ApoB, LDL-C, Lp(a), and insulin as risk factors for cardiovascular disease [AMA 43 sneak peek]

1. 0:00 – 0:08

   Intro

   1. PAPeter Attia0:00

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

2. 0:08 – 9:15

   A racecar analogy for understanding atherosclerotic cardiovascular disease

   1. SPSpeaker0:10

      Peter, welcome to another AMA. How you doing?

   2. PAPeter Attia0:14

      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.

   3. SPSpeaker0:27

      Ah, 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 wanna tell people about your shirt?

   4. PAPeter Attia0:39

      I have a, I have a Red Hot Chili Peppers shirt. You have a, you have a Senna 1988 MP4/4 McLaren shirt, which I really like.

   5. SPSpeaker0:49

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

   6. PAPeter Attia0:53

      I'll have to find it.

   7. SPSpeaker0:55

      All right. Perfect. So Peter, for today's AMA, um, what we did is we just gathered a lot of questions, uh, that have come from past content, podcast content as relates to ASCVD. Um, 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 risk with Lp (a) and Ben Waugh, which is AMA two... Or which was episode 210, ApoB with Alan Sniderman, which was episode 185, and then insulin with Gerard Shulman, which was episode 140. And that was also one we recently rebroadcast, 'cause 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 kinda wondering how they fit together, right? They know ApoB, like, can increase risk. You know Lp (a) can increase risk. Insulin, you know, 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 (a) 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 gonna cover here today. So it's a little bit related to Formula 1, but not quite fully there. Um, but on the plus side, you, much like Formula 1, you do like talking about cardiovascular disease, so at least it's an interest there. But anything you wanna add before we get started?

   8. PAPeter Attia2:41

      Uh, no, but just for the record, I, I do prefer talking about Formula 1 over ApoB. Uh, but I think ApoB is more important, so I probably spend more time talking about it, just to clarify.

   9. SPSpeaker2:53

      Is there an analogy that you can use that ties ApoB to cardiovascular disease as it relates to Formula 1?

   10. PAPeter Attia3:04

       Not off the top of my head, but I, uh, I accept the challenge.

   11. SPSpeaker3:08

       All right. Like that's something... That, I feel like that's a good thing for you to work on, 'cause 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.

   12. PAPeter Attia3:21

       Well, actually I do now that I think about it. [lip smacks] So if you imagine, um... And if, this could really be applied to other things, but I think with ASCVD there's a pretty good application, right? So if you imagine your lifespan is the length of time it takes you to drive, uh, 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 are you, how hard are you pressing on each one? Now, in this, um, [lip smacks] analogy, there's never a point when the car is not moving towards the end of the, uh, edge of the cliff. Um, but you can do things that really speed up the drive, which means you're moving towards death more quickly. Uh, and obviously that's, you know, that would mean you're pressing much more on the throttle than you are on the brake. Conversely, you could have minimal pressure, 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, um, some of those things are kind of, you know, not under your control. So ApoB... I mean, pardon me, Lp (a) is not under your control. So Apo... So sorry, Lp (a) is just a low level of maintenance throttle that is put on the pedal. So somebody who's born with a low Lp (a) has a very low throttle application. [lip smacks] Someone who's born with a high Lp (a) would have a higher throttle application, so we would just call this sort of baseline maintenance throttle. [lip smacks] Now, your ApoB is also going to be a part of that. So the question is: Do you do things that lower ApoB? Uh, obviously there's dietary things that do so, but, 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. [lip smacks] 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 the person has, for example, type 2 diabetes, which we'll talk about in a second, they, that is generally accompanied by hyperinsulinemia. Well, what, what is hyperinsulinemia doing in this equation? It is pressing harder on the throttle. It is accelerating through mechanisms, uh, like, uh, you know, upregulation of ApoC3 expression, which regulates ApoB in the wrong direction, right? So more ApoC3 means more ApoB. Uh, it impacts the LDL receptor, the LDL receptor-related protein. It moves all of these things in the wrong direction. So insulin is, um- Um, basically changing the amount of, uh, LDL particle that you have in, in circulation. Um, so anyway, I don't know. I, I guess I could build that out a little bit more. Obviously smoking, what would that be? Smoking is hammering on the throttle, right? Uh, having high blood pressure and lowering high blood pressure, those, those are really the big things. So if you... So what are the big three things that are driving ASCVD? Smoking, hypertension, apoB. And then of course you have other things like Lp (a) , hyperinsulinemia. So I guess that would be my analogy, right? Which is, you know, we have a car that we can't actually stop, um, but we can really slow it down to a dull roar. Um, and that's going to be through some combination of manipulating the brake and the throttle.

   13. SPSpeaker7:11

       I, I think that's good. And 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 gonna be a result also of how old you are, right? And so when you look at risk and how you think about risk, you know, it's something you and Alan Sniderman talked is do you ha- 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 3.0, medicine 3.0 approach? Because if you wait until like y- like 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 gonna have to press on that brake, but that still might not be enough with based on where you're at.

   14. PAPeter Attia8:08

       [lip smack] Yep. I, I think that's exactly right, and that's another thing I, I guess I, I like about that analogy the more I think about it is, um, if you're 100 feet from the end of the cliff and you're traveling fast, uh, you better get ready to lock up the brakes. Um, and if you have a mile between you and the cliff, uh, then, you know, you can be a lot more judicious in your use of the brake pedal.

