407 ‒ Preventing cardiovascular and Alzheimer’s disease: lowering LDL early, APOE4, and more

1. 0:00 – 0:11

   Intro

   1. PAPeter Attia0:01

      Hey everyone, welcome to "The Drive Podcast." I'm your host, Peter Attia.

2. 0:11 – 7:54

   Michael’s path to lipidology, and his passion for primary prevention

   1. PAPeter Attia0:11

      Michael, thank you so much for coming out, and, uh, it is hard to believe that this is our first meeting in person given how many years we've worked together electronically and in other ways.

   2. MDMichael Davidson0:22

      Right, yes. It's great to be here, Peter.

   3. PAPeter Attia0:25

      For folks who might not be familiar with your work, although we've certainly referenced it a lot on the podcast, and it-- your work speaks for itself, so you certainly don't need us referencing it. Um, maybe tell folks a little bit about yourself, starting with what you do clinically.

   4. MDMichael Davidson0:38

      Right. So I'm, I'm a cardiologist, lipidologist, and, uh, I run the lipid clinic at University of Chicago. I'm, I'm a professor. So I see patients actually, you know, four full days a month. It-- and, and that's, and, and that's a pretty loaded prevention focused practice.

   5. PAPeter Attia0:54

      And what's the path to that, right? Because, uh, lipidology is not necessarily a subspecialty within cardiology, although-

   6. MDMichael Davidson1:01

      Right

   7. PAPeter Attia1:01

      ... of course, people who listen to this podcast are very familiar with it, and Tom Dayspring has been on a number of times. But what was your path towards that from your training? Were you always interested in prevention?

   8. MDMichael Davidson1:10

      Well, it, it's a passion because, um, my father died at age forty-seven of a, of a heart attack. I was sixteen. Um, I had abnormal lipids, uh, ru- ran in my family, so I, uh, got very interested in lipids in medical school. So I did the original niacin trials that went back into the '80s, late '70s, actually. And then after, uh, uh, training residency, I started doing research in my fellowship on omega-3 fatty acids, lipids for the lipid effects. I was the first one to use fish oil capsules to treat lipid disorders. And then from there, I got involved with all the statin trials, and so that's-- it's been my passion is to be, you know, involved in clinical trials, and that's how I got... So I got into the, the card... I still am a cardiologist, did the usual stuff that cardiologists do, uh, but then-- and then focused primarily on, on prevention. So I opened a prevention center right out of, out of my fellowship, along with a re-research company that did all the clinical trials, and that's been my path, you know, ever since. And then the biotech startups started happening about, um, about fifteen years ago.

   9. PAPeter Attia2:17

      And we have some overlap in some of those companies, one of which we'll talk about. Um, but maybe even before we get into some of the really exciting things going on in pharma, maybe we can just speak a little broadly about prevention and, um, because there really isn't, at least as I see it, a uniform consensus around how aggressively one should be trying to prevent ASCVD. Um, sometimes I feel like, uh, people look at me as though I have multiple heads-

   10. MDMichael Davidson2:48

       Right

   11. PAPeter Attia2:49

       ... when I talk about preventing, you know, taking steps towards prevention in thirty-year-olds, for example. Um, because by any sort of calculable metric, their ten-year risk is very low and would not necessarily justify the steps we might take. But you're, you're more thoughtful, you're, you're more s- you're more, you know, astute when it comes to all these things. I, I'd like to hear your point of view on how you think about primary prevention, and we can differentiate that from secondary later on.

   12. MDMichael Davidson3:17

       Right. Now listen, it, it always is a hard sell to get a thirty-year-old to start taking a statin, for example. And so I explain the primordial prevention concept, which is, you know, basically you wanna stop plaque from forming before it's there. And it's a lot easier to stop it from forming than it is to reversing it when it already exists. So we have this path in right now today, which is the mainstream, is that you wait till someone has significant plaque buildup or even a heart attack or a stroke, then you treat super aggressively to get the LDL down. But we know from genomics that if you have a low LDL throughout your whole lifetime, uh, it, it prevents heart disease on a much greater degree. You know, you know, for example, I mean, if you lower LDL before you have a heart attack, it's very effective. If you have a heart attack and you lower LDL, it still has benefit. But once you have heart failure, there's no benefit to lowering LDL. And so the earlier you start, the better. And, um, what I like is the, um, the eight gram rule, which is that eight grams of cholesterol in your lifetime lead to heart disease. So, so that is two hundred milligrams per deciliter times forty years is eight grams, or a hundred milligrams per deciliter times eighty years is eight grams, or eighty milligrams per deciliter times a hundred years-

   13. PAPeter Attia4:39

       A hundred years

   14. MDMichael Davidson4:39

       ... is eight grams. So you can think about it in, in that sense that if you-- we-- the data says that if you keep your LDL below eighty throughout your lifetime, you don't get heart disease. So I think you said this as well. I mean, we have the knowledge to prevent heart disease now. It's applying it earlier in life that really makes the difference, and that's the, that's my pitch to the, uh, to the thirty-year-old. And, you know, and, and, and, and there's a lot of pushback, and I, and I try to then, if necessary, provide more information to them, uh, which is, you know, we can do genetic testing, we can do polygenic risk scores. If they're old enough, we can do cal- coronary calcium scanning or more advanced, you know, plaque analysis. We can look at, you know, other risk factors like Lp (a) or CRP, things like that, wh-which give us more, you know, kind of information about who's at higher risk. Of course, family history is, is so important. Um, but believe it or not, I would think family history would be one of the most powerful, you know, kind of motivators, but it's not, not always the case.

   15. PAPeter Attia5:45

       Well, it certainly was in you. Um, I've shared my story about how rampant heart disease is in my family and how it was sort of my foray into even thinking about all of these cardiometabolic diseases. Uh, your story, by the way, is just incredible in that it's identical to that of my father-in-law. My father-in-law's father, so, uh, you know- whatever my wife's grandfather also died at 47 in the hands of his 16-year-old son.

   16. MDMichael Davidson6:12

       And it's even-- So my brother had bypass at age 44. So it's like even... And then here's the story that why I'm so passionate about early is that so I was 16, my brother was 14. My father died. My uncle, family doctor, checked our lipids. They both were equally bad. So I then went on to start medical school. I took niacin in med school. As soon as statins became available, I started taking a statin. My brother, who's also a family doctor, went on and he become a vegetarian, really strict diet, and did not take statins until much later than at age 44 has bypass surgery and very significant coronary disease. So I think that kind of like it's an N of one, but it's pretty good comparison. Two brothers, one starts statin early, one starts statin later. And so actually that decade, the 30, that 40 decade and even maybe 20 to 30, such an important timeframe when the plaque itself is starting to form relatively rapidly. And that's when you want to have your most effective treatment there to prevent it. And that's why I become an advocate for earlier in life, the better when it comes to statin therapy. Now with women, we have to be careful about the whole pregnancy issue and stuff like that. And we also still balance that as well, but it's really coming that type of information. I know people bring up relative risk, absolute risk, 10-year risk. And I think it's really we're talking about more about preventing heart disease when you're 80 or 90, not 10 years

3. 7:54 – 14:11

   Reframing prevention around causal drivers rather than time horizon

   1. MDMichael Davidson7:54

      from now.

   2. PAPeter Attia7:55

      Yeah. I guess the other point that for me was a really wonderful way to think about it that I would credit to Alan Sniderman, who wrote a paper, I feel like it was about 12 years ago, but he, at least for me, was the first time somebody repositioned the argument of rather than talk about treating five-year risk, 10-year risk, 15-year risk or trying to stretch that out, reframe it as we treat causal drivers of disease.

   3. MDMichael Davidson8:24

      Mm-hmm.

   4. PAPeter Attia8:25

      And if that's the case, then the discussion changes entirely. And people who have listened to this podcast have probably heard me use the analogy, but it's why we target smoking cessation so aggressively. It's not that everyone who smokes gets cancer, and it's not that everyone who gets cancer smokes, right?

   5. MDMichael Davidson8:44

      Mm-hmm.

   6. PAPeter Attia8:45

      Those states are true. It is that smoking is causally related to cancer, and therefore the time to quit smoking is before you start. And if you've already started, the time to quit smoking is today, regardless of your risk going forward. So if a person has been smoking for one year, a pack a day, they have a one pack year history of smoking. That does not really increase your probability of getting cancer.

   7. MDMichael Davidson9:11

      Mm-hmm.

   8. PAPeter Attia9:12

      It's probably not till you hit 15 or 20 pack years that your risk really steps up. But there's not a single doctor on the planet that I would imagine saying, "Listen, Michael, I know you've been smoking a pack a day for a year. Keep it up for another 10 years, 15, 20 at the most, but then we're going to have to cut this out." Why? And that's an absurd example, but it gets to the point of causality. And so inasmuch as LDL is causally related to ASCVD, which you pointed out the Mendelian randomizations, let alone the clinical trials, this would be one of the most assured parts of biology. It does become a little frustrating that it's not more widely understood that you have to treat a causal risk factor regardless of the time horizon.

   9. MDMichael Davidson10:02

      Right. And the analogy goes, it's very good. Smoke is a really good one, but also blood pressure, diabetes. We don't wait for stroke and heart failure to treat hypertension. We don't wait for-

   10. PAPeter Attia10:11

       That's right

   11. MDMichael Davidson10:11

       ... blindness and kidney disease to treat diabetes. So I don't know why LDL gets this like stepchild type of role when it comes to how we manage, but it is causal and we know that. And so why not treat it early as you can in life? And I think that's what we advocate for. We're not always successful, but I think we get the message across and we try to, like I said, we have the tools now if we just apply them much more effectively.

   12. PAPeter Attia10:38

       Why do you think that? I mean, not that we should waste too much time sort of speculating, but I don't have a great answer for it, right?

   13. MDMichael Davidson10:44

       Right.

   14. PAPeter Attia10:44

       So I don't understand why we understand that nobody should be walking around with untreated hypertension, even if they're young and even if they're asymptomatic, because most young people with hypertension would be asymptomatic. And you could argue, well, is the anti-LDL issue really all about drugs? Is it that people view it as sort of a pharma conspiracy or something like that? I mean, what is your take on why this one issue around LDL has become so contentious?

   15. MDMichael Davidson11:21

       I think it's multiple reasons, but one actual reason I think is that people believe that LDL cholesterol can be totally managed with lifestyle. And just if they ate one less egg or one less piece of meat or something like that, their LDL would come miraculously down to normal. And I think what we're learning from the genomic studies that we do a lot of genetic testing in the lipid clinic, we find that it's almost always a genetic factor involved. And so when people realize it is genetics and there's nothing they can do about other than they're already doing great lifestyle and so forth, that becomes, I think, part of the motivation to get them to do something about it. But people don't like taking drugs. I get it. It is about the statin, but we try to find other Other ways to get the LDL down if necessary. But I wish there was, you know, more kind of we-- Another problem we have, of course, is the prevent, primary prevention guidelines by the, like, American Heart are, are not very effective. They're, they're, they're, they don't really emphasize as much as like you and I, if we were writing the guidelines, we, we'd have a very different approach to how we manage, uh, elevated LDL.

   16. PAPeter Attia12:36

       Yeah.

   17. MDMichael Davidson12:37

       We would, we would be advocating a much earlier intervention in life. We just don't have those guidelines that are there to help kind of get physicians on board as well.

   18. PAPeter Attia12:45

       It's interesting about the lifestyle point because ironically, lifestyle has a far larger impact on managing high blood pressure, where, you know, weight loss and exercise, uh, individually and collectively have a greater impact on hypertension, which still means there are a lot of people out there, by the way, who don't respond, as you know, fully to those interventions and can be exercising, of normal weight, and still have essential hypertension and require medication. But I still don't see the reluctance or resistance to it the same way I do with managing dyslipidemia. So I don't know. I, I don't, I don't, uh, I don't have any great insight into it, but it, it does, um, uh, it does, it does make me sad for people who become ultimate victims of it.

   19. MDMichael Davidson13:28

       I do, very. I see it. I s- I see the, the clinical ramifications of it, and it, it is sad 'cause it's, it's preventable.

   20. PAPeter Attia13:36

       Yeah.

   21. MDMichael Davidson13:37

       But, uh, we'll keep, we'll keep, uh, advocating. I think we're starting to see the trend happen. I mean, how many more trials do you need to show that LDL, no matter how you lower it, results in a clinical benefit? I think we'll talk about obicetrapib. That might be the last, you know, kinda mechanism. Once that, once that study prevails, the PREVAIL trial, and then we have a, like, our tenth d-different mechanism action of LDL lowering and benefit, then I think hopefully the, um, you know, all the obstacles will go away and people say, "Let's just start treating LDL a- as, as early in life as, as feasible."

