#384 - Special episode — Obicetrapib: The CETP inhibitor with cardiovascular benefits and potential Alzheimer's prevention

View the Show Notes Page for This Episode https://peterattiamd.com/obicetrapib/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260316-pod-obicetrapib&utm_content=260316-pod-obicetrapib-podfeed Become a Member to Receive Exclusive Content https://peterattiamd.com/subscribe/?utm_source=podcast-feed&%20obicetrapib%20=referral&utm_campaign=260316-pod-obicetrapib&utm_content=260316-pod-obicetrapib-podfeed Sign Up to Receive Peter's Weekly Newsletter https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260316-pod-obicetrapib&utm_content=260316-pod-obicetrapib-podfeed In this special episode, Peter takes a deep dive into obicetrapib, an investigational drug that has captured his attention and renewed interest in an entire class of therapies known as CETP inhibitors. He explains what obicetrapib is and how it works, revisits the history of CETP inhibitors and why earlier versions of these drugs failed—sometimes dramatically—and breaks down the key clinical trials designed to evaluate their impact on cardiovascular risk. Peter examines how obicetrapib influences major lipid biomarkers, including LDL cholesterol and lipoprotein(a) [Lp(a)], and discusses emerging evidence from a study that explored the drug's effects on Alzheimer's-related blood biomarkers. He also highlights intriguing findings in individuals carrying the APOE4 allele and reflects on what these early results may mean for both cardiovascular disease prevention and potential implications for Alzheimer's risk, as well as how he is thinking about this therapy in the context of caring for his own patients. We discuss: Introducing obicetrapib: CETP inhibitor history, lipid biology, and early Alzheimer's biomarker signals in APOE4 carriers [2:15]; CETP biology explained: lipoproteins, reverse cholesterol transport, and how CETP inhibition alters HDL and LDL particles [5:15]; The early CETP inhibitor story: why raising HDL cholesterol alone failed to deliver cardiovascular protection [13:45]; The rise and fall of early CETP inhibitors: torcetrapib, dalcetrapib, evacetrapib, and anacetrapib [18:30]; Why obicetrapib may succeed where earlier CETP inhibitors failed [23:30]; The BROADWAY trial: obicetrapib's effects on LDL, ApoB, Lp(a), and residual cardiovascular risk [26:00]; Brain lipid metabolism and APOE4: how CETP inhibition may influence cholesterol transport in Alzheimer's disease [30:45]; Findings from the substudy of the BROADWAY trial which looked at changes in biomarkers of Alzheimer's disease [40:00]; Interpreting the BROADWAY Alzheimer's biomarker results: limitations, cautious optimism, and the need for a dedicated prevention trial [46:45]; Why Peter is optimistic about obicetrapib: cardiovascular benefits, Lp(a) reduction, and the path toward approval [50:00]; and More. Connect With Peter on Twitter https://twitter.com/PeterAttiaMD, Instagram https://www.instagram.com/peterattiamd/, Facebook https://www.facebook.com/peterattiamd/ and YouTube https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:11Dr. Peter Attia?

  Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive, member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you

• 0:54Dr. Peter Attia?

  want to learn more about the benefits of our premium membership, head over to peterattiamd.com/subscribe.

• 1:04Dr. Peter Attia?

  Welcome to a special episode of the Drive. In this episode, I take a slightly different approach where I'm going to walk you through a single topic in depth, breaking down the science behind, in this case, a drug that caught my attention and has me very excited. The drug is called obacetripib. So I'm going to explain what it is, why it's generating renewed interest in cardiovascular medicine, at least as a class of drug, and why the emerging data may also have implications for Alzheimer's disease, particularly for those who carry an E4 allele. So in this episode, I'm going to discuss what obacetripib is, how it works as a class of drug called a CETP inhibitor, the history of these drugs, and why the previous

• 1:45Dr. Peter Attia?

  versions of them have failed, and in some cases spectacularly, the key clinical trials behind obacetripib, and why they were designed, what they were designed to measure, the drug's effect on the major lipid biomarkers, including LP-A, all very interesting, a study called the Broadway Biomarker Study and its findings in Alzheimer's-related blood biomarkers, again, including a very interesting subgroup in APOE carriers, and I guess, most of all, what these results mean, how do they have me thinking about this drug for my patients? So without further delay, I hope you enjoy this special episode of the Drive.

• 2:25Dr. Peter Attia?

  So if you spend any time thinking about Alzheimer's disease research, you get pretty familiar with the emotional whiplash that accompanies it. You know, one week you're going to see a biomarker that moves and people talk about it and you'll see reportings all over the sort of lay press. And then the next week, some trial misses and the whole idea gets dismissed. And I think that's understandable for reasons maybe beyond the scope of what I want to talk about today. And I think it's also really true in the cases of prevention because prevention trials are hard to conduct. They take a long time, they're very expensive and early signals can look compelling even before something's actually proven.

• 3:04Dr. Peter Attia?

  So with that as background, today I'd like to talk about a drug called obacetrepib. Now, this is a drug that's primarily being investigated because of its ability to reduce LDL cholesterol and with it APOB. And I'm going to talk about that as part of the story. But more broadly, I want to talk about this drug in the spirit of cautious optimism as it pertains to Alzheimer's disease. So here's why it's interesting. Obicetrapib is a CETP or CTEP inhibitor, which is a class of drug with a very complicated and quite honestly, a very fascinating history in cardiovascular disease medicine. I'm going to actually talk about this in detail because I think it's important to the story.

• 3:44Dr. Peter Attia?

