Rhonda: So let's talk about the number. So the LDL... I'm sorry, the ApoB number, because if most people go to a standard lab and they measure their ApoB, there's a reference range. And it says, okay, if you're less than 80 milligrams per deciliter, then you're okay. Where does that number come from? And has anyone measured ApoB levels across the lifespan? Do we know, like, is there a correlation with ApoB levels and the beginnings of atherosclerosis? Has someone done those studies? That sort of thing.

Peter: Yeah. So the reference ranges are purely population-based distribution questions. So every lab will have a different way of doing this, but a general philosophy for labs is... So the lab we use... And by the way, we completely ignore these reference ranges, but they're there. We can't avoid them. They're there. And we explain to our patients that we're going to editorialize on top of them. The reference lab we use will say ApoB below 80 is wonderful. Well, 80 just happens to be the 20th percentile of the population. It will say 80 to 120, it says is intermediate risk, and above 120 is very high risk. So for the lab we use, we know that 80 is the 20th percentile, 120 is the 80th percentile or the 60th percentile. I can't remember. So it's literally just putting you up against a population distribution and that's it. Now, our philosophy on ApoB is completely different. And as you may recall, I devote actually quite a bit of real estate to this in the book because I think it is such an important concept. And it is, in my opinion, certainly top three failures of medicine 2.0 is in failing to appreciate the point I'm about to make, which is that once you understand the causality of ApoB, meaning once you understand that ApoB is not just associated with cardiovascular disease, but it's causally linked to it, meaning it causes ASCVD, to get into this discussion about managing 10-year risk, thinking about being in this percent versus this percent makes no sense. When you have causal things that cause disease, you eliminate them. And the analogy I use is cigarettes with lung cancer. So nobody disputes that cigarettes are causally linked to lung cancer. They are. It's as clear as Tuesday follows Monday. But people forget that causality doesn't mean everybody who smokes will get lung cancer and it doesn't mean that every person with lung cancer smoked. So you don't need to be necessary and sufficient, necessary or sufficient to still be causal. But our approach to patients who smoke is very clear, which is never smoke. And if you do smoke, stop immediately. Do we look at people who smoke and say, well, once your 10-year risk of lung cancer reaches this threshold, we're going to tell you to stop smoking. Or once your pack year smoking is above the 50th percentile or the 80th percentile, we're going to tell you to stop. Absolutely not. You immediately eliminate smoking. And so similarly, it makes no sense that we would look at a causal driver of ASCVD in the case of ApoB and kind of take an approach of, well, being at the 20th percentile or the 30th percentile, the 40th percentile is acceptable. None of those things really make sense. You have something that is causing the disease, you should eliminate it as soon as possible because it is an area under the curve problem. So atherosclerosis begins at birth. When you do autopsies on people who are very young, in fact, in the book include a photo of a guy who, a man, I forget, I think maybe 26 years old who was a victim of a homicide or something. So a completely unrelated death. But you look at the autopsy sections of his coronary arteries, he already had very advanced atherosclerosis. Now, it wasn't clinically relevant. It wasn't going to kill him anytime soon. But the point is, this is a disease that takes decades to progress. And one of the biggest drivers of it, in addition to things like high blood pressure and smoking and insulin resistance, is ApoB. So to be able to take that off the table sooner rather than later certainly has the potential to take atherosclerosis off its pedestal at the top of the list of killing.

Rhonda: And so what do you... I mean, you obviously can't take it off the table completely, right? We need ApoB. But what can you do?

Peter: So let's think about it. Yeah. So let's start with what we know. ApoB rises with age, right? We don't really know. There are probably a lot of little reasons. So there are endocrine changes, insulin resistance, senescence that might involve the decreased life of LDL receptors. There's no clear reason, actually.