4. 14:11 – 24:38

   What CETP inhibition does, the evolutionary biology of CETP, the HDL-raising rationale, and Pfizer's torcetrapib failure

   1. PAPeter Attia14:11

      Well, let's, let's talk a little bit about obicetrapib. Um, your colleague, John Kastelein, was a guest on this podcast, gosh, I wanna say three, maybe four years ago. Um, certainly one of the more enjoyable discussions I've had because I tend to really enjoy talking about these things. Um, but I think it would be a fair assumption that many people listening to us now have either not heard that podcast, and if they did hear it, do not remember the ins and outs of CETP inhibition. So let's assume that, you know, pe- we're starting from, from scratch, and, uh, let's, let's talk about this, this totally new class of drugs. Let's also just acknowledge, as a disclosure, you are currently the CEO of a company called NewAmsterdam Pharmaceuticals, which is the manufacturer of a particular drug we're going to talk about in this class.

   2. MDMichael Davidson15:02

      Right.

   3. PAPeter Attia15:02

      Um, so take us back to, oh, well, I don't know when the drug entered clinical trials, but I know when it ended, which would've been about 2006?

   4. MDMichael Davidson15:16

      Eight. I think it was '08.

   5. PAPeter Attia15:18

      Okay.

   6. MDMichael Davidson15:18

      About torcetrapib?

   7. PAPeter Attia15:19

      Yeah.

   8. MDMichael Davidson15:19

      It could have been 2006. Yeah.

   9. PAPeter Attia15:20

      I think, I feel like it was the fall of '06. But anyway.

   10. MDMichael Davidson15:22

       It might, it might have been. You're right. It was definitely Christmas, uh, December, got the call.

   11. PAPeter Attia15:26

       Yeah.

   12. MDMichael Davidson15:27

       Somewhere in that range. Yeah. So it's, uh-

   13. PAPeter Attia15:29

       All right. So first, so this is the fir-- And this was Pfizer-

   14. MDMichael Davidson15:32

       Pfizer

   15. PAPeter Attia15:32

       ... combining this with-

   16. MDMichael Davidson15:34

       A torvastatin

   17. PAPeter Attia15:34

       ... a torvastatin in a clinical trial.

   18. MDMichael Davidson15:36

       Yeah. Right.

   19. PAPeter Attia15:36

       Okay. So go back to, go back from that a decade into the discovery of yet another mechanism, 'cause you've already alluded to this, which is lowering LDL is the goal, but there are many paths to get there. Statins have taken one path, which is we're gonna inhibit cholesterol synthesis. The liver will overcompensate by trying to pull more LDL into the liver, and that will lower LDL. We're gonna come and ta-- I wanna come back and talk about bile acid sequestrants. We probably won't get to ezetimibe. We might mention PCSK9 inhibitors. But CETP inhibitors are totally different.

   20. MDMichael Davidson16:07

       Right.

   21. PAPeter Attia16:07

       So just explain what they do.

   22. MDMichael Davidson16:08

       Right. So I think it's good to start, um, about what exactly CETP does. It's called cholesterol ester transfer protein. It, it transfers cholesterol, you know, from HDL into LDL. So when you block it, HDL goes up, LDL goes down. And it, but it also d- it's many other reasons. It, it also improves H- LDL clearance from the liver like a statin does. We've proven that. It, it does help clear LDL as well. So animals that lack CETP, like the rat, the dog, uh, they have very low LDLs, very high HDLs. And they go- they don't get atherosclerosis unless you, uh, give the, give the rat or the mouse, uh, CETP transgenically. Then they get high LDL, low HDL, and they get atherosclerosis. Like the dog, you know, we, you know, the whole, uh, don't get atherosclerosis. They're carnivores. They don't have any CETP. Monkeys have CETP. Rabbits have CETP. Humans have CETP. We have, you know, uh, relatively speaking, uh, high LDL, low HDL. So in effect, one of the most prominent, um, atherosclerotic animal models is to give the, the, the mouse CETP, and that, and that's what we use in a lot of our studies to show, yeah, you can induce atherosclerosis, and a different therapy can reduce atherosclerosis. So it's a very, very much a modulator of the LDL, HDL levels in, in mammals.

   23. PAPeter Attia17:31

       Do you have a sense, given that everything you just described is a mammal, um, which means evolutionarily, while we look different today, we're coming from a very narrow part of the tree.

   24. MDMichael Davidson17:41

       Right.

   25. PAPeter Attia17:41

       Why do you think that difference exists, and is there, is there a reason you can, you can speculate on?

   26. MDMichael Davidson17:46

       It, it, it's conservatory. In other words, you didn't have the, chasing the wooly mammoth, you didn't have a lot of cholesterol available to you, uh, in the, in the, in the diet.

   27. PAPeter Attia17:56

       But why wouldn't dogs have the same issue then?

   28. MDMichael Davidson17:58

       Well, they, they, you know, they, they, uh, they have plenty of meat. They eat, all they eat is meat and all that kind of stuff. They, they have plenty of cholesterol. Uh-

   29. PAPeter Attia18:05

       Hmm. So we think it was truly just a scarcity issue then?

   30. MDMichael Davidson18:07

       Yeah, scarcity, I think, uh, and so-
5. 24:38 – 28:29

   Why raising HDL is thought to be beneficial, a quick review of the functions of HDL, and how this connects to torcetrapib

   1. PAPeter Attia24:38

      aside from the fact that epidemiologically we could observe that people with high HDL, low triglycerides, and low LDL did better, was there any sense of mechanistically why would raising HDL do something? In other words, how did, how was causality established as opposed to association?

   2. MDMichael Davidson25:00

      That's a great question, but th- there's a lot of work that went into the HDL function. You know, what does HDL do? So HDL is a, uh, a lipoprotein that is, um, also y- kind of made, made by the liver and the intestines, and it goes to different organs, and it basically picks up cholesterol. It, it's, it effluxes cholesterol into the lipoprotein. It goes from an empty garbage truck to a loaded garbage truck and, and, and an empty pita pocket to a spherical, however you want to describe it. It's, uh, and it, and it matures. It goes from this, this pancake up to a, a big ball, uh, filled up with cholesterol, and there's different enzymes along the way that, that kind of help, you know, maturate the, the particle. And once the spherical particle is, is mature, it goes to the liver and gets cleared. And, and, and actually pr- the predominant, uh, route, i- i-- mo- most people don't realize this, but m- the majority of bile that the liver makes comes from HDL. It comes from HDL. That's the bile. The, the mo- mo-- it goes funnel more into the biliary system and then, then out into the intestine. So HDL is the, the precursor. It, it-- but it has a lot of functions that are, um, really interesting. I mean, it, it's a, it's a, uh, it picks up a lot of garbage along the way. It picks up all these, uh, inflammatory components, the cytokines. Um, uh, and it's like a, it's like a dump truck. It's picking up stuff, and it takes it back to the liver for, for clearance. That's what, that's what the purpose of it is. Um, and part of that is cholesterol, and so people thought it's going to the plaque. It's picking up cholesterol. Reverse, we call it reverse cholesterol transport, and it, it, it picks up the, the cholesterol and removes it from the plaque, and that's why you get less heart disease with, with HDL. So it was all mechanistically, you know, based on, on that finding, even though, uh, the amount of cholesterol that it got from the plaque was, was actually minuscule. Yeah, minuscule, and it, compared to what it does to other organs. It's... But it, but it's the, um, it's the vehicle for, for cholesterol transport, uh, and it's also has other functions. It's very important, uh, in immune function and, and trying to, um, you know, battle i- innate, you know, kind of pathogens and things like that. So it, it has a lot of other important roles to play i- in human health, but, but that was the reason why we thought, you know, HDL being high was good, uh, and then it functioned by removing cholesterol from the artery wall and taking it back to the liver for clearance. And, and obviously things should be, learned it's a lot more complicated than that, but that, that's was our thinking back in 2006 when torcetrapib unfortunately, um, kind of failed. And, and just to be honest, uh, where I was, I mean, I was a big fan of torcetrapib even though the blood pressure went up because the HDL raising the magnitude of that benefit would be greater than a three-point increase in blood. So I was kind of thinking, "Okay, if any of it raises blood pressure a little bit, it raised HDL, you know, 75%, we, we should get a net benefit." But it turns out it was much more m-- it was much more complicated than that as far as the side effect profile, yeah.

   3. PAPeter Attia28:06

      How much did HDL go up with torcetrapib?

   4. MDMichael Davidson28:08

      About 75%.

   5. PAPeter Attia28:09

      Wow. So despite that, it, I mean, that's just perf-- that really tells you the off-target effects were devastating.

   6. MDMichael Davidson28:16

      Right. Yes.

   7. PAPeter Attia28:17

      Um, did it have an effect on LDL very much? I don't remember.

   8. MDMichael Davidson28:19

      About, about 15%, 10.

   9. PAPeter Attia28:21

      Okay.

   10. MDMichael Davidson28:21

       At most, maybe 10% to 15% lower.

   11. PAPeter Attia28:23

       Okay.

   12. MDMichael Davidson28:24

       It was mo- it was really not even something people even paid attention to, the LDL effect.

6. 28:29 – 37:13

   The graveyard of CETP inhibitors: Roche's dalcetrapib, Lilly's evacetrapib, and Merck's REVEAL trial

   1. PAPeter Attia28:29

      Okay. So then the Roche compound comes along.

   2. MDMichael Davidson28:32

      Right.

   3. PAPeter Attia28:32

      What was the story with that trial?

   4. MDMichael Davidson28:33

      It's a weak CETP inhibitor, and they even called it a CETP modulator, a very safe drug, uh, and it, uh, lo- raised HDL 50, uh, sorry, 30%, maybe, maybe 40 in some trials. So now a much weaker, uh, HDL-raising effect, very-- no LDL effect. Uh, so went into a, a large outcome study, very safe, you know, no, no issues. It, it reduced the risk of diabetes, whi- which we'll come to later. That was one of the things about the HDL-raising benefit that we can talk about. Reduced the risk of diabetes but had no MACE benefit. Did not cause any MACE benefit.

   5. PAPeter Attia29:12

      Major adverse cardiac events.

   6. MDMichael Davidson29:13

      Yeah, right, right. So major adverse, right. Heart attack or stroke reduction was, was, was nothing. There was no benefit there. Not even a trend. It was just completely flat, but, but very safe. And so that was the second failure, you know, high-profile failure. Actually went to another trial later, still, still neutral. No, you know, no, no, no, no ad- no ad- no benefit on major adverse cardiac events. That's number two. Yeah.

   7. PAPeter Attia29:37

      Yep. And then Merck?

   8. MDMichael Davidson29:39

      No, then, then Lilly.

   9. PAPeter Attia29:40

      Oh my gosh. Okay.

   10. MDMichael Davidson29:41

       Then Lilly, uh, which was evacetrapib. Now that one was a, that one's a good molecule. Uh, it, uh, again, very safe and, uh, was studied. Uh, again, it was a time when Lilly did not have the resources it has now, obviously. And so they were trying to go fast. Like, everyone's trying to go fast because again, this was the, you know, could be a huge opportunity to reduce heart disease, so it was all about H. So they went into a study with acute coronary syndrome primarily and, and they showed, again, um, LDL lowering about 15% to 20%, HDL raising again 75% or so. I mean, a very good, um, HDL-raising effect and, uh, they, they only went two years, though. uh, post starting the trial, and they stopped for futility for no benefit on, on major adverse cardiac events, on MACE.

   11. PAPeter Attia30:35

       In secondary prevention.

   12. MDMichael Davidson30:36

       Secondary prevention. It was a, a high-risk secondary prevention.

   13. PAPeter Attia30:39

       By the way, Michael, the first two studies were primary or secondary?

   14. MDMichael Davidson30:42

       All, all secondary.

   15. PAPeter Attia30:43

       These are all secondary prevention.

   16. MDMichael Davidson30:44

       Yep. Okay. Yeah.

   17. PAPeter Attia30:44

       Yeah.

   18. MDMichael Davidson30:45

       So what's important about that trial is ezetimibe, which is now a well-known-- Like, we use ezetimibe all the time, Zetia, for lowering LDL. They, they also did an ACF, acute coronary syndrome trial, which was similar to what was done in the ACCELERATE trial, which is the Lilly trial. So we, we know that two years is too short because in a similar trial with ezetimibe, which is a well-proven LDL-lowering drug, it has bene- everyone recognizes the benefit of ezetimibe, that it took more than two years for the lines to separate. In other words, after two years, their, their lines were, uh, there's no difference in, in major adverse cardiac event. But after two years, they separated.

   19. PAPeter Attia31:25

       Mm-hmm.

   20. MDMichael Davidson31:25

       And so the similar would, would have happened, we believe, with, uh, with evacetrapib in the ACCELERATE trial.

   21. PAPeter Attia31:32

       With Repatha and Praluent, we did see benefit at about two years.

   22. MDMichael Davidson31:36

       But, but this was only a fifteen percent LDL lowering.

   23. PAPeter Attia31:39

       Yeah, yeah, yeah. Yeah, yeah.