  But in a recent large phase three lipid trial, there was a pre-specified biomarker study that looked at Alzheimer's related blood biomarkers for a period of about 12 months. And in these studies, or in this study, rather, the investigators saw an attenuation of P tau 217 progression with a very strong signal in the APO E44 individuals. So this combination, which is basically a revived drug, a drug that there's lots of examples of this class of drug in the graveyard, plus a coherent biomarker movement coupled with real genotype specificity is, in my mind,

• 4:27Dr. Peter Attia?

  what makes this a very exciting topic that I want to kind of share with you all today. So to set expectations, I'm not going to come away from this proving that Obicetrapib prevents Alzheimer's disease or delays even cognitive benefits. But I will say that I haven't been as excited about any drug in the market or a drug that's about to enter the market as I am with respect to this drug. So what do I want to accomplish here today? First, I want to kind of revisit the story of CTEP inhibitors, why so many of them have failed. I want to explain why maybe this drug is not failing, explain why lipid biology intersects with Alzheimer's disease, especially in the E4 carriers. I want to walk through the very specific study that is leading me to have this optimism. It's called the Broadway Study.

• 5:11Dr. Peter Attia?

  And I want to talk about what I hope happens next so that we can figure out whether this needs to be a part of everybody's life who's at risk. So to start, let's get into CETP or CTEP biology. Now, to understand why this class of drug works, you have to understand something called reverse cholesterol transport. And to understand how reverse cholesterol transport works, you kind of got to go back and understand lipoproteins. So apologies in advance for those of you that are already completely up to speed on lipoproteins, but I just want to make sure everybody's playing on the same level. Now, the way I talk about this with my patients is the way I'm going to kind of talk about

• 5:53Dr. Peter Attia?

  it with you, which is to say that there are broadly speaking, two classes of lipoproteins. Let's not forget why we have lipoproteins. Lipoproteins exist so that we can move cholesterol through our bloodstream. Why is that important? Well, there are several factors. The first is every cell in the body needs cholesterol. It's a vital ingredient for our existence. If we didn't make cholesterol, we wouldn't actually be alive. And not every cell can necessarily make enough at every moment in time. So while every cell can make it, cholesterol needs to be shared across the body. Now, the problem with cholesterol is it is not water soluble. So the fancy word for that is it is hydrophobic. And so something that is hydrophobic, or something that repels water,

• 6:37Dr. Peter Attia?

  can't be transmitted through the blood, because the blood is water. Our blood is plasma and a bunch of proteins. So the body has to come up with a slick way to do this. Again, the body has no trouble transporting things that are water soluble, right? So proteins, electrolytes, ions, these things move easily through the blood. Glucose, for that matter, right? Just doesn't need anything to carry it. Not the same for cholesterol. So we evolved these cool things called lipoproteins, which, as the name suggests, are part lipid, part protein. The lipid, or cholesterol, fits on the inside, so it's shielded from the hydrophilic exterior. And the proteins are on the outside, which is what allows it to transmit through the blood. Now, you can broadly divide these into two classes.

• 7:21Dr. Peter Attia?

  There's an Apo B class, and there's an Apo A1 class. The Apo B class is the one you've heard me talk about a ton, because those Apo B lipoproteins are the ones that cause atherosclerosis. Now, they're mostly LDLs. But we shouldn't forget how they start. They start out as VLDLs, very low-density lipoproteins, which are big, really big. And they show up in all sorts of sizes. There's like, they cascade from, you know, a V6 to a V1 in size. They spend a tiny, tiny fraction of time as IDLs, intermediate-density lipoproteins, before ultimately maturing as LDLs, or low-density lipoproteins. And so if you did a blood test, you might look at the cholesterol concentration of these. You would never be able to catch an IDL,

• 8:05Dr. Peter Attia?

  but you would certainly catch the VLDL cholesterol. And that level might be, you know, 15 to 20, maybe as high as 30 mg per deciliter. And then you would look at the LDL cholesterol, and you would see a much bigger number. Now, remember, the LDLs are actually smaller, but you have so many more of them than the VLDLs. And therefore, you're going to, in aggregate, find much more cholesterol per unit volume of plasma. Now, on the other side of the ledger, we have these things called HDLs, or high-density lipoproteins, and they're structurally different. They come from a different lineage, and they have a different lipoprotein that wraps around them. And that lipoprotein is called ApoA1. This is going to be important as we get into our story.

• 8:49Dr. Peter Attia?

  So, what is reverse cholesterol transport? Well, historically, it has simply been viewed as HDLs returning cholesterol molecules from the body to the liver. And so, you know, if you asked me 10 years ago to tell you what RCT, or reverse cholesterol transport, was, that's what I would have said. I would have said it's when HDLs take, they delipidate, you know, for example, plaques in the coronary arteries, and they'll, or they take a sort of cholesterol out of other tissues, and they bring it back to the liver. But I think we would now want to more technically refer to that term as HDL, or ApoA1 mediated trafficking of cholesterol.

• 9:31Dr. Peter Attia?

  And again, that process is when a peripheral cell exports excess free cholesterol to that protein, the ApoA1 protein that forms the HDL particle. That cholesterol is then packaged into a more stable form, carried with the HDL particle, returns back. Okay, now, the direct RCT, or reverse cholesterol transport, is when the HDL delivers that cholesterol straight into the liver, sometimes the intestine, and it unloads it there via a receptor, called the sterol receptor binding 1, or SRB1. I only mention that because I'm going to bring it up later. I don't actually care if you remember that. But just remember that HDLs can take cholesterol directly to the liver, and they deliver it through that receptor. But, there's also something called indirect RCT.

• 10:15Dr. Peter Attia?

  And I don't think I even learned what indirect RCT was until maybe eight or nine years ago, which is not to say it wasn't understood before then. I'm just telling you, I didn't understand this before then. And here is where, this is actually kind of cool. The HDL doesn't deliver the cholesterol itself. Instead, it exchanges its cholesterol ester.

