Cardiovascular disease & why we should change the way we assess risk | The Peter Attia Drive Podcast

Hey everyone welcome to the drive podcast i'm your host peter etia hey alan thanks so much for uh making time to sit down today this is uh kind of one of those discussions i've been meaning to have for over a decade and i suspect much of what we speak about today will be reminiscent of things we've spoken about usually in person over a meal over the past decade so uh welcome to the show And uh sorry that we can't be doing this in person thank you so much so i think listeners of the show will

be pretty familiar with your name because certainly i've brought it up before as have other people on the show most notably probably tom dayspring i've also probably referenced on at least one or two occasions the textbook you gave me god probably about eight years ago do you remember do you remember what book You gave me uh i'm trying to remember which the two was i think it was the book i did with jacqueline de graaf no the that that is one of them but the one i'm the one i'm referring to is actually i think

it's herbert starry the pathology book oh right right right right right right right oh now i'm with you yeah yeah yeah which which i you just kind of immediately blew my Mind and um i then went out you know and bought as many of them as i could find on amazon and they were prohibitively expensive but tell me tell me and tell the listeners why why did you give me that book i'm trying to try to recall atherosclerosis it's a disease in the tissue And and almost everything that lipid people talk about is in plasma

and if we don't understand the natural history of the disease how can we construct a strategy to prevent it and although much of my work has been on april b the more important part i think has been on [Music] understanding how the natural history of atherosclerosis should direct our prevention strategy and what that leads to is that every major guideline in the world bases their selection of subjects for statin prevention on the 10-year risk of disease and and that was a huge step forward in 1980 and 1990 But but it totally or not totally but

it it it very fundamentally makes prevention alma of premature disease almost impossible do you want me to explain why yes definitely when you plug in the numbers to calculate somebody's risk for Any of the risk algorithms the american college of cardiology 2019 aha multi-society you you plug in numbers that belong to the that particular patient and what comes out is what you think is the risk for that particular patient and it it actually isn't but what drives that calculation Is the age and the sex of that patient things like cholesterol blood pressure they contribute minimally

to the actual calculation of 10-year risk so what that means is if you're 35 well there is a risk calculator for you but if you get to 40 almost everybody's risk is low at age 40. And it is until you get to about 55 60 that risk gets you over the threshold for the american prevention guideline treatment so prevention really starts at 55 to 60. but half almost half of all infarcts and strokes occur before the age of 60. so How can that be what starry and his colleagues established was for the first three decades

or so of life the disease begins gets a foothold in the artery but it's only in the fourth decade that you start to develop the lesions that can actually precipitate a clinical event but risk is low and yet the event rate is high how can that possibly be Well the answer is stunningly obvious which we've published there are a ton more people under 60 than over 60. so the rate of events is low but the absolute number of events is high that's problem number one problem number two is say you get to 60 and you

didn't have an event well the disease was developing and Extending during your 30s 40s and 50s so by the time we start to try and prevent an event the disease is well advanced in the arteries that to me is a are the two fatal flaws in the 10-year risk approach and we we published a paper pointing this out in in jama cardiology a few years ago Board nordiskart and his colleagues have done exactly the same thing with the european guidelines the you can't beat these numbers so rather than what steri taught me and it took

some years before we could develop the methodology was that we should be basing prevention of course risk is a good concept Of course it is but we should be selecting people also based on causes i can measure your apo b pretty precisely i could measure your non-hdl cholesterol a little less precisely but pretty well and i know it's yours when i calculate the risk if i said okay peter you're my patient you're a healthy guy I calculate your risk is 4.1 now what does that number mean is that your risk nope it means that out

of a hundred people at 4.1 percent 4.1 of them will have an infarct but we know that within that category there's a tremendous variance in real risk not everybody's at 4.1 Some are higher some are lower some are dead on so if i had two risk algorithms do you know the philosopher aj ayer the english the logical positive he was he was actually darn good on probability and and there's a real challenge predicting singular events i'm either going to have an infarct in The next year or i'm not it's not really a probability it's i

either am or i'm not and if if one algorithm said i had a 10 risk and another one said i had a 15 or 20 whether i have an infarct or not both of them were right because they said there was sort of a chance you could and there was a far larger chance you wouldn't When we say people have a risk should be treated with a risk above 7.5 percent that means 92.5 percent of the time nothing will happen well that's not a great incentive i think for helping people understand what's truly going to