   24. MDMichael Davidson31:40

       Okay. And, and then, and then even, uh, with, um... So what's also interesting, in the, um, in the, uh, ODYSSEY outcome study, which is the, uh, Praluent, which is the other-

   25. PAPeter Attia31:52

       Yep

   26. MDMichael Davidson31:52

       ... PCSK9 inhibitor, um, if you look at the populations that had LDLs, uh, below a hundred, which is what this po- they also didn't separate until after two years. I mean, so there's-

   27. PAPeter Attia32:02

       Same with FOURIER. Which one was more heavily-

   28. MDMichael Davidson32:04

       No, FOURIER was, uh-

   29. PAPeter Attia32:05

       Was Repatha

   30. MDMichael Davidson32:06

       ... was, was Repatha.
7. 37:13 – 40:23

   The causality of LDL in cardiovascular disease

   1. MDMichael Davidson37:13

      in a cardiovascular benefit.

   2. PAPeter Attia37:14

      And now you, you've referred to this a couple of times, so I just want to make sure people understand why this is the case, and it actually goes back to sort of our argument earlier about causality. Um, when you line up all of the primary prevention trials, full stop, all of the secondary prevention trials, full stop, all of the Mendelian randomizations, and all of the epidemiology, and you plot on the X-axis LDL-C and on the Y-axis event rate, they're all a bunch of lines going down.

   3. MDMichael Davidson37:47

      Right, right, right.

   4. PAPeter Attia37:47

      Right? So they're four distinct lines, different slopes based on different... And therefore, given how tight those regressions are, it becomes very, uh, easy to predict what you're getting at, right?

   5. MDMichael Davidson38:01

      Mm-hmm.

   6. PAPeter Attia38:01

      And that's, that's wh- I just want to make sure the listener understands why it is that you're saying if you have a-

   7. MDMichael Davidson38:06

      Yes

   8. PAPeter Attia38:06

      ... 17% reduction in LDL-C from 60 to 49, you would expect an event reduction on a relative basis of 9% that's et cetera.

   9. MDMichael Davidson38:15

      Uh, yeah. It's a well-known, it's a-- The formula is, is easy. It's well, well-established. For a, um, one millimole, which is 38.8 milligrams per deciliter of LDL, you get a 22% relative risk reduction.

   10. PAPeter Attia38:31

       Yeah, and that's largely linear.

   11. MDMichael Davidson38:32

       It's linear, right.

   12. PAPeter Attia38:33

       Yep.

   13. MDMichael Davidson38:33

       It's absolute is the, is the key.

   14. PAPeter Attia38:35

       Yeah.

   15. MDMichael Davidson38:35

       Not, not, not percent.

   16. PAPeter Attia38:36

       Yep.

   17. MDMichael Davidson38:36

       You know, so you, you, you gotta look at the absolute LDL lowering, and then you can calculate the benefit. We, and, and we're doing that for our, obviously our outcome study. We, we can have a predicted benefit based on our absolute LDL lowering that we hope to achieve in, in our, in our, in our PREVAIL trial. You can then, you can power studies accordingly. You can see what the benefits. As long as you go long enough, too, that was the other key thing. The f- in the first year of treatment, you, you, you get, you get half the benefit at best. It takes time for the lines to separate.

   18. PAPeter Attia39:05

       Yeah. And that's what gets back to the other point you made earlier, which is all of these regressions are independent of how you do it. The Mendelian randomization says we're gonna lower it genetically, right?

   19. MDMichael Davidson39:17

       Correct.

   20. PAPeter Attia39:17

       It's the genetic lottery that determined your LDL versus mine. The primary and secondary prevention trials are based on a potpourri of drugs. Same with the epidemiologic stuff, which combines both genetic and drugs. So again, it speaks to this idea that reinforces the causality of LDL because independent of how it's lowered, you're getting the same effects. You'll often hear people say things like, "Well, you know, it's hard to deny that these drugs improve outcomes," but it must be something different than LDL lowering if you want to deny that LDL plays a role. They'll talk about pleiotropic effects of these drugs or things like that, but obviously, those arguments become a little bit silly in the, when you consider the totality of the evidence.

   21. MDMichael Davidson39:59

       Right, right. I've never been a pleiotropic. In fact, I was the one always debated that issue. Yeah, I've always been, it's LDL, it's, it's LDL. I mean, and, and you can-- Now I think the argument is stronger that there's nothing special about statins other than they're, you know, very effective and well-tolerated, but there's nothing special about the LDL lowering about statins that result in a greater benefit than any other LDL-lowering drug that can achieve the same,

8. 40:23 – 49:21

   Reviving obicetrapib at NewAmsterdam, and confirming the benefit is LDL lowering: the TULIP data, the abandoned statin-intolerance path, and the Mendelian randomization verdict on HDL

   1. MDMichael Davidson40:23

      uh, levels in a patient.

   2. PAPeter Attia40:25

      So with all of that as, um, as background, now let's talk about obicetrapib, the work that you and John did, how, you know, and the team of course, but, but let, let's just talk about how you decided it was worth, you know, going after this for a fifth time.

   3. MDMichael Davidson40:44

      Right. So, uh, so I had, I had sold my previous company an interleukin-6 antibody, uh, for heart disease, uh, inflammatory. It's a IL- I don't know if you're familiar with IL-6, but it's the, the key inflammatory cytokine, and that study's actually coming out this year. It's called the ZEUS trial. It's a big, big study coming up. So I, I had sold Corvidia, and John, uh, said, "Let's get, let's get obicetrapib, uh, back, you know, from Amgen." Uh, Amgen had put it on the shelf, uh, because Repatha, uh, had struggled on its launch, and they, they p- they deprioritized it, so they kind of had it sitting there ready to go into, you know, phase two, maybe ph- maybe even right into phase three potentially. So we, we, uh, teamed up together and started NewAmsterdam Pharma.

   4. PAPeter Attia41:34

      How many years ago was this?

   5. MDMichael Davidson41:35

      This is five, almost this is our sixth year now, so.

   6. PAPeter Attia41:39

      So-

   7. MDMichael Davidson41:39

      So

   8. PAPeter Attia41:39

      ... that's so interesting because Repatha launches in 2015.

   9. MDMichael Davidson41:45

      Right.

   10. PAPeter Attia41:46

       It-- They kept Obi on the shelf for five years?

   11. MDMichael Davidson41:49

       I think they bought it in 2017. They bought it in 2017.

   12. PAPeter Attia41:53

       Interesting.

   13. MDMichael Davidson41:54

       Yeah. But they did, they did, they did actually did a lot of great work on the manufacturing, the process. They made a much more f- they worked on the, the, made it much more cost-effective manufacture, but they didn't do any clinical trials. They just-

   14. PAPeter Attia42:05

       Yep

   15. MDMichael Davidson42:05

       ... kept it on the shelf.

   16. PAPeter Attia42:06

       And sorry, it already had an IND in the U.S., or this was all-

   17. MDMichael Davidson42:10

       It already had phase two data. We already-

   18. PAPeter Attia42:11

       In the U.S.?

   19. MDMichael Davidson42:12

       In the U.S., yeah.

   20. PAPeter Attia42:13

       Okay.

   21. MDMichael Davidson42:14

       It was ready to go. So we initially, um, you know, thought about, you know, statin intolerance and using it for those patients, uh, as a quick route to the market. Um, but we realized, you know, with the FDA view on, on CETP inhibition because of the history, we really didn't have a path there. Stat- the FDA does not like statin intolerance as an indication. They're, they're very- They're very wary of it even really it being a true thing, but believe it or not. I mean, we, you and I, I see it. I don't know if you... We all see it, but-

   22. PAPeter Attia42:44

       Sure

   23. MDMichael Davidson42:45

       ... but no, but, but the, the, in the academic world and in the FDA, it's, they don't really believe it is a true pheno- 'cause when we look at the placebo-controlled trials, it's, it's very low, you know, very low-

   24. PAPeter Attia42:57

       It's about 4.9%, isn't it?

   25. MDMichael Davidson42:58

       Yeah. But even true statin tolerance is very hard to find. I mean, it's, in the, in the trials. I mean, it's... But anyway, it, it exists. It exists. But anyway, that was our first, uh, path. Uh, however, once we met with the FDA and realized that we, we, we need to go, uh, into a full, a full boat, you know, LDL-lowering path, which is a much more larger program, and so, uh, and also we, we, we, we know we had to have outcome study, uh, at the time of the launch of the drug because of the history. We-

   26. PAPeter Attia43:30

       But what were the Phase 2 data that you had at the time of acquisition?

   27. MDMichael Davidson43:33

       We had a TULIP study, which was the, uh, done, sort of John had led, uh, in a predecessor company.

   28. PAPeter Attia43:38

       Yeah. Can you remind me and the listeners what that study-

   29. MDMichael Davidson43:41

       So it showed that-

   30. PAPeter Attia43:41

       Yeah
9. 49:21 – 56:07

   Phase 2 and phase 3 trials of obicetrapib—ROSE, BROOKLYN, BROADWAY, and TANDEM—and the PREVAIL outcomes trial, with the European and US approval paths

   1. PAPeter Attia49:21

      when John was on the podcast, again, I think it was four years ago-ish, but, um, you know, a lot has happened since then. So, so let's, let's talk about where we are today. Where, where are y- wh- you know, what is the state of understanding of obicetrapib? And let's start with cardiovascular because what John predicted at the time was this is gonna have benefits in cardiovascular disease, but it's going to have benefits in metabolic disease. It's gonna have benefits in Alzheimer's disease. So let's take them in, in that order. So let's start-

   2. MDMichael Davidson49:54

      Sure

   3. PAPeter Attia49:54

      ... with what is known today, uh, based on the, is the ROSE, uh, trial is the most recent?

   4. MDMichael Davidson50:01

      Well, no. BROADWAY-

   5. PAPeter Attia50:01

      BROADWAY is most recent

   6. MDMichael Davidson50:02

      ... was TANDEM, yeah.

   7. PAPeter Attia50:03

      Okay.

   8. MDMichael Davidson50:03

      Yeah, those are all-- So we've now done, um, you know, two more, you know, Phase 2 trials and, and three very large Phase 3 trials, and they're all been completed and were actually filed in Europe, you know, for approval. In the U.S., we're waiting to time it on the outcome study called PRE- So we started PREVAIL. So we had the, like, I hope the courage and the foresight to start our outcome study at the same time as our Phase 3 trial. So as a small company, we, we able to, th- knock on wood, even though we'd have the money to finish the trials, you know, start the trials, uh, get them completed, and then we raised money along the way to now we have plenty of cash to finish the trial, the PREVAIL trial. So we feel it really worked out well for us 'cause the, the, the success of the Phase 3 trials allowed us to fund the finishing the other trial, so it kinda timed it extremely well, you know, for, for our, our efforts. So, um, the, we r- had ROSE and ROSE 2, you know, both show the, uh, again, the forty-five to fifty percent, you know, monotherapy benefit and then, uh, in combination with ezetimibe were, you know, in that, you know, fifty-five percent ran higher, be- you know, be- better LDL lowering. So then we, um, we then did, you know, uh, the, what was called BROOKLYN, which is a familial hypercholesterolemia trial. I know you've done multiple podcasts on this, it's a g- autosomal dominant genetic disorder, you know, very high, uh, LDL. You know, showed a forty percent LDL lowering over a year, so it's a, a one-year study.

   9. PAPeter Attia51:31

      And tell me about those patients. They were already on-

   10. MDMichael Davidson51:34

       All, all, all on maximal, uh, almost all were on high-intensity statins. Many were on ezetimibe or PCSK9 inhibitors already. These were very well treated, but their LDLs were still too high.

   11. PAPeter Attia51:44

       How high on average?

   12. MDMichael Davidson51:45

       The average LDL is roughly around a hundred, something like that. So-

   13. PAPeter Attia51:48

       Okay. So in other words, the inclusion criteria is not limited to exactly which drug you're on. It's just that you're on maximum therapy and your LDL is still above a certain threshold.

   14. MDMichael Davidson51:57

       Right, right.

   15. PAPeter Attia51:58

       Okay.

   16. MDMichael Davidson51:58

       And, and so then we had did, um-

   17. PAPeter Attia52:00

       So sorry, adding-- So on the familial hypercholesterolemia patients, when you show up at a LDL-C of a hundred on whatever combi- combination you're on, obicetrapib lowered it by an additional-

   18. MDMichael Davidson52:12

       Forty percent

   19. PAPeter Attia52:13

       ... forty percent.

   20. MDMichael Davidson52:13

       Forty percent, yeah.

   21. PAPeter Attia52:14

       So lowered it from a hundred to sixty milligrams per deciliter on average.

   22. MDMichael Davidson52:16

       Approximately. That was, I think those, those are approximate numbers. About forty percent was the reduction at the end of twelve months versus placebo, versus placebo.

   23. PAPeter Attia52:25

       Yeah.

