#23–Tom Dayspring Part IV of V: statins, Zetia, PCSK9 inhibitors, niacin, cholesterol & the brain

1. 0:00 – 0:04

   Intro

   1. PADr. Peter Attia0:00

      [upbeat music]

2. 0:04 – 9:16

   Early cholesterol drugs and the first statin outcome trials

   1. PADr. Peter Attia0:04

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

   2. TDDr. Tom Dayspring2:36

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

   3. PADr. Peter Attia3:11

      Neomycin, the antibiotic?

   4. TDDr. Tom Dayspring3:12

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

   5. PADr. Peter Attia3:44

      This is the LRC study.

   6. TDDr. Tom Dayspring3:46

      Yes. So there was a little proof that not only what Framingham said is true, cholesterol is a risk marker, risk factor, depending on how you want to label it, but lowering it r- does reduce clinical events. To me, the tragedy of that is for the next twenty to thirty years, the only thing that the pharmacological, uh, industry focused on was cholesterol as their metric of, "That's all we gotta do. We gotta find stuff that lowers cholesterol metrics or improves cholesterol metrics in one or the other direction." And bile acid sequestrants do raise HDL cholesterol a milligram or two milligrams percent, which turns out to have some statistical significance. So-

   7. PADr. Peter Attia4:32

      Potentially without any physiologic significance.

   8. TDDr. Tom Dayspring4:35

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

   9. PADr. Peter Attia6:07

      So these patients had FH.

   10. TDDr. Tom Dayspring6:08

       In retrospect, they're FH patients. You know, who's got an LDL cholesterol, one, it's definition, one of the definitions of FH. And giving them a dose of simvastatin got you 25 so percent reduction in clinical events. So outcome data, bingo, great drug. And right behind them was Bristol Myers Squibb, who had the much weaker statin, pravastatin, sold originally as the branded Pravachol. Let's study Irishmen who have not had a clinical event, but also their LDL cholesterol is 180, 190. Some more FH Irishmen.

   11. PADr. Peter Attia6:46

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

   12. TDDr. Tom Dayspring6:50

       Yeah. And lo and behold, reduced virtually every atherothrombotic clinical event.

   13. PADr. Peter Attia6:54

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

   14. TDDr. Tom Dayspring6:58

       They were all... You, you, you know, some of it had to do with the base number. It was down in the 20s. You know, it was very good for both of them. They were just a little higher in 4S because they were sicker people.

   15. PADr. Peter Attia7:06

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

   16. TDDr. Tom Dayspring7:10

       No, it was probably 40 to 50 in West of Scotland.

   17. PADr. Peter Attia7:13

       But still.

   18. TDDr. Tom Dayspring7:13

       But, you know, it was good. But these are nightmare primary preventions. And-

   19. PADr. Peter Attia7:17

       And what, these were, how long were these trials? Five years? Six years?

   20. TDDr. Tom Dayspring7:19

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

   21. PADr. Peter Attia7:34

       But this is an important point to make, and this is kind of... I've learned a lot from you, I've learned a lot from Ron, I've learned a lot from Alan, I've learned a lot from everybody in this space, but if there's one person who really got me to understand the limitations of clinical trials, it's Alan, with his long-

   22. TDDr. Tom Dayspring7:51

       Oh, yeah

   23. PADr. Peter Attia7:51

       ... view of this disease. You know, I've told this story before, but Alan's the guy who bought me my very first copy of Starry's pathology textbook and, you know, is really the guy that got me looking at these autopsy pictures of kids and realizing, "Hey, buddy, this disease starts when you're born." So the thing that I think most people misunderstand when it comes to lipid-lowering trials is they're always handicapped.

   24. TDDr. Tom Dayspring8:15

       Very much.

   25. PADr. Peter Attia8:16

       They're behind a loaded gun, which it's pointing directly at them, which says, "We're only going to give you five years to impact the course of a disease that has been going on for 50 years until now." You start, you take a bunch of 50-year-olds and you put them in a trial where you're going to study them till they're 55. You have five years to try to move the direction of a ship that's been setting its course for 50 years. I'll give you-

   26. TDDr. Tom Dayspring8:42

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

   27. PADr. Peter Attia8:48

       That's right. So-

   28. TDDr. Tom Dayspring8:48

       So you better have a miracle drug

   29. PADr. Peter Attia8:49

       ... so that's, and, and we'll talk about the miracle drug-

   30. TDDr. Tom Dayspring8:52

       Yep
3. 9:16 – 15:20

   Triparanol, HMG-CoA reductase and why LDL-receptor drugs work

   1. PADr. Peter Attia9:16

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

   2. TDDr. Tom Dayspring9:39

      Early in the chain

   3. PADr. Peter Attia9:39

      ... prior to the bifurcation of the cholesterol synthetic pathway.

   4. TDDr. Tom Dayspring9:42

      Yes. It's still a flat lipid molecule.

   5. PADr. Peter Attia9:44

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

   6. TDDr. Tom Dayspring9:58

      Triparanol.

   7. PADr. Peter Attia9:59

      Triparanol. So Triparanol comes along and says-

   8. TDDr. Tom Dayspring10:01

      It was that 24 carbon. It didn't allow you to unsaturate the-

   9. PADr. Peter Attia10:05

      It, it did not allow you to turn desmosterol into cholesterol

   10. TDDr. Tom Dayspring10:09

       ... into cholesterol.

   11. PADr. Peter Attia10:09

       And so now that's at the very bottom of this pathway.

   12. TDDr. Tom Dayspring10:12

       Penultimate last step.

   13. PADr. Peter Attia10:13

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

   14. TDDr. Tom Dayspring10:21

       But what would go up?

   15. PADr. Peter Attia10:22

       Desmosterol went up.

   16. TDDr. Tom Dayspring10:24

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

   17. PADr. Peter Attia10:36

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

   18. TDDr. Tom Dayspring10:48

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

   19. PADr. Peter Attia11:20

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

   20. TDDr. Tom Dayspring11:38

       And there have been several other cholesterol syn- squalene synthase inhibitors that have failed for one reason or another. So it is a mega investment, and this, this is sure probably far worse where if I say 999 out of 1,000 drugs don't come anywhere close to a commercial success, it's probably way smaller than that.

   21. PADr. Peter Attia11:57

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

   22. TDDr. Tom Dayspring12:09

       Yeah, there is some recovery time too. Other pathways can pick up

   23. PADr. Peter Attia12:11

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

   24. TDDr. Tom Dayspring12:25

       Sure. 'Cause-

   25. PADr. Peter Attia12:26

       So that would be another unintended benefit, right?