happen so the way we can deal with this and what we've done is develop what's called the causal benefit model is we measure non-hdl or apob And and we can project the risk over 20 or 30 years if you're 30 years old the period of time you should care about is up to age at least to 60. and so if you were in a group let's say and let's say i make you 35 again and i say your chances of having an infarct or a stroke before you're 65 are 30 Now that's a number you

can deal with that's a number that has meaning and we could also calculate how much the risk can be reduced by starting at age 35 or how much you lose by starting at age 45 or how much more you lose by starting at age 55 so when i gave you that book i was starting my own journey On trying to construct an alternative to the present risk model in which with the help of my colleague here at mcgill george stanislas and michael pincina from duke and carol panzina from harvard we've done now something about it

alan that also brought home another message that had been somewhat left in the garage of my brain um as you may recall i trained in general Surgery so the kids in med school who are going to go into surgery we're not the sharpest tools in the shed like the kids that go into internal medicine right so um but i still remembered a couple of things from my pathology class and one of the things i remembered from pathology a so it's the first of the three major classes you take in pathology was something that the professor

said Which is he said no doctor has more experience with what it is to have heart attacks than pathologists because 50 percent of the people who have a heart attack die on their first heart attack so he said i'm seeing 50 of the people who have a heart attack and their first presentation is death Right so i kind of remembered that and it's a very sobering fact right to think that half the time and again i don't think that's true today but i think 25 years ago that was the case the numbers are probably a

bit better today it might be a third of first events or fatal but nevertheless it was sobering so you have this sort of weird factoid that's again off in the recesses of my brain somewhere and then you hand me this textbook And it actually made sense with what he said because in addition to going through in great detail the pathological staging of atherosclerosis it had many i mean it was littered with autopsy sections of coronary arteries of people who had died for other reasons um and notably they were quite young right so here's a 26

year old male Victim of a gunshot wound here's a 27 year old female who died in a motor vehicle accident here's a so-and-so and so and so and when you look at their coronary arteries you realize they already have atherosclerosis they already have oxidized apob bearing particles engulfed by macrophages and thickened intima and While they may not have calcification in their arteries yet or the types of plaque that would rupture within the ensuing weeks or days or months they nevertheless had atherosclerosis and they were in their 20s and in their 30s so all of a

sudden what this professor said 20 some odd years earlier made sense which is this this was now an explanation this was a bridge to explain what otherwise seemed hard to understand That that's the thing i took away from it in the in the instant you handed it to me as we were literally looking at it in the restaurant and and it's and it's how the thing i'd emphasize is how when you have atherosclerosis i mean as a cardiologist and you we're so used to looking at angiograms we say oh there's a there's an led lesion

well there's an led lesion but the whole damn artery Is diseased and when you destroy the normal architecture of the artery you can't restore it so a lot of our statin prevention therapy is to prevent the complications of disease not to prevent the disease and statins lower apo b particle number that's how they work Fewer apob particles in plasma fewer get into the arterial wall fewer get trapped it's not that complicated so let's back up for a minute because i think everything we've just talked about for the last whatever it's been 10 minutes is in

many ways the advanced advanced seminar on prevention of atherosclerosis so now let's go back and set the stage For this because they're going to be a number of people listening to this who perhaps have not heard previous discussions i've had on this subject matter so let's back way up and start with what is cholesterol and how does it relate to this thing called apob that you've mentioned a number of times already because most people would have heard of cholesterol And most people understand that you can measure it when you take somebody's blood but this apo

b thing might be new to some people cholesterol is obviously a fat lipid it's a critical element in cell structure it's in all cell membranes the amount that's in the cell membrane is is determinative of the function of the membrane All the cells in the body can synthesize cholesterol only the liver can really break it down in any amount and and excrete it so for reasons that aren't when we eat we absorb cholesterol and and fatty acids in the form of triglycerides and they get re-synthesized in the intestine into particles you can't you can't transport

Cholesterol and triglyceride triglycerides are the fatty acids tacked onto a glycerol backbone they don't they don't mix with water they're not soluble so you have to put them in particles like soap bubbles and there are a variety of different particles the ones from the intestine that take the the fat that we absorb the cholesterol and the triglyceride They're very large particles they're very few of them they have a protein called apob-48 on the outside surface which gives integrity to the particle structural integrity there are also a bunch of other proteins the column microns deposit they

go to skeletal muscle adipose tissue in the heart and the fatty acids Are taken out they're liberated from the triglycerides and rapidly taken up by the these three tissues the particle that's left is now much smaller because most of the triglyceride has been taken out of it and it goes to the liver and drops the cholesterol off so the cholesterol we eat in the diet goes to the liver and it tends to reduce the synthesis of cholesterol in the liver The liver gets inundated with fatty acids and cholesterol from all over the place kind of