   24. MDMichael Davidson52:25

       Okay, then and then the, uh, the BROADWAY trial was our, our other-- These are all, um, atherosclerotic cardiovascular disease patients. Again, all on maximal statins, m- majority on high-intensity statins, like seventy percent were on f- you know, twenty or forty of rosuvastatin or forty or eighty of atorvastatin. They're all, are all very well treated. Uh, and we got, um, you know, roughly around a, a, around a thirty-five percent LDL lowering benefit, um, and then adjusting for placebo a li- a little bit less than that, but it was, it was around that percent change at twelve weeks and then it then continued for, for fifty-two weeks. Uh, and so that was our two pivotal phase three trials. And then, and then in combination with ezetimibe, we did another trial called TANDEM where the LDL lowering was, was, was very, very much fifty percent. So we c- we have a combo pill we're developing, uh, the two drugs together. But what's important about BROADWAY, though, that really helped us a lot was we showed in that study a, uh, a twenty-one percent reduction in, in major adverse cardiac events-

   25. PAPeter Attia53:30

       In one year?

   26. MDMichael Davidson53:30

       In one year. It was not statistically significant because this is a, you know-

   27. PAPeter Attia53:35

       Such a short-

   28. MDMichael Davidson53:35

       It's, it's twenty-five hundred patients but, but it was the right direction and it was pretty powerful. We-- If you look at, you know, kind of a landmark analysis, we divide, take the first six months away, it starts to become significant. So you c- and then remember, it takes time for these curves to separate. So we, um, uh, everyone got excited. Again, we're trying to obviously leverage that with, you know, with PREVAIL 'cause it's almost identical population in PREVAIL, which is ninety-five hundred patients, and it's a ASCVD, atherosclerotic cardiovascular disease population. LDL again, you know, in the higher end, we, that's, that's the key. You have to try to get higher LDL levels but not being too high where it becomes you get too much drop into therapies or you get unethic issues, ethical issues. So these are all on maximally tolerated statins. That's called PREVAIL and that study now is approaching, uh, we're, we're in the, in the year three of the study now and so we, we-

   29. PAPeter Attia54:31

       And this study will read out when?

   30. MDMichael Davidson54:33

       Well, we're, we're, we're, we have two f- two factors to stop the trial. One is that we have a minimum follow-up of two and a half years. Again, the learnings from the-
10. 56:07 – 1:04:41

    Discordance among LDL-C, LDL-P, and apoB with CETP inhibition, and obicetrapib's Lp(a)-lowering effect

    1. PAPeter Attia56:07

       So I went through the ROSE 2 trial the other day, and one of the things that I found interesting was the-- And we'll link to the study so folks can see it. But the LDL-C lowering, there was also an NMR for LDL-P lowering.

    2. MDMichael Davidson56:22

       Right.

    3. PAPeter Attia56:22

       And then there was ApoB, and there was quite a discordance between those. The ApoB lowering, I don't remember, was maybe 16%.

    4. MDMichael Davidson56:30

       Right, right.

    5. PAPeter Attia56:30

       But it was much more modest than the others. What do you think accounts for that?

    6. MDMichael Davidson56:34

       It's something we're looking at very carefully because I know a lot of our good friends, Tom, Alan, they're all ApoB. I'm more of an LDL-P person for a couple reasons. One, it's easier to get in our lab at the-

    7. PAPeter Attia56:50

       Really?

    8. MDMichael Davidson56:50

       Yeah, easier actually. ApoB is still pretty easy but-

    9. PAPeter Attia56:53

       I mean, I feel like ApoB is the easiest thing to order.

    10. MDMichael Davidson56:55

        Yeah, but LDL-P, but also LDL-P to me is more commonly discordant than ApoB. You can see it more easily because ApoB, LDL is 80, ApoB comes back 85. Is that really discord-- That kind of thing. You usually would typically have with LDL-P of LDL 70, LDL particles 1,500. It's very easy to see the discordance a lot easier.

    11. PAPeter Attia57:24

        Which assay did you use for NMR? This was the-

    12. MDMichael Davidson57:27

        This is the LipoScience.

    13. PAPeter Attia57:29

        LipoScience one.

    14. MDMichael Davidson57:29

        Yeah.

    15. PAPeter Attia57:29

        Which is owned by LabCorp now?

    16. MDMichael Davidson57:31

        It's owned by LabCorp, yes.

    17. PAPeter Attia57:32

        Yeah.

    18. MDMichael Davidson57:33

        But we just used the-

    19. PAPeter Attia57:33

        That's Jim Cromwell's old assay from back in the day.

    20. MDMichael Davidson57:34

        Right. Actually, we used the LipoScience, yes.

    21. PAPeter Attia57:37

        Yeah.

    22. MDMichael Davidson57:37

        That was the assay that we used.

    23. PAPeter Attia57:39

        Okay, so that is the most reliable one to my knowledge.

    24. MDMichael Davidson57:41

        Right, right. Exactly right. And so we're doing a lot of work confirming that. And Tom actually published a paper when LDL-P and ApoB are discordant, what is driving that? Which is not very common, but you do see it. And it is insulin resistance and a lot of small particles. You get discordance in ApoB and LDL-P. And then there's a study done at the C-

    25. PAPeter Attia58:06

        Sorry, you said ApoB and LDL-P. Did you mean ApoB and LDL-C?

    26. MDMichael Davidson58:10

        No, LDL-P when they're discordant.

    27. PAPeter Attia58:12

        Oh.

    28. MDMichael Davidson58:12

        In other words, when ApoB is not high and LDL-P is high, what explains that? What is the reason why you have-

    29. PAPeter Attia58:20

        Got it

    30. MDMichael Davidson58:21

        ... a normal ApoB and a very high LDL-P?
11. 1:04:41 – 1:12:03

    Where obicetrapib fits in the lipid-lowering toolkit, the case against high-dose statins, and the problem of drug pricing

    1. PAPeter Attia1:04:42

       So from a purely cardiovascular standpoint, how do you see obicetrapib being used should the, um, outcome trial end in the fashion that you would expect? Where do you, where do you think it fits into the current, um, you know, toolkit we have with respect to pharmacologically lowering LDL?

    2. MDMichael Davidson1:05:02

       I want to say, again, your, your, your question is the right way to frame it. We, we have to have a positive PREVAIL trial, and we have to show the benefits of the drug on top of statins. However, when you think about, you know, what statins do well and what they don't do so well, so statins lower LDL, and they're well-tolerated, and they, and they, uh, um, reduce cardiovascular events, and they're generic, and they're, they're, they're very easy to prescribe.

    3. PAPeter Attia1:05:26

       Super cheap. Yep.

    4. MDMichael Davidson1:05:27

       Yeah, right. So that's all the good things. What do statins not do so well? It, it raises the risk of diabetes slightly. Um, it raises the Lp (a) and it, and it lower, it does not lower small particles very well. It lowers mostly the, the non-small particles. What does obicetrapib do well? It lowers the risk of diabetes based on our, our BROADWAY trial data, as well as other CETP inhibitors. It lowers Lp (a) in that 50% range, in that m-moderate band, and it, um, and it, and it, and it, it lowers, yeah, I mentioned that and it, and it lowers the risk of diabetes, lowers Lp (a) and lowers the small particles by 90%. And so it would be a great companion drug to statins. And so we b- we believe it becomes the go-to drug after statins for those reasons. It makes the, it makes the, the statin liability issues, it m-mostly go away, and it, it really is a good companion drug to a statin for that reason. Now we have the combo pill with ezetimibe, which puts us in the same range as the PCSK9 inhibitors or, or the, or even the n-upcoming oral PCSK9 inhibitor.

    5. PAPeter Attia1:06:33

       There, there is another issue, John, with statins that I don't think gets enough attention because I realize it hasn't demonstrated a clinical, um, harm, but there's something that always, and, and I guess we just out of an abundance of caution pay attention to it, which is it, it can have a pretty significant impact on transaminases-

    6. MDMichael Davidson1:06:55

       Mm-hmm

    7. PAPeter Attia1:06:55

       ... especially when combined with ezetimibe. Um, and we see that. I honestly, I think we see that far more than it's re-reported in the literature.

    8. MDMichael Davidson1:07:02

       Mm-hmm.

    9. PAPeter Attia1:07:04

       I understand what the guidance says. The guidance says if the AST and the ALT rise by less than 3X, you can ignore it. It's not clinically significant. But that means you're going to be tolerating patients on, you know, Crestor and Zetia walking around with AST and ALT of 80.

    10. MDMichael Davidson1:07:20

        Right, right.

    11. PAPeter Attia1:07:21

        And the reality of it is I just have a hard time believing that that's, that that makes sense. Uh, what, what's your view on that? Do you think I'm just being too, do you think I'm being too much of a Puritan?

    12. MDMichael Davidson1:07:30

        Not really. I, I kind of feel the same way. You know, y- I'm a first do no harm kind of guy. I mean, but I do, do bring up a, you bring up a, a very big point for me cl- and I'm, in my clinical practices. I don't like high-dose statins. I don't like 80 milligrams of atorvastatin in particular. I don't like 40 milligrams of rosuvastatin. Um, I don't wa- want-

    13. PAPeter Attia1:07:48

        Have you seen Tom Dayspring put out a beautiful figure from the-- Like he, he, it's one of like-

    14. MDMichael Davidson1:07:52

        Yeah

    15. PAPeter Attia1:07:52

        ... your classic Tom figures that he pulled out of all the literature, and it shows the dose response of every statin.

    16. MDMichael Davidson1:07:58

        Right.

    17. PAPeter Attia1:07:58

        And we now show it to our patients, especially those that come in on high-dose statins, and it's, I'm sure it demonstrates exactly what you're about to say, which is you're getting virtually all the bang for your buck at that lowest dose, and that curve is so concave down that it's almost unjustifiable to be on a statin above 50% of its max dose.

    18. MDMichael Davidson1:08:19

        Yeah, I mean, it's like the number needed to harm versus the number needed to treat benefit is just not, not desirable, you know, from when you think about a high-- So I don't, I d- I try to cut the statin. Patients, by the way, they, they don't want high-dose statins either. So I, I think the whole, uh, the whole high-dose statin kind of guideline paradigm sh- is, is off. It d- d- it doesn't work and-

    19. PAPeter Attia1:08:37

        Well, and, and, and in defense of it, look, I, I, I want to be charitable to everybody. It made sense 25 years ago, 'cause 25 years ago you didn't have Repatha, you didn't have Praluent, you didn't have ezetimibe, you didn't have bempedoic acid, you didn't have C- you had nothing.

    20. MDMichael Davidson1:08:52

        Right.

    21. PAPeter Attia1:08:53

        So, so if you, you know, this was your, this was your drug.

    22. MDMichael Davidson1:08:55

        And we, and we didn't have evidence of benefit either on top of these drugs, and so that now we have many studies showing the benefits. So I think we, uh, and you can see the, the, the, the tide is turning. People are now advocating, uh, guideline. Europe is already on board with more combo therapy early-

    23. PAPeter Attia1:09:10

        Yep

    24. MDMichael Davidson1:09:11

        ... just to get combo therapy. So I think obicetrapib then becomes, in my view, you know, b- based on our data, should become the next go-to drug, and if you need even more potent, you can add the ezetimibe combo pill. So we believe that with obi alone and obi with ezetimibe, 90% of patients are done with their lipid treatment, and so that's how we think. And that, and that, for primary care doctors, that's what they're looking for. They're, they're looking for something they can just add to a statin, and then they can call it a day.

    25. PAPeter Attia1:09:40

        Why-- E- explain something to me. Um, so if you go and buy branded Zetia today, it's not that expensive. If you go and buy branded Nexletol, I mean, it's as-

    26. MDMichael Davidson1:09:54

        Yeah

    27. PAPeter Attia1:09:54

        ... expensive as an injectable-

    28. MDMichael Davidson1:09:56

        Right

    29. PAPeter Attia1:09:56

        ... monoclonal antibody.

    30. MDMichael Davidson1:09:57

        Yes.
12. 1:12:03 – 1:17:12

    The case for obicetrapib in Alzheimer's: the APOE4 and CETP genetics, the animal models, and funding Alzheimer's research

    1. PAPeter Attia1:12:04

       John predicted we are going to see big effects on metabolic disease.

    2. MDMichael Davidson1:12:08

       Right.

    3. PAPeter Attia1:12:09

       Okay, that was an easy prediction to make, right, based on everything you'd seen before it. But the other prediction he made was even more intriguing to me, which is it might be, and I'm paraphrasing, but something to the effect, it might be that the most impressive thing about this drug is its effect on Alzheimer's disease.

    4. MDMichael Davidson1:12:27

       Right.

    5. PAPeter Attia1:12:27

       So tell me what it is that made you and John feel that way four or five years ago, and have you been validated in your predictions?

