The Peter Attia Drive - #238 – AMA #43: Understanding apoB, LDL-C, Lp(a), and insulin as risk factors for cardiovascular disease

Episode Date: January 16, 2023

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this “Ask Me Anything” (AMA) episode, Peter answers questions related to the leading cause of death in both men and women—atherosclerotic cardiovascular disease (ASCVD). He highlights the most important risk factors for ASCVD, such as apoB, LDL, hyperinsulinemia, and Lp(a), and explains the mechanism by which they confer risk and how these factors are interrelated. Peter also dives deep into the data around apoB to try to answer the question of how much residual risk is conferred for ASCVD through metabolic dysfunction once you correct for apoB. He also looks at the data around lifetime risk reduction of ASCVD in the context of low apoB. If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #42 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: A racecar analogy for understanding atherosclerotic cardiovascular disease [2:00]; Defining and differentiating apoB and LDL-C [10:00]; The interrelated nature of insulin levels, apoB, triglycerides, and ASCVD parameters [13:00]; Another way that hyperinsulinemia plays a role in endothelial dysfunction [18:00]; Why Peter uses the oral glucose tolerance test (OGTT) with all patients [20:15]; Is there any evidence that hyperinsulinemia is an independent contributor to ASCVD? [23:00]; Thinking through risk in the context of high-fat diets resulting in improved metabolic metrics but with an elevation of apoB/LDL-C [27:30]; Thinking through risk in the context of low apoB but higher than normal triglyceride levels [32:15]; The importance of lowering apoB for reducing ASCVD risk [38:15]; Data on men and women with familial hypercholesterolemia that demonstrates the direct impact of high apoB and LDL-C on ASCVD risk [47:45]; Importance of starting prevention early, calcium scores, and explaining causality [52:30]; Defining Lp(a), its impact on ASCVD risk, and what you should know if you have high Lp(a) [56:30]; Lp(a) and ethnic differences in risk [1:00:30]; Why someone with elevated Lp(a) should consider being more aggressive with apoB lowering strategies [1:05:00]; Addressing the common feeling of hesitancy to taking a pharmacologic approach to lower ASCVD risk [1:07:15]; Peter’s take on the 2022 Formula 1 season and thoughts on 2023 [1:15:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to a sneak peek, ask me anything, or AMA episode of the Drive Podcast. I'm your host, Peter Atia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to PeterittiaMD.com forward slash subscribe. So without further delay, here's today's sneak peek of the Ask Me Anything episode. Welcome to Ask Me Anything episode number 43. I'm once again joined by Nick Stenson. In today's episode, we answer a lot of follow-up questions we've had on some recent podcasts, topics specifically around insulin hyperinsulinemia, APOB, LPLitLA, and how they all relate to how

a person should be thinking about their risk of atherosclerotic cardiovascular disease, which is, just as a reminder, the number one leading killer in the US worldwide for men, for women. So one of the things we try to do in this podcast is really get at the data around how much residual risk is conferred for ASCVD through metabolic dysfunction once you correct for APOB. And there are some things that I think we have data that we can speak to and we talk a lot about those things. So for example, we get into the mechanism by which hyperinsulinemia increases the risk of ASCVD. And of course, the question is once APOB is corrected forward, is that risk still exist? Well, we attempt

to tackle that. We also talk about what Mendelian randomization tells us about lifetime risk reduction of ASCVD in the context of low APO-B. So these are just a couple examples of some of the topics that we get into at a pretty nuanced level in this podcast. If you're a subscriber and want to watch the full video of this podcast, you can find it on the show notes page. And if you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy AMA number 43. I'm doing well, although looking at your t-shirt and realizing that you probably bought that at Coda, I'm a little less good because I'm realizing I somehow missed that shirt and didn't buy one myself.

Yeah, it's a good looking shirt. And we didn't plan this, but we're both wearing the white, black, and red today, just a little different fonts on the front. Do you want to tell people about your shirt? I have a Red Hot Chili Pepper shirt. You have a Senna 1988 MP4 4 McLaren shirt, which I really like. Well, next year we'll make sure to track one down for you. I have to find it. All right, perfect.