   15. SPSpeaker8:34

       Yeah. And I mean, another way to say it, and we don't have to get into it because we covered it a lot in AMA 34, 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 (a) showing? Which we'll get into here shortly. So, ha, look at us. We're able to bring in a, uh, race car analogy early on, which is always a positive.

   16. PAPeter Attia9:12

       Yep.

   17. SPSpeaker9:14

       So

3. 9:15 – 12:36

   Defining and differentiating apoB and LDL-C

   1. SPSpeaker9:15

      the first question is, you know, I don't think we need to go into this level of detail. You've maybe covered it in other podcasts, but just kinda 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 apoB, LDL-C? And maybe before we... Sorry, before we say that, um, 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 their apoB and so they only know their LDL-C.

   2. PAPeter Attia9:55

      Yep.

   3. SPSpeaker9:56

      So do you maybe just wanna give like that 30-second 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 wanna say on that just to flush out for the whole conversation?

   4. PAPeter Attia10:16

      Well, I think, I think it's important for people to understand what they are. So LDL-C 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, a stickler, but if somebody says, "What's your LDL?" There's no answer to that question. Uh, 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 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 (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 (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 apoB concentration as the metric we are, um, using as our goalpost.

   5. SPSpeaker12:19

      Perfect. And again, for anyone who wants to dive deeper into that Um, AMA 34 and also, um, episode number 185 with Alan Schneiderman really gets into a lot more in the weeds there, if that's of interest and people haven't gone back and listened to

4. 12:36 – 18:17

   The interrelated nature of insulin levels, apoB, triglycerides, and ASCVD parameters

   1. SPSpeaker12:36

      those. But with that being said, let's kind of get back to the question, which is, you know, are the relationships between... are there relationships between insulin levels and other lipid ASCVD parameters like apoB?

   2. PAPeter Attia12:49

      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, and 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, 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, 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, so we have this observation, which is people with type 2 diabetes are about twice as likely, um, maybe 50% to, 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 apoC-3. Uh, so apoC-3 is an, is another lipoprotein, so uh, apolipoprotein C-3. It's a very interesting one. It's probably come up on a previous podcast, perhaps where I... It might have been on the one with Nir Barzilai. Um, I know I write about it in the book, but it is one of the, uh, genes, so the apoC-3 gene is one of the, the sort of centenarian genes. So centenarians are more likely to have a version of that gene that results in lower expression. Uh, so in other words, you can think of it that that's a good thing. So the bad version of that is, you know, what we see the expression, uh, 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, um, uh, is an enzyme that, uh, sits on cells that basically, uh, performs a function of controlling lipolysis. So it, um... So, so one of the side effects we see of blocked LPL activity is less utilization of triglyceride, uh, and an increase... 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, 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's es- it is especially atherogenic. So if we are reducing, um, um... Sorry. If we are increasing expression of apoC-3 and blocking the action of lipoprotein lipase, we're going to see, um, a net increase in triglyceride, and furthermore, we're going to see a s- a specific increase in a type of LDL which is triglyceride rich. So, um, 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 they're also, 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. So I, I would say that's, you know, probably, uh, the, the most common... or I would say that's the most important mechanism, and, you know, the way we basically see that is we, you know, we, we're gonna see high plasma levels of triglycerides and we're gonna see, um, you know, other, other things as well. I didn't get to this, but you know, you're also gonna see HDL cholesterol concentration go down, and that's probably due to, um, the, the, the change in activity of a protein called cholesterol ester, uh, ester transfer protein, CETP, which I don't think we'll get into now 'cause I think that we'll save that for 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, uh, hyperinsulinemia is, um, is a, is a, is a risk factor that also increases, uh, both directly and indirectly the risk of, of, of ASCVD.

5. 18:17 – 23:56

   Another way that hyperinsulinemia plays a role in endothelial dysfunction

   1. SPSpeaker18:18

      Yeah. Peter, that makes sense, and I know in your answer you said, you mentioned there was two things that really affect it, and you covered one of them. Do you wanna also cover the second?

   2. PAPeter Attia18:26

      Yep, yep. Thanks. Sorry, I for- I got a little carried away on apoC-3. Um, I think the other thing where insulin, uh, 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, uh, 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, um, 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, um, well, monocytes that become macrophages undergo the phagocytosis of the oxidized LDL, um, particles and become foam cells, that creates sort of an inflammatory milieu in the subendothelial space that increases more endothelial, that, that, 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, um, drive this endothelial dysfunction. Now, this is a much harder thing to demonstrate because we don't really have great clinical, uh, commercial assays for endothelial function. We have a bunch of indirect things. Um, but if you do look at, uh, cultured endothelial cells and you alter insulin concentration, you're going to see, um, signaling pathways in the endothelium that suggest that they are becoming less functional. So, um, I guess I would say that this is probably not as well studied and easy to demonstrate as the other mechanism I mentioned, but, uh, I, I think there's reasonable evidence that, that endothelial dysfunction is also a manner through which hyperinsulinemia impacts the risk of ASCVD.

   3. SPSpeaker20:33

      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 learn my current state?

   4. PAPeter Attia21:25

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Episode duration: 24:08