   26. TDDr. Tom Dayspring12:28

       Uh-

   27. PADr. Peter Attia12:29

       If you deprive the liver-

   28. TDDr. Tom Dayspring12:30

       At least it's been theorized-

   29. PADr. Peter Attia12:32

       Yeah, yeah

   30. TDDr. Tom Dayspring12:32

       ... because the pharmacokinetics of a statin, let's face it, the real place you want to inhibit cholesterol synthesis is not per se in cells, but in the liver, because that's the s- uh, tissue that can upregulate the most LDL receptors to get rid of your LDL particles. So I'm not really interested in stopping cholesterol synthesis in other tissues in your body, 'cause they can get rid of it. I, I-
4. 15:20 – 21:24

   How ezetimibe works in both gut and liver

   1. PADr. Peter Attia15:20

      Though ezetimibe's main mechanism of action is in the gut.

   2. TDDr. Tom Dayspring15:23

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

   3. PADr. Peter Attia17:12

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

   4. TDDr. Tom Dayspring18:00

      Well, they never, no, they never did a monotherapy clinical trial.

   5. PADr. Peter Attia18:03

      Oh, they didn't even do a monotherapy?

   6. TDDr. Tom Dayspring18:04

      I think it would work if you pick the right person.

   7. PADr. Peter Attia18:06

      Well, that was always my argument-

   8. TDDr. Tom Dayspring18:07

      Yeah

   9. PADr. Peter Attia18:07

      ... which was it might have been a mistake in patient selection. You didn't select hyperabsorbers. But what you're saying would suggest that that would dilute my argument, right? Because if it only worked at the Niemann-Pick C1-like-1 transporter, the argument would be target your hyperabsorbers. But if it also works at biliary cholesterol, eh, it shouldn't matter that much, should it?

   10. TDDr. Tom Dayspring18:30

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

   11. PADr. Peter Attia18:37

       But is the liver also then going to be a dominant source of where we'll see sitosterol, campesterol, et cetera?

   12. TDDr. Tom Dayspring18:44

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

   13. PADr. Peter Attia19:25

       I see. So, so-

   14. TDDr. Tom Dayspring19:25

       "And you made it to the... We're getting ready. We're the backup police."

   15. PADr. Peter Attia19:29

       Yeah, so now you're the VIP lounge bouncer.

   16. TDDr. Tom Dayspring19:31

       Yeah. Right. "So boom, out you go again. Now, I realize those dopes may let you in again, but you're gonna come right back here and I'm getting you out again."

   17. PADr. Peter Attia19:40

       [laughs]

   18. TDDr. Tom Dayspring19:40

       You know? So great analogy, Peter, the VIP bouncer. Yes. [laughs]

   19. PADr. Peter Attia19:44

       Yeah, yeah, yeah.

   20. TDDr. Tom Dayspring19:45

       So who's to say? Ezetimibe's taking out or reducing the functioning of the Niemann, and I think it's in both areas. Merck knows this. Merck didn't want to... That's too much education to give. Let's just tell them it blocks cholesterol absorption. The gut would make sense to most people. Most people, including lipidologists, don't even know the liver's involved in the process, so it was like li- advanced lipid study and stuff. We don't have to confuse people with that. I've written a number of articles on it, as Peter Toth and I, I think, did one of the oral class articles on the mechanisms of it and stuff.

   21. PADr. Peter Attia20:17

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

   22. TDDr. Tom Dayspring20:20

       I'm bad with my, uh, years, but it's probably, I don't know, 2010, something like 2008. Uh, but it's really with great diagrams, of course, showing you and explaining where Niemann-Pick is and every-

   23. PADr. Peter Attia20:34

       And that's Toth, T-O-T-H?

   24. TDDr. Tom Dayspring20:35

       Yeah. Peter is-

   25. PADr. Peter Attia20:36

       Yeah. So we'll, we'll make sure we link to that

   26. TDDr. Tom Dayspring20:37

       ... one of the genius and certainly mentors in my life. And of course, Peter and Mike Davidson's had me write the chapter in the book, Therapeutic Lipidology, on phytosterolemia.

   27. PADr. Peter Attia20:46

       So Davidson's at Northwestern, right?

   28. TDDr. Tom Dayspring20:48

       Uh, he's at University of Chicago.

   29. PADr. Peter Attia20:49

       University of Chicago.

   30. TDDr. Tom Dayspring20:50

       Yeah. And look, very early on, probably 'cause I was just such a, a good educator on lipids, lipoproteins, and statin mechanism of action, I was in, very early in Merck's investigation of cholesterol absorption and became a very effective educator on that too, and, and therefore had great contact with a lot of the Merck scientists, the Swedes who all invented all these absorption markers and stuff, and really became-
5. 21:24 – 28:28

   Ezetimibe trials: IMT, SEAS, SHARP and IMPROVE-IT

   1. PADr. Peter Attia21:24

      Well, why do you think that the Zetia combination simvastatin trials... So, so the main trial with Zetia was with and without simvastatin, correct?

   2. TDDr. Tom Dayspring21:32

      No.

   3. PADr. Peter Attia21:32

      Or sorry, simvastatin with and without Zetia.

   4. TDDr. Tom Dayspring21:34

      The, the, the reason why Zetia, ezetimibe is taking so many damn hits is Merck's poor thinking of the type of trials that let's bring to market to show that this is a great drug. And instead of just doing the damn outcome data, even doing a select outcome trial in the right person, primary prevention, as well as, of course, do your secondary prevention trials, even do that first if you want to, and if that fails, you're not gonna do anything with it. But let's... They wanted to just get so much to market. What's the easiest thing to do? IMT. So let's take people with, uh-

   5. PADr. Peter Attia22:09

      So let's ex- tell people what IMT is

   6. TDDr. Tom Dayspring22:09

      ... a lot of lipid abnormalities, carotid intimal thickening, which is an ultrasound measurement of the thickness of your carotid artery, which has some correlation with subclinical atherosclerosis and clinical events, and that's unarguable. And therefore, they're at risk. They have lipid abnormalities. Let's give them a z- they're, you know, they're on a statin because we have to give them statins if their LDL is at a, metric is out of whack. Let's give them one half of the group ezetimibe and the other half placebo ezetimibe, and let's follow their IMTs. We only have to do that for a year or two, and we'll see IMT progression in one ar- arm and no IMT progression in the other. Well, we did that. Virtually every lipid parameter, including ApoB, got better. Every inflammatory markers got better, and the IMT didn't change whatsoever.

   7. PADr. Peter Attia23:00

      Meaning simvastatin had the same IMT as simvastatin plus ezetimibe.