• 10:34Dr. Peter Attia?

  Which are the cholesterol molecules bound to long-chain fatty acids. So that's a cholesterol ester and cholesterol are cousins. It exchanges those things for the triglycerides inside the ApoB particle, which is usually the LDL. So let's just go back and say that again. So you've got an HDL that's full of cholesterol ester. It bumps into an LDL in the periphery, which has got a bunch of triglycerides in it. They swap triglyceride for cholesterol ester. And then those LDL particles, quote unquote, bad guys, do a good thing. They take cholesterol back to the liver. Now, it's important to understand that an enormous amount of reverse cholesterol transport

• 11:18Dr. Peter Attia?

  takes place via this route. Some 40 to 50% of it. So it's important to understand that LDLs aren't all bad. They are doing this one good thing. Now, I know what you're thinking. If we lower our LDLs, does that mean we get less reverse cholesterol transport? No, the direct pathway just picks up the balance. But it's just an interesting thing to observe here. Okay, now what does all this thing have to do with CTEP? Well, what does CTEP stand for? I said it, I think, at the beginning. It stands for cholesterol ester transfer protein. And so at a high level, you can think of the CTEP as a molecular shuttle that exchanges the cholesterol ester in the HDL for the triglyceride molecule in the LDL as part of this indirect reverse cholesterol transport pathway.

• 12:01Dr. Peter Attia?

  Now, because CTEP mediates an exchange of cholesterol ester from HDL for triglyceride in the ApoB-containing particles, it doesn't just move cholesterol. It actually reshapes the particles themselves. And so when CTEP activity is high, more cholesterol esters enter, pardon me, leave the HDL and move into the LDL. So HDL becomes cholesterol poor and triglyceride-rich, while LDL becomes cholesterol-rich and triglyceride-poor. Okay, but remember.

• 12:37Dr. Peter Attia?

  While we like the idea of cholesterol going back to the liver, if you just load those LDLs of cholesterol, we know where they're ultimately going to end up. So this is not a condition we want. So the problem with too much CTEP activity is that the triglyceride enriched HDL is unstable. It gets rapidly trimmed down by enzymes called lipases, both in the liver and at the endothelium. These produce smaller HDL particles that can either be rebuilt or cleared from circulation. But what happens is that you have those cholesterol enriched LDL particles that will ultimately go back to the liver, but may not, right? They may also end up ending up in artery walls.

• 13:20Dr. Peter Attia?

  So that's what's happening when CTEP is activated. And so what happens if you inhibit CTEP? The opposite happens. So less cholesterol ester leaves HDL. This results in much larger cholesterol-rich HDL particles. So HDL cholesterol, the biomarker, goes up. And LDL cholesterol, the biomarker, goes down. All right, so with that as background, I think we can now talk about the, what I think is a very fascinating history of this class of drug called CETP or CTEP inhibitors. Now, it's important to understand the context of this. So in the 90s, I think, around the 90s, when this class of drug were first developed,

• 14:04Dr. Peter Attia?

  the excitement was almost entirely around the HDL story. What do I mean by that? Well, the CTEP inhibitors, these first versions, which we'll talk about, dramatically raised HDL cholesterol, oftentimes doubling it, okay? Now, at the time, this term that still exists today, unfortunately, was even more prevalent, which was that HDL was good cholesterol. And so the thinking was really straightforward in its reductionist manner, which was if low HDL is bad, because it's associated with more cardiovascular risk, then raising HDL should be good. And therefore, giving a drug that raises HDL cholesterol is a good thing.

• 14:48Dr. Peter Attia?

  And that was the rationale for going forward with this. Now, I discussed this in a podcast a couple of years ago with John Kestelin, and it turned out that that assumption was overly simplistic, although it wasn't known at the time. So since that time, Mendelian randomizations have been done and have actually failed to support the hypothesis that HDL cholesterol is causally linked to favorable cardiovascular disease outcome. By the way, that's the exact opposite of what the Mendelian randomizations have showed us about LDL cholesterol. Every Mendelian randomization that has looked at the level of LDL cholesterol, again genetically controlled to a large extent,

• 15:30Dr. Peter Attia?

  has found the opposite, that it is indeed causally related to bad outcomes. But we don't see that with HDL. I would like to think that if people knew that 30 years ago, it might have saved some of the pain that was coming our way, but at the same time, maybe we wouldn't have obesetropib today. So I don't want to be too much of a revisionist on history. The point here is, the Mendelian randomizations would suggest to us that simply raising HDL cholesterol is not going to reduce cardiovascular events by itself. Another point that wasn't known at the time, that is known today, that's been reinforced by human genetics, is that individuals who have a loss of function variance in CTEP have markedly elevated HDL cholesterol, and in some analyses at least have lower cardiovascular

• 16:15Dr. Peter Attia?

  disease risk, but that benefit appears to track with reductions in their non-HDL cholesterol, not with the increase in HDL cholesterol. In contrast, loss of function mutations in the HDL receptor SRB1, remember I talked about how when we were dealing with direct versus indirect reverse cholesterol transport, the direct route is what allows the HDL to take cholesterol straight to the liver or to the gut and transport it through the SRB1? So if you have a loss of function mutation in the gene that codes for SRB1, what's going to happen? You're going to have a defective transporter, your HDLs are not going to do

• 17:00Dr. Peter Attia?

  a good job in getting cholesterol out of them into where they need to go. The HDL cholesterol is actually going to go up, isn't it? So those patients walk around with very high HDL cholesterol, and yet they have a higher increase in coronary artery disease risk. Just as an aside, a very, very close friend of mine, who I've known for almost 20 years, has always had very high HDL cholesterol and low LDL cholesterol. And we used to always marvel at his lipid panels. You know, this was literally 20 years ago. And as I got deeper, deeper, deeper into the weeds of this, a few years ago, I said to him, hey, brother, I know your HDL cholesterol is 110 or 120 mg/dL and your LDL cholesterol is 60 or 70 mg/dL. And that almost assuredly portends a good outcome here.