    6. MDMichael Davidson1:12:37

       Sure. Yeah, really, it's a, it's very exciting for me to talk about it 'cause that was one of, when I came to New Amsterdam with John, you know, Jo- you know, John said, uh, you know, "Michael, I wanna hear your story about Alzheimer's." And I said, "Let, let me go through it with you." 'Cause we had, what we had at the time was a, um, a Mendelian randomization. We had the, the famous, you know, Bronx aging study where people who, uh, 400 Ashkenazi Jews Uh, over close to 100 or older, uh, had, uh, they found out what was the most common gene, and that was CTP loss of function. So they had a CTP, and they had less-- Then later came the data showing that if you have ApoE4 and you have the CTP loss of function, your, your, your risk of Alzheimer's is significantly mitigated. So we had genomics validation.

    7. PAPeter Attia1:13:31

       What was the phenotype lipid-wise of those patients?

    8. MDMichael Davidson1:13:33

       Well, they have high HDL.

    9. PAPeter Attia1:13:36

       I see. So these are, these are ApoE4 patients who phenotypically have very favorable lipid profiles, but until you do the genetics, you wouldn't know it's-

    10. MDMichael Davidson1:13:45

        Right

    11. PAPeter Attia1:13:46

        ... due to-

    12. MDMichael Davidson1:13:47

        And they have very low small LDL, and they have very high large LDL particles. I mean, it's just what CTP inhibition does.

    13. PAPeter Attia1:13:54

        Got it. Michael, what was the degree of risk reduction in those ApoE4 patients?

    14. MDMichael Davidson1:13:59

        Well, you look at the curves, it, it basically took the E4 risk away. That was, you know, again, this is one study. Um, and so they basically became the, the risk of a non-E4 by having the CTP loss of function.

    15. PAPeter Attia1:14:13

        Wow.

    16. MDMichael Davidson1:14:13

        So that's a po-profound benefit. Uh, and, um, so that's one. And then it's been validated by other, other genomic studies since then. The, the, the, we've done a lot of work ourselves on the-- But also in Canada, at McGill, a, a PhD researcher had done some really great work on CTP. So you remember, the mouse does not have CTP. When you give the mouse the, uh, amyloid precursor protein gene, they get, they get amyloid and, and dementia.

    17. PAPeter Attia1:14:43

        Devastating.

    18. MDMichael Davidson1:14:44

        And then when you give them the CTP gene with it, it gets a lot worse. It gets a lot worse. Uh, and then if you give the, the mouse a CTP inhibitor, you improve the dementia in that animal model. So they, then they do nesting. They, yeah, so.

    19. PAPeter Attia1:15:00

        Wait, wait, I'm a bit confused. You're saying you take a mouse that doesn't have CTEP-

    20. MDMichael Davidson1:15:05

        CTEP, and you give it CTEP.

    21. PAPeter Attia1:15:07

        And you give it a CTEP inhibitor?

    22. MDMichael Davidson1:15:09

        Right.

    23. PAPeter Attia1:15:09

        Why would that change anything if they don't have it in the first place?

    24. MDMichael Davidson1:15:12

        No, but you, you gave them the CTP g-- You gave them CTP.

    25. PAPeter Attia1:15:15

        Ah, oh, got it. Okay.

    26. MDMichael Davidson1:15:16

        You gave the mouse the CTP gene.

    27. PAPeter Attia1:15:18

        Yep. Then you, then you block it.

    28. MDMichael Davidson1:15:19

        Basically. Giving CTP, first of all, made it, made the dementia-

    29. PAPeter Attia1:15:22

        Yes, understood. Yep

    30. MDMichael Davidson1:15:22

        ... worse, and then you give it a block, uh, CTE inhibitor, it blocked it. So we had, we had that data. So I, when I started with John, I said, "John, can we study Alzheimer's?" And we went to our investors, and they said, "Yes, you can have a slight amount of money to, to look it up." 'Cause unfortunately, uh, in the biotech world, Alzheimer's does not, uh, it's a big, a huge graveyard.
13. 1:17:12 – 1:29:11

    Brain cholesterol metabolism and the APOE4 mechanism: the blood-brain barrier, astrocyte cholesterol efflux, the amyloid-tau cascade, the role of HDL, and why statins don't cause Alzheimer's disease

    1. MDMichael Davidson1:17:12

       lipid gene.

    2. PAPeter Attia1:17:13

       Yeah.

    3. MDMichael Davidson1:17:13

       And so-

    4. PAPeter Attia1:17:13

       Yeah, that's a, that's a fair point, actually. Let's back up a little bit and-

    5. MDMichael Davidson1:17:16

       Let's back up and talk about what about ApoE4 is, is detrimental. I mean, that, that's the key, 'cause when, when you talk about where does obicetrapib fit in, we, you know, we have the, we have the, the LPLA, we have the, the diabetes benefit, the small particles. But also, the fourth leg of that is for ApoE4, you, you also have high LDL as well and, and lower HDL. So it becomes a, uh, another good drug to consider, you know, for your Apo. That's 25% of the population. So you can see where obicetrapib becomes a really good add-on to statin option if you have any of those characteristics, yeah.

    6. PAPeter Attia1:17:52

       Let's talk about the homozygous E4 patient. So what is happening in their brain as a result of the homozygosity? Those, those, that-- Because again, it's a, it's a very subtle change in their ApoE protein due to that, uh, that gene, and how does it manifest itself in the brain cholesterol metabolism wise?

    7. MDMichael Davidson1:18:15

       Right, right. So yeah, it's very complicated and, and, and everything I'm saying is, is, is still, you know, there's still a lot of gaps in our knowledge about, you know, what exactly happens with ApoE4. But the brain, first of all, the brain is a very cholesterol-rich organ. Um, if you look at, like, don't hold me to exact numbers, but, you know, 2% of the dry weight of the brain is, is, represents 50% of your body cholesterol. And so you have tremendous amount of cholesterol in the brain and, um, and then you have a lot of fat, you know, mostly, you know, DHA, a lot. So fat and cholesterol make up a big, big part of the brain, uh, m- uh, mass. I mean, it's a big, big part of what the brain is all about. And, uh, and cholesterol is synthesized very avidly by the, the neurons during your childhood growth phase, and then aft-after you become adult, the neurons stop making cholesterol and, and, and myelin, by the way, is, is, is 50% cholesterol. So a lot, a lot of cholesterol goes into making myelin, and then astrocytes are involved in making, they continue to make cholesterol and they're there to help kind of repair neurons and also they're like the neurons are the wiring and make the thinking and all that stuff that brain function does. But the astrocytes are involved in the nourishment and the garbage collection, all that stuff that are involved in maintaining normal brain homeostasis. Now, the complicating thing is the blood-brain barrier completely separates off the brain lipid metabolism from the rest of the body. There's no ApoB in the brain. There's no ApoB. It's all ApoE and HDL in the brain. There's no connection between LDL in the plasma and LDL. There's no LDL in the brain. And so the brain has its own cholesterol metabolism homeostasis. And the particles, the lipoproteins in the brain are HDL-like particles that have ApoE. And so ApoE, in fact, if you do a liver transplant and you're ApoE4 before the donor and you give somebody an ApoE3 liver, they still have ApoE4 in the brain. There's no, the brain stays whatever. There's no connection.

    8. PAPeter Attia1:20:46

       I had never even thought of that, Michael.

    9. MDMichael Davidson1:20:48

       Yeah. So that's the connection. So there's no-

    10. PAPeter Attia1:20:50

        Do you think there's any clinical significance to that in organ transplant?

    11. MDMichael Davidson1:20:54

        Well, in other words, if you can't... So the question is, with gene therapy now, if you could convert someone from an E4 to an E3, can you do it in the liver and correct the risk for... We don't think so.

    12. PAPeter Attia1:21:09

        We don't think so.

    13. MDMichael Davidson1:21:11

        That's where we don't know. It's still a thought, I think.

    14. PAPeter Attia1:21:14

        That's super interesting.

    15. MDMichael Davidson1:21:15

        Yeah. So ApoE4, which is basically there's a two, three, and four. Most people are three threes. There's about 20, 25% are three fours and then about 2%, so 3% are homozygote E4s. So E4s, you're homozygote about 10 times risk of Alzheimer's. The three fours about three times risk. Three threes are average. And then if you're a two, which is the best, your risk is lower and you have longevity. So it's one of the best longevity genes to be an ApoE2. So that's the breakdown. So when you have ApoE4, what happens, so ApoE is made by the astrocytes and it appears that they have impaired cholesterol efflux and lipidation when you have ApoE4. And so the neurons don't get the same nourishment or they can't clear cholesterol, it becomes toxic. And once cholesterol becomes toxic, it can be something called 24-hydroxycholesterol, which can go through the blood-brain barrier, 24-7, another cholesterol. So the blood-brain barrier, it protects all that. But there's one cholesterol that goes through, it's 24-hydroxy or 27-hydroxy. They can transverse the blood-brain barrier. So the ApoE4 patients have impaired clearance of cholesterol and then that sets up a toxic situation where it gets inflammatory and then amyloid and tau follow. And so when Alois Alzheimer's first described Alzheimer's, it was amyloid plaques, tau tangles, and basically lipid deposits. And so when you have ApoE4, you can't clear the lipid as well and that sets up the whole Alzheimer's cascade and then they get Alzheimer's roughly, one four gives you Alzheimer's about 10 years earlier and then two fours 20 years earlier, that kind of thing. So it's a very well-established risk having the ApoE4 genotype. So that's the background about ApoE4 and it's a lipid gene and what is important about obacetrapib is that we had that genomic data, we had the animal data, and then we know that HDL is the one lipoprotein that does interface with the brain. We're not positive, we don't think ApoA1 is actually made in the brain. This comes from the periphery, ApoA1 being the protein carrier of HDL.

    16. PAPeter Attia1:24:03

        Yeah, I thought it was made in the liver. You're saying if the brain's ApoA1 is made in the brain or made in the liver.

    17. MDMichael Davidson1:24:09

        Most of it we believe comes from HDL from the plasma, not from the-

    18. PAPeter Attia1:24:16

        Not from the brain, yeah.

    19. MDMichael Davidson1:24:18

        It may be made in the brain, but we don't think so. We think it's made and comes across the blood-brain barrier. And so we know that for sure in the choroidal plexus, which is the blood-brain barrier interface that HDL-

    20. PAPeter Attia1:24:30

        And this is just mechanical.

    21. MDMichael Davidson1:24:32

        Yeah.

    22. PAPeter Attia1:24:32

        It's because HDLs are so much smaller than LDLs.

    23. MDMichael Davidson1:24:34

        Right, small HDLs. But SRB1, which is the receptor for, we talked about that, is heavily in the blood-brain barrier and the choroidal plexus. So the only thing that really interfaces with the brain from the outside of the brain is HDL. And so having high HDL can help remove the excess cholesterol that ApoE4s can't metabolize effectively. And also we prove this, it delivers antioxidants to the brain, very important in reducing inflammatory response. So we know that, and also maybe DHA even can be delivered by HDL. But certainly it's acting like it does. It's the removal system, amyloid even. Amyloid can be removed by HDL. So we believe that the HDL going up and interfacing with the brain can help mitigate the ApoE4 related uh, Alzheimer’s risk and that’s, that’s what we-

    24. PAPeter Attia1:25:32

        What about in the non-4s? Do we have any insight?

    25. MDMichael Davidson1:25:34

        We, we think, we think it’s the same true. I mean, even obviously non-4s get Alzheimer’s.

    26. PAPeter Attia1:25:38

        Yeah.

    27. MDMichael Davidson1:25:38

        And so, but it, it’s later. It’s, it’s later in life. It’s late 80s or 90s instead of, instead of 70s, you know, 60s or 70s even. So it, it, it, it’s, um, we think of the same things are happening, you know, the, the, you, 'cause you, again, if you stop, you stop making cholesterol in the neurons, you, you, your neurons are dependent on, on astrocyte cholesterol function and, and, and so forth. And, and as you get older, you know, these things, you know, tend to get less effective. So we think that, that, that part, you know, we think could also be mitigated by, by raising HDL through obacetrapib’s, uh, uh, mechanism of action.

    28. PAPeter Attia1:26:15

        And what do you say to folks who say, "Well, aren’t statins causing Alzheimer’s disease?" Because if the brain's cholesterol depot is the most important cholesterol depot in the entire body, and we give a person a statin, and we know that some statins can actually cross the blood-brain barrier, shouldn't statins, even though the clinical trials would suggest the opposite, like just on an individual basis, is there some risk that statins would be driving Alzheimer's disease?

    29. MDMichael Davidson1:26:41

        Well, we, I mean, just the opposite actually. I mean, the, the, the thing is it, we think that-

    30. PAPeter Attia1:26:45

        Yeah, I guess my question, sorry, should be why do we not see that? Why do we see the opposite in the clinical trials?
14. 1:29:11 – 1:41:33

    The biomarker evidence: the CSF pilot study, Alzheimer's as a disease of middle age, the pharma graveyard problem, and the p-tau 217 results from BROADWAY

    1. MDMichael Davidson1:29:11

       Alzheimer's.

    2. PAPeter Attia1:29:12

       So let's talk a little bit about what you saw in your biomarkers to kind of validate all of these hypotheses.