microns uh hdl uh ldl particles and it and and it it there's a system to regulate the mass of cholesterol and triglyceride in the liver and that's the vldl apob system The ldl particles have a molecule of apob 100 which is longer twice as long as april b48 and that gives the structural integrity of the particle does one other thing i'll get to and that particle removes triglyceride and cholesterol from the liver to maintain the balance in the liver the triglyceride just as in the case of chylomicron gets Dropped off in adipose tissue and skeletal

muscle and cardiac muscle so the vldl particle gets smaller and more cholesterol rich and it eventually becomes an ldl particle and an ldl particle is a cholesterol-rich particle with relatively little triglyceride in it when we measure the cholesterol in the blood the total cholesterol is the cholesterol In the vldl particle the ldl particle and the hdl particle the good guys quote unquote the non-hdl part cholesterol is the mass of cholesterol in vldl particles and ldl particles now isn't that enough is that all we really need to know and the answer is it tells you a

lot no Question but i'm going to give you two people one person they both have the same ldl cholesterol their cholesterol is 125. one of them tends to have larger ldl particles one of them tends to have smaller ldl particles in order to carry the same amount of cholesterol there got to be more little Ones than big ones so their ldl cholesterol is the same is there any difference in their anthrogenic risk and the answer is yes yes yes and yes the one with the increased number of particles has higher atherogenic risk because any cholesterol

in the artery only got there within an apob particle it doesn't just float in it gets there within an apob particle Either vld or ldl that gets into the arterial wall and gets stuck there that's the cause of atherosclerosis there are lots of things that contribute to multiplying or diminishing the cause but that's the cause sticking of an apob particle within the wall and Because cholesterol gets in there within the particles knowing the number of particles is more important even than knowing the cholesterol level alan when did that historically become apparent if we if we

take a step way way way back right if we go back into the 1950s ansel keyes was potentially one of the first people To utilize the then nascent assay for measuring total plasma cholesterol so to your point earlier that number let's say you measure 200 milligrams per deciliter that's simply telling you that that's the sum total of cholesterol in all of the lipoproteins and what ansel keys and others observed and this was by now we're probably into 1957 1958 was hey if you stratify People at the bottom five percent and people at the top five

percent so that might be people whose total cholesterol is less than maybe a hundred milligrams per deciliter and people whose total cholesterol is more than 200 milligrams per deciliter there's a stark difference in their mortality or rather in their risk of cardiovascular disease and that became very interesting it turned out that There wasn't a great way to predict that so the amount of cholesterol a person ate did not seem to predict that but nevertheless other dietary factors saturated fat uh intake for one seem to predict that difference it would be what maybe 20 less than

20 15 years later that friedrichs and levy lees and others would start to fractionate those Lipoproteins and realize that well actually there's different versions as you alluded to there are some that have low density there are some that have high density and it's not i don't know exactly when it became clear just how nuanced that was that you know that apo a is on one and apob is on the other but when did it become clear that there was a discordance between the cholesterol concentration In the ldl particle and the number of ldl particles i

think bob lee's in 1971 he had a paper in science and and and he he was measuring ldl apob the number of ldl particles and and he showed it had no clear relation to plasma triglycerides or to the cholesterol i mean there was sort of a relation but it wasn't exact And and ron cross of course and his colleagues and and i did uh at least one paper one or two papers with them at the very beginning were the ones who actually showed the coming in the john goffman uh tradition from berkeley showed that the

the the the there were important differences in size and these related to differences in the amount of cholesterol mass per particle So ron krause and the group there and then a whole bunch of other people and deserve i think the the credit but but but we're we're way back in the 70s late 70s 1980 was my first paper uh clinical paper showing with peter quitterrich the late pete quitter rich from hopkins and and we looked at A bunch of patients with coronary angiography and we compared people with clean coronaries like clean to people with diseased

coronaries like disease and there was there was a little difference in triglyceride there was a difference in cholesterol but there was a marked difference in apop and and that Was the first i think clinically solid observations along with an italian group that had much close to the same observations slightly ahead of us for that matter uh saying that look particles could be more important than cholesterol and it seems like forever since then 1980 to now trying to And i think largely now succeeding in developing the evidence that you can say incontrovertibly particles more than cholesterol

now that hasn't moved the american guidelines but on the evidence side uh there there are there are a handful of studies That show that non-hdl cholesterol may be equal to b there are more studies that actually show apob is better but we developed an a way of looking at it called discordance analysis to identify people who had a high non-hdl cholesterol which is the total cholesterol in the apob particles but a low apob total number of particles Versus low non-hdl high apob so if you're a cholesterol maven you got a bet on the one with