• 17:45Dr. Peter Attia?

  Do me a favor and just get a calcium score because I just want to be sure you don't have one of these SRB1 mutations. And if you do, you would look exactly like you do, but you'd be riddled with heart disease. And unfortunately, that turned out to be the case. And so he did have a very aggressive finding on his calcium scan and had a lot of calcium there. Fortunately, none of it was so far along that, you know, he's not going to be totally fine. And he's now being treated and everything's going to be fine. But I point that out to just say, do not assume that because a person has high HDL cholesterol or low LDL cholesterol, that they're necessarily safe. Okay, so all of this is to say that the biology here is super, super complicated.

• 18:28Dr. Peter Attia?

  Okay, so let's now talk about the various C-Tep inhibitors. So the very first of these, which again, we talked about this on the podcast with John a few years ago, was torcetropib. And this is the one I talked about because I really remember this one well. This was a Pfizer drug. It was put into a study paired with atorvastatin, which was about to come off patent. And everybody was excited because, you know, atorvastatin had all of its benefits that were demonstrated over and over again in lowering LDL cholesterol and lowering cardiovascular events. They then pair it with this drug, which doesn't just further lower LDL, but raises HDL. Everybody thinks this is going to be a home run. Drug gets stopped prematurely in 2006 because of increased mortality, which was secondary to it raising blood pressure.

• 19:13Dr. Peter Attia?

  Now, this turned out to be an off-target toxicity. Meaning the drug was doing something that was raising blood pressure that had nothing to do with CTAP. And it's unfortunate for that drug and that company, but none of the CTAP inhibitors that have followed have suffered that limitation. So fast forward about six years to dalcetrepib, which is a Roche drug. This raised HDL cholesterol by 30 to 40%, but it didn't really meaningfully lower LDL or ApoB. And not surprisingly then, given what we know today, which is it's not the rise of HDL that matters, it's the fall of LDL or ApoB that matters. This didn't move the needle and the drug was abandoned. So it just didn't, you know, it looked like it had favorable findings in biomarkers, but

• 19:56Dr. Peter Attia?

  there were no good outcomes, no bad outcomes, no safety side effects, but the drug was pulled by Roche in 2012. Fast forward a little bit more to evacetrepib. This was a drug that Eli Lilly was working with. This had a much bigger effect on HDL. It was increasing it by over 100%, so more than doubling HDL cholesterol. LDL cholesterol was falling by about 30%, ApoB falling by about 15% and even LP little A, which I'm going to talk about in a minute, declined by about 20%. But ultimately that trial was terminated after a median follow-up of just about two years.

• 20:35Dr. Peter Attia?

  And in retrospect, when you looked at all of the data, it seems that the initial belief of the LDL reduction was probably overstated, whereas when you looked at the relevant metric of ApoB reduction, it was about 12 mg per deciliter, probably not big enough to move the needle over two years. Now, a 12 mg per deciliter reduction in ApoB over the course of your lifetime, of course, would move the needle, but not over a couple of years. So they did another study that also failed to find a benefit and then Lilly pulled the drug on that drug in 2015. That was followed up by another study called REVEAL.

• 21:17Dr. Peter Attia?

  In this drug, it's certainly in this trial, Merck was looking at a drug called anacetropib and it was adding it To atorvastatin therapy to reduce coronary events. This study, I believe, did see a reduction in coronary events of nine or 10% over a median follow-up of about four years. And there's an extended follow-up of another two years that demonstrated a further reduction of events to about 12% over about six years. And, you know, the magnitude of that benefit was consistent with what would be predicted from the degree of ApoB lowering. So it was a modest effect.

• 22:01Dr. Peter Attia?

  This was not kind of a banger effect. And we've got to remember when this is happening. This is happening as the PCSK9 inhibitors are coming online and these things are like blowing the doors off of these metrics. But here's what was important about this study is that it really was a proof of concept that C-Tep inhibitors could reduce cardiovascular events, they could lower ApoB particles, and they were largely risk-free if you didn't have these off-target effects. But because this drug had another odd side effect, which is it was, it had a very long half-life and it was retained in fat cells. Now, to be clear, no one was able to demonstrate that this posed a problem, but Merck decided to pull the plug.

• 22:46Dr. Peter Attia?

  Now, I don't, I mean, I'm totally making this up and speculating. We all remember that Merck had what I consider one of the best drugs ever, ViOx, and was probably too late to put a black box warning on that, which is what they should have done. Instead, they ultimately got called out, had to pull this drug off the market. To this day, many patients, myself included, resent that and wish that they had just put a black box warning on it. And so maybe they were a little bit gun-shy in this regard. But nevertheless, that drug got yanked. So you go, what is that, five drugs or four drugs that go 0 for 4, or at least three of them go 0 for 3, and maybe the fourth one kind of hits, but has this weird issue of getting held up in fat cells and therefore they decide, forget it, we're not going to take that risk.

• 23:30Dr. Peter Attia?