   8. TDDr. Tom Dayspring23:04

      At, right. In a short time.

   9. PADr. Peter Attia23:05

      Yeah.

   10. TDDr. Tom Dayspring23:05

       And w- of course, we now know that what happens to IMT with any drug has virtually no relationship to clinical outcomes. So that's not a tool you should be using to follow up and saying, "Look at all..." It's like the coronary calcium score you... It's not the tool you should be using to demonstrate the effica- They should have looked at, "But look at this ApoB reduction beyond what simvastatin can do. Look at the triglyceride reduction. Look at the CRP reduction beyond what simvastatin can do."

   11. PADr. Peter Attia23:31

       Or oxLDL or any of these things. Yeah.

   12. TDDr. Tom Dayspring23:34

       That doesn't mean anything, but they had already polluted the minds that IMT was the best way to check for drugs

   13. PADr. Peter Attia23:40

       Yeah, so another one, obviously nothing trumps a hard outcome. If you can reduce MACE, that's the way to go. Uh, sorry, major adverse cardiac event.

   14. TDDr. Tom Dayspring23:46

       So you're taking a shortcut

   15. PADr. Peter Attia23:47

       But they picked the wrong shortcut, is basically what it comes down to.

   16. TDDr. Tom Dayspring23:50

       Amen.

   17. PADr. Peter Attia23:50

       There were better shortcuts you could take.

   18. TDDr. Tom Dayspring23:51

       And who did that turn off big time? The imagists of the world, the cardiologists who instantly dismissed ezetimibe as the world's most useless drug. Most cardiologists don't even know what ApoB is, and never mind that, "Hey, look at this as a potent thing." I, I hinted to you last night, I was very much involved with the roloxin, the first SERM that came to the market. A as good an ApoB-lowering drug as ezetimibe is, which might have portended great cardiovascular benefit to the SERM roloxin, which I believe it still has. In fact, we have some... They did a big cardiovascular outcome trial where it was no, didn't hurt anybody, but it didn't reduce events. But if you looked at the primary prevention people in that trial, it did lower events. Now, post hoc hypothesis generating data, but an 8%, a 5% lowering of ApoB mattered, and I think the right trial done with ezetimibe and outcomes, it would matter.

   19. PADr. Peter Attia24:46

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

   20. TDDr. Tom Dayspring25:31

       Th- th- no, but-

   21. PADr. Peter Attia25:32

       If you've picked the right patient

   22. TDDr. Tom Dayspring25:33

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

   23. PADr. Peter Attia25:36

       Yes. You take a bunch of highly, highly statin-intolerant patients.

   24. TDDr. Tom Dayspring25:40

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

   25. PADr. Peter Attia26:28

       Yeah

   26. TDDr. Tom Dayspring26:28

       ... surgery, for God's sakes.

   27. PADr. Peter Attia26:29

       Yeah, yeah. I mean, again, that just-

   28. TDDr. Tom Dayspring26:31

       Yeah. [laughs]

   29. PADr. Peter Attia26:31

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

   30. TDDr. Tom Dayspring26:35

       But again, post hoc analysis, they did reduce ischemic events in that trial with ezetimibe. So MIs went down, angina went down, but that's post hoc analysis.
6. 28:28 – 36:57

   FOURIER and the noise around statins and PCSK9

   1. PADr. Peter Attia28:28

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

   2. TDDr. Tom Dayspring29:08

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

   3. PADr. Peter Attia29:14

      It is... I was s... I mean, I had been following this story even before I became interested in lipids, just out of interest in the sort of the novelty of you see a natural experiment, which is PCSK9 hyperfunctionings, PCSK9 hypofunctionings, MR drug. It just became a beautiful, elegant model. And then I remembered that-

   4. TDDr. Tom Dayspring29:35

      Well, everything in real life takes decades to express itself

   5. PADr. Peter Attia29:37

      That's right

   6. TDDr. Tom Dayspring29:37

      Right

   7. PADr. Peter Attia29:37

      And this all took a decade, and I remember thinking, especially once I got interested in lipids On the one hand being excited, on the other hand thinking, "There's no goddamn way this trial can work."

   8. TDDr. Tom Dayspring29:47

      Right.

   9. PADr. Peter Attia29:47

      You could not reduce events in 2.2 years.

   10. TDDr. Tom Dayspring29:51

       Right.

   11. PADr. Peter Attia29:51

       And they did, and of course this is how naive I am, and this is why whenever people ask me for advice, friends'll say, "Hey, should I invest in this company or that company?" My advice to them is, "Don't listen to a single thing I say because you're asking a question will the market value something, which I have no input on. I can provide you plenty of, you know, input on whether it makes scientific sense, but you have to talk to somebody with a different skill set-

   12. TDDr. Tom Dayspring30:14

       Mm

   13. PADr. Peter Attia30:14

       ... to understand if that's an investable thesis." And so I remember Amgen kinda got hammered when the trial came out because people thought, "Eh, that wasn't enough of an improvement," at which I thought it's amazing... A- and, and in reality, in fairness to the market, I think what the market was basically saying is if you did the math based on that trial under those circumstances, it would be, you know, a million dollars or more to save a life. Well, that's a fair question for the market to assess, but if you look at it from a scientific standpoint, that you could take that patient population and achieve that outcome, I think it's one of the most remarkable things in cardiovascular medicine. And to your point, it doesn't even speak to the patients that I have on PCSK9 inhibitors. My patients who take PCSK9 inhibitors are patients whom prior to this drug we were flailing with what? Maybe some niacin, maybe some monotherapy Zetia, maybe the smallest dose of Livalo that a human could tolerate, and getting woefully inadequate coverage.

   14. TDDr. Tom Dayspring31:13

       As you know, you're doing that off FDA label 'cause they would wanna try-

   15. PADr. Peter Attia31:16

       And they're paying, and they're, and they're paying out of pocket for it

   16. TDDr. Tom Dayspring31:18

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

   17. PADr. Peter Attia32:18

       How many-

   18. TDDr. Tom Dayspring32:18

       Are you gonna be mad at me in 20 years or 15 years 'cause I put you in the CCU? I don't know.

   19. PADr. Peter Attia32:24

       Yeah. H- how many Nobel Prizes have been awarded within the field of lipid science? At least three, right?

   20. TDDr. Tom Dayspring32:30

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

   21. PADr. Peter Attia32:42

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

   22. TDDr. Tom Dayspring34:30

       Yeah, and-

   23. PADr. Peter Attia34:30

       ... disconnected

   24. TDDr. Tom Dayspring34:30

       ... and you've already mentioned one example. There are several others where a drug has come to market and then some harm develop it, so therefore you castigate every drug-

   25. PADr. Peter Attia34:39

       Right, right

   26. TDDr. Tom Dayspring34:39

       ... that's ever been invented as aha.