So, Peter, for today's AMA, what we did is we just gathered a lot of questions that have come from podcast content as relates to AACVD. We've talked about this so much with AMA34, we covered what causes AACVD. We've had podcast guests dive deeper into things that can mechanistically contribute to increase risk with LP Lale and Benoit, which is episode 210, Apo B with Alan Snyderman, which was episode 185, and then insulin with Gerard Schullman, which was episode 140. And that was also one we recently rebroadcast, because we know we have a lot of new listeners who may not have heard that and the importance there. And so what we did is we combined a lot of these questions, because there's a lot of people

who are kind of wondering how they fit together, right? They know ApoB can increase risk. You know, L.P. the like and increase risk. insulin, not good for AACVD, but the question is kind of how can they collectively influence the risk of someone? You know, there's questions around if my ABOB is low, but my L.P. the L.A. is high, you know, if my insulin is good, but my LDL or ABOB is raised, how do I think about that?

And so we compiled those questions, and that's what we're hopefully gonna cover here today. So it's a little bit related to formula one, but not quite fully there, but on the plus side, much like formula one, you do like talking about cardiovascular disease So at least it's an interest there, but anything you want to add before we get started No, but just for the record I do prefer talking about formula one over

APOB, but I think APOB is more important So I probably spend more time talking about it just to clarify Is there an analogy that you can use that ties APOB to cardiovascular disease as it relates to Formula One? Not off the top of my head, but I accept the challenge. All right. I feel like that's a good thing for you to work on because I'm surprised that you don't have one off the top of your head.

Usually race car analogies as it relates to health, you're pretty good at whipping those out. Well, actually, I do know that I think about it. So if you imagine this could really be applied to other things, but I think with ASCVD, there's a pretty good application rate. So if you imagine your lifespan is the length of time it takes you to drive a race car from point A to point B where point B is driving it off a cliff.

And you have two feet and two pedals, right? So you have the accelerator and you have the break and your feet are always on both pedals. So it's really just a question of how hard are you pressing on each one? Now, in this analogy, there's never a point when the car is not moving towards the edge of the cliff, but you can do things that really speed up the drive, which means you're moving towards death more quickly. That would mean you're pressing much more on the throttle than you are on the brake. Conversely, you could have minimal pressure on the throttle and much more pressure on the brake and really slow your forward progress. So then the question becomes, what are the factors that you could be doing that accelerate the drive towards the cliff

and what are the things that you can be doing that slow that trajectory. So some of those things are kind of not under your control. So APO B, pardon me LP. LPLL A is not under your control. So LP. LL is just a low level of maintenance throttle that is put on the pedal. So somebody who's born with a low LP. LL has a very low throttle application. Someone who's born with a high LP little A would have a higher throttle application. So we would just call this sort of baseline maintenance throttle. Now, your APO B is also going to be a part of that.

So the question is, do you do things that lower APO B? Obviously, there's dietary things that do so. But if we're really talking about reducing APOB to the levels that we call physiologic, that's really going to be the application of pharmacotherapy. So that would be kind of pressing much harder on the break, the more you're lowering ApoB, the harder you're pushing on the break. The person has, for example, type 2 diabetes, which we'll talk about in a second, that is generally accompanied by hyperinsulinemia.

Well, what is hyperinsulinemia doing in this equation? It is pressing harder on the throttle. It is accelerating through mechanisms like up regulation of ApoC3 expression, which regulates ApoB in the wrong direction. So more ApoC3 means more ApoB impacts the LDL receptor. The LDL receptor-related protein. It moves all of these things in the wrong direction. So insulin is basically changing the amount of LDL particle that you have in circulation.

I guess I could build that out a little bit more. Obviously, smoking, what would that be? Smoking is hammering on the throttle, having high blood pressure and lowering high blood pressure. Those are really big things. So what are the big three things that are driving a CVD, smoking, hypertension, APOB. And then of course, you have other things like LP, little A, hyperinsulinemia. So I guess that would be my analogy, right? Which is, we have a car that we can't actually stop, but we can really slow it down to a dull roar, and that's going to be through some combination of manipulating the brake and the throttle. I mean, the other piece of that, which to tie in other things we've talked about, is also

how much space do you have between where your car is now, and the cliff is going to be a result also of how old you are. And so when you look at risk and how you think about risk, you know, it's something you announced. And I've been talked is do you only look at 10 year risk when it comes to a cbd, which is kind of that medicine 2.0 approach, or do you look at 50 year risk when it comes to that, which is that medicine 3.0 approach, because if you wait until the earlier you work

on the throttle and brake, the more time you have to make interjections in the longer you wait, the harder you're gonna have to press on that brake, but that still might not be enough with based on where you're at. Yep, I think that's exactly right. And that's another thing I like about that analogy, the more I think about it is,

if you're 100 feet from the end of the cliff and you're traveling fast, you better get ready to lock up the brakes. And if you have a mile between you and the cliff, you can be a lot more judicious in your use of the brake pedal. Another way to say it, and we don't have to get into it because we covered a lot in AMA 34, if anyone hasn't listened to beginning of that, is basically no matter what age you are, don't tune out on this conversation because you need to care about these things.