  And so all of that is prelude to where we are with Obicetrapib. So these CTEP inhibitors clearly have a complicated history and it begs the obvious question, right, was what in the world would make the fifth shot on goal, in this case, Obicetrapib, any different? And I kind of remember that being my mindset when I interviewed John three years ago, or whenever I interviewed John, who by the way is one of the founders of the company that makes Obicetrapib. And I think the argument was, look, the failure of these four CTEP inhibitors could be traced to issues, right? Which is basically two issues. Either they had off-target toxicity, again, in the case of torcetropib's blood pressure

• 24:10Dr. Peter Attia?

  effects, or maybe even this fat accumulation issue, or because they just didn't lower LDL cholesterol and APOB enough despite raising HDL a lot. And so the hope with Obicetrapib is they went through, you know, the process of marching into phase one and phase two was, look, as long as it's not having off-target toxicity and as long as it's really producing a robust LDL response, this drug could be a banger. And so that's exactly what has shown to be the case. So in the phase true trial, known as the ROSE trial, Obicetrapib was added to high statin or high intensity statin therapy, and the drug produced reductions in LDL cholesterol that were enormous, an additional 50% reduction in LDL cholesterol on top of high statin

• 24:55Dr. Peter Attia?

  therapy or high intensity statin therapy, and an APOB reduction of 30%. When you looked at another trial called the OCEAN trial, also a phase two trial, the drug was combined with 10mg of azetimibe, it reduced LDL by 52%. And when you looked at the ROSE II trial, where high intensity statin and azetimibe were combined with Obicetrapib, you saw a decrease in LDL of over 60%. All of this then feeds into the phase three trials, which are Broadway, which was looking at Obicetrapib on top of maximum lipid lowering therapy, and Brooklyn, which was a trial

• 25:36Dr. Peter Attia?

  done specifically in patients with familial hypercholesterolemia, or FH, on top of maximum tolerated lipid modifying therapies. So basically, take those patients with FH who are very high risk, put them on whatever maximum cocktail of drugs you can put them on, and then add Obicetrapib. And then another study called PREVAIL, which was looking actually at cardiovascular outcomes in patients with existing cardiovascular disease. So. Three trials there to talk about, but the one I really want to talk about is Broadway. So Broadway enrolls 2,500 patients with established atherosclerotic disease, or FH, familial hypercholesterolemia, who are already receiving maximum therapy. So why am I highlighting this study?

• 26:18Dr. Peter Attia?

  Because these are the two patients where you see the maximum amount of residual risk. What is residual risk? That's the risk that remains when you've controlled everything you can control. So in these patients, when 10mg daily of Obicetrapib was added to background therapy, LDL cholesterol fell by an additional 30% three months out compared to a 3% increase in the placebo group. So the placebo group was on maximum drugs, but nothing else. And over time, it just drifted up 3%, which is probably noise. But what was not noise and was statistically significant was this 30% reduction in the OB group. ApoB, remember, it's not going to decline as much. It went down 16% compared to 1.8% in placebo.

• 27:02Dr. Peter Attia?

  The HDL cholesterol, for what it's worth, just going through this, went up by 125%, which was, you know, we always expect that with CTEP inhibition. And LP little a fell by a third. I want to take a second to explain that, by the way, because that's super interesting. I won't give a full primer on LP little a, but I know that people who listen to this podcast regularly are no stranger to what's going on there, which is to say LP little a is an independent and genetically determined cardiovascular risk factor that's really difficult to modify. And it's surprisingly common, right? Anywhere from 1 in 8 to 1 in 12 people are going to carry this risk. But, you know, the fact that a CTEP inhibitor is reducing it by a third is pretty promising. So how do we think it's happening?

• 27:46Dr. Peter Attia?

  Well, there's a number of possible mechanisms, but what it appears to be doing is decreasing the synthesis of apolipoprotein little a. So if you decrease the synthesis of apo little a, you're going to make less LP little a, which is made out of an LDL and an apo little a. Now, there's also some speculation that it increases the expression of hepatic HDL receptors, and it's proposed that those could be receptors for LP little a clearance. But I think that's speculation at the moment, and I would probably rather not comment on it too much further than to just observe the outcome. Now, there's one other thing that I think is worth kind of talking about here.

• 28:30Dr. Peter Attia?

  And that is that across all of these CETP programs, there appears to be either kind of a neutral effect, or even possibly a favorable effect on incident diabetes. Now, again, we're going to see more of that in obesetripib because we have more trials. And while I think it's too soon to say if these are definitive, they are notable because, as we've talked about in the past, statins are indeed associated with a small but real increase in the risk of type 2 diabetes. And so I just want to point out that if, in fact, this benefit is confirmed of what we would call metabolic neutrality, or even benefit, I think it tells us a couple of things.

• 29:13Dr. Peter Attia?

  One, it says that the negative impact that statins have on insulin resistance are not necessarily a product of the reduction in cholesterol, and rather must be some other issue associated with the statins. We've talked about this elsewhere, that it might have to do with the impact that statins have on the gut. But more importantly, I think it says that if we have a drug that is lowering LDL-C and APO-B and LP-A, and it's metabolically beneficial, boy, this is a drug that has a lot of potential benefits. So, all of this is to say, we've got a drug that lowers LDL, APO-B, reduces LP-A, remodels HDL particles,

• 29:58Dr. Peter Attia?

  potentially, you know, at best, probably no adverse metabolic trade-offs, maybe some benefits. And all of this is looking very promising. We are awaiting the results of the PREVAIL Phase 3 trial, which is a cardiovascular outcome study. So just a word on the differences in approval. In Europe, where this drug has already been approved, or the data at least are sufficient for approval, the drug should be on the market in Europe in Q4 of 2016. Europe is able to approve drugs based on well-understood biomarkers, and this is clearly an example of that. In the US, we will wait until hard outcomes are done. So until you see a mortality benefit, or a MACE reduction, major adverse cardiac event reduction, this will not be approved. So the US is going to lag by a couple of years here.

• 30:43Dr. Peter Attia?

