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

00:00:00.000 hey everyone welcome to a sneak peek ask me anything or ama episode of the drive podcast

00:00:16.400 i'm your host peter atia at the end of this short episode i'll explain how you can access

00:00:20.840 the ama episodes in full along with a ton of other membership benefits we've created

00:00:25.460 or you can learn more now by going to peter atia md.com forward slash subscribe so without further

00:00:32.140 delay here's today's sneak peek of the ask me anything episode

00:00:35.840 welcome to ask me anything episode number 43 i'm once again joined by nick stenson in today's

00:00:46.680 episode we answer a lot of follow-up questions we've had on some recent podcast topics specifically

00:00:52.200 around insulin hyperinsulinemia apo b lp little a and how they all relate to how a person should be

00:00:59.200 thinking about their risk of atherosclerotic cardiovascular disease which is just as a

00:01:04.220 reminder the number one leading killer in the u.s worldwide for men for women so one of the things

00:01:10.940 we try to do in this podcast is really get at the data around how much residual risk is conferred for

00:01:18.320 ascvd through metabolic dysfunction once you correct for apo b and there are some things that i think

00:01:26.080 we have data that we can speak to and we talk a lot about those things so for example we get into

00:01:30.220 the mechanism by which hyperinsulinemia increases the risk of ascvd and of course the question is

00:01:36.680 once apo b is corrected for does that risk still exist well we attempt to tackle that we also talk

00:01:42.320 about what mendelian randomization tells us about lifetime risk reduction of ascvd in the context of

00:01:50.160 low apo b so these are just a couple examples of some of the topics that we get into at a pretty

00:01:56.000 nuanced level in this podcast if you're a subscriber and want to watch the full video of this podcast

00:02:00.540 you can find it on the show notes page and if you're not a subscriber you can watch a sneak peek

00:02:04.660 of the video on our youtube page so without further delay i hope you enjoy ama number 43

00:02:10.620 peter welcome to another ama how you doing i'm doing well although looking at your t-shirt

00:02:21.960 and realizing that you probably bought that at coda i'm a little less good because i'm realizing i

00:02:28.300 somehow missed that shirt and didn't buy one myself yeah it's a good looking shirt and we didn't plan

00:02:34.580 this but we're both wearing the white black and red today just a little different fonts on the

00:02:41.100 front do you want to tell people about your shirt i have a red hot chili peppers shirt you have a

00:02:46.380 senna 1988 mp44 mclaren shirt which i really like well next year we'll make sure to track one down for

00:02:54.020 you have to find it all right perfect so peter for today's ama what we did is we just gathered a lot

00:03:00.020 of questions that have come from past podcast content as relates to ascvd we've talked about

00:03:05.940 this so much with ama34 we covered what causes ascvd we've had podcast guests dive deeper into things

00:03:13.700 that can mechanistically contribute to increased risk with lp little a and ben wa which is episode 210

00:03:20.500 apob with alan snyderman which was episode 185 and then insulin with gerard shulman which was episode 140

00:03:28.260 and that was also one we recently rebroadcast because we know we have a lot of new listeners

00:03:33.300 who may not have heard that and the importance there and so what we did is we combined a lot of

00:03:38.900 these questions because there's a lot of people who are kind of wondering how they fit together

00:03:43.700 right they know apob can increase risk you know lp little a can increase risk insulin not good for ascvd

00:03:52.500 but the question is kind of how can they collectively influence the risk of someone

00:03:58.660 you know there's questions around if my apob is low but my lp little a is high you know if my insulin is

00:04:06.180 good but my ldl or apob is raised how do i think about that and so we compiled those questions and

00:04:12.180 that's what we're hopefully going to cover here today so it's a little bit related to formula one but

00:04:18.260 not quite fully there but on the plus side much like formula one you do like talking about

00:04:24.500 cardiovascular disease so at least it's an interest there but anything you want to add before we get

00:04:31.380 started no but just for the record i do prefer talking about formula one over apob but i think

00:04:38.260 apob is more important so i probably spend more time talking about it just to clarify is there an

00:04:43.940 analogy that you can use that ties apob to cardiovascular disease as it relates to formula

00:04:52.020 one not off the top of my head but i accept the challenge all right i feel like that's a good thing

00:04:57.780 for you to work on because i'm surprised that you don't have one off the top of your head usually race

00:05:02.820 car analogies as it relates to health you're pretty good at whipping those out well actually i do now that

00:05:08.260 i think about it so if you imagine this could really be applied to other things but i think

00:05:13.700 with ascbd there's a pretty good application right so if you imagine your lifespan is the length of time

00:05:20.980 it takes you to drive a race car from point a to point b where point b is driving it off a cliff