a high non hdl if you're an apob aficionado you bet on the one with the lower non-hdl higher a b they all show its apo b now is the argument going it sort of Interrupt if the if one argues that in the at least equivalence of if not superiority of non-hdl cholesterol as the superior metric or at least equivalent metric is it because you're arguing a different mechanism of action that it's or does everybody agree on the mechanism of action and they're simply saying measuring cholesterol content is a good enough proxy for counting the Number

of particles nobody suggests there's a different mechanism there are some people who argue that vldl particles are more atherogenic than ldl particles and i think they've got a long way to go to prove that what people did argue was there were problems with the apob assay and that it costs money and the reality is the apob assay was standardized back in 1994 The measurement of hdl cholesterol is not standardized the measurement of ldl cholesterol not standardized the measurement of triglycerides not standardized well the other argument in terms of the cost argument because i actually had

that argument with a physician as recently as three months ago who accused me of getting apob on patients As a way to up charge them even though i don't make any money on labs but i actually called the lab that we use and said what's your cash price for apob you want to know what it was please two dollars and fifty cents right that's a real it's a real money it's a real money maker yeah yeah you know how much it is in my hospital it's two dollars Okay it the the the there's a there's

a i'm trying to say this moderately this cost argument has been used without documentation as a as a killer argument and and there were labs that charged way too much welcome to america Okay uh you're in general your your charges are higher than ours in my little country but that's a function of how much somebody's billing not a function of what the assay costs and and apob it really ticks me off because if you take india for a moment or or almost anywhere If a doctor gets a report now he gets total cholesterol triglycerides non-hdlc

ldlc hdlc five numbers do you think he actually looks at any of those numbers if he try he's trying to do a good job he does but let's say the triglycerides are high Can he do anything with that nope because everything is based on ldlc so he's got in reality four numbers that are doing nothing well let's explain that to people alan because you and i know the ins and outs of that very well but i think most people here don't understand the difference between the calculated and measured ldl so let's start with that and

then let's talk about How vldl has been estimated and let's bring this all back in terms of some other work you've done which is understanding the role of triglyceride in apob so let's start with the basic you go to the doctor you get a set of labs done and the ldl number comes back at 140 milligrams per deciliter is that actually what it is or is that an estimation that's an estimation it's it's almost Always a calculation and there are at least eight different methods to calculate ldl cholesterol so if there are eight different methods

they don't all give the same answer or you wouldn't have eight different methods ldl cholesterol can also be measured directly that assay has never been validated in disease patients and no one has ever published a paper Showing that it's more accurate in terms of disease identification than calculated ldl cholesterol and yet people have paid good money for that lab test there's no question that the number of ldl particles is a more accurate index of risk than the ldl cholesterol vldl cholesterol is the cholesterol it's in the via very Low density lipoprotein particles the particles that

come out of the liver that cholesterol is atherogenic and there's a lot of triglyceride in that particle so the people who measure triglycerides say well the triglycerides are high that must be the problem and there's no question that people with high triglycerides are at increased risk of heart disease But the people with the high triglycerides who are at increased risk of heart disease have a higher number of ldl particles and vldl particles it's the particle and when you're measuring the triglyceride you're just measuring a blob of liquid in a bunch of particles and you need

to know the number of them so it's an important number in the sense of If you're a lipoprotein guy trying to figure things out if it's extremely high it increases the risk of pancreatitis but i haven't seen any solid evidence that the triglyceride itself is pro-atherogenic what's atherogenic is the cholesterol inside the vldl particles and it's the number of those particles that get into the wall now there's a a complicating reality Because in general all i need to know is the apob but there is a disorder called remnant type 3 dyslipoprotinemia and that's a very

specific highly atherogenic condition that manifests with high triglycerides high cholesterol but get this you know low apob so when i measure my lipids in april b i can recognize that But if you don't measure the apob and this applies to most of the people who are listening to this podcast if they go to see their doctors that condition can't be diagnosed can you explain that condition walk us through what's happening pathophysiologically how does that person have high cholesterol low apob high triglyceride i said before that the The i'll try that the normal metabolism is the

vldl particles get broken down sequentially as the triglyceride is removed and they get converted to ldl particles some of them are removed by the liver along the way in type 3 that process breaks down and for reasons that are not well understood on the age of 30 35 or 40 People develop high triglycerides and high cholesterol because the vldl particles aren't being broken down to ldl particles that process stalls those particles circulate a long time in the blood and while they're circulating cholesterol gets deposited into them so they become very cholesterol rich like really really

