's on a research sabbatical in Spain for two years. So

01:44:46.220 I'll probably interview him by telephone, but I would like to eventually have him on the podcast. But

01:44:50.440 he's done some of the most impressive work on looking at this sort of vascular hypothesis of

01:44:55.360 Alzheimer's disease. My hypothesis is this. On average, you take a group of patients with terrible

01:45:02.660 dyslipidemia, you give them a stat, and you improve their vascular complications, which include

01:45:08.000 atherosclerosis, and you're probably actually reducing Alzheimer's disease in those patients.

01:45:12.240 In other words, all things coming, are you better at being at the 90th percentile or the 10th percentile

01:45:16.840 of ApoB with respect to Alzheimer's disease? You're better off being at the 10th percentile.

01:45:21.100 However, I think, to your point, there's going to be a subset of patients in which you go too far.

01:45:27.600 These are patients who don't synthesize a boatload of cholesterol. They're probably

01:45:30.720 hyposynthesizers to begin with, and you statinize the hell out of them, and you are increasing their

01:45:37.300 susceptibility. Now, again, the problem with everything I just said is it takes more than a

01:45:42.200 tweet. And for anybody who throws it in your face, there's no evidence of that in any statin trial.

01:45:47.920 I'll say, oh, my God, I've read the FDA package insert of every single statin that's on the market,

01:45:53.120 and cognitive impairment is listed as a potential side effect of every single statin. Did the FDA

01:45:58.020 just make that up? No. It's been seen in clinical trials.

01:46:01.400 Now, did the FDA make this link? Because I'm talking about papers. There are actually papers

01:46:06.520 that show, and we will absolutely link to this because I think this is one of the better papers.

01:46:11.140 It's about six years old, but it looks at desmosterol as a continuous variable. So in the

01:46:18.980 same way that you might look at PSA as a continuous variable, it can be anything, and try to decide the

01:46:24.260 question, at what cutoff does having a high PSA suggest that you have a high enough risk of prostate

01:46:30.500 cancer? But using desmosterol as a continuous variable and using a statistical technique called

01:46:35.500 Receiver Operating Characteristic Curve Production, they showed that once desmosterol fell

01:46:42.620 below 0.5, the AUC, the area under the curve of the Receiver Operating Characteristic was somewhere

01:46:51.000 between 0.8 and 0.87, depending on the study and depending on gender. And again, maybe it's more

01:46:56.640 detailed than people want, but the higher that number, which varies basically between 0.5 and 1,

01:47:02.500 1 is a perfect study. 1, there's no such thing as a diagnostic test with a 1. 5 is a coin toss.

01:47:09.460 When you get into the 0.8 territory, that's a very powerful predictor.

01:47:14.420 Correct. So I think it's careless to dismiss that as a potential player. We've given you a lot of

01:47:19.940 plausibility and there's even more. If you tell me you are a doctor who has prescribed a lot of statins,

01:47:26.360 and look, I was in practice 37 years, 20 of which I was writing as much statins as anybody.

01:47:32.500 If you tell me you've never seen cognitive impairment in a patient, you've started on a 0.99

01:47:37.740 statin, you're a liar or you're a fool or you're not questioning your patients when they come back 0.99

01:47:42.240 because it does occur. I don't know what, a lot of reasons it could occur. And look, 1.00

01:47:47.380 who doesn't have a day where you wake up thinking I'm a little foggy today for sun and it's nothing

01:47:52.000 to do, but it happens. So we've now got a plausible explanation why it happens.

01:47:57.740 If the real reason you're prescribing a statin is ApoB reductions, I got a lot of ways of getting

01:48:03.360 your ApoB to go without maximizing a statin. So in my mind, if desmostrol is below a certain

01:48:10.480 population percentile cut point, I've inhibited cholesterol synthesis probably. I probably get

01:48:16.560 no bang for the buck on further LDL or particle lowering, ApoB lowering by having you continue to

01:48:23.200 take that. I can clear ApoB furthers by stopping cholesterol absorption back into the liver and

01:48:29.660 the intestine with ezetimibe that does nothing to cholesterol synthesis, a PCSK9 inhibitor.