   27. PADr. Peter Attia34:41

       Even though we just-

   28. TDDr. Tom Dayspring34:42

       They're all poisons

   29. PADr. Peter Attia34:42

       ... yeah, even though we just illustrated, right? You can take two drugs that inhibit two enzymes-

   30. TDDr. Tom Dayspring34:49

       And get different results
7. 36:57 – 41:18

   Lab assays, phytosterols and ezetimibe as reverse cholesterol transport

   1. PADr. Peter Attia36:57

      Well, one of the things that I've been pleased with is once I got back into medicine, I realized I didn't know that stuff, and I have been really fortunate. Every lab I have reached out to, to come and actually come to the lab and see how it works, including THD, they've all opened the doors and said, "Come on in, Peter" You know?

   2. TDDr. Tom Dayspring37:17

      Oh, they're more than happy.

   3. PADr. Peter Attia37:19

      And they overdo it. I love it. They literally will walk me from every station to every... This is where the specimen arrives, so you can see where the FedEx box dumps off the specimen. This is how we take it out. This is how it's handled. This is boom, boom, boom, all the way to here are the magnets where we're doing the NMR. And I've, and I've got Precision Analytics has also been great. I went up and spent two days with them a few years ago, and I agree. I mean, again, not every physician, I think, has the luxury of time-

   4. TDDr. Tom Dayspring37:43

      Of course

   5. PADr. Peter Attia37:43

      ... because they're clinically so much busier than I am. So I don't, I certainly don't fault physicians for not doing that, but I do wish there was a way to make that sort of experience more available to physicians because the more you understand how these tests are done, the more you understand what your blind spots can be.

   6. TDDr. Tom Dayspring37:59

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

   7. PADr. Peter Attia38:34

      So it just knows it's not a stanol.

   8. TDDr. Tom Dayspring38:35

      So when, when, when you get LDL ch- it, it's even me- It'll measure a stanol too, but they, they would likely be a small part of it. So LDL cholesterol is really LDL cholesterol plus LDL sitosterol plus LDL-

   9. PADr. Peter Attia38:47

      Plus LDL desmosterol

   10. TDDr. Tom Dayspring38:48

       ... s- and the other 48, then a little bit of whatever stanols got a, may have made their way into your body too. So they don't know that. So, and a person with phytosterolemia, a large part of that LDL cholesterol value is a-

   11. PADr. Peter Attia39:01

       Is the phytosterol.

   12. TDDr. Tom Dayspring39:02

       Yeah. [chuckles] So, but they don't realize. So they don't even know could ezetimibe have a b-- If phytosterols are injurious, and I can make that case, I would-- If I did a one-hour lecture to you using proper slides, you would be pretty convinced, "I, I want phytosterols not in my body." Ezetimibe is the only way to keep them out there. And wherever you go next, the f- my final word on ezetimibe would be if you're a big believer in this reverse cholesterol transport process, which I've certainly expounded on now, what is the number one pharmacologic agent that increases the amount of cholesterol that's winding up in your toilet bowl 'cause it's in your stool? It, that would be-

   13. PADr. Peter Attia39:43

       Gotta be Zetia

   14. TDDr. Tom Dayspring39:43

       ... at best reverse cholesterol transport, 'cause the final common pathway to reverse cholesterol transport is it's out of the body. Ezetimibe by far. So I can make the case that if I wanted a lipid-lowering drug in the drinking water as first line, it would be ezetimibe, not a statin. You know? So very interesting.

   15. PADr. Peter Attia40:04

       And very controversial. [laughs]

   16. TDDr. Tom Dayspring40:07

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

   17. PADr. Peter Attia40:21

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

   18. TDDr. Tom Dayspring40:24

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

   19. PADr. Peter Attia40:29

       So the one that we've left out before we get... I want to come back to niacin from a trials perspective, but let's take a break right now, and then we'll come back, and we'll pick it up with... Well, I want to talk about the fibrates, and then obviously I want to talk about niacin through a clinical trial standpoint, and then we'll get into the PCSK9. So we'll take a break right now, and we will come back. Okay, guys, so we are now back. We're going to slice this beginning into where we finished off. So we had sort of more or less finished talking about ezetimibe, also known as Zetia. So we'll use this as an opportunity to go into the next drug. So, all right, so Tom, that was pretty, pretty insightful stuff on Zetia, also known as ezetimibe.

8. 41:18 – 1:05:28

   Fibrates: gemfibrozil, fenofibrate and who benefits

   1. PADr. Peter Attia41:18

      Let's move to another class of drugs that doesn't get a lot of use. I can probably count on two hands the number of times I've prescribed it, which is fenofibrate or more broadly, its class of fibrates. What the heck are these drugs? How do they work, and when should we use them?

   2. TDDr. Tom Dayspring41:34

      Um, well, if you practice in the United States, you do have two choices. You have fenofibrate, and you have gemfibrozil. And they're both out there. They're-- both can be, uh, attained generically nowadays, so probably... Fenofibrate still comes in branded forms-

   3. PADr. Peter Attia41:50

      That's the TriCor

   4. TDDr. Tom Dayspring41:51

      ... but you, you don't have to... That's one of them.

   5. PADr. Peter Attia41:52

      Yeah.

   6. TDDr. Tom Dayspring41:53

      There are other, uh, branded forms available out there. Gemfibrozil is a pro-drug. It has to be converted into the active fibric acid, whereas fenofibrate is the active form right away. So it's a little bit more bioavailable than it. It's kind of interesting for the purists of the world. Gemfibrozil has a monotherapy outcome trial given to veterans with coronary artery disease who had low HDL cholesterol and high triglycerides, and it reduced events as much as a statin did in any trial. So There's outcome evidence

   7. PADr. Peter Attia42:24

      Was this independent of triglyceride level?

   8. TDDr. Tom Dayspring42:26

      Yeah, it was independent, although they enrolled people, but there's some... Many of the men, the triglyceride levels were certainly not at super-

   9. PADr. Peter Attia42:35

      Hmm

   10. TDDr. Tom Dayspring42:35

       ... super high levels or so. But it was mostly low HDL cholesterol, and virtually all of those people have some degree of triglyceride elevation. But they, uh, tried to recruit people with what at the time was considered a normal LDL cholesterol also, so.

   11. PADr. Peter Attia42:51

       Which trial was this?