Rhonda: What about... So you were talking about clearance versus synthesis. And I remember our mutual friend, Ron Krause. I've had many conversations with him. I did my post-doc down the hall from his lab, right? And I remember him telling me that ApoB, basically, your liver is constantly producing it. You're making VLDL, just churning it out, right? It's just going, going.

Peter: And we also make LDL de novo, by the way.

Rhonda: Right.

Peter: Yeah. There's a de novo pathway plus the VLDL to LDL pathway.

Rhonda: But the thing is that he was saying, well, from an evolutionary perspective, you're making this VLDL because, as you mentioned, it's transporting things throughout the body to other organs, right? Cholesterol, triglycerides, fatty acids. It's also transporting, and this is where I was so intrigued, inflammatory proteins. So cytokines, C-reactive protein, also are being transported through VLDL. Now, that was important pre-antibiotics, pre-everything that we do now to combat infectious disease and viruses and bacteria, parasites, whatever. But before that time, that VLDL did serve that purpose too. And that's why he thinks it's kind of a relic left over where the reason why we're constantly making it is because it's a very large protein in size. It's like tens of millions of the unit versus like 50,000 or something. It's very big. And so, it takes time to make it. And so, I was thinking, well, inflammation also does make it go up even further at the level of synthesis. I don't know exactly the clearance, how it's regulating clearance, but do you think the aging process is mostly affecting the clearance of it or?

Peter: My intuition is yes. My intuition is that it's primarily impacted on the clearance level, which is going to be, again, some facet of LDLR, LDLR meeting LDL receptor. So is it, we are making less of them, they are surviving less, the proteins that, and that can basically done. There are many ways to regulate that process, but that's my intuition is it's less a conformational change in the LDLR and more a number of them and or a reduced amount of time that they stay present. One thing I'll add on the evolutionary front, I had a guy named John Kastelin on my podcast a few months ago, and he proposed a really interesting idea, which completely makes sense evolutionarily, which you could argue sort of like, we don't really need ApoB. This is the other thing, most species don't have ApoB. They don't require LDL. But how, I mean- They have cholesterol, but they don't require- Transporting all these- You can do it with HDL.

Rhonda: You can transport everything with HDL?

Peter: Yeah. They don't need the LDL.

Rhonda: I thought HDL was always going in reverse, like it was bringing everything back to-

Peter: No, it's actually much more complicated. I mean, in us, LDL is doing the majority of what's called reverse cholesterol transport. So RCT, which is kind of like the good movement of cholesterol, you sort of think of the bad movement as taking cholesterol into the arteries, the good movement is taking it back to the liver. In us, LDL is doing the majority of that. So HDLs are typically transferring their cholesterol to LDLs and LDLs are bringing them back to the liver. But John made an interesting point, right? Which is that in sort of following up on what you said, the evolutionary cost of making cholesterol is enormous. I mean, it's a very labor intensive step, right? I can't remember the number of ATPs that are required to make a molecule of cholesterol, but it's in the tens, right? Like it could be 40 or something to that effect. And so we evolved to have a system that prioritized having a lot of cholesterol, being able to keep a lot of it around. Because again, this was an energy conserving system. Now this serves us no benefit today, because today we can make plenty of it. We are in an energy abundant environment, which we were not in hundreds of thousands of years ago. And so this is a bit of an unfortunate vestige of our past. Much in the way that a lot of the things that lead to insulin resistance are a vestige to things that were once very valuable. I mean, the things that allowed us to leap up out of the swamp with big brains was primarily our capacity to store excess energy in a way that even primates can't. Again, it served us really well until 150 years ago. And I think the same is probably true of cholesterol and ApoB. So going back to your question, how much ApoB is enough? Well, it turns out you don't really need any of it to be perfectly fine. So if you look at a child, they're born with an LDL cholesterol or ApoB level, typically below 20 milligrams per deciliter. So a kid, if you think about it, has the greatest need for growth, right? So you think about the cholesterol demand of myelinating the entire central nervous system, all of the enormous explosion of stroidal tissue, all of these things are done with lipoprotein levels that are incredibly low. Again, what we call physiologic levels of LDL cholesterol and ApoB are on the order of 10 to 30 milligrams per deciliter. And yet there are no negative consequences to such low levels of that lipoprotein burden. And it's only when we become teenagers and in our 20s that we start to see those numbers go up. And again, that's really just reflected by a reduction in clearance than some need for additional LDL. We don't have it. The majority of what we need is actually before the age of 20.