  Let's talk about what I really wanted to talk about. It's not that I didn't want to talk about all this stuff, I really did. But I want to now get into the part that is super exciting to me, which is brain biology and APOE. So the brain is one of the most lipid-rich organs in the body. And of course, cholesterol is one of the most important structural components of neuronal membranes, synapses, and myelin. So without cholesterol, the brain is not going to function. But there's a catch, right? The brain lives behind a paywall. We call it the blood-brain barrier. It's not really a paywall, but I just wanted to say that. So the brain lives behind a blood-brain barrier. And that blood-brain barrier separates the brain's cholesterol economy from the rest of the body. So the lipoprotein particles that we measure in the blood

• 31:28Dr. Peter Attia?

  are essentially sequestered from the brain. And as such, the brain cannot rely on circulating cholesterol the way the liver can. Instead, the brain runs its own semi-independent lipid management system, which transports its own lipoproteins. Now, in the periphery and the rest of the body, outside of the blood-brain barrier, cholesterol balance depends on a very coordinated system of lipoprotein particles. We've talked about this, right? So we talked about the HDL particles, which are built around APOA1. They accept cholesterol from cells, transport back to the liver, sometimes give them to LDLs to take them back to the liver. All of this stuff is going on. And I didn't even get into the rest of that stuff, but we know that as the liver excretes bile, bile travels through the gut.

• 32:13Dr. Peter Attia?

  The gut has another check in there where it gets to bring cholesterol in, determine if we need it or not. If not, we excrete it. If yes, we bring it back in. There's like, the body is really, really pretty marvelous when it comes to this. But the brain uses a very different set of proteins to mediate this. Now, instead of using APOA1, which is the protein on the HDL that is largely responsible for this accounting, its lipoproteins, the one in the brain, are organized around something called apolipoprotein E or APOE. So astrocytes and microglia synthesize APOE-containing particles that shuttle cholesterol and phospholipids to neurons. These particles support membrane repair and synaptic remodeling

• 32:58Dr. Peter Attia?

  and basically the overall lipid homeostasis within the CNS. Now, the efficiency of that system, of course, turns out to be highly genotype-dependent.

• 33:09Dr. Peter Attia?

  So, most people carry two copies of an isoform for the gene that makes this protein called APOE3. So, there are three isoforms, APOE2, APOE3, and APOE4. This is a bit of the problem with the nomenclature here. Whenever I'm talking about the gene, I'm talking about the all-caps version. So, capital A, capital P, capital O, capital E, and then the number, 2, 3, or 4. You get two of those, two genes, one from mom, one from dad. So, if, so there are six possible combinations, right? 2-2, 2-3, 2-4, 3-3, 3-4, 4-4. Each of those will yield a slightly different protein.

• 33:50Dr. Peter Attia?

  The protein is called APOE, no number, just APOE, and it's no caps. So, it's just little a, P-O-E, no caps. So, that's how you know if you're looking, thinking about the protein, or thinking about the gene that codes for the protein. So, if you look at the APOE protein that is made by two copies of the APOE3 gene, we call this the wild type, it handles cholesterol transport in the brain really well. But if you look at the protein, the APOE protein, that is made by one or two copies of the APOE4 gene, it does not. So, if you look at the protein made from one or two copies of an APOE4 gene, it's less efficiently lipidated, it interacts differently with transporters,

• 34:33Dr. Peter Attia?

  and it forms lipoprotein particles that are less structurally stable and less effective at moving cholesterol. And what's really amazing, by the way, as an aside, is all of this comes down to a single amino acid substitution. And for anybody who cares, it's a cystine to an arginine substitution at position 112. And that one little change alters the protein's shape and all of its downstream behaviors. And of course, this isn't unique here. If you look at something like sickle cell disease, it's the same sort of thing. It's one amino acid substitution that completely changes the way a red blood cell functions. In this case, you know, through hemoglobin. So, why do we care? Well, we care because if cholesterol isn't properly transported, it's going to build up and lip-

• 35:19Dr. Peter Attia?

  Droplets that form inside of astrocytes and microglia, they cause problems, right? The membrane composition shifts, oxidative stress, because remember cholesterol is highly sensitive to oxidative stress. That's what's leading to atherosclerosis. It increases amyloid clearance becomes less efficient. And inflammatory signals rise. And if that sounds like a bad thing, then you understand enough about Alzheimer's disease already, which is amyloid accumulates, inflammation increases. And over a long enough period of time, often decades, this impaired ability to traffic lipids is what contributes to synaptic dysfunction and ultimately to neuronal death. So this is why APO E4 is a concern.

• 36:02Dr. Peter Attia?

  If an individual has one or two copies of this gene, they are at an increased risk for Alzheimer's disease. Now, we also know that this is not a deterministic gene. There are lots of people that are walking around with APO E4 genes that are doing just fine in advanced age. So I don't want to be sitting here sending fear signals to those individuals. But we have to acknowledge that on average, statistically speaking, if you have one or two copies of that gene, you are basically getting sped up in your brain aging. And what that effectively means is if you have two copies of an APO E4 gene, your probability of developing clinically significant cognitive decline is going to be about two decades sooner than a person

• 36:47Dr. Peter Attia?

  who's got two copies of an APO E3 gene. Again, that's on average. It's not for everybody. There are lots of things that can modify this. We've talked about some of them. We've talked about clotho, K L V S. We've talked about all the lifestyle factors that can make a difference. But, you know, I just want to acknowledge the obvious here. Now, I think, kind of at first glance, I think, you know, CTEP inhibition might not really matter to this discussion because it operates in plasma, where it facilitates the exchange, as we talked about, between cholesterol ester, between the different particles of lipoproteins, right? The cholesterol esters that move between HDL and LDL.