00:05:29.060 and you have two feet and two pedals right so you have the accelerator and you have the brake

00:05:38.260 and your feet are always on both pedals so it's really just a question of how hard are you pressing

00:05:44.500 on each one now in this analogy there's never a point when the car is not moving towards the edge

00:05:51.460 of the cliff but you can do things that really speed up the drive which means you're moving towards death

00:06:00.260 more quickly that would mean you're pressing much more on the throttle than you are on the brake

00:06:05.380 conversely you could have minimal pressure on the throttle and much more pressure on the brake and

00:06:11.460 really slow your forward progress so then the question becomes what are the factors that you

00:06:17.940 could be doing that accelerate the drive towards the cliff and what are the things that you can be

00:06:23.300 doing that slow that trajectory so some of those things are kind of not under your control so apob

00:06:30.340 i mean pardon me lp little a is not under your control so lp little a is just a low level of

00:06:35.380 maintenance throttle that is put on the pedal so somebody who's born with a low lp little a has a

00:06:42.180 very low throttle application someone who's born with a high lp little a would have a higher throttle

00:06:48.500 application so we would just call this sort of baseline maintenance throttle now your apob

00:06:53.940 is also going to be a part of that so the question is do you do things that lower apob obviously

00:07:01.140 there's dietary things that do so but if we're really talking about reducing apob to the levels

00:07:06.100 that we call physiologic that's really going to be the application of pharmacotherapy so that would be

00:07:12.020 kind of pressing much harder on the brake the more you're lowering apob the harder you're pushing

00:07:17.940 on the brake the person has for example type 2 diabetes which we'll talk about in a second that is

00:07:22.820 generally accompanied by hyperinsulinemia well what is hyperinsulinemia doing in this equation it is

00:07:28.340 pressing harder on the throttle it is accelerating through mechanisms like upregulation of apoc3

00:07:35.700 expression which regulates apob in the wrong direction so more apoc3 means more apob impacts the ldl

00:07:43.380 receptor the ldl receptor related protein it moves all of these things in the wrong direction so insulin

00:07:49.940 is basically changing the amount of ldl particle that you have in circulation i guess i could build

00:07:58.100 that out a little bit more obviously smoking what would that be smoking is hammering on the throttle

00:08:02.980 having high blood pressure and lowering high blood pressure those are really big things so what are the

00:08:07.380 big three things that are driving ascbd smoking hypertension apob and then of course you have other

00:08:14.420 things like lp little a hyperinsulinemia so i guess that would be my analogy right which is

00:08:21.060 we have a car that we can't actually stop but we can really slow it down to a dull roar and that's

00:08:27.300 going to be through some combination of manipulating the brake and the throttle i mean the other piece

00:08:32.660 of that which to tie in other things we've talked about is also how much space do you have between where

00:08:39.380 your car is now and the cliff is going to be a result also of how old you are and so when you look

00:08:46.740 at risk and how you think about risk you know it's something you and alan snyderman talked is do you only

00:08:53.460 look at 10 year risk when it comes to ascbd which is kind of that medicine 2.0 approach or do you look at

00:09:01.380 50 year risk when it comes to that which is that medicine 3.0 approach because if you wait until

00:09:08.660 the earlier you work on the throttle and brake the more time you have to make interjections and the

00:09:14.500 longer you wait the harder you're going to have to press on that brake but that still might not be

00:09:20.340 enough with based on where you're at yep i think that's exactly right and that's another thing i like

00:09:25.140 about that analogy the more i think about it is if you're 100 feet from the end of the cliff

00:09:29.860 and you're traveling fast you better get ready to lock up the brakes and if you have a mile between

00:09:36.580 you and the cliff you can be a lot more judicious in your use of the brake pedal another way to say

00:09:43.460 it and we don't have to get into it because we covered a lot in ama34 if anyone hasn't listened

00:09:48.180 the beginning of that is basically no matter what age you are don't tune out on this conversation

00:09:54.660 because you need to care about these things even if you're 30 35 40 you may feel you're in good

00:10:01.540 health your insulin may be low but what is your apob what is your lp little a showing which we'll

00:10:08.180 get into here shortly so look at us we're able to bring in a race car analogy early on which is

00:10:15.220 always a positive so the first question i don't think we need to go into this level of detail you've

00:10:22.740 maybe covered in other podcasts but just kind of summarizing for the rest of the conversation to

00:10:28.500 set the stage a little bit are there relationships between insulin levels and other lipid as cvd

00:10:36.100 parameters such as apob ldlc before we say that it might be important we might interchange throughout

00:10:43.940 these questions apob and ldlc you know sometimes we get apob specific questions sometimes people don't