cholesterol rich And those people have a very high risk of coronary disease peripheral vascular disease it's a commoner syndrome than familial hypercholesterolemia that gets day and night press day and night this one is easily treatable almost all the time fh needs to be treated much more challenging but type 3 cannot be diagnosed in most patients in The united states because apob is not measured the technology that we used to use to diagnose it it's all gone nobody uses it anymore it's old-fashioned but but it can be diagnosed based on the triglycerides total cholesterol and apob

there's a formula that we that we devised so we can recognize those people and say hey you may be 38 years old But you've got a big problem here and and with treatment we can take your big problem away and so the phenotype of that patient is that they have relatively few particles but they have so much cholesterol because the vldls are so large and so cholesterol full yeah that's right so what is it given the relative lack of particles that makes that such a Dangerous condition i'm not sure we know really okay uh there

it it there compared to normal there are 40 or 50 times as many of these particles but i'm not sure i understand why it's so dangerous in terms of particle number i do know that it means you can't just use the apo B when you're trying to make a diagnosis it seems that an analog go ahead and sorry yeah no when i follow a patient i really just look at the apob for normal patients that i'm treating with statins i only have to get one number right it seems that those particles are more atherogenic sort

of in the way that an lp little a is more atherogenic so if You did a thought experiment and you said you know you take three people who all have the same apo b concentration but they could have three very different predicted risks if one of them has a very very high lp little a concentration another one has a normal phenotype and another one has a type three as we've just described yeah the the the first and the third have a Much higher risk suggesting that on a particle-per-particle basis they have more atherogenic particles or

particles that contribute to clinical events yeah i agree yeah the for me and for my practice uh i measure a light lipid panel i measure an lp little a in everybody And i measure a pob i measure the lp little a once when lp little a is high but apob is normal lp little ape may not add that much to risk but when you got two of them it's a double whammy and that i use as an another piece of information in trying to frame for the patient the potential futures that they face and so

alan what is the treatment for The patients that are type threes these patients with um many cholesterol-rich vldls despite a normal apob statins and or fibrates and the they usually respond very well and the and the the fibrates in that patients remind me their triglycerides are normal or elevated no their triglycerides are elevated They're quite elevated they're vldl particles so the triglycerides are elevated we made up a a algorithm that's um i think it's the w the apo b app apo b app where you could plug in the total cholesterol triglyceride napo b and you

get the diagnosis of any of the atherogenic capable dystrophies yeah that was a fantastic app i can Still use it on my desktop but for some reason it stopped working on the phone does that am i the only one that has that's right it stopped working on on google and app but it's on the web yeah and remind me remind everybody available from the yeah what's the what's the url www dot apo b app dot app right app i think no i think it's just apob app okay do it I i saved it in my

browser because i remember it was a counter-intuitive play i just actually relied on it i looked i looked something up a month ago on it so it's a great little yeah and he walks you through all the diagnostics he walks you through all this diagnosis and and it look a lot of people the part of the argument against um apob people say it makes things too complicated If i explain to a patient that they've got a lot of bad particles cholesterol particles they get it when when i review the results of how well somebody's doing

on statins if their triglycerides were high to begin with they're unlikely to normalize the hdl cholesterol is unlikely to normalize i i so their apob is good they're good that's my target of therapy And because it's the total number of um uh of atherogenic particles and nordisguard had a lovely paper recently in uh was it jammu cardiology uh on on a discordance analysis of non-hdl cholesterol and apob and showing that apob was a more accurate index on statin treatment than non-hdl cholesterol it's a lovely paper yeah i mean frankly i find it much Easier to

explain to patients what apob is than to explain what non-hdl cholesterol is i do too i mean a non-number is hard to explain and it's interesting to me that with all the emphasis that's so many of the lipid guidelines have put on non-hdl cholesterol they all still say ldl cholesterol and the american guidelines clearly state apob and non-hdl are better than Ldl but the world is has remained and it's a phenomenon that i'm that i don't really understand how resistant the lipid world has been to change but i think it's important to understand because we'll

understand things like afghanistan and the financial crisis in 2008 and a whole series of bad decisions By good people thinking as hard as they could but when everybody in the room has the same opinion going in it's a bad way to solve problems yeah i mean are you optimistic i mean is this just a question of time i mean in in 10 years will kids in med school be learning about apob instead of ldl I'm pessimistic uh europe the 2019 guidelines were very pro-apopey and the evidence from mendelian randomizing like the newer technologies mendelian randomization