Rhonda: Do you think... So if you were to then estimate or speculate a level of ApoB that you could say safely... Well, I guess there's two things. One, you're not going to die of atherosclerosis if you maintain a level below...

Peter: Yeah. So Peter Libby from the Brigham, who's one of the authorities on this topic, has argued, and I reference him in my book, that if you had an ApoB level below about 30 milligrams per deciliter, 20 to 30 milligrams per deciliter, it wouldn't be possible to develop atherosclerosis.

Rhonda: What about not dying from atherosclerosis? Like what about like if it's the major cause of death globally? Yep. And let's say like what it takes to get down to 30 probably is pretty aggressive.

Peter: Yeah. Most people cannot get down to 30 without a pharmacologic intervention. Yeah. Yep.

Rhonda: Do you think that you would die of atherosclerosis if you had, you know... If you're at 60.

Peter: Well, it comes down to a couple of other things. So the first thing is, how long are you at 60? So if you say, I've never exceeded 60, that's very different from saying, hey, I showed up and I was at 120 and you now lowered me to 60. So again, I think of, you know, I imagine like everybody walks around and you've got a graph that on the x-axis is time and on the y-axis is ApoB and you have a curve and you want to figure out what the area under that curve is and that we want to minimize the area under that curve. So if you took... A lot of exposure. Exactly. So if you took... So again, very similar to smoking, right? Right. We talk about risk in pack years of smoking. So if a person smokes a pack a day for 20 years or two packs a day for, you know, 10 years, you know, you have a way of kind of comparing apples on those things. So to have a lifetime ceiling of 60 would also be a very, very low risk individual. 60 milligrams per deciliter is about the fifth percentile at the adult population level.

Rhonda: So then that comes back to my question... Sorry, one other thing I would add across the lifespan. When do you start measuring this? Like people aren't measuring their ApoB in their, you know, teenage or 20s.

Peter: Yeah. I mean, I would argue we should be, but I want to go back and say one other thing about your question, which I should have mentioned earlier, which is it also depends on other risk factors. So there are really four big things that are driving risk causally. ApoB is one, insulin resistance is one, hypertension is one, and smoking is one. Those are the big four. So you have to take everything we're saying on the ApoB front and acknowledge that those other things are also causally linked to ASCVD. So again, it's a difficult situation to imagine, but it's certainly at least theoretically plausible. You have somebody whose ApoB is at 60, but they have uncontrolled hypertension, type two diabetes, and they smoke. I mean, you could certainly arrive at that situation pharmacologically. You're probably not going to arrive at that situation naturally. Would I say that that person is free and clear? No, I wouldn't. So at the outset, I mentioned how the downside of talking about ASCVD is it's the number one killer. I mean, in fact, when you talk about it globally, the gap between ASCVD and cancer is even bigger. It's like 19 million people annually to 12 or 13 million for cancer. I mean, it's an enormous difference. But the good news is our understanding mechanistically of what drives this is so clear and our tools for prevention are some of the best and most benign.

Rhonda: Okay. So let's say that a person is relatively healthy, they're a committed exerciser, they're not insulin resistant. I do want to talk about hypertension and insulin resistance, but okay, healthy, generalized quote unquote healthy person, right? Wants to lower their ApoB. They want to try everything through diet, through lifestyle. And you mentioned there are some major dietary factors that can increase ApoB. So let's talk about those. What are the major...