00:10:50.500 know their apob and so they only know their ldlc yeah so do you maybe just want to give that 30 second

00:10:56.980 version of oftentimes they are in concordance sometimes they're in disc concordance you always

00:11:03.140 prefer to know apob but if someone doesn't know apob and they only have their ldlc that can be

00:11:10.900 a predictor as well is there anything maybe you want to say on that just to flush out for i think

00:11:14.980 it's important for people to understand what they are so ldlc is a laboratory measurement that measures

00:11:21.460 the concentration of cholesterol contained within the ldl particles ldl by itself is not a laboratory

00:11:30.180 measurement so not to be sort of too much of a stickler but if somebody says what's your ldl

00:11:37.220 there's no answer to that question meaning ldl low density lipoprotein is not a laboratory measurement

00:11:43.460 so it's either ldlc the cholesterol concentration within or ldlp the number of ldl particles i prefer

00:11:52.340 apob which is the concentration of all particles that carry the apob lipoprotein which includes ldl

00:12:02.020 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

00:12:12.180 summary then your ldl cholesterol concentration is a predictor of risk the higher it is the more

00:12:20.660 likely your risk but the apob is a better predictor of risk because it captures not only the

00:12:27.060 concentration of ldl and we know that it's the number of particles more than the cholesterol

00:12:32.020 concentration of the particles that drives risk but also because it includes the other atherogenic

00:12:39.140 particles namely the vldl because the lp little a is generally captured inside of the ldl though

00:12:47.780 we like to know that separately because in people for whom it's very high and we'll probably get to

00:12:52.260 this later today our best strategy at the moment to reduce residual risk of course is to obliterate

00:12:58.420 apob concentration so we measure all of these in our patients but at the end of the day we look

00:13:06.100 heavily at apob concentration as the metric we are using as our goal post perfect and again for

00:13:13.540 anyone who wants to dive deeper into that ama 34 and also episode number 185 with alan snyderman

00:13:22.020 really gets into a lot more in the weeds there if that's of interest and people haven't gone back

00:13:26.820 and listened to those but with that being said let's kind of get back to the question which is you know

00:13:31.780 are there relationships between insulin levels and other lipid ascvd parameters like abob yeah i mean

00:13:38.500 to me the two most obvious ways in which well let me take a step back so let's explain the observation

00:13:44.740 the observation that is unequivocal is hyperinsulinemia is associated with worse outcomes in ascvd

00:13:52.740 the most obvious example of that is type 2 diabetes which is just a very extreme manifestation of

00:13:57.780 hyperinsulinemia of course type 2 diabetes is defined by glucose level but again as we talked

00:14:04.980 about with jerry shulman we've talked about this in many podcasts what is the precursor to that right

00:14:09.300 what's the canary in the coal mine years before a person shows up at their doctor and the doctor says

00:14:14.500 hey you've got type 2 diabetes if you knew where to look you would see hyperinsulinemia now sometimes

00:14:20.020 that doesn't occur at fasting sometimes that's in a postprandial state and that for us is typically the

00:14:24.980 true canary in the coal mine is it's a postprandial challenged glucose response where glucose is

00:14:31.940 normal but insulin is distorted insulin is elevated so when we see that 30 60 minutes after you've been

00:14:38.020 challenged with glucose you have elevated insulin we know that you're on the path towards insulin

00:14:43.940 resistance okay so we have this observation which is people with type 2 diabetes are about twice as

00:14:49.460 likely maybe 50 to 2x likely of developing ascvd and in fact all cause mortality so now the question is

00:14:56.980 why what's the mechanistic explanation for this i think the two that are most important are the impact

00:15:04.020 that insulin and insulin resistance has on the expression of apoc3 so apoc3 is another lipoprotein

00:15:11.140 so apolipoprotein c3 it's a very interesting one it's probably come up on a previous podcast it might

00:15:17.300 have been on the one with near barzillai i know i write about it in the book but it is one of the

00:15:22.740 genes so the apoc3 gene is one of the sort of centenarian genes so centenarians are more likely to

00:15:31.860 have a version of that gene that results in lower expression so in other words you can think of it

00:15:36.980 that's a good thing so the bad version of that is you know what we see the expression uh pattern in

00:15:44.500 people with hyperinsulinemia and insulin resistance is that we kind of upregulate that and if we do

00:15:49.300 that if we increase the expression of that it blocks the activation of something called lipoprotein lipase

00:15:53.940 or lpl and lpl is an enzyme that sits on cells that basically performs a function of controlling

00:16:04.900 lipolysis so one of the side effects we see of blocked lpl activity is less utilization of