Even if you're 30, 35, 40, you may feel you're in good health. Your insulin may be low, but what is your APOB? What is your LPOB like showing, which we'll get into here shortly? So, ha, look at us. We're able to bring in AI race car analogy early on, which is always a positive. So, the first question,

I don't think we need to go into this level of detail. You may be competent in other podcasts, but just kind of summarizing for the rest of the conversation to set the stage a little bit, are there relationships between insulin levels and other lipid, ASCVD parameters such as ABOB LDLC? Before we say that, it might be important. We might interchange throughout these questions,

ABOB and LDLC. Sometimes we get ABOB specific questions. Sometimes people don't know their ABOB and so they only know their LDLC. So, do you maybe just want to give that 30-second version of, oftentimes they are in concordance, sometimes they're in disc concordance. You always prefer to know ApoB, but if someone doesn't know ApoB and they only have their LDLC,

that can be a predictor as well. Is there anything maybe you wanna say on that just to flush out for a whole lot of things? I think it's important for people to understand what they are. So LDLC is a laboratory measurement that measures the concentration of cholesterol contained within the LDL particles. LDL by itself is not a laboratory measurement. So not to be sort of too much of a stickler,

but if somebody says, what's your LDL, there's no answer to that question. Meaning LDL, low-density lipoprotein is not a laboratory measurement. So it's either LDL-C, the cholesterol concentration within, or LDL-P, the number of LDL particles, I prefer APO-B, which is the concentration of all particles that carry the APO-B lipoprotein, which includes LDL, and that's the lion's share of them, but also VLDL and LP little A, which is a subset of the LDL. So in summary then, your LDL cholesterol concentration is a predictor of risk, the higher it is, the more likely your risk, but the APOB is a better predictor of risk because it captures not only the concentration of LDL, and we know that it's the number of particles more than the

cholesterol concentration of the particles that drives risk, but also because it includes the other atherogenic particles, namely the VLDL, because the LP little A is generally captured inside of the LDL though we like to know that separately because in people for whom it's very high and we'll probably get to this later today. Our best strategy at the moment to reduce residual risk of course is to obliterate APOB concentration. So we measure all of these in our patients but at the end of the day, we look heavily at APOP concentration as the metric we are using as our goalpost. Perfect.

And again, for anyone who wants to dive deeper into that, AMA34 and also episode number 185 with Alan Snyderman really gets into a lot more in the weeds there, if that's of interest. And people haven't gone back and listened to those. But with that being said, let's kind of get back to the question, which is, you know, are there relationships between insulin levels and other lipid, ACVD parameters like apopie? Yeah, I mean, to me, the two most obvious ways in which, well, let me take a step back. So let's explain the observation. The observation

that is unequivocal is hyperinsulinemia is associated with worse outcomes in ASCVD. The most obvious example of that is type 2 diabetes, which is just a very extreme manifestation of hyperinsulinemia. Of course, type 2 diabetes is defined by glucose level, but again, as we talked about with Jerry Shulman, we've talked about this in many podcasts. What is the precursor to that? What's the canary and the coal mine? Years before a person shows up at their doctor and the doctor says, hey, you've got type 2 diabetes. If you knew where to look, you would see hyperinslenemia. Now, sometimes that doesn't occur at fasting. Sometimes that's in a post-pran deal state. And that,

for us, is typically the true canary in the coal mine. It's a post-prandial challenged glucose response, where glucose is normal, but insulin is distorted. Insulin is elevated. So when we see that 30, 60 minutes after you've been challenged with glucose, you have elevated insulin, we know that you're on the path towards insulin resistance. Okay, so we have this observation, which is people with type 2 diabetes are about twice as likely, maybe 50% to 2x likely of developing ASCVD, and in fact, all cause mortality. So now the question is why? What's the mechanistic explanation for this? I think the two that are most important are the impact that insulin and insulin resistance has on the expression of ApoC3. So ApoC3 is another lipoprotein.