01:48:35.740 So with, and in most people, baby statin and ezetimibe will give you the exact same ApoB reduction

01:48:41.760 of your gorilla statin. And we have outcome evidence in the improve it trial that ezetimibe and

01:48:48.280 statin for the guys. Oh, I got to see outcome data. You got it. So therefore I use it as a tool

01:48:54.120 to monitor statin therapy on most people. And they also, these people would argue you, I will bet as

01:49:00.860 much money as I have in my bank account. They's never, they couldn't even tell you what desmostrol

01:49:05.820 is. They've never read anything about the cholesterol synthetic pathway and they don't know what they're

01:49:10.780 talking about. Yeah. I mean, look, in the end, I think this is such a contentious topic because

01:49:16.280 we're getting so nuanced on something now and the world has lost its appetite for nuance.

01:49:22.920 People want to know statins are good or statins are bad. And everything we've just said says it

01:49:28.000 depends, right? It depends on how you use them. You can give too much of these things. That doesn't

01:49:34.680 mean they're bad because what we've also done, I realize, and I've been very deliberate about this

01:49:39.380 because I think it's important to show both sides of this. We've also given the statin deniers and the

01:49:43.840 statin, you know, the statin conspiracy theorists a great ammo, which is, aha, if Dayspring and Atia

01:49:49.100 are sitting there bashing statins and talking about mild cognitive impairment and they take

01:49:53.240 that discussion out of context, they're going to say, well, statins should be outlawed.

01:49:57.220 Yeah. But of course, any reasonable doctor, if a patient came in complaining of statin or a

01:50:03.260 cognitive impairment, they'd pretty much stop all drugs because that's the first explanation a

01:50:07.720 drug is causing it. So it's not like I'd continue to force you to take a statin if you were

01:50:12.420 cognitive. I mean, if the listener is sort of saying, what the hell is the takeaway from this?

01:50:16.680 I think it's a couple of things. One is statins are not bad. Statins are still the mainstay

01:50:21.600 backbone of antilipid therapy. Be thoughtful about which ones you use. You know, Tom, I have

01:50:26.860 moved more to Crestor over Lipitor, though I still use Lipitor quite a bit. And in many ways,

01:50:33.960 I'm sort of slowly migrating patients who seem to have no difficulty from Lipitor to Crestor.

01:50:40.060 Two, I'm actually going back and using Prevastatin much more than I used to. I'm surprised at how

01:50:46.300 much I find myself reaching for Prevastatin in a patient who doesn't tolerate, who has a slight

01:50:51.360 CK bump, even if they're not complaining of pain. If they're getting a CK bump that, you know,

01:50:56.000 their CK goes from a baseline of 50 to 300, even if they're asymptomatic, I don't like it.

01:51:01.280 So I'm going to switch that.

01:51:02.080 By the way, I would chip in that CK elevation has nothing to do with statin toxicity or

01:51:06.720 statin. So it's a silly biomarker to follow. You think so? Totally. Oh, I didn't realize that.

01:51:11.260 Evidence would totally support that. Well, I know it doesn't correlate that well with

01:51:13.780 my site. Not at all. First of all, before you ever do that, make sure you have a baseline CK. Yes,

01:51:17.960 of course. Because a lot of people, especially African-Americans, not even working out. They 0.89

01:51:21.640 just have high CK levels, African-Americans. So, but I didn't realize that. You know when you 1.00

01:51:26.280 should stop a statin with a CK? When there's like a 10,000 fold elevation of CK, then you might

01:51:31.020 start to worry. So CK, there's any number of guidelines issued on statin. It's not a biomarker

01:51:37.160 that is of any use to you. And all you do by doing CK is when somebody goes from 50 to 300,

01:51:42.660 they get the bejesus scared out of them and they stop their statin when there's no reason.

01:51:47.860 The reason you should stop a statin is if they're having myopathic symptoms, aches, or weakness.

01:51:53.200 Then I don't care what their CK level is. I did not realize that.