    3. MDMichael Davidson1:29:19

       Sure. So we in, so we got the first study that was a pilot study, uh, showed that we did in fact reduce, um, 24-hydroxy and 24/7, the, the, the, the sterols in the b- in the CSF went down. Do not see that w- you're not seeing that with statins, so it was a difference. I mean-

    4. PAPeter Attia1:29:35

       And sorry, how did you, did you happen to do-

    5. MDMichael Davidson1:29:37

       By CSF.

    6. PAPeter Attia1:29:37

       You had to do CSF, okay.

    7. MDMichael Davidson1:29:38

       Right. We measured CSF in these patients, and we saw that the 24 and 27-hydroxy went down. We saw stabilization of, of, um, of biomarkers, and we saw, uh, cognition stable. It was, we also saw, had, had a few anecdotal, uh, cases of patients really having quite a beneficial effect on cognition. But it was, it was a pilot study, you know, it was not powered, open label. But we saw target engagement with 24 and 27-hydroxy going down. We also in a, in another analysis showed o- antioxidants in the CSF going up. So we, we believe we had target engagement, that we are in fact removing these, these potentially toxic sterols and improving antioxidant levels, uh, in the CSF. So that's a, um, that was the proof of concept study that we did.

    8. PAPeter Attia1:30:27

       And sorry, what, tell me about those patients. Did you say those had MCI?

    9. MDMichael Davidson1:30:30

       MCI. All had MCI, yeah.

    10. PAPeter Attia1:30:31

        And just explain to folks clinically how patients with MCI would be behaving.

    11. MDMichael Davidson1:30:36

        So they, they have, um, uh, they, they do a cognitive testing, and so they, and they, and they have, uh, there's all different types of scoring systems. But when you do the memory testing and functional testing, uh, they, they, they score showing they have impairment. Um, but what's important about Alzheimer's and why we're focusing on it is that, um, what we're learning now, the, the, the abnormality starts like 20 years before there's even MCI. There's a long lag period between, uh, when we start seeing the pathology, the amyloid and the tau and all the biomarkers going up and, and actual MCI. And MCI, of course, then has different levels until you get to the functional impairment where you're now, you know, y- it's not just, uh, this, this is actually subjective cognitive impairment where people think Uh, they have impairment, but when they do the testing, they're, they're pretty-- they're, they're still pretty okay, and then you have those that are truly-

    12. PAPeter Attia1:31:35

        Yeah

    13. MDMichael Davidson1:31:35

        ... um, cognitively impaired. Yeah, so.

    14. PAPeter Attia1:31:37

        So just so folks understand what we're talking about here, which is, um, Alzheimer's is not a disease of old age. It's a disease of middle age that presents in old age, and that's exactly what you just said in a different way. Um, so I, I mean, that's in some ways a frightening thing to think about, but it's, it's just the reality of the disease, and it also speaks to the lens through which we wanna consider prevention. Um, I would argue the same is true of cardiovascular disease. It's a disease not-- It's a disease of middle age.

    15. MDMichael Davidson1:32:05

        Right.

    16. PAPeter Attia1:32:05

        It presents in old age for most people. Unfortunately, for someone like your father, it presented in middle age. But, um, it starts effectively the moment you've got these LDL particles circulating. And so, um, what would you say is the canary in the coal mine? Would you say it is the-- th-that is measurable? I, I should clarify that.

    17. MDMichael Davidson1:32:26

        Right.

    18. PAPeter Attia1:32:26

        Would you say that it is the presence of, of p-tau?

    19. MDMichael Davidson1:32:29

        Yep.

    20. PAPeter Attia1:32:30

        Okay.

    21. MDMichael Davidson1:32:31

        That's what's exciting about the field right now in, in my-- The w-- I, like I said, I came from the LDL kind of world. You know, LDL became a great, uh, causal pre-- We've, we-- Well, I, I was, uh, when I was involved, they weren't even sure LDL was really treatable, you know, when I started. I mean, they weren't even sure that you could reduce LDL and prevent heart disease. So that, we're talking about in the-

    22. PAPeter Attia1:32:51

        Yeah. That's remarkable

    23. MDMichael Davidson1:32:52

        ... in the eight-- in the, in the, in the '80s. Yeah, I mean, so, so then for-- And then, uh, I mentioned already, once you already have heart failure, you can't really-- Lowering LDL doesn't seem to matter anymore. So the-- I think, and with Alzheimer's, I think we're seeing the same thing. Once you have MCI and once you already have functional impairment, it's already too late. The brain is already, uh, had, has shrunk, and you got neurodegeneration. And so I think we're way too late in how do we treat Alzheimer's, so if we can find a prevention therapy-

    24. PAPeter Attia1:33:20

        And do you think that's why your statement earlier about how much this is a graveyard for pharma is basically the case? Which is, on the one hand, it's very difficult to develop drugs for primary prevention 'cause the trials would take too long, so you have to treat an active disease. But in this particular disease, if you treat the disease as dementia, you're hosed. It's almost like had cardiologists had the misfortune of trying to use lipid-lowering therapy to treat heart failure, we may never have developed lipid-lowering drugs.

    25. MDMichael Davidson1:33:55

        That's right. In fact, if, if they would've started with heart failure, it would've all been failures, frankly. We, we did heart failure trials, and it didn't work. I mean, so with statins, for example.

    26. PAPeter Attia1:34:02

        Yeah. So that's kind of the interesting thing, isn't it? Right? Which is with Alzheimer's disease, we don't have the equivalent of the MI.

    27. MDMichael Davidson1:34:08

        Right.

    28. PAPeter Attia1:34:08

        The survivable MI where if you intervene from a secondary prevention standpoint, we can develop those things because all of those tools that were developed for secondary prevention can now be deployed for primary prevention and have the maximum impact on saving lives.

    29. MDMichael Davidson1:34:22

        Right.

    30. PAPeter Attia1:34:23

        And yeah, so it's a very unfortunate consequence of the pathology, though an understandable mistake on the part of pharma because that's the-
15. 1:41:33 – 1:50:32

    Whether obicetrapib translates into clinical benefit for Alzheimer’s disease: the risk of fooling yourself, the persistence of the amyloid dogma, ARIA in APOE4 homozygotes, and the next prevention trial

    1. MDMichael Davidson1:41:33

       Alzheimer's disease.

    2. PAPeter Attia1:41:34

       Now how do we know how to interpret whether those will end up being cl-- I mean, maybe the answer is we don't. But, um, do we have a sense of if this could translate to a clinically meaningful benefit, to a reversal of disease, a halting of disease, something of that effect? Or is it your belief that that could probably only happen if we establish causality through trials like this, and then take the same playbook that we took with cardiovascular disease, which is move up twenty years, start treating before any of these things are even remotely present, and just, you know, hope that that alone prevents even the development of the pathology?

    3. MDMichael Davidson1:42:12

       Yeah. It's a really great question because the answer is I don't know. W-we're hoping that the field is evolving, and we, and the regulators have to help out here because right now p-tau two seventeen cannot be a, a, an endpoint for regulatory approval. It, it does require, you know, improvement in cognition, uh, which, which might be an impossible thing to show, uh, unless you st-- Like we, we-

    4. PAPeter Attia1:42:36

       Unless you took for decade, you know, a decade or-

    5. MDMichael Davidson1:42:37

       So but what we're, what we, what we can say is that for us, you know, we're, we're gonna, we're gonna, we're gonna go ahead with another study. Uh, we do, we do know that, um, the APOE4 community, you know, the, there's a, there's a new alliance of patients out there that are advocating for, you know, for, uh, treatment. It's like any genetic disorder. There's, you know, there's, there's, um, they don't, they wo- they don't wanna wait ten years. They want something now, uh, for, for treatment. Uh-

    6. PAPeter Attia1:43:06

       But don't you think it'll just be used off-label for that reason anyway?

    7. MDMichael Davidson1:43:09

       Well, we, we, we u- we can't, you know, we can't unfortunately, um-

    8. PAPeter Attia1:43:13

       I mean, you, you have nothing to do with that, but I'm just saying like the-- Look, people were using PCSK9 inhibitors off-label for Lp (a) reduction the moment it became clear that it was lowering Lp (a) , you know, twenty to thirty percent. Now we have no idea if lowering it twenty to thirty percent mattered, but, but it seems that it's not unheard of for people to take off-target use. There are plenty of people using GLP-1 agonists today for neuroprotection, even though that would still be considered sort of off-label as well.

    9. MDMichael Davidson1:43:39

       Yeah. I mean, uh, uh, unfortunately, I can't talk about that as a CEO of a biotech company about-

    10. PAPeter Attia1:43:44

        Yeah

    11. MDMichael Davidson1:43:44

        ... off-label, off-label use. But I think the, um, the th- the key is that I think p-tau 217, with enough, um, advocacy, you know, can become a regulatory endpoint, um, for this reason. I mean, it's so good. I mean, it's such a good endpoint.

    12. PAPeter Attia1:44:00

        But let's take the flip side of that, the, you know, the, the Feynman argument that in science, the easiest person to fool is yourself.

    13. MDMichael Davidson1:44:06

        Yeah.

    14. PAPeter Attia1:44:07

        And-- or the goal of science is not to fool yourself-

    15. MDMichael Davidson1:44:09

        Right

    16. PAPeter Attia1:44:09

        ... and you're the easiest person to fool. So what would be the flip side argument? If-- What would be the, the case for p-tau ultimately does not translate to clinical benefit? What would be true if that were-- If we, if we had a crystal ball that showed us that, what would you sit here and say today as to why? What would the explanation be?

    17. MDMichael Davidson1:44:28

        Well, the, the-- Like you said, I, like you ha- you have a-- You're proving a biomarker, but you're not treating the underlying disease. You know, that-

    18. PAPeter Attia1:44:34

        Yeah

    19. MDMichael Davidson1:44:34

        ... would be the-- But, but it is the disease. I mean, that's, it's pta- It's the actual tau that's in the brain that leaks out into the plasma. So it is a me- If you're, if we're using these anti-amyloid antibodies or, or now they're working on anti-tau antibodies to, uh, and they're still got a ways to go. Uh, obviously, those anti-amyloid antibodies, um, you know, have some very modest benefit, but not for APOE4 homozygotes. So I do feel that, um, the homozygotes in particular, which are the ones that we know 100% go on to get Alzheimer's if they live long enough, we, we should hope that we could get, like even-- Like a lot of other rare diseases allow these surrogates, uh, to get approval, you know, based on a s- on a surrogate that which may or may not translate to a, a clinical benefit.

    20. PAPeter Attia1:45:19

        Yeah, I'm thinking less of it from a regulatory question and more just from a, a biologic question of it's easy to get fooled, right? I mean, we're all-

    21. MDMichael Davidson1:45:30

        Yeah

    22. PAPeter Attia1:45:30

        ... we can all be fooled. I mean, HDL fooled everybody for decades, right?

    23. MDMichael Davidson1:45:36

        Yeah.

    24. PAPeter Attia1:45:36

        For decades, people were chasing the wrong thing, and they had all the epidemiology to back it up. Um, but at the end of the day, it didn't matter. And so I just, I just-- I'm, I'm not saying this is the case. I'm not even suggesting that it looks likely that that's the case, and I certainly hope it's not the case. But I always find it interesting to imagine if we're sitting here in twenty years having a podcast talking about, "Oh, that whole p-tau thing that took us down a rabbit hole."

    25. MDMichael Davidson1:46:04

        Yeah.

    26. PAPeter Attia1:46:04

        "What a waste of time and money that was. We didn't save a single life," I wonder what the story would be. What would be-

    27. MDMichael Davidson1:46:09

        Right

    28. PAPeter Attia1:46:09

        ... the revisionist explanation of that?

    29. MDMichael Davidson1:46:11

        Here's what I'm also saying. In the last few months, there's been some supportive data that came out that's helpful. One, one is the GLP-1 trials, the, uh, Evoke and Evoke Plus, and no improvement in cognition, no effect on p-tau 217. On the other hand, the trailblazer anti-amyloid trials with Lilly showed a, a, a pretty high, a high correlation between improvement in cognition and p-tau 217 going down. So we ha- We're getting more data, and we're gonna do our own study. We are gonna do a study, uh, with three hundred patients that have, um, pre-Alzheimer's, you wanna call it. You know, not-- They have evidence of higher tau levels based on their APOE.

    30. PAPeter Attia1:46:51

        With MCI?
16. 1:50:32 – 1:57:50

    Fish oil, EPA, and DHA: the cardiovascular trials and the challenge of delivering DHA to the brain

    1. PAPeter Attia1:50:32

       Yeah, there's so much more we could talk about on this. But I do want to spend time on a topic that we talk about from time to time, but I have a feeling you're going to add a lot of value to my somewhat limited knowledge, which is the most up-to-date thinking on the role of fish oils, DHA and EPA. You want to talk about it through cardiovascular disease first or talk about it through-

    2. MDMichael Davidson1:50:57

       Alzheimer's?

