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

Hey everyone. Welcome to a Sneak Peek, Ask Me Anything or AMA episode of the Drive podcast. I'm your host Peter Attia. 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 Peteratti md.com 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 podcast topics, specifically around insulin, hyperinsulinemia, apob, lp, 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 for, does 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 apob. 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.

Peter, welcome to another ama. How you doing?

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 MP44 McLaren shirt, which I really like.

Well, next year, we'll make sure to track one down for.

You 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 past podcast content as it relates to ASCVD. We've talked about this so much with AMA 34. We covered what causes ASCVD. We've had podcast guests dive deeper into things that can mechanistically contribute to increased risks. With LP, Laloa and Benoit, which is episode 210, APOB with Alan Snyderman, which was episode 185, and then insulin with Gerard Shulman, 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. They know APOB can increase risk. You know, LP can increase risk. Insulin, not good for ascvd. But the question is kind of how can they collectively influence the risk of someone? You know, there's questions around if my APOB is low, but my LP is high, you know, if my insulin is good, but my LDL or APOB is raised, how do I think about that? And so we compiled those questions, and that's what we're hopefully going to 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'd 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, now 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. 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 brake 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 apob, I mean, pardon me, LP is not under your control. So LP is just a low level of maintenance throttle that is put on the pedal. So somebody who's born with a low LP has a very low throttle application. Someone who's born with a high LP would have a higher throttle application. So we would just call this sort of baseline maintenance throttle. Now, your APOB is also going to be a part of that. So the question is, do you do things that lower apob? 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 brake. The more you're lowering apob, the harder you're pushing on the brake. If a 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 upregulation 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 the big things. So what are the big three things that are driving, ascvd, smoking, hypertension, apob, and then of course you have other things like LP 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 and Alan Snyderman talked is do you only look at 10 year risk when it comes to ASCVD, 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 and the longer you wait, the harder you're going to 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 a hundred 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 it a lot in ama34, if anyone hasn't listened, the 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 LP showing? Which we'll get into here shortly. So look at us, we're able to bring in a 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've maybe covered in other podcasts, but just kind of summarizing for the 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 APOB ldlc? Before we say that it might be important, we might interchange throughout these questions APOB and LDL C. You know, sometimes we get APOB specific questions. Sometimes people don't know they're apob and so they only know their LDL C. So do you maybe just want to give that 32nd version of oftentimes they are in concordance, sometimes they're in disconcordance. You always prefer to know apob, but if someone doesn't know APOB and they only have their LDL C, that can be a predictor as well. Is there anything maybe you want to say on that? Just to flush out for a little bit?

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 ldlp, the number of LDL particles. I prefer apob, which is the concentration of all particles that carry the APOB lipoprotein, which includes ldl, and that's the lion's share of them, but also VLDL and lp, 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 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 APOB concentration as the metric we are using as our goalpost.

Perfect. And again, for anyone who wants to dive deeper into that AMA 34 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 ASCVD parameters like apob?

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? Right. What's the canary in 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 hyperinsulinemia. Now, sometimes that doesn't occur at fasting. Sometimes that's in a postprandial state. And that for us is typically the true canary in the coal mine is it's a postprandial 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 D 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 apolipoprotein C3. It's a very interesting one. It's probably come up on a previous podcast. It might have been on the one with Nirbarzalai. I know I write about it in the book, but it is one of the genes. So the APOC3 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 a good thing. So the bad version of that is what we see. The expression pattern in people with hyperinsulinemia 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 lipoprotein lipase 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 APOB bearing particles, namely the VLDL particle, which is itself very atherogenic. In fact, if it sticks around a long time and becomes a remnant, it is especially atherogenic. So if we are increasing expression of Apoc3 and blocking the action of lipoprotein lipase, we 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. And 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 and that's probably due to the change in activity of a protein called cholesterol ester transfer protein ctep, which I don't think we'll get into now because I think we'll save that for an. An upcoming podcast where we will go. We have a dedicated podcast coming up that's gonna go into all things hdl. So I say we leave it at that and say that hyperinsulinemia 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 wanna also cover the second?

Yep. Thanks. Sorry, I got a little carried away on Apoc 3. I think the other thing where insulin, especially hyperinsulinemia, is playing a role is with endothelial dysfunction. So, again, if you take a step back and ask the question, what is the cascade of events that leads to ascvd? Endothelial 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 subendothelial space that increases more endothelial that, you know, sort of drives endothelial dysfunction and leads to a greater and greater cascade of more APOB 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 cells and you alter insulin concentration, you're going to see signaling pathways in the endothelium that suggest 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 endothelial dysfunction is also a manner through which hyperinsulinemia impacts the risk of ascvd.

And for people who might be kind of listening to this and thinking to themselves, okay, you know, how are my insulin levels? There's 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.

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Sam.