   12. TDDr. Tom Dayspring42:52

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

   13. PADr. Peter Attia42:56

       Oh, VAHIT.

   14. TDDr. Tom Dayspring42:57

       VAHIT. Right.

   15. PADr. Peter Attia42:57

       Yeah, yeah, yeah. I didn't realize that was VAHIT. Okay.

   16. TDDr. Tom Dayspring42:59

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

   17. PADr. Peter Attia43:38

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

   18. TDDr. Tom Dayspring44:00

       Sure. You've taken out one path you're trying to prove with a certain class of drug that via these mechanisms, very different, it works, and then all of a sudden you're getting rid of all the ApoB particles via the statin, so.

   19. PADr. Peter Attia44:12

       Yeah, and it's understandable.

   20. TDDr. Tom Dayspring44:13

       And the statin is not given in a randomized fashion either. Somebody takes it, somebody don't, some docs says you take this, don't take it.

   21. PADr. Peter Attia44:19

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

   22. TDDr. Tom Dayspring44:52

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

   23. PADr. Peter Attia44:57

       No, no.

   24. TDDr. Tom Dayspring44:57

       Yeah, so-

   25. PADr. Peter Attia44:57

       Yeah

   26. TDDr. Tom Dayspring44:58

       ... they were legitimate trials that were ethical.

   27. PADr. Peter Attia45:00

       Whereas with the PCSK9 trials, it was statin standard of care.

   28. TDDr. Tom Dayspring45:03

       You couldn't do it.

   29. PADr. Peter Attia45:04

       You couldn't have a no statin arm in those trials.

   30. TDDr. Tom Dayspring45:06

       Right. That being said, these are all factors that go into the post hoc at least interpretation of some of these trials. But anyway, so gemfibrozil worked, and it's kind of interesting. You couldn't explain the benefit of gemfibrozil in the VAHIT trial, but even though it did raise HDL cholesterol, it was like a milligram and a half increase, and it lowered triglycerides, but not to a significant extent, so why did it work? Or were there other-
9. 1:05:28 – 1:23:44

   Niacin: forms, trials and why it failed

   1. PADr. Peter Attia1:05:28

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

   2. TDDr. Tom Dayspring1:06:29

      Two types of time release forms

   3. PADr. Peter Attia1:06:30

      Oh, I didn't even realize that

   4. TDDr. Tom Dayspring1:06:31

      Intermediate s- uh, release and sustained release

   5. PADr. Peter Attia1:06:34

      So Niaspan, the Abbott version is-

   6. TDDr. Tom Dayspring1:06:36

      That's intermediate release

   7. PADr. Peter Attia1:06:37

      That's intermediate release

   8. TDDr. Tom Dayspring1:06:38

      And that's a prescription only product-

   9. PADr. Peter Attia1:06:39

      Yeah

   10. TDDr. Tom Dayspring1:06:39

       ... which you're not gonna get covered by any therapy payer

   11. PADr. Peter Attia1:06:41

       No, no, no. I learned that the hard way 'cause I had-

   12. TDDr. Tom Dayspring1:06:43

       Yeah

   13. PADr. Peter Attia1:06:43

       ... a patient that was on it a few years ago, and he got a bill for like, they wanted $3,000 for [laughs]

   14. TDDr. Tom Dayspring1:06:49

       Yeah. [laughs] I didn't know it was that high

   15. PADr. Peter Attia1:06:50

       ... for some B vitamins. That's ridiculous

   16. TDDr. Tom Dayspring1:06:52

       But if you want to, you somehow believe in niacin and want to give it a trial, immediate release, and you gotta give it three, four times a day at massive doses. You'll flush your brains out, most people. You're gonna make a case you're not flushing, niacin isn't working in you. Okay.

   17. PADr. Peter Attia1:07:08

       So let's talk about what-

   18. TDDr. Tom Dayspring1:07:08

       But the sustained release is cheap. You can get sustained release, but the biggest problem was in clinical trials, niacin being the toxic drug it is, there's way more hepatotoxicity with sustained release niacin than there is with the short release or the extended release, where there's no hepatotoxicity

   19. PADr. Peter Attia1:07:26

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

   20. TDDr. Tom Dayspring1:07:34

       Yeah, and r- better yet, raised HDL cholesterol. That's what everybody always focus on.

   21. PADr. Peter Attia1:07:39

       Yeah

   22. TDDr. Tom Dayspring1:07:39

       Everybody, since low HDL cholesterol is a risk factor, we now know ApoB related, but whatever. Therefore, if low HDL cholesterol is bad, raising HDL cholesterol has to be good, and niacin is the best product you had at the time. And then so trials were done with niacin, and it was kind of funny 'cause I listened to the podcast you and Ron Krauss did, and it was kind of cool 'cause you made the case a little bit for niacin, Ron did. But at the end, as you just said, you're ambivalent to it, and even Ron says, "I don't use it much anymore." And then you maybe wind up saying, "Okay, it's a fourth line drug if everything else has failed. All right, I'm not gonna smack you around too much if you say that." [laughs]

   23. PADr. Peter Attia1:08:17

       [laughs]

   24. TDDr. Tom Dayspring1:08:17

       And you can't prescribe a PCSK9 inhibitor 'cause of cost. All right. But I think at the end of your... Go back and listen to you. You both admitted you don't use the darn drug anymore

   25. PADr. Peter Attia1:08:27

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

   26. TDDr. Tom Dayspring1:08:44

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

   27. PADr. Peter Attia1:09:12

       You make them hyperthyroid

   28. TDDr. Tom Dayspring1:09:13

       You make them hyperthyroid. [laughs] Not exactly good if you have coronary ar- So that drug failed. They used a primitive fibrate, clofibrate, and there was some question of a mortality adversity there. So that was hit number one on the whole f- Nobody in America us- uses clofibrate anymore. It's probably still available in Europe. I don't think anybody uses it. So fibrate arm of that trial failed, and they used estrogen given to men because, hey, women don't get heart disease 'cause they have high estrogen levels.

   29. PADr. Peter Attia1:09:46

       [laughs]

   30. TDDr. Tom Dayspring1:09:46

       If we just gave estrogen to men, they wouldn't get heart attacks, and they had to immediately stop the trial by precipitating heart attacks in men by prescribing estrogen. So, uh
10. 1:23:44 – 1:29:29

    PCSK9 genetics and mechanism of action

    1. PADr. Peter Attia1:23:44

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

    2. TDDr. Tom Dayspring1:24:02

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

    3. PADr. Peter Attia1:24:08

       Oh, no, no. Sorry. I mean the thing-

    4. TDDr. Tom Dayspring1:24:09

       ... uh, high, uh, PCSK9 expression or-

    5. PADr. Peter Attia1:24:11

       No, sorry. No, I mean the actual family of PCS-

    6. TDDr. Tom Dayspring1:24:13

       Oh

    7. PADr. Peter Attia1:24:13

       ... the PCS family. Yeah, I, I believe-

    8. TDDr. Tom Dayspring1:24:15

       Oh, PCS, look, there's at least 10 members in the family.