    3. PAPeter Attia1:50:57

       Alzheimer's or both or however you want to talk about it.

    4. MDMichael Davidson1:50:59

       I think the cardiovascular part, well, I'll get that. I think a quick answer to that, because I was involved in developing omega-3 for heart disease called Epanova. We went to an outcome study and it didn't work, but it was DHA and EPA, but mostly EPA had some DHA.

    5. PAPeter Attia1:51:17

       And that was four grams? How much?

    6. MDMichael Davidson1:51:19

       That was four grams, yeah.

    7. PAPeter Attia1:51:20

       Yeah.

    8. MDMichael Davidson1:51:20

       It was called the STRENGTH trial. I think what I learned, because I'm always a big advocate for omega-3s for triglyceride lowering. But there's really two reasons why omega-3s can reduce risk. One is triglyceride lowering and the other is by antithrombotic effects. EPA antagonizes the arachidonic acid pathway and has like a antithrombotic effect, anti-inflammatory effect. And so there was really two reasons to think why omega-3s could lower risk. And one was through the EPA antithrombotic effect. The other is triglyceride lowering. And so what STRENGTH was set up to do was really a triglyceride lowering trial and it didn't work overall. There was a hint of benefit in the secondary prevention arm. It was 50-50 primary. And so if I had to do it all over again, I would have made it all secondary, just like mostly the REDUCE-IT trial was, which is the EPA only trial. So the REDUCE-IT trial showed a benefit and it could have been, it likely had some effects of the mineral oil placebo kind of tilting it a little bit.

    9. PAPeter Attia1:52:26

       Yeah, say more. I've heard this explanation before, but say a little bit more about why mineral oil as a placebo could have been harmful.

    10. MDMichael Davidson1:52:32

        But he'd actually looked at the inflammatory signaling and it increased inflammation. And so it had some inflammatory. Paul Ridker helped now analyze that from the REDUCE-IT study. It also may have affected absorption of statins because the LDL levels went up. The LDLs level went up about 10%, so 9 to 10%. But nevertheless, I think it showed that EPA works. EPA works. It may not have been the 25% that people think it was, but it still worked. You take all that away, it still worked. EPA only worked. And then the STRENGTH trial didn't work overall. It may have worked more on the second. It may have worked on secondary prevention in a post, not post-hoc, but in that population.

    11. PAPeter Attia1:53:15

        And the placebo in STRENGTH was what?

    12. MDMichael Davidson1:53:17

        Was corn oil.

    13. PAPeter Attia1:53:18

        I see. Yeah, just so folks understand what we're talking about here.

    14. MDMichael Davidson1:53:22

        Yeah.

    15. PAPeter Attia1:53:22

        In the EPA only trial, the placebo was mineral oil, but the hypothesis was that the mineral oil itself probably increased events slightly, which made the EPA look better alone than it might've been. But in the combined trial, the DHA, EPA trial, the placebo was corn oil inert.

    16. MDMichael Davidson1:53:44

        Yeah, corn oil.

    17. PAPeter Attia1:53:44

        And you're doing apples to apples in terms of-

    18. MDMichael Davidson1:53:45

        Yeah, corn oil might have its own. We had a hard time coming up with a placebo because it's not easy to find an oil placebo. Mineral oil has that advantage. It is truly inert, but it does have that intestinal effects.

    19. PAPeter Attia1:53:56

        Yeah.

    20. MDMichael Davidson1:53:56

        So I think the mineral oil controversy is, I still think REDUCE-IT shows a benefit for pure EPA. Now then we had the PROMINENCE study, which is a triglyceride lowering trial with a fibrate. Pemofibrate showed no benefit. It's very similar to the STRENGTH trial-

    21. PAPeter Attia1:54:14

        Yep

    22. MDMichael Davidson1:54:15

        ... population. And so what that says is that EPA does work on reducing events.

    23. PAPeter Attia1:54:22

        But not through triglyceride lowering?

    24. MDMichael Davidson1:54:23

        Not through triglyceride lowering. It's more for the antithrombotic, anti-inflammatory effect, which brings me to DHA. So DHA, I still think has a lot of health values that we should talk about, especially for the brain, because the brain is predominantly DHA. That's the fatty acid in the brain. Now, the problem is with DHA, we tried DHA supplementations on cognition, didn't really show much. You've had Usseyn here and he's talked a lot about, but APOE4 people, one of the other things is they don't get as much DHA to the brain. They have a true DHA deficiency in the brain to some degree. But a new discovery, which is very exciting, is the MFSDA2 transporter, MFSDA2 transporter. It's a transporter across the blood-brain barrier for DHA. It turns out that DHA prefers the lyso-PC form, a lysophosphatidylcholine form of DHA. That's the preferred substrate for DHA to cross the blood-brain barrier. And so now for the first time, you can now get lyso-PC DHA. It's coming. It's on the horizon. And so we're actually, we're going to be, as part of Jocasta, we're going to be doing studies with lyso-PC DHA. On showing a-- for APO-- getting across the blood-brain barrier better.

    25. PAPeter Attia1:55:46

        Completely independent of the clotho work?

    26. MDMichael Davidson1:55:48

        Right, exactly. Yeah. So, um, so that's, so that's exci- that's coming, and I, and I've used it, been on omega-3. One of the things I really-- until this receptor was identified, we couldn't understand why, you know, why DHA doesn't get, you know, int-int-into the blood-brain barrier like you think it, 'cause it, it, it does have to-- you don't ma-- you can't-- there's-- you, you-- most of your DHA and ARA has to come from the blood. It has to get there. It has to get there. You don't-- your, your brain cannot make that much DHA from other fatty acids, uh, if at all. I mean, I think it can make some, but, um, but, but you, you have to get DHA from the, from the periphery, across the blood-

    27. PAPeter Attia1:56:26

        So your belief today would be that if an individual is not consuming much fatty fish, you measure their red blood cell membrane concentration of EPA and DHA, and it's very low, four percent.

    28. MDMichael Davidson1:56:39

        Right.

    29. PAPeter Attia1:56:40

        And they were to supplement with a very high quality, uh, over-the-counter EPA and DHA, um, and they were to get that to ten percent.

    30. MDMichael Davidson1:56:48

        Right.
17. 1:57:50 – 2:06:22

    Two open problems: using AI to reform clinical trials, and the statin–diabetes signal

    1. PAPeter Attia1:57:51

       you've been involved in so many clinical trials over the course of your, your life, and there's so much discussion about AI in medicine and the impacts it can have. But I c-- I'd have a hard time thinking of a more important impact that AI could have on medicine than if it could speed up the, the time it takes to do a clinical trial by a log, and if it could reduce the cost by a log. So if you could take it from four billion dollars a drug to forty million or, you know-

    2. MDMichael Davidson1:58:22

       Right

    3. PAPeter Attia1:58:22

       ... I, I mean, frankly, if you could take it to four hundred million, right? So, um, and if you could take it from ten years to one year, I mean, y-you would, you could change the course of, of human history. Where do you see AI factoring into what appears to be the long pole in the tent, which is doing clinical trials?

    4. MDMichael Davidson1:58:41

       Yeah, it's hard, it's a hard thing. And until there's regulatory reform, I ha- I hate to say it. I mean, uh, I know that's a tough thing to advocate for because y-you g-- you firstly have to figure out how do you do the data. It's still, like, everyone's tried to say, "Can we, can we make clinical trials a lot more, uh, streamlined?" You know, less data collection. But also, to me, I, I wrote a paper about this. You know, what-- why can't we look at clinical trials, you know, based on using AI? Who, who, if you took the drug the right way, how well did it work? Instead of, we have to, we have to worry about, we have to get diluted by everyone who stopped the drug, who's-- wasn't compliant.

    5. PAPeter Attia1:59:22

       Yeah, so in other words, make the efficacy not based on intention to treat, but on actual compliance.

    6. MDMichael Davidson1:59:28

       Right. And that would be a huge difference already, 'cause we, we, we-- your, your effects are diluted so much by, especially for long studies. You have the drop in, drop-- And so you can use AI modeling even to show that for those who took the drug, took it the right way, the benefit was s- worked well.

    7. PAPeter Attia1:59:48

       When you look at a trial like either BROADWAY or ROSE two, what was, h- what percentage of the patients enrolled in those trials do you believe were nearly a hundred percent compliant?

    8. MDMichael Davidson1:59:59

       We, we actually, there's what's called on-treatment analysis or, um, or, you know, kind of looking at PK, you know, who, who was the right, taking the right drug. It, it always works so much better. And we wish, we wish we could present that-

    9. PAPeter Attia2:00:10

       But in a, but in a drug like a once-a-day pill, which is as easy as it gets for the most part-

    10. MDMichael Davidson2:00:16

        Right

    11. PAPeter Attia2:00:16

        ... I guess maybe an injectable every few weeks would be similarly compliant. Um, what, what is, what is expected compliance?

    12. MDMichael Davidson2:00:24

        Well, you wanna see eighty percent. That's the, kind of the benchmark. Yeah, in fact, when you, when you do your per protocol analysis, you say anyone below eighty percent compliant, we take out of it. But they, but no one accepts per proto-

    13. PAPeter Attia2:00:35

        But the FDA will never accept per protocol analysis.

    14. MDMichael Davidson2:00:37

        No, no. [chuckles]

    15. PAPeter Attia2:00:38

        Yeah.

    16. MDMichael Davidson2:00:39

        And for-- But they should. I mean, that's the thing. I'm, I-- W-When I put in this paper, I said, "If we could find a way to, to streamline drug development, that, that's one thing." But e-- but AI could help a lot even more. I mean, we could say we could do a study, instead of being ten thousand, it could be two thousand, and it just took the people that took the-- that we can make, like, you get to your log reduction.

    17. PAPeter Attia2:00:57

        Yeah.

    18. MDMichael Davidson2:00:57

        That's just one example. I mean, um, like, I don't know, I don't know how much longer we can keep doing LDL tri-- I mean, LDL trials with different MOAs. I mean, mecha-- We-- It's, it's gonna be, it's gonna be s-- it's getting harder and harder to do these studies. And so we're gonna have to-

    19. PAPeter Attia2:01:14

        Because of the ubiquity of drugs on the market already-

    20. MDMichael Davidson2:01:16

        Right. And, and-

    21. PAPeter Attia2:01:17

        ... and then the amount of LDL lowering that's already in the baseline?

    22. MDMichael Davidson2:01:20

        Right. You know, yes, you have to, you have to be ethical. You can't withhold-

    23. PAPeter Attia2:01:23

        Yeah

    24. MDMichael Davidson2:01:23

        ... treatment to patients. So we, we, we, we have a, you know, where the, we have a, a, a lot of patients that, that can access to other drugs, and you just, you can't, you can't deny that to patients in a, in a trial. So it's, it's gonna be harder and harder to do these studies.

    25. PAPeter Attia2:01:37

        So let's come back to statins for a moment. What, um... What do you think is the best explanation for the increase in the incidence of type 2 diabetes that we see in statins? Again, it's not small, but it's a real signal and it's-- I'm sorry, it's not large, it is small, but it's a, it's a real and undeniable signal. And, and by the way, I would say that it's not just patients going on to get type 2 diabetes, it's insulin resistance, right? So pa-patients who don't progress all the way to type 2 diabetes, we do see an increase in insulin resistance. What do you think is explaining that?

    26. MDMichael Davidson2:02:03

        Well, first of all, uh, it looks like all LDL-lowering drugs, even PCSK9s, have a little bit of a diabetes signal, except for obicetrapib, I mean, just the opposite.

    27. PAPeter Attia2:02:13

        Which is the opposite.

    28. MDMichael Davidson2:02:14

        Yeah. So, so i-it is about LDL-

    29. PAPeter Attia2:02:17

        But that's not entirely true. Don't bile acid sequestrants, which lower LDL, albeit somewhat weakly, show an improvement-

    30. MDMichael Davidson2:02:23

        Yeah
18. 2:06:22 – 2:15:31

    What it takes to develop a drug, the biotech investment landscape, and the klotho program

    1. MDMichael Davidson2:06:22

       of taking the statin.

    2. PAPeter Attia2:06:23

       How many other, uh, CETP inhibitors are in the pipeline at the moment?

    3. MDMichael Davidson2:06:26

       To our knowledge, no others. Yeah. We're, we're kind of the, we're, we're it. You know, so if we're successful, there'll be a lot, there are gonna be a lot more. But it's very hard to beat obicetrapib. It's, it's got a low dose, extremely, uh, well-tolerated in our clinical trials. We saw-

    4. PAPeter Attia2:06:42

       What, remind me, the molecule that when you guys bought it came from-

    5. MDMichael Davidson2:06:46

       Well, Amgen through Mitsubishi. It's Mitsubi- a Japanese company first discovered it, and it was sold to Amgen and-

    6. PAPeter Attia2:06:53

       And how did, what, what were they doing? What was Mitsubishi doing when they were discovering it? Were they doing it specifically for the purpose of following the earlier-

    7. MDMichael Davidson2:07:00

       Yeah

    8. PAPeter Attia2:07:00

       ... CETP inhibitors, and then they sort of abandoned and that-

    9. MDMichael Davidson2:07:02

       Well, they wanted, they wanted to make a better CETP inhibitor. It was the, so one that had, you know, no fat uptake, much lower dose, more potency, more bioavailable. And so they gave us, we got a great drug. We got a great drug to work with. And so, um, uh, it's gonna be very hard to, to match the profile that obicetrapib has from a phar-pharmacokinetic perspective and then of course-

    10. PAPeter Attia2:07:24

        And to give folks again just a sense of what does it take to develop a drug. So if you look at the money you paid to acquire the drug, what you had to raise through the clinical trials, and what it would take to get to approval, what's the approximate dollar amount to, to do that?