they've just been slam dunk for apob let's explain that to folks because i want to talk about the causality of this and this might be the perfect way to to to actually explain the causality of apob in the context of this tool so can You explain to folks what a mendelian randomization is the word people see this all the time in studies but i don't i don't think it's entirely clear for the average person what it means i'll try okay it's not my expertise but i'll try the the conventional ways of taking things apart with

prospective observational studies like framingham There's a there's a limited amount you can [Music] of the certainty of your conclusions because of confounding you can't deal with you you take measurements at age 20 and you follow someone for the next 30 years well a lot of things change in the next 30 years that you don't have a handle on and so you your inferences are probable but not causal What mendelian randomization allows you to do is to come a lot closer to causality for example you can identify groups of genes that are associated where changes in

the gene are associated with a little lower cholesterol or a little higher cholesterol and when you lump together a bunch of those different genes that can have different makeups because you can change the makeup of a Gene pretty easily you can see fairly substantial differences in cholesterol so what you've got is information on somebody that's in that's fixed at birth and you see is that associated with a difference in outcome then you're you've gotten rid of a lot of stuff in the middle and what what a number of mendelian randomizations have shown is that apob

Includes all the information in triglycerides ldl cholesterol and even hdl cholesterol it sums them which in the sense of vldl and ldl makes perfect sense so this is a very high it's a there's a there are caveats in mendelian randomization you can't just push a button and say give me the answer But george davey smith uh really arguably one of the founders of mendelian randomization or not arguably yes he's the author of a number of the mendelian randomization saying apob incorporates and therefore beats triglycerides and ldl cholesterol so that's a huge level of information That

isn't even mentioned in almost any of the guidelines yeah so let's let's make sure people understand everything you just said because you said a lot of things in there when you prospectively follow a cohort the way the framingham cohort was followed or the framingham offspring or the mesa cohort or any of these cohorts have been followed You can take a bunch of people and you could measure their apo b or their ldlc or whatever metric it is that you're trying to determine if it in fact has a causal relationship to the disease of interest you

can follow them over decades and you would demonstrate as has been demonstrated that the people with higher b higher ldlc higher non hdlc and lower hdlc All have a higher risk of developing atherosclerosis over time but it's hard to say that that's causal just based on that information because over the ensuing 20 years that you follow them they are free to make other choices that may impact those variables of interest and other variables so the mendelian randomization attempts to get around that by saying At the time of i was going to say birth but really

at the time of conception we all get randomized to a set of genes we get assigned a set of genes i guess they're not perfectly random because they come from our parents but for the purpose of not changing they are indeed a random assignment that is fixed if we can identify which genes map to which phenotype and we can figure out The genes that map to the phenotype of our interest namely driving up or down a variable of interest such as apo b then we don't really have to worry about the confounders that occur in

between because the genes can't change and therefore no no go ahead you're doing you're doing that yeah so i mean i think just to put a bow on that basically now when you see a difference in outcome It's much more likely to be causally related to the phenotype of interest because the gene has not changed that underlies it now what are some of the ways that we can get tripped up with mendelian randomization i mean there's some pretty big ones yeah before we get there hdl cholesterol was the rage okay the total rage because the

epidemiological evidence Couldn't be clearer in fact it was four times more clear my recollection was that framingham demonstrated low hdlc was four times more predictive of cardiac events than high ldlc am i am i remembering that correctly oh yeah i'm not sure it's that multiple yeah but it's it's multiples and and it turns out as we know now at least from the ctp inhibitors that you can't manipulate hdl and change Outcomes and that's one of the elements of demonstrating an overall causal relationship and the mendelian randomization show hdl is not causal whereas they show apob

is those are two very important studies alan i mean and both of those have been in the last 10 years yeah and and it's it's a Incredible technical advance in being able to examine questions that and look at numbers of people that are would be unimaginable in conventional studies the mendelian random they're always talking hundreds of thousands of people because they've got these huge data banks with genes and and those numbers get you around the confounding of things you have huge numbers so you get But it's like any methodology no method is and this one

can mislead you too when you've got particularly when you've got a sequence of associated variables for example people showed using mr that triglycerides were quote causal or associated with increased risk but when you took into account the non-hdl cluster or the apob It disappears so when you've got a linked metabolic chain you've got to be careful that you've gone to the end of it you've got the real actor not act one leading t that you've got the real persona dramatus which is why it's surprising that hdl didn't at least at the first order demonstrate causality