• 37:27Dr. Peter Attia?

  And this creates a larger HDL particle where APO A1 stays on longer and it's cleared more slowly. So again, APO A1 concentrations increase. That's why we see HDL cholesterol go up. So what does this have to do with the brain? Well, APO A1 is a relatively small protein. And Therefore, small lipid-poor HDL particles, which contain ApoA1, can indeed cross the blood-brain barrier in limited amounts. So by increasing the circulating pool of ApoA1, the CTEP inhibitors can increase the availability of functional ApoA1 within the CNS. And so in the context of ApoE4 patients,

• 38:12Dr. Peter Attia?

  where endogenous lipid transport is less efficient, a greater concentration of ApoA1 could augment cholesterol efflux and at least partially offset the impaired functioning ApoE protein, right, the ApoE-mediated trafficking of that protein. Now, in addition to that, of course, Obicetrapib confers all the usual cerebrovascular benefits through the well-established atherosclerotic actions by lowering ApoB, et cetera. In addition, functional HDL particles can carry lipophilic antioxidants as well and move them.

• 38:55Dr. Peter Attia?

  So basically, increasing HDL concentration, especially HDLs that are small but yet functional, that can still get into the CNS, may raise the antioxidant content within the circulating HDLs and to a limited extent, within the CSF. So enhanced antioxidant availability could help attenuate the oxidative stress and lipid peroxidation process, which of course is also known to amplify neuroinflammatory signals. Now, again, this framework is somewhat speculative, but it is biologically coherent. It also offers a plausible explanation for why the most pronounced biomarker effects in the Broadway sub-study,

• 39:40Dr. Peter Attia?

  which I'm going to discuss here in a second, are observed in the ApoE4 E4 individuals. Because this is a group in whom lipid trafficking is the dysfunction of lipid trafficking, I should say, is the most noted. And therefore, this group, in theory, should benefit the most from everything I just said. Okay, so let me, let me just go back to the study because I'm kind of getting ahead of myself in the spirit of trying to explain the biology. So let's go back to the Broadway study. So remember, this is the one where there was a pre-selected endpoint.

• 40:13Dr. Peter Attia?

  So the investigators pre-selected a subset of this study to look at the biomarkers of Alzheimer's disease. And the primary endpoint was a change in plasma phosphorylated tau 217, known as P tau 217, over a period of 12 months, from baseline to a year out. They also looked at some secondary endpoints, which were changes in the ratio of P tau 217 to amyloid beta 42 to 40 ratio, and then P tau 181, something called glial fibrillary acidic protein, or GFAP, and neurofilament light chain, or NFL.

• 40:54Dr. Peter Attia?

  I just want to point out that P tau 217 is probably the most important of these, at least we believe that today, because it is the most highly correlated with the findings that we see on a type of PET scan that is used to measure tau. And that PET scan and its results tend to be the most highly correlated with the clinical outcomes that we see. So that's why they chose P tau 217 as the primary endpoint. The participants were stratified by their APOE genotypes. Specifically, they looked at three threes, three fours, and four fours, and then all the related subgroups. Okay. So in the final biomarker analysis, there were over 1,500 participants, median age

• 41:38Dr. Peter Attia?

  of 67, 2/3 of them are male. Now, these are patients without dementia or cognitive impairment, but they did have cardiovascular disease. It's always important to just remember what your patient population was. Let me spend one more second just going over the biomarkers. So as I said, plasma P tau, probably the strongest predictor we have in the periphery that correlates with Alzheimer's pathology. Again, I mentioned why, right? Amyloid PET positivity and tau aggregation are probably the best thing we can do to predate clinical stage symptoms. AB 42 40 ratio reflects amyloid biology, so as AB 42 becomes sequestered into plaque with the brain circulating.

• 42:22Dr. Peter Attia?

  AB42 declines relative to 40, which lowers that ratio. If you look at PTau217 to that ratio, it just integrates these two. GFAP is a marker of astroglial activation. And NFL is a marker of axonal injury and neurodegeneration. It's not specific to Alzheimer's disease, by the way, but when it, when levels are rising, it indicates neuronal damage. So if we take these things together and look at the results, what did we see? So across all participants, Obicetrapib significantly attenuated the increase in PTau217, the primary outcome, compared to placebo over 12 months.

• 43:06Dr. Peter Attia?

  So if you take everybody, the adjusted mean percentage increase in the placebo group was 5%. So PTau217 went up by 5% across everyone in the study over a year and in the placebo group. And then the Obicetrapib group, it only went up 2%. Now, what's interesting is if you start to look at the subgroups. So in the subgroups, if you look at the, just those that had an E4. So this was people who were E3, E4, or E4, E4. The difference is a little more stark. In the placebo group, you saw an increase of PTau217 by over 7%.

• 43:50Dr. Peter Attia?

  Whereas in the Obicetrapib group, it only went up about 1.5%. Now, what if you just looked at E3, E4, and E4, E4 in people over the age of 70? So again, what we're doing is we're taking that same population, but now we're looking at the people who are at even higher risk, just based on age. And here, we saw that in the placebo group, PTau217 over the course of a year rose by almost 15%, but it went up only by 6% in the Obicetrapib group. Again, that was statistically significant. But the most interesting finding for me, and I think anybody who would look at the

• 44:29Dr. Peter Attia?

  paper, is what happened in the admittedly small subset, 29 people of E4 E4s of any age. In this population, the placebo group saw an increase of almost 13%, 12.7% of PTau217 over the course of a year. And yet, in the group on Obicetrapib, they actually saw a reduction in PTau217 by nearly 8%, creating a difference of over 20% between those treatment groups. And that was, again, highly statistically significant, despite the small number.