01:51:56.500 I'll get some info to you on that. So stop monitoring CK. And if they come in and tell

01:52:02.360 you, hey, Peter, I'm feeling pain, or you somehow are doing some muscular strength testing, or 0.98

01:52:08.000 they tell you, I don't get out of the chair as much proximal muscle weakness, stop the darn 0.99

01:52:12.540 statin. 0.99

01:52:12.940 Yeah. Well, those are, those are the easy cases.

01:52:15.180 But don't use CKs to dictate your statin therapy.

01:52:19.520 I think the bit of the point here is I can't imagine giving any lipid lowering therapy without

01:52:25.180 being able to measure phytosterols, stanols, and desmostrol.

01:52:29.900 So I'm with you there. Most lipidologists would not be, but they just have not studied

01:52:33.960 the data like they should. And even if what we're just talking about is pure hypothesis,

01:52:39.560 what harm would you be doing by lessening the dose of a statin and substituting a little

01:52:44.480 azetamide, or if they could afford it? You can make the case if it was free as pravastatin,

01:52:49.940 let's just use PCSK9 inhibitor, for God's sakes. Because, you know, whatever other minor

01:52:55.900 side effects of statins, I don't think we've seen much with PCSK9 inhibitor.

01:52:59.680 No, I mean, of course not.

01:53:00.500 Grant it, more time to go.

01:53:01.380 I was just about to say that the skeptic will counter that, Tom, and say, but we only have

01:53:05.360 three and a half years of data with these drugs, or four years of data.

01:53:08.040 So right now, we're not going to use that except for people who can afford it, or our nightmare

01:53:11.460 patients where a third party will finally pay for it or so. So it's not like docs are going to run

01:53:16.680 out tomorrow and start injecting everybody with a PCSK9 inhibitor. They're not, because there's

01:53:21.660 handcuffs on them. But there's no handcuffs on you using generic azetamide to a baby statin,

01:53:27.460 as you have to buy on to. LDL-C is not your best surrogate of atherogenic lipoproteins,

01:53:34.440 APO-B or LDL particle count is. And if that's your real goal of therapy,

01:53:38.460 then you got a lot of options available to you.

01:53:41.680 Now, the one thing, I used to use the combo lowest dose statin possible coupled with azetamide if

01:53:48.620 there was some evidence of even mild elevation of phytosterol and stanol. One thing I've noticed,

01:53:55.420 and again, I've just been a little delinquent. I don't think I've gone back and looked at the

01:53:58.620 trials. Did the trials show an increase in transaminases with that combo?

01:54:03.220 No. And I think the only trial that you'd have to look back at sees where sharp where they use the

01:54:10.460 simbastatin and azetamide improve it. Yeah. And there was nothing more than...

01:54:14.680 I don't know what it is.

01:54:16.060 Not at all.

01:54:16.520 I don't know what it is. I keep seeing these LFTs double.

01:54:19.300 And again, I will tell you, there's not a package insert in the world that tells you

01:54:22.500 you should even be following aminase to judge statin or anything going on in the liver as a

01:54:28.060 result of a statin. There's no correlation whatsoever. So I'm repeating them in all the time

01:54:33.600 because maybe it's a biomarker of fatty liver or something else, but not a statin toxicity.

01:54:38.100 It's not. So don't ever let a patient stop because they've doubled their AST,

01:54:45.880 whatever aminase you're measuring level on the statin. Not related to anything.

01:54:51.360 You've got great medical legal safety because that's what the guidelines are telling you to do.

01:54:55.760 There's not a statin in the world that they're all out of the package insert that you should be

01:55:00.080 following liver function tests. Yeah. Again, I think part of the problem is like you,

01:55:04.040 I'm going to follow liver function tests regardless. I have a very different view of

01:55:07.640 how these things should be. I mean, yeah. So they have other use and who's not going to do,

01:55:12.600 it's part of your chemistry profile that you're probably doing on every patient every time. So

01:55:16.540 you're going to see them, but you don't necessarily have, but be prepared when the patient calls you

01:55:20.900 up in a panic, that's not in your differential diagnosis of why the aminases are changing.