So Apo-lipoprotein C3, it's a very interesting one. It's probably come up on a previous podcast. It might have been on the one with Near Barsalai. I know I write about it in the book, but it is one of the genes, so the APO C3 gene is one of the sort of centenarian genes. So centenarians are more likely to have a version of that gene that results in lower expression. So in other words, you can think of it, that's the good thing. So the bad version of that is, you know, what we see the expression pattern in people with hyperinsulinamine and insulin resistance is that we kind of upregulate that. And if we do that, if we increase the expression of that,

it blocks the activation of something called LIPE-approteen light paste, or LPL. And LPL is an enzyme that sits on cells that basically performs a function of controlling lipolysis. So one of the side effects we see of blocked LPL activity is less utilization of triglyceride. So if you're using them less, what's happening? You're increasing the amount of triglyceride you have. So now let's think back to what does that mean. So if you increase the concentration of triglyceride, and again, clinically, that's very obvious. You measure that in a standard lipid panel.

We know that risk goes up, but the question is through what mechanism? Well, it goes up through APOB. Why? Because triglycerides like cholesterol are not water soluble. They're fat soluble, which means they can't be trafficked on their own. They can't just freely float through plasma. They need a chaperone. And the most common chaperone we use to move cholesterol are apobabaring particles, namely the VLDL particle, which is itself very arthrogenic. In fact, if it sticks around a long time and becomes a remnant,

it is especially arthrogenic. So if we are increasing expression of ApoC3 and blocking the action of lipoprotein lipase, we're going to see a net increase in triglyceride. And furthermore, we're going to see a specific increase in a type of LDL, which is triglyceride rich. So we really don't want to see these triglyceride rich LDLs. We want the triglycerides to be utilized because if you have now triglyceride rich LDLs and their purpose there is to really carry cholesterol, what does the body do? It has to make more LDLs and that means the concentration of apob is going up. I would say that's probably the most common, I would say that's the most important mechanism.

The way we basically see that is, we're going to see high plasma levels of triglycerides and we're going to see other things as well. I didn't get to this, but you're also going to see HDL cholesterol concentration go down. That's probably due to the change in activity of a protein called cholesterol ester transfer protein C-TEP, which I don't think we'll get into now, because I think we'll save that for an upcoming podcast where we will go, we'll have a dedicated podcast coming up that's going to go into all things HDL. So I say we leave it at that and say that hyperinslenemia is a risk factor that also increases both directly

and indirectly the risk of ASCVD. Peter, that makes sense. And I know in your answer, you mentioned there was two things that really affected and you covered one of them. Do you want to also cover the second? Yep, thanks, sorry. I got a little carried away on ApoC3.

I think the other thing where insulin, especially hyperinsulinemia is playing a role is within the ethereal dysfunction. So again, if you take a step back and ask the question, what is the cascade of events that leads to ASEVD? And the ethereal dysfunction is an important risk factor. Why? Because if the endothelium is not working. The apoB particles have an easier time getting through the gaps and into the subendothelial space. And furthermore, we know that that's what sort of propagates the risk.

So as the apoB particles get retained and oxidized and the immune cells, namely macrophages, well, monocytes that become macrophages undergo the phagocytosis of the oxidized LDL particles and become foam cells, that creates sort of an inflammatory milieu in the subendithelial space that increases more endothelial, that, you know, sort of drives endothelial dysfunction and leads to a greater and greater cascade of more apoby particles being retained, oxidized, et cetera. Well, insulin itself seems to drive this endothelial dysfunction. Now, this is a much harder thing to demonstrate because we don't really have great clinical commercial assays

for endothelial function. We have a bunch of indirect things, but if you do look at cultured endothelial function. We have a bunch of indirect things, but if you do look at cultured endothelial cells and you alter insulin concentration, you're going to see signaling pathways in the endothelium that suggests that they are becoming less functional. So I guess I would say that this is probably not as well studied and easy to demonstrate as the other mechanism I mentioned, but I think there's reasonable evidence that endothial dysfunction is also a manner

through which hyperinsulinemia impacts the risk of acidity. And for people who might be kind of listening to this and thinking to themselves, okay, you know, how are my insulin levels? There is a very clear definition of type 2 diabetes, which is you get your blood checked, your A1C is like above X amount. But for people, you kind of mentioned earlier in the conversation, you also look at a different test, which is an OGTT test, which is something that someone can do, which maybe is that canary in the coal mine. You just want to let people maybe know a little bit about that OGTT in case anyone's wondering

to themselves, like, look, based on my blood work, I know I don't have type 2 diabetes, but now I'm kind of curious what my insulin level is, and if this is something I should be worried about, how do I find out more to learn my current state? Thank you for listening to today's sneak peak AMA episode of the Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a member. We created a membership program

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