• 45:09Dr. Peter Attia?

  So, all of this is to say that something really interesting could be happening in these APOE4 patients. Now, again, as I want to say, it's a very small subgroup, right? So this is a 1,500-person trial. 29 of those people were E4 E4. As a general rule in the population, E4 E4 is about 2% of the population. But E3 E4 is about 20% to 25% of the population. So there's still a lot of people out there who would benefit from this. We're just seeing an enormous impact in these people. In the overall population, again, the effect size is statistically significant. We don't know if it's clinically significant. I won't go into all the other biomarkers, just for the sake of time, but we're going

• 45:54Dr. Peter Attia?

  to link to the study in the show notes, so you can look and see all of the other biomarkers. But everything moved in the right direction. There was not a single biomarker for which Obicetrapib didn't do exactly what you would want it to do. This was true in PTau217, this was true in NFL, GFAP. Of course, the impact was most notable and most significant in the E4 E4. So there's one figure that you can look at, where you see the effect on the E4 E4s, and it's profound. So I'll go over that figure, because I already gave you the PTau217, where you see a 20% difference between placebo and

• 46:35Dr. Peter Attia?

  Treatment in the NFL, it's a 17% difference in the GFAP. It's a 15% difference in the PTW 181. It's almost a 14% difference in the AB 42 to 40 ratio. It's about an 8% difference. And in the ratio of the ratio, the PTW to the AB 4240, it's almost a 23% difference. So how do we interpret this? Well, let's be cautious here. Okay, so first and foremost, this is a biomarker study. It's not a cognitive outcomes trial. There were no formal cognitive tests that were included here. And we don't know for certain if these biomarker changes would translate into preserved cognition or a slower decline or, you know, reduced incidence of dementia.

• 47:20Dr. Peter Attia?

  As I said, PTW 217 is a very well validated biomarker. So everything looks very optimistic, but without the outcome trial, we don't know. Second thing we don't know is this is a short study. It was only 12 months. Alzheimer's is a disease that unfolds over decades. Do we know if we looked at over a long enough period of time, would this benefit be maintained? I already talked about the size of the subclass, very small group. Sometimes you can see extraordinarily results in small groups, and it's a bit of a weird statistical outlier, and we don't know what it's going to look like in a larger cohort. I think the last point I would make here is less of a knock, but it's just a, we don't know exactly why this is happening. Now, to be clear, we don't know why Clotho works either, and yet we still think it's very exciting and interesting. We don't know how Clotho works.

• 48:04Dr. Peter Attia?

  I mean, we don't even understand how Clotho impacts its targets in the brain, since it doesn't appear to cross the blood brain barrier. So all of that is to say, we know a bunch of things that opiceptropib does. We know that it modifies HDL particles and lowers LDL and APOB, reduces LP little a. But it's hard to say which of these are the ones that are contributing. And I personally find the HDL APOA1 story to be the most compelling argument here.

• 48:31Dr. Peter Attia?

  So what can we conclude? So I think we can say, look, this is a biomarker study that was internally coherent and very genotype specific, and I think it has very high biologic plausibility. I think we have to be cautious because biomarkers don't necessarily establish clinical benefit. We need more data, but I'm very excited. And I think personally that this signal is strong enough to justify a dedicated prospective prevention trial that should include cognitive outcomes, imaging, longer follow-ups, and frankly, larger genomic stratified groups. Now, such a study would need to be enriched for APOE4 carriers. So we'd want lots of E3 and E4.

• 49:15Dr. Peter Attia?

  So I'd want, if I were designing that study, I'd want, you know, I'd want as many, I'd want every E44 on the planet that I could get enrolled in that study, and I'd want basically 2/3 of the patients to be at least a 3, 4. In my mind, you want people who are completely cognitively intact in midlife or slightly older, so these are probably people in their 60s, maybe 70s, but again, completely cognitively intact, no evidence of MCI. And you're going to need to track these people for quite a long period of time. So it's going to need to have longitudinal cognitive endpoints that are going to be sensitive to early decline. It's going to have to have serial plasma biomarkers, maybe some imaging studies, including amyloid or tau PET, and it needs to run for several years.

• 50:00Dr. Peter Attia?

  So, look, I'm not suggesting that this is an easy thing to do. I'm just suggesting that if we lived in a parallel universe where resources were unlimited, that's the study that you would do to figure this out. So, look, it's hard for me to mask my personal optimism around this. I love the biological plausibility of this, and I think that Obicetrapib has done something that its four predecessors has failed to do. And I think if it did nothing else but have the impact that I think it's going to have from a cardiovascular disease standpoint, which is to say it's going to have a significant impact on LDL-C and APOB, I believe it will likely show a reduction in events, certainly over a long enough Period of time, the impact on LP little a is very interesting to me.

• 50:45Dr. Peter Attia?

  And the fact that it is metabolically neutral or potentially positive is also very exciting. And then you layer this on as well. This is, this is a drug I'm very excited about and look forward to learning more about the approval process in the United States. Again, I don't, I don't, I don't know exactly where it is in that life cycle, but I know it'll probably still be a couple of years after the European approval, which will lead to the launch of this drug in the second half or last quarter of 2026. So that'll wrap up our story on Obicetrapib. Hope you guys found that as interesting as I did. Thank you for listening to this week's episode of The Drive.

• 51:26Dr. Peter Attia?

  Head over to peteratia MD dot com forward slash show notes. If you want to dig deeper into this episode, you can also find me on YouTube, Instagram and Twitter, all with the handle peteratia MD. You can also leave us a review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment.

• 52:10Dr. Peter Attia?

  Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratia MD dot com forward slash about where I keep an up to date and active list of all disclosures.