because there's no doubt that phenotypically the high triglyceride low hdl phenotype is so Associated with metabolic syndrome that it makes up two of the five criteria that's an incomplete description sure okay that's like you describing your self as six feet tall i wish i wish okay and and uh and not giving your weight and letting me guess your bmi you cannot characterize any phenotype without the apo b It really drives me around the bend and i mustn't go around the bend on your podcast when people speak saying i got somebody because i got their triglycerides

in their hdl well i say okay what's their apob how can you pretend you've evaluated the system when you haven't counted the number of anthrogenic particles because they could be normal they could be High or you could have a type three they don't know and it's not a phenotype there is no phenotype without putting an apob in there because they're lipoprotein particles they're disorders of lipoprotein particle metabolism of course the triglycerides and cholesterol are Important but my analogy i didn't do a good analogy there but it's so fundamental that it it drives me to distraction

as to why you wouldn't want to know a core element of knowledge and um but it doesn't seem to bother Many of my friends so let's talk about another way that people try to stratify risk um actually no before i do that i want to go a step backwards and talk about something else that you've alluded to which is you walked through the the pathophysiology of how the apo b bearing particle Wreaks havoc in the artery wall many many years before we see clinical events and you also mentioned that there are other factors that can

amplify or exacerbate that i can't remember exactly how you said it but that was the gist of it well two of those things that are widely accepted to exacerbate risk are smoking and hypertension in fact smoking and hypertension probably carry a greater risk for Atherosclerosis than apob or is that not the case well it all depends the way you think about it because if you just say what's the risk somebody with hypertension faces they have high risk i no question but then you say what is hypertension now the last 30 or 40 years there have

been Almost an infinite number of basic science studies on hypertension and when you were in medical school and even before that when i was in medical school we talked about pathophysiology of hypertension and what strikes me is we don't talk about the pathophysiology of hypertension anymore but the basic science goes on in rats It just is healthier than ever and there isn't anything i know of that's come out of that basic science that's been clinically useful in the last 30 years the drugs we use we use them because they work so is hyper what is

hypertension it's a higher blood pressure than we should have and where is the disease that produces that higher blood pressure I don't think we i don't think we know i mean we don't have a clue okay we don't have a clue and and and and it strikes me it's the same thing as much of the debate and lipids about apob or the the the drunk looking for the key under the light because like this is where the light is not where he lost it there's a the everybody who's anybody has the same viewpoint my bet

is it's in the proximal aorta My bet is that it's it isn't that complicated we lose elastance in the proximal aorta and that's systolic hypertension thank you very much and and what could what could accelerate that process okay by the way what's the what's the mainstream view that this is renal well i'm not sure it when i read hypertension i get lost because i i get page after page after page of Peripheral arteriolar tone and very complex metabolic studies and very sophisticated animal models so there's some renal left uh it's a miasma for me an

absolute miasma i hadn't heard about the proximal aorta so so say a bit more about that what would i mean well i would say this is me okay okay this is what i think okay say more The approximately order is the is is elastic so that and and and if you look at a at a flow curve a hydrostatic pressure curve when we're young it it's rounded because as the left ventricle ejects blood rapidly into the aorta the aorta expands so it absorbs some of that energy and then you get you know that wind kessel

that they mentioned in school It's not that big a deal but the energy is is partially captured partially regained but the wall isn't battered the wall can give way i me personally just in the middle of my brain imagine that If those elastic fibers start to go then the walls stiff so now when the left ventricle ejects blood the pressure goes up more rapidly and it falls more rapidly in diastole and that's why you get systolic hypertension with normal diastolic pressures so my bet would be if i was not the age i am i would

be looking at factors like cardiac output again which Used to be way back when or factors that alter the behavior of the proximal aorta as much as something that's to me pathophysiologically much more likely to be involved so once i got hypertension okay then i've got a driving force to push particles into the wall and so you think it's it's this it's the it's the actual increase in the pressure of the plasma and the response of the Wall i think there are responses to the wall the wall thickens up it gets harder for particles to

go through does it also damage the endothelium do you think that plays a role that way that's right but i i just i don't understand endothelial dysfunction it's more a language thing to me than it is a reality i know the endothelium is critically important but i and i know it it gets it functions Abnormally and that's endothelial dysfunction how that fits into the overall thing i don't know i i my bet is apob particles are part of the process of inducing endothelial dysfunction but i don't know that clearly experimentally so so going back then