    9. PADr. Peter Attia1:24:18

       There, there are.

    10. TDDr. Tom Dayspring1:24:18

        They've been around forever.

    11. PADr. Peter Attia1:24:19

        Yeah, yeah. And I, and I, I think it's-

    12. TDDr. Tom Dayspring1:24:20

        I, I, I don't know who discovered number nine.

    13. PADr. Peter Attia1:24:22

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

    14. TDDr. Tom Dayspring1:24:36

        Yeah, Helen Hobbs did the genetic evaluation at gain of function, loss of function, explains outcomes.

    15. PADr. Peter Attia1:24:41

        And the gain of functions were discovered first, correct?

    16. TDDr. Tom Dayspring1:24:44

        Yeah.

    17. PADr. Peter Attia1:24:45

        So- I'll explain this really quickly and briefly. You can expand upon it. PCSK9 degrades LDL receptors. So if you have a gain of function, you are more rapidly degrading LDL receptors-

    18. TDDr. Tom Dayspring1:25:00

        Right

    19. PADr. Peter Attia1:25:00

        ... on the liver. You're going to have a decrease in your clearance of LDL. You will have a higher LDL. These patients had very high events. In fact, these patients are makeup, what? 5 to 10% of what we would-

    20. TDDr. Tom Dayspring1:25:11

        Yeah, that's-

    21. PADr. Peter Attia1:25:11

        ... diffusely refer to as familial hypercholesterolemia.

    22. TDDr. Tom Dayspring1:25:13

        That's correct.

    23. PADr. Peter Attia1:25:14

        Yeah.

    24. TDDr. Tom Dayspring1:25:14

        It's one of the many, uh, and I think-

    25. PADr. Peter Attia1:25:16

        There's like 2,000

    26. TDDr. Tom Dayspring1:25:16

        ... in one of your podcasts-

    27. PADr. Peter Attia1:25:17

        Yeah

    28. TDDr. Tom Dayspring1:25:17

        ... people don't understand FH could be a thousand different disorders.

    29. PADr. Peter Attia1:25:20

        Yeah, FH is a phenotype, not a genotype.

    30. TDDr. Tom Dayspring1:25:22

        And they're not all autosomal dominant. Some are heterozygote disorders-
11. 1:29:29 – 1:34:58

    Statin choice and the case for hepatoselectivity

    1. PADr. Peter Attia1:29:29

       Now, we're gonna come back to this 'cause I wanna talk a little bit about the brain, and you alluded to it earlier, but I don't wanna derail us now, so I'm saying this just as much to remind me as to remind you. You can come up with multiple ways to lower LDL. Uh, when I say LDL, I'm talking the actual particle number.

    2. TDDr. Tom Dayspring1:29:48

       Yeah, LDL.

    3. PADr. Peter Attia1:29:49

       You can inhibit the synthesis of cholesterol, which in turn also activates the clearance, or you can just go directly after the clearance, so the former would be how a statin works. The latter would be how a PCSK9 inhibitor works.

    4. TDDr. Tom Dayspring1:30:01

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

    5. PADr. Peter Attia1:30:21

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

    6. TDDr. Tom Dayspring1:30:35

       No, you can't make LDL zero.

    7. PADr. Peter Attia1:30:36

       Well, not only can you... I think, I think... Let me rephrase that. What they're basically arguing is the lower you drive LDL, the better, and I do take a little bit of issue with that 'cause I think it depends how you lower it, and it also def- depends, depends on what you define as better or worse. If you're talking about lowering LDL reduces the risk of atherosclerosis, I think that's pretty clear, but at some point, my concern has always been if you lower LDL through cholesterol synthesis inhibition a lot, do you impact other organs, namely the brain?

    8. TDDr. Tom Dayspring1:31:12

       Well, you don't know. Uh, remember, when you're measuring whatever LDL metric, it's what's in s- floating around your plasma. The only place I'll make that's irrelevant, you know, you're not measuring cellular cholesterol-

    9. PADr. Peter Attia1:31:25

       Correct

    10. TDDr. Tom Dayspring1:31:25

        ... based on an LDL cholesterol. So you tell me what your LDL cholesterol level is, I have really no clue, are your cells synthesizing-

    11. PADr. Peter Attia1:31:33

        Yep

    12. TDDr. Tom Dayspring1:31:33

        ... or not synthesizing, exporting, effluxing or whatever to particles that carry cholesterol. But as I think we indicated earlier in our talk today, look, it is integral, cells do have to make cholesterol, so you certainly wouldn't want to stop s- cholesterol synthesis in probably any cell in your body, 'cause the cell membranes, if nothing else, requires it. And we talked about the brain, certainly it's the only way it has cholesterol is it makes it. So if we did know we were inhibiting cholesterol synthesis in the brain, would you be really that comfortable with that? And if you were, is there certain limits where, oh, I wouldn't mind reducing it a little bit, but how much? 'Cause that brain really needs it, and the brain has no other source of cholesterol, and like-

    13. PADr. Peter Attia1:32:22

        Now, nowadays, it, with the exception of patients who have been on a statin for a long, long period of time, when it comes to patients that are relatively new to statins, there are really only a handful we're really looking at today, right? Lipitor and Crestor are doing the lion's share of the work. They're, you know-

    14. TDDr. Tom Dayspring1:32:40

        Well

    15. PADr. Peter Attia1:32:40

        ... for some patients who are very sensitive, we'll use Livalo or we'll use Pravastatin, but we're not really doing much in the way of Simvastatin or any of these older drugs, correct?

    16. TDDr. Tom Dayspring1:32:50

        No, no. If you're following guidelines, what you're doing is prescribing high potency statins or at least moderate intensity statins. So if you want to follow the guidelines, you'll, the only choices you have are Rosuvastatin or Atorvastatin, Lipitor or Crestor at a 40 milligram or above dose for Atorva or a 20 milligram-

    17. PADr. Peter Attia1:33:11

        20 or higher

    18. TDDr. Tom Dayspring1:33:11

        ... above dose for Rosuva. If you're stuck, you, they would allow you to sneak Simva 40 milligrams into there, but that's at best a moderate dose statin. 80 milligrams of Simva has been taken off the market. That used to be a choice.

