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

hey everyone welcome to the drive podcast I'm your host Peter attia here 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 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 you want to tell people about your shirt I have I have a Red Hot Chili Pepper shirt you have uh you have a Senna 1988 mp44 McLaren shirt which I really like well next next year we'll make sure to track one down for you I'll have to find it all right perfect so Peter for today's AMA um what we did is we just gathered a lot of questions that have come from past podcast content as relates to as CBD we've talked about this so much with AMA 34 we covered what causes as CBD we've had podcast guests dive deeper into things that can mechanistically contribute to increase risks with LP lolohe and Benoit which is AMA 2 or which was episode 210 April B 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 right they know APO B like can increase risk you know LP little a can increase risk and some one 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 APO B is low but my LP little 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 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 you 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 I do prefer talking about Formula One over APO B uh 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 I accept the challenge all right like that's something that 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 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 petals 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 are you how hard are you pressing on each one now in this um analogy there's never a point when the car is not moving towards the end of 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 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 or 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 APO B I mean pardon me LP little a is not under your control so APO so sorry LP little a is just a low level of Maintenance throttle that is put on the pedal so somebody who's born with a low LP little a 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 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 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 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 uh like you know upregulation of apoc3 expression which regulates apob in the wrong direction right so more APO C3 means more APO B 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 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 big things so if you what are the big three things that are driving ascvd smoking hypertension APO B and then of course you have other things like LP little 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 but we can really slow it down to a dull Roar um and that's going to be through some combination of manipulating the break in the throttle I think that's good and I mean the other piece of that which to tie on 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 right and so when you look at risk and how you think about risk you know it's something you and Allen snyderman talked is do you have do you only look at 10-year risk when it comes to ascbd which is kind of that medicine 2.0 approach or do you look at 50 or risk when it comes to that which is that 3.0 medicine 3.0 approach because if you wait until like like the earlier you work on the throttle and Brake the more time you have to make interjections the longer you wait the harder you're going to have to press on that break but that still might not be enough with based on where you're at yep I think that's exactly right that's another thing I I guess I like about that analogy the more I think about it is um if you're a hundred 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 then you know you can be a lot more judicious in your use of the brake pedal 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 APO B what is your LP level is 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 yep so the first question is you know 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 rest of the conversation to set the stage a little bit are there relationships between insulin levels and other lipid as CBD parameters such as apob ldlc and maybe before we Sorry before we say that um it might be important we might interchange throughout these questions apob and ldlc you know sometimes we get apob specific questions sometimes people don't know their APO B and so they only know their ldlc so do you maybe just want to give like that 30-second version of oftentimes they are in concordance sometimes they're in disc concordance you always prefer to know APO B 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 want to say on that just to flush well I think 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 ldlc the cholesterol concentration within or ldlp 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 APO B 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 that 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 goal post perfect and again for anyone who wants to dive deeper into that ama 34 and also um 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 the relationships between are there relationships between insulin levels and other lipid as CBD parameters like able B 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 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 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 APO C3 is an is another lipoprotein so April lipoprotein C3 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 near barceli I know I write about it in the book but it is one of the uh 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 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 hyperinsuline 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 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 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 APO B bearing particles namely the vldl particle which is itself very athrogenic in fact if it sticks around a long time it becomes a Remnant it is especially atherogenic so if we are reducing um um sorry if we are increasing expression of APO C3 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 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 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're going to see high plasma levels of triglycerides and we're going to see um you know other other things as well I didn't get to this but you know you're also going to 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 transfer protein ctep which I don't think we'll get into now because I think that 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 uh hyperinsulinemia is um is a is a is a risk factor that also increases uh both directly and indirectly the risk of of ascbd yeah Peter that makes sense and I know in your answer you said you mentioned there was two things that really affected and you covered one of them do you want to also cover the second yep yep thanks sorry I forgot I got a little carried away on apoc3 um 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 uh endothelial dysfunction is an important risk factor why because if the endothelium is not working the APO B particles have an easier time getting through the gaps and into the sub-endothelial space and furthermore we know that that's what sort of propagates the risk so as the APO B particles get retained and oxidized and the immune cells namely macrophages um 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 sub endothelial 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 Etc 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 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 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 scbd and for people who might be kind of listening to this and thinking 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 um 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 ogt 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 peek 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 to bring you more in-depth exclusive content without relying on paid ads membership benefits are many and Beyond the complete episodes of the AMA each month they include the following ridiculously comprehensive podcast show notes that detail every topic paper person and thing we discuss on each episode of the drive access to our private podcast feed the qualities which are a super short podcast typically less than five minutes 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Channel: Peter Attia MD

Views: 120,218

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Id: MAw4KMoBTPo

Length: 24min 9sec (1449 seconds)

Published: Mon Jan 16 2023