01:55:25.100 Yeah. I don't know, Tom. I still, I'm going to look at extensively. I'm going to go back and look

01:55:29.960 at this entire documents where they've analyzed all the data in the world on aminase and statin

01:55:36.520 therapy. It's inconsequential. But I mean, I'll give you a silly example, which is I have seen the

01:55:41.700 following at least four times. You take a patient, you make, they're on a statin. There's no other

01:55:46.500 change. And the only thing you do is you add Zetia and then their next blood test, their transaminases

01:55:52.120 have doubled. And then the only thing you do is stop the Zetia and it returns to baseline. 0.75

01:55:57.640 All right. So something is happening, but as a doubling of a transaminase of that etiology of

01:56:02.800 any concern to you. So fine. If you want to stop it and see, go ahead. And if that's going to

01:56:08.040 occasionally limit how much is that, am I, you're going to use in a patient. Okay. Figure out how else

01:56:12.900 to lower it will be. So fine. I understand there are things that'll come into play in an individual

01:56:18.260 patient where the data doesn't support it, but you're making an individual decision.

01:56:23.480 That's my point. That's my point. You've got to be able to make an individual decision,

01:56:27.020 which is what we're saying with the, with the desmostrol level. Again, I think most patients,

01:56:32.880 again, if someone's listening to this and they're freaking out, cause they're like,

01:56:35.700 what the hell are these guys talking about? We are not saying that statins are causing dementia.

01:56:39.720 What we're saying is, at least what I'm saying, I'll let Tom clarify for himself.

01:56:43.300 There are going to be a subset of patients whose risk of dementia does go up with a statin and it's our job

01:56:48.080 if we're prescribing those drugs to know exactly who those patients are. And to the best of my

01:56:53.240 reading of the literature, plus understanding the nature of the biology, it's probably the patients

01:56:59.360 in whom we overly suppress synthesis for whom they don't make that much to begin with.

01:57:03.880 Suppressed cellular synthesis, which has nothing to do with the amount of cholesterol you measure in

01:57:08.760 the blood. Great point. And has not, cholesterol synthesis is not affected per se by PCSK9 inhibitors.

01:57:16.520 Because azetamide is interesting. If you go with azetamide monotherapy, you'll actually get a

01:57:21.320 little reflex increase in cholesterol synthesis and vice versa. If you go with statin monotherapy,

01:57:27.200 you're hyperabsorbed statin. So there's a little bit of physiologic homeostasis going on there too.

01:57:32.080 But that's not changing levels to these toxic levels.

01:57:35.180 And that, believe it or not, has become one of the times when I like using Zetia, is if I've got a

01:57:39.900 patient who really needs a statin, because when you just look at their numbers, you get the sense that

01:57:45.000 this is an LDL clearance deficiency, but you want to boost their synthesis a little bit,

01:57:49.680 you do it concomitant with the Zetia, and you'll sometimes get that reflex.

01:57:52.920 And I argue with clinicians too, who they are doing sterile testing. So I, Tom, I identify my

01:57:59.360 hyperabsorbers and I surely make sure azetamide is on board my ApoB lowering therapy in that patient.

01:58:04.920 But I'll make the case for you, even if you do those markers and you're a normal absorber of

01:58:11.360 cholesterol, but you have an ApoB problem, even by taking a normal absorber of cholesterol and

01:58:17.440 making them a hypoabsorber, the genetic model is they live longer if they have genetic loss of

01:58:23.120 function of a Niemann-Pick C1-like protein. So even in a patient who's not hyperabsorbing

01:58:29.540 cholesterol, you do get additional ApoB lowering, maybe not at the same magnitude, but you get it.

01:58:34.420 And you're changing them into the genetic model of longevity, maybe.

01:58:38.100 You know, you're certainly keeping phytostoros out of them. 1.00

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01:59:47.900 diagnoses, or treatment.

01:59:49.640 Users should not disregard or delay in obtaining medical advice for any medical condition they have

01:59:54.140 and should seek the assistance of their healthcare professionals for any such conditions.

01:59:58.380 Lastly, and perhaps most importantly, I take conflicts of interest very seriously.

02:00:03.460 For all of my disclosures, the companies I invest in and or advise,

02:00:07.300 please visit peteratiamd.com forward slash about.

The Peter Attia Drive - October 18, 2018

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

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