Peter: So the big two are anything that contributes to insulin resistance. So we'll start with that. And that does so mostly through the VLDL triglyceride pathway. So we talked earlier about it, how there are really two ways we make LDL. We make LDL directly, but most of the LDL is made through VLDL. So if you're exporting a lot of VLDL, what you're doing is both making a lot of that lipoprotein, but you also have a lot of triglyceride in it. Now, something I didn't mention a moment ago that's worth restating or stating in the first place, the LDL is carrying around both cholesterol and triglyceride. And the more cholesterol there is, all things equal, the more LDL you need. But the same is true with triglyceride. So the first mechanism in which we see a very clear relationship between diet and ApoB is the higher the burden of triglycerides, the higher the burden of ApoB. To state this another way, if you take two people who have the exact same level of LDL cholesterol and the same total cholesterol, but one has very high triglycerides and one has very low triglycerides, the former is going to have a much higher ApoB and therefore be at a much higher risk of atherosclerosis because they have more cargo and therefore require more ships in the analogy of cargo being cholesterol and triglycerides and the ships being the lipoproteins. So step number one is lower the triglyceride as much as possible. And the triglyceride being low is an enormous proxy for insulin sensitivity. So this is one of the important ways in which managing insulin resistance is a key to keeping ApoB in check. And of course, there are other issues as well. So insulin and glucose by themselves when elevated also create problems at the endothelial level, which becomes another mechanism by which this is problematic. It's pretty clearly observed from a dietary pattern perspective that carbohydrate restriction is the most effective tool at triglyceride reduction. All carbohydrates?

Rhonda: I mean like vegetables, fruits- No, no, no.

Peter: Yeah, refined and starchy carbohydrates. Yeah. But that actually feeds really nicely into the next observation, which is what's the next dietary pattern that impacts ApoB and that's saturated fat consumption. And the reasons for that are twofold. So the first is that saturated fat directly impacts cholesterol synthesis. Now this is not true equally of all saturated fats, but we don't really have great data on if certain saturated fats have a greater impact on cholesterol synthesis relative to others. For example, a C16 might be potentially more so than a C18 or a C19. But again- What foods would you find a C16 versus? Oh, like a C16 would be more in, I believe like a coconut oil or a palm oil or something like that. Versus? Also, by the way, you would also see that more a C16 like a palmitate would be more of a saturated fat you see in response to insulin resistance. So it actually be a de novo saturated fat synthesis. So I think that's a big part of it. I think cholesterol synthesis is a big part of it. I think a bigger part of it might be that excess saturated fat inhibits the sterol binding, the sterol regulatory binding protein in the liver that results in fewer LDL receptors being made. So saturated fat therefore has two things that it's doing that are driving up ApoB and the susceptibility of this varies from different individuals. So I was on a ketogenic diet for three years. I was not one of the people who seemed to suffer from this. So even on a ketogenic diet where I was getting 80% of my calories from fat and probably half of that was saturated fat, I did not have any sort of obnoxious increase in my ApoB or LDL-C or any of these metrics. Similarly, we have some patients who were on very low carb, very high fat diets. Some of them have completely normal levels of lipids and some of them have lipids that go absolutely haywire. So it's not entirely clear what the difference is, but clearly there are different genes that will allow certain people to metabolize that saturated fat safely while others do not. So I'm not in the camp that believes that, and there is an entire camp of people who believe this, that if you're on a low carb, high fat diet and your ApoB and LDL-C go through the roof, it's not problematic. I don't believe that at all. I think that that's a very bold claim and I would not be willing to play that game. I think if your ApoB goes haywire, even if you're very insulin sensitive and even if you're in energy balance and all the other wonderful things that might come with your ketogenic diet, I think you have to pay very close attention to if your lipids get out of whack. So those are basically your big manipulations dietary-wise. It's the composition of fat, the quantity and composition of fat, and the dietary choices that address insulin sensitivity.