    19. PADr. Peter Attia1:33:26

        Yeah, the side effects are quite high with Simva.

    20. TDDr. Tom Dayspring1:33:27

        Well, uh, well, Simva, because of a variety of pharmacokinetic reasons, has a ton of drug-drug interactions, and we're in a polypharmacy world, whereas there's far less with Atorva and infinitely less with Rosuvastatin and the Pitavastatin you mentioned, Livalo or so. But I would make the case that if you want the statin has the most data that you're gonna do good, it would be Pravastatin. And Pravastatin, very cheap. It's almost free if you go to a drugstore for it.

    21. PADr. Peter Attia1:33:56

        Yeah. It's just not that potent, right?

    22. TDDr. Tom Dayspring1:33:57

        Well-

    23. PADr. Peter Attia1:33:57

        Even at 80 milligrams

    24. TDDr. Tom Dayspring1:33:58

        ... you know, but if you use the outcome trials, they got the exact same 25% reduction as any Atorva or [laughs] Rosuva trial ever did. So again, Bristol used to explain that to magical mystery pleiotropic effects of Pravastatin. But I would make the case that, all right, if ApoB LDLP is your goal-

    25. PADr. Peter Attia1:34:16

        I would also argue though patients are sicker today. I, I think patients are more metabolically ill today-

    26. TDDr. Tom Dayspring1:34:21

        Whatever

    27. PADr. Peter Attia1:34:21

        ... than they were.

    28. TDDr. Tom Dayspring1:34:21

        But-

    29. PADr. Peter Attia1:34:22

        Uh, meaning I think the Crestor trials have a higher bar to cross than the Pravus trials, but then again, that's just my bullshit speculation.

    30. TDDr. Tom Dayspring1:34:28

        Oh, I, I think the, uh, l- lipid level enrollments with the West of Scotland were twice as horrific as any Rosuvastatin trial ever.
12. 1:34:58 – 1:50:13

    Statins, desmosterol and brain cholesterol

    1. PADr. Peter Attia1:34:58

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

    2. TDDr. Tom Dayspring1:35:00

       Well, we'll get to that. And, uh, look, I jumped on Rosuvastatin bandwagon k- 'cause being a giant Pravastatin guy, 'cause it's one of the, uh, oh, uh, what I would call hepatoselective statins. It's hydrophilic. It goes right into the liver. It doesn't need transporters. So you don't need much in a drug to get in the liver, inhibit cholesterol synthesis, and upregulate LDL receptors. So Rosuvastatin five milligrams is all a lot of people need. You don't need-

    3. PADr. Peter Attia1:35:25

       Mm-hmm

    4. TDDr. Tom Dayspring1:35:25

       ... 40. They want you to use 40 'cause in a trial that's the dose they use where they got heart attack reduction, but since it all comes back to ApoB reduction, use whatever it takes to get your ApoB down, in my mind. Y- you know, that's not how the guidelines exactly figure out how to do it. They like to k- give level one star rated evidence or so. Mine would be a lesser degree of evidence. [laughs] So, uh, you pick. So they get in. The other drugs are not as hydrophilic, so the only way they get into the liver is various receptors pull them in. There's a whole variety of transporters that pull molecules into the liver, but they're subject to interference with a ton of other drugs that may be in your system or other molecules. So you don't have the clean pharmacokinetics like you do with Pravastatin or Rosuvastatin. That being said, we, you're talking you want to introduce the brain into the discussion. Now, all statins can get into the brain. They can cross the blood-brain barrier, but the statins that cross it much easily are the lipophilic statins, 'cause they have to pass a lipid membrane, the blood-brain barrier. So Atorvastatin, Simvastatin get into the brain more easily than do Lovastatin, Simvastatin, and Atorvastatin.

    5. PADr. Peter Attia1:36:40

       Oh, wait, say that again. The most lipophilic one.

    6. TDDr. Tom Dayspring1:36:42

       The, the lipophilic statins, easier to-

    7. PADr. Peter Attia1:36:44

       Yeah, which is-

    8. TDDr. Tom Dayspring1:36:45

       ... cross the blood-brain barrier

    9. PADr. Peter Attia1:36:45

       ... Atorvastatin and Simvastatin are the two biggest.

    10. TDDr. Tom Dayspring1:36:47

        And, uh, Lovastatin-

    11. PADr. Peter Attia1:36:48

        Yeah

    12. TDDr. Tom Dayspring1:36:48

        ... would probably be the worst, [laughs] you know?

    13. PADr. Peter Attia1:36:50

        Whereas Pravastatin would be less.

    14. TDDr. Tom Dayspring1:36:51

        Pravastatin would be far less, Ed, would, would Rosuvastatin.

    15. PADr. Peter Attia1:36:55

        Yeah.

    16. TDDr. Tom Dayspring1:36:55

        You have that Fluvastatin, sort of a water soluble statin is probably more in the class of Rosuvin, uh, trials.

    17. PADr. Peter Attia1:37:01

        And what about Livalo?

    18. TDDr. Tom Dayspring1:37:01

        Well, Livalo would be the same.

    19. PADr. Peter Attia1:37:03

        Yeah.

    20. TDDr. Tom Dayspring1:37:03

        It's a, uh, non-lipophilic statin. So, um- If you're worried about statins getting into the brain, you might want to choose the hydrophilic ones or so. But the only concern I might have is, well, if those statins are getting into the brain, it's great to reduce cholesterol synthesis in the liver. I'm going to upregulate LDL receptors. I, I don't know that I want to do it in every cell in the body, but I'm probably not to- I, I sh- I know I'm not with any of them totally inhibiting cellular, uh, synthesis cholesterol. But the brain, it's way more dependent on cholesterol. And then we have studies of people with Alzheimer's disease and other cognitive, their brains seem to be depleted of cholesterol to variable degrees.

    21. PADr. Peter Attia1:37:44

        Now, Tom, I'm just going to stop you right here because if I had a dollar for every time I had a brutal argument with a cardiologist about this point, 'cause up until this point in the discussion, if you're a card-carrying lipidologist or a cardiologist who really understands lipids, you're kind of on board. You're in the camp of-

    22. TDDr. Tom Dayspring1:38:02

        Right

    23. PADr. Peter Attia1:38:02

        ... let's lower LDL. But I do get patients from time to time who are more than at their LDL goal, meaning their LDL cholesterol is 40 milligrams per deciliter. Their LDL particle number is 500 nanomole per liter. These are people in primary prevention, but, you know, let's assume they have a calcium score of 800 or something. I mean, they're very high risk. But I look at that and I say, "Well, gosh, their desmosterol level's unmeasurable."