    11. MDMichael Davidson2:07:37

        Well, we've ra- It's, it's well over a billion. I mean, this, but this is not even counting what was cost up until, you know, we got, we got it. I mean-

    12. PAPeter Attia2:07:43

        Yeah, it's a billion of, of New Amsterdam plus all the money that came before it to get it into phase two.

    13. MDMichael Davidson2:07:49

        Right, right, right, right.

    14. PAPeter Attia2:07:49

        Yeah. So the average drug right now is about three to four billion dollars to approval.

    15. MDMichael Davidson2:07:54

        Right, right. That, that, that accounts for the failures too. It, it, it, but it might be even more if you account for the failures. But it, it's, it's a lot. It's a, it's a lot of money. We're, like I said, it's a, um It's a high risk, high reward investment. So we, we, uh, we feel that we, uh, been able to get to this point, and we're, we're hoping to have the drug to patients as soon as possible.

    16. PAPeter Attia2:08:18

        What do you think overall of the landscape of biotech investing? I mean, we live in this world now where AI is clearly the most interesting and exciting thing to invest in. Capital is flying into AI. It doesn't really matter that, you know, lots of people are saying, "Hey, look, this is a bubble. We need to, you know, be a little more cautious with how we do this. This feels like 1999 for the internet," et cetera, et cetera. Um, but it's so interesting when you look at biotech companies that it's, I mean, it's very, very difficult to raise money. Um, where do you think we are in the biotech life cycle, and why-- Uh, do you think biotech is just forever going to be complicated because of the time horizon?

    17. MDMichael Davidson2:09:00

        The latter is true, of course. But, um, what's really important i-is the, the macro issues, is that we have all these big pharma companies that have, you know, big sales forces and companies, and they have pipelines that are the big, big gaps, and the cliff, the patent cliffs are coming. All of them, they can't grow. You know, they-- if they in order to grow, they have to get new product. We have, uh, I think in the way the system's set up, you know, everything ultimately goes generic. And so if you see where that is, I mean, if, if, if we're talking about if, if companies even want to grow three or four percent per year, which is pretty minuscule growth, they got, they gotta, they gotta add a lot of new products to their pipeline. And, uh, and a, and a way it's worked out is the big companies also have become pretty dysfunctional on innovation about developing new drugs. And it's just that, it's just the w-- you know, the comp- the small companies can be a lot more nimble, a lot more flexible, a lot more risk, take more risk and, and don't have to worry about, you know, corporate, you know, kind of hierarchy to make a decision. So, um, we, we feel that biotech is right now in a, in a really good position. Um, and I think AI is gonna help a lot on, on coming up with the right... Like you, I, I hope you can, we can figure out a way to make clinical trials a lot more cost effective and, and lower cost. But even drug discovery, we have, um, uh, China, uh, for example, is, um, is just become a, a, a huge investment in... Like for every chemist in the United States, there's probably ten thousand in China. I mean, we, we have, uh, they, they have the capabilities that really surpass, you know, anything that we can do from a drug development perspective just by the person power that they have. And so that, but that sets up an opportunity. I mean, we-- I still think we have the science and the innovation, and we have, you know, the creativity that could lead the world in, in coming up with the new ideas. But, but China is gonna, gonna be able to have us be able to take it to the next level, um, with how they get a drug produced and, and then made to, to make it to the human data as quickly as possible. Like klotho is a good example. I mean, um, the hardest part about klotho before we got involved was, uh, no one could manufacture it. No one could make it effectively. Uh, and, um, then we went to, uh, China, Wuxi, and they, and they figured out a process, and now it's, it's very robust process, and it's going very well, so we hope to be in cl- in, in human clinical trials pretty soon. I mean, so, so I mean, I mean, we, we, we, I think we have the, uh... If you look at it from a global perspective, if, if everyone could work well together, you know, we have the, the makings of a, of a biotech revolution, but we, we gotta find the right-- We have to continue to have, uh, a high benefit to, to risk kind of ratio, too. I mean, so we have to see how that plays out.

    18. PAPeter Attia2:12:03

        Well, Michael, this is, this is really exciting. I love when, when we can sort of string together podcasts over a series of years and get kind of an update from, um, one very exciting idea to another. I was incredibly excited about obacetrapib when, when we spoke about it the first time with John. And, um, everything you've updated us on today only makes that [chuckles] you know, just... Look, we just can't wait to get this, this, this drug, um, um, into the hands of people, and hopefully not just for cardiovascular disease, but perhaps even more excitingly, um, for, for Alzheimer's disease, especially in those E4 patients. Um, so anything else you wanna talk about on the klotho front? I know we didn't ta- we didn't spend too much time on it, but, um-

    19. MDMichael Davidson2:12:49

        Yeah

    20. PAPeter Attia2:12:49

        ... um, you know-

    21. MDMichael Davidson2:12:50

        Well, I was-

    22. PAPeter Attia2:12:51

        You and I are both involved, which is why I'm a little bit coy to talk about it. I don't wanna, I don't like to talk about things that I'm directly involved in as well.

    23. MDMichael Davidson2:12:57

        Right. Right. I think, uh, we're-- it's moving along well. I mean, it's, it's, um, it-- like I said, the Chine- Chinese, the Wuxi made, made a, make it a great protein. And I think the MOA part is still, the me- mechanism of action is still... So what we decided, you know, just to kind of step back, um, where we were, you know, a year, a couple years ago, we had this genomic validation that if you have the klotho gene, you're protected against, uh, Alzheimer's E4 in particular. Um, we had, uh, this great animal data consistently showing that if you inject klotho peripherally, you improve cognition. It went to a m- uh, a primate study and showed great data in the primates, got published in Nature, you know, um, journal. Uh, and so, um, we, we, we, we believe we had, you know, a, a well-validated, uh, target and, and, and drug, but the, the missing part was the MOA. No one knows how it works. I mean, and, and, and turns out I, I-

    24. PAPeter Attia2:13:55

        And by the way, that's pretty, that's, that's a painful point, right? I mean, there's only-

    25. MDMichael Davidson2:13:58

        It's a pain. That's why we have-

    26. PAPeter Attia2:13:59

        Only up to three percent of FDA approved drugs do not have a clear mechanism of action.

    27. MDMichael Davidson2:14:04

        Yeah, metformin does, and as it, you know.

    28. PAPeter Attia2:14:05

        Right. Tylenol.

    29. MDMichael Davidson2:14:06

        Ty- [chuckles] yeah, right. We have other examples of where the MOA is not known. So when you and I, you know, embarked on, okay, how are we gonna uh, get this to humans, what we had to decide to do was we, we basically, we have to sort of give up on trying to figure out the MOA exactly 'cause, uh, uh, we just have to find people willing to fund the, the studies up until human data and, and prove that it does improve cognition, uh, in a human trial. Then I think it's, then it's gonna be hopefully a solid going forward, not just, um, hopefully Al- hopefully Alzheimer's as a, as a treatment, you know, as a treatment for Alzheimer's, uh, disease. Hopefully even a prevention too 'cause it, it does have all those criteria. We still don't know the MOA. We do think the, um, the latest is that the, uh, the full length, yeah, the full length klotho doesn't likely cross the blood-brain barrier, but, uh, there's a f- there's a, um, a new f- uh, fragment that, that, that may be cleared that does cross the blood-brain barrier, and that, that could be the mechanism of actual... We know that peripherally giving it does-

    30. PAPeter Attia2:15:07

        Yep
19. 2:15:31 – 2:19:15

    Closing reflections: what to do if you carry APOE4, balancing motivation against over-testing, and the need for multiple therapies

    1. PAPeter Attia2:15:31

       It is. It's very high risk, but, but it's, um, you know, it's... Uh, I, I know so many of, obviously, the investors in, in Jocasta, and, and many of them really come at this through the lens of, um, you know, this is partially a financial investment, but many of them also think of it as philanthropy without the tax break.

    2. MDMichael Davidson2:15:49

       Right.

    3. PAPeter Attia2:15:49

       Which is, um, uh, I'm not just doing this, you know, I'm not just putting my money into this company because I wanna make money. I-- That would be great, but what would be greater is if this drug actually works.

    4. MDMichael Davidson2:16:00

       Mm-hmm.

    5. PAPeter Attia2:16:00

       Um, and I feel like a lot of people take that approach in biotech, especially when it comes to a disease like Alzheimer's disease, where, um, we just, we're, we're just watching people suffer so much right now.

    6. MDMichael Davidson2:16:13

       Right, right.

    7. PAPeter Attia2:16:14

       With nothing to offer them.

    8. MDMichael Davidson2:16:15

       We, we gotta, we have to keep working at it. It's, uh, uh, yeah, I just lost a, a, a, a double first cousin. So my, uh, so my parent-- I had two-- My mother's brother married my father's sister, so we have all the same grandparents, and then she just died at age seventy-two of Alzheimer's. He was an E4, yeah, so it's, uh, so I, I've seen it. It, it's, it's-- And I've seen, of course, a lot of patients struggle with it, uh, and, uh, and I wish we had better advice about what to do. But we do know, I, I, I do think, of course, ex-- We, so one, one question we, we maybe should end with is, what do you do? What, what if you're an APOE4? Like, like there are some that say, "Oh, but don't even bother checking it because what can you do about it?" I think that's a wrong approach. I mean, knowing you have it, you, you can obviously better lifestyle, exercise. I think the, this new taking some DHA, if and even though you may not get enough into the brain is still, and then keeping your, obviously no diabetes, the, the, the s-

    9. PAPeter Attia2:17:08

       Normal blood pressure, not smoking, managing lipids.

    10. MDMichael Davidson2:17:11

        All, all, all, all, everything that you can do.

    11. PAPeter Attia2:17:11

        Yeah, there's a lot you can do. I, I agree with you. I find it very frustrating when people suggest that-- And, and by the way, I totally respect a person who says, "I don't wanna know." Totally fine. Would never force that on anybody. But to suggest that knowing that couldn't provide the motivation to do the things that are hard to do when you're thirty and forty years old, long before this disease takes hold, um, you know, I, I, I think that's, I, I think, I think that's, that's probably the wrong side of that bet for me. But at the same time, you know, Michael, I s- I do see a lot of people going too far, and I, I would almost put myself in that camp of where I was maybe four or five years ago, trying to look too much at, at, at, at biomarkers that, that I think in retrospect probably weren't, weren't important enough.

    12. MDMichael Davidson2:17:55

        Mm-hmm.

    13. PAPeter Attia2:17:55

        And, and I think that that can, you know, I think when you're looking so hard for things, you start to make signal out of noise.

    14. MDMichael Davidson2:18:00

        Mm-hmm.

    15. PAPeter Attia2:18:01

        And, and I also think that that can create too much anxiety and, and quite frankly, I, I, I, I, I can think of at least two examples where I think a, a patient suffered more anxiety than they needed to over something that I just don't know that I would take to the bank as an actionable and treatable and modifiable, uh, biomarker. So, um, I am just, you know, I'm just, I'm pulling for klotho, I'm pulling for obacetrapib, and, and then of course, if they're successful, what that's gonna do is open up the door for more things. But what I love about the two of them is the, the potentially they're working by a different mechanism.

    16. MDMichael Davidson2:18:36

        Right.

    17. PAPeter Attia2:18:36

        Right? So I love when you can go after complicated diseases from multiple vantage points.

    18. MDMichael Davidson2:18:41

        And, and, and it's clear we're gonna need, we're gonna need multiple therapies. That's the thing.

    19. PAPeter Attia2:18:44

        Yep.

    20. MDMichael Davidson2:18:44

        You're, you're gonna need, uh, obacetrapib alone, uh, it, it could be a preventive strategy, uh, but I think you might gonna, you're gonna need more. It's, it's gonna be, you're gonna need something else as well-

    21. PAPeter Attia2:18:56

        Yep

    22. MDMichael Davidson2:18:56

        ... to, uh, to make a difference.

    23. PAPeter Attia2:18:57

        Well, Michael, thank you for the amazing work you're doing, and thanks for taking the time to come out here today. It was so much fun talking with you.

    24. MDMichael Davidson2:19:02

        Yeah, so much fun, Peter. Thank you. [outro music]

Episode duration: 2:19:15