00:16:13.940 triglyceride so if you're using them less what's happening you're increasing the amount of

00:16:18.260 triglyceride you have so now let's think back to what does that mean so if you increase the

00:16:23.140 concentration of triglyceride and again clinically that's very obvious you measure that in a standard

00:16:28.260 lipid panel we know that risk goes up but the question is through what mechanism well it goes up

00:16:34.740 through apob why because triglycerides like cholesterol are not water soluble they're fat soluble which means

00:16:42.820 they can't be trafficked on their own they can't just freely float through plasma they need a chaperone

00:16:50.340 and the most common chaperone we use to move cholesterol are apob bearing particles namely

00:16:56.020 the vldl particle which is itself very atherogenic in fact if it sticks around a long time and becomes a

00:17:01.940 remnant it is especially atherogenic so if we are increasing expression of apoc3 and blocking the

00:17:08.820 action of lipoprotein lipase we're going to see a net increase in triglyceride and furthermore we're

00:17:15.380 going to see a specific increase in a type of ldl which is triglyceride rich so we really don't want

00:17:22.740 to see these triglyceride rich ldls we want the triglycerides to be utilized because if you have now

00:17:29.220 triglyceride rich ldls and their purpose there is to really carry cholesterol what does the body do it has

00:17:34.580 to make more ldls and that means the concentration of apob is going up i would say that's probably

00:17:42.420 the most common i would say that's the most important mechanism and the way we basically

00:17:49.460 see that is you know we're going to see high plasma levels of triglycerides and we're going to see

00:17:55.140 other things as well i didn't get to this but you're also going to see hdl cholesterol concentration

00:17:59.940 go down and that's probably due to the change in activity of a protein called cholesterol ester

00:18:06.900 transfer protein ctep which i don't think we'll get into now because i think we'll save that for

00:18:10.900 an upcoming podcast where we will go we'll have a dedicated podcast coming up that's going to go

00:18:15.540 into all things hdl so i say we leave it at that and say that hyperinsulinemia is a risk factor that

00:18:23.460 also increases both directly and indirectly the risk of ascbd peter that makes sense and i know in

00:18:30.020 your answer you mentioned there was two things that really affected and you covered one of them do

00:18:34.500 you want to also cover the second yep thanks sorry i got a little carried away on apoc3 i think the

00:18:39.620 other thing where insulin especially hyperinsulinemia is playing a role is with endothelial dysfunction so

00:18:46.660 again if you take a step back and ask the question what is the cascade of events that

00:18:52.340 leads to ascvd endothelial dysfunction is an important risk factor why because if the endothelium

00:19:00.660 is not working the apob particles have an easier time getting through the gaps and into the subendothelial

00:19:09.780 space and furthermore we know that that's what sort of propagates the risk so as the apob particles

00:19:17.060 get retained and oxidized and the immune cells namely macrophages well monocytes that become macrophages

00:19:25.460 undergo the phagocytosis of the oxidized ldl particles and become foam cells that creates

00:19:33.860 sort of an inflammatory milieu in the subendothelial space that increases more endothelial that

00:19:39.620 you know sort of drives endothelial dysfunction and leads to a greater and greater cascade of more

00:19:45.380 apob particles being retained oxidized etc well insulin itself seems to drive this endothelial

00:19:54.260 dysfunction now this is a much harder thing to demonstrate because we don't really have great

00:19:59.380 clinical commercial assays for endothelial function we have a bunch of indirect things

00:20:04.260 but if you do look at cultured endothelial cells and you alter insulin concentration you're going to

00:20:12.180 see signaling pathways in the endothelium that suggests that they are becoming less functional

00:20:17.940 so i guess i would say that this is probably not as well studied and easy to demonstrate as the other

00:20:24.660 mechanism i mentioned but i think there's reasonable evidence that endothelial dysfunction is also a manner

00:20:30.740 through which hyperinsulinemia impacts the risk of acvd and for people who might be kind of listening

00:20:36.580 to this and thinking to themselves okay you know how are my insulin levels there's a very clear definition

00:20:43.780 of type 2 diabetes which is you get your blood checked your a1c is like above x amount but for people you

00:20:52.660 kind of mentioned earlier in the conversation you also look at a different test which is an ogtt test which

00:20:59.620 is something that someone can do which maybe is that canary in the coal mine you just want to let

00:21:05.300 people maybe know a little bit about that ogtt in case anyone's wondering to themselves like look

00:21:10.340 based on my blood work i know i don't have type 2 diabetes but now i'm kind of curious what my insulin

00:21:16.580 level is and if this is something i should be worried about how do i find out more to learn

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The Peter Attia Drive - January 16, 2023

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

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