    24. TDDr. Tom Dayspring1:38:26

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

    25. PADr. Peter Attia1:39:02

        I'm gonna go with no.

    26. TDDr. Tom Dayspring1:39:03

        [chuckles] Yeah. It'd be a tough sell.

    27. PADr. Peter Attia1:39:06

        [chuckles]

    28. TDDr. Tom Dayspring1:39:06

        Oh, by the way, don't leave. I'm gonna come back and just do a quick spinal tap on you today. [laughs]

    29. PADr. Peter Attia1:39:11

        [laughs] Hang on, hang on. Just wait, just wait there in the waiting room.

    30. TDDr. Tom Dayspring1:39:13

        Yeah.
13. 1:50:13 – 1:55:26

    CK and liver enzymes are poor statin monitors

    1. PADr. Peter Attia1:50:13

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

    2. TDDr. Tom Dayspring1:51:02

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

    3. PADr. Peter Attia1:51:09

       You think so?

    4. TDDr. Tom Dayspring1:51:09

       Oh, totally.

    5. PADr. Peter Attia1:51:10

       Oh, I didn't realize that.

    6. TDDr. Tom Dayspring1:51:11

       And the, uh, evidence would totally support that.

    7. PADr. Peter Attia1:51:12

       Well, I know it doesn't correlate that well with myositis, but-

    8. TDDr. Tom Dayspring1:51:14

       Not at all. First of all, before you ever do that, make sure you have a baseline CK.

    9. PADr. Peter Attia1:51:17

       Yes, of course.

    10. TDDr. Tom Dayspring1:51:18

        There's a lot of people-

    11. PADr. Peter Attia1:51:19

        Yeah, they're working out

    12. TDDr. Tom Dayspring1:51:19

        ... especially African Americans, not even working out, they just have high CK levels-

    13. PADr. Peter Attia1:51:23

        Yeah, yeah, yeah

    14. TDDr. Tom Dayspring1:51:23

        ... African Americans.

    15. PADr. Peter Attia1:51:23

        So, so, but I didn't realize that.

    16. TDDr. Tom Dayspring1:51:25

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

    17. PADr. Peter Attia1:51:55

        I did not, I did not realize that. All right.

    18. TDDr. Tom Dayspring1:51:56

        Yeah. And, and I'll get some info, uh, to you on that.

    19. PADr. Peter Attia1:51:58

        Please, please.

    20. TDDr. Tom Dayspring1:51:59

        So stop monitoring CK, and if they come in and tell you, "Hey Peter, I'm feeling pain," or you somehow are doing some muscular strength testing, or they tell you, "I don't get out of the chair as much," proximal muscle weakness, stop the darn statin.

    21. PADr. Peter Attia1:52:13

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

    22. TDDr. Tom Dayspring1:52:15

        Yeah. But d- don't use CKs to d- dictate your statin, uh, uh, therapy.

    23. PADr. Peter Attia1:52:19

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

    24. TDDr. Tom Dayspring1:52:28

        Yeah, me either

    25. PADr. Peter Attia1:52:29

        ... and ezetimibe.

    26. TDDr. Tom Dayspring1:52:29

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

    27. PADr. Peter Attia1:52:59

        No, I mean, of course not.

    28. TDDr. Tom Dayspring1:53:00

        Grant it more time to go, yeah.

    29. PADr. Peter Attia1:53:01

        I, I was just about to say-

    30. TDDr. Tom Dayspring1:53:02

        Yeah
14. 1:55:26 – 2:00:15

    Synthesis reflexes, ezetimibe and personalizing therapy

    1. PADr. Peter Attia1:55:26

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

    2. TDDr. Tom Dayspring1:55:27

       It's been looked at extensively, Peter. It's-

    3. PADr. Peter Attia1:55:29

       I, I'm going to go back and look at this Zetia-

    4. TDDr. Tom Dayspring1:55:30

       I'll send you entire documents-

    5. PADr. Peter Attia1:55:32

       Yeah

    6. TDDr. Tom Dayspring1:55:32

       ... where they've an- analyzed all the data in the world on aminase and statin therapy. It's inconsequential.

    7. PADr. Peter Attia1:55:38

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

    8. TDDr. Tom Dayspring1:55:53

       But-

    9. PADr. Peter Attia1:55:53

       And then the only thing you do is stop the Zetia, and it returns to baseline.

    10. TDDr. Tom Dayspring1:55:57

        Oh, all right. So something is happening. But is the doubling of a transaminase of that etiology of any concern to you? So fine, if you want to stop it and see, go ahead, and if that's going to occasionally limit how much ezetimibe you're going to use in a patient, okay. Figure out how else to lower-

    11. PADr. Peter Attia1:56:13

        Yeah

    12. TDDr. Tom Dayspring1:56:13

        ... ApoB. So fine. I understand there are things that'll come into play in an individual patient-

    13. PADr. Peter Attia1:56:19

        Well, that, that, that's-

    14. TDDr. Tom Dayspring1:56:20

        ... where the data doesn't support it.

    15. PADr. Peter Attia1:56:21

        Yeah, that's my point.

    16. TDDr. Tom Dayspring1:56:21

        But you're, you're making an individual decision.

    17. PADr. Peter Attia1:56:23

        That, that, that's my point.

    18. TDDr. Tom Dayspring1:56:24

        Sure. Of course.

    19. PADr. Peter Attia1:56:24

        That, that, that's my point.

    20. TDDr. Tom Dayspring1:56:25

        Yeah.

    21. PADr. Peter Attia1:56:25

        You've got to be able to make an individual decision, which is what we're-

    22. TDDr. Tom Dayspring1:56:27

        Yeah. Just don't generalize.

    23. PADr. Peter Attia1:56:28

        Yeah, yeah, which is what we're saying with the, with the desmosterol level.

    24. TDDr. Tom Dayspring1:56:31

        Yeah.

    25. PADr. Peter Attia1:56:31

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

    26. TDDr. Tom Dayspring1:57:03

        And, and a suppressed cellular synthesis, which has nothing to do with the amount of cholesterol you measure in the blood-

    27. PADr. Peter Attia1:57:09

        Great point

    28. TDDr. Tom Dayspring1:57:10

        ... and has not... Cholesterol synthesis is not affected per se by PCSK9 inhibitors. Ezetimibe is interesting. If you go with ezetimibe monotherapy, you'll actually get a little reflex increase in cholesterol synthesis.

    29. PADr. Peter Attia1:57:24

        Yes.

    30. TDDr. Tom Dayspring1:57:24

        And vice versa.

Episode duration: 2:00:15