to the question at the top does it make sense to even compare Hypertension to apob they both seem to play a causal role is one more causal than the other or is that a silly question because they're not binary and static i think that's not the right question i think like our blood pressure goes up as we age i mean hypertension involves so much of the population it's not clear to me what the word disease means The the prevalence as we age is so high that that to me it's becoming almost a aging process because

we're lasting a lot longer than we were probably designed to go so you have this repetitive injury to the proximal aorta and it gets a little progressively less able to deal with it and then so with a time where 50 what percent 60 have higher blood pressure I mean the figures are staggering is it really that high so if we're if we're going to you're not sure if we're don't quote me on that okay but but it's high high high it's high high but doesn't apob also rise with age a bit it does rise with

age but not that much when we when we look at people at age 35 we can pretty accurately categorize the Group they belong to at age 35 not that they won't change someone so if you're high at age 35 you got about a 95 chance of staying high five percent will go out of the high zone they won't go low low okay so if you're high at age 35 i wouldn't bet anything's going to move you down that's why i think it's such a Good signal for when we should start thinking about treating people because

it's it's and if you're low some people go from low towards high but but it's but the majority don't and we keep following them but if you're high no we've published a fair amount of this if you're high it's not a hundred percent but it's about 90 that you're going to be high Is there a gender difference at least clinically i seem to see women as they go through menopause experience uh dyslipidemia that that men wouldn't experience over that same decade or even five year transition yeah no i think women i think there are changes

and apob goes up with menopause i'd like there to be more data i think part of the reason it's held apob back is that people didn't measure It so they were sort of well what i measured has to be important because i can't answer your question so i there should be more data and and hopefully more data will be coming but i but i agree with you people can change the menopause so i'm not saying we don't keep looking at people but when you have somebody at age 35 to 40 who's high the odds are

high that they're going to Stay high are we doing a better job treating hypertension than dyslipidemia i have no idea see i wouldn't imagine we're doing a very good job either interesting um okay i mean i think that look somebody said the incidence of coronary disease is going up in the last five years And that's despite statin therapy and that's the obesity diabetes so i think we've been too quick to congratulate ourselves at how well we're doing and i think that part there are many reasons that treatment is not succeeding as well as it should

and i think the complexity of the lipid phenotype of the lipid model Is part of the answer uh it's easy for me i get the apob where i want it to go yeah i mean an explanation for your observation would be if in the last five to ten years the incidence of atherosclerosis or major adverse cardiac events is rising despite the advances we have you would argue or could argue that if we're measuring ldlc And that's our proxy for treatment you can eat but as as dyslipidemia is growing in the metabolic context meaning if you

have more medicine and more insulin resistance and more type 2 diabetes we know that those phenotypes are associated with greater discordance between apob and ldlc suggesting that you have a greater and greater portion of the population that is being undiagnosed Or being under-diagnosed because you're treating their ldl-c and you believe that it's lower than their risk actually is because their apob is higher i know you know what i just said i hope the listener understands what i just said yeah what you just said was important where the the it's it's another example An unfortunate sad

example they're trying to quiet quantify lipoproteins based just on lipids is not adequate you're not capturing all the information that you should so let's talk about smoking for a second do you have a sense i know it's again not the thing that you study day and night but what is it about smoking that drives risk of atherosclerosis so much Truth is i don't know yeah it certainly does um and it drives a treatment decision you know i think i think smokers are wonderful human beings who deserve to be treated as human beings but but i

don't think that if you choose to continue smoking that should prioritize you for statin treatment whereas based on my concern about people who Have high ecobee levels they should be treated because of their longer term risk you know smoking gets you up the category to have your life saved so bad behavior gets you closer to having your life saved is that a canadian thing no it's an american thing it's in your it's in your risk calculator if you're a smoker you're risk oh i see What you're saying not based on a coverage issue but simply

based on a change in prioritization i see that's right because everything is risk bad behavior indeed increases risk so you get more medical attention now i think bad behavior is our responsibility to help people deal with but i don't think it should put you to the head of the line for preventive therapy I mean i would argue there is no line anybody who wants preventative therapy should be getting it right is there is there i don't view it as uh are we resource limited on that front no but what we but we're we're we're not

using the we're not giving patients the information that they deserve we put we published a paper in circulation i think it's 2019. which i've referred to before looking at What are the costs of delay of intervention starting at age 35 45 and 55 and and if your non-hdl is low yes you'll get some gains starting at 35 but it's not a lot it's actually quite small your gain is in the people with a high non-hdl so we don't have to be giving pills to everybody at the age of 35. If we use our physiological and

epidemiological knowledge there's there's about 20 percent of the population is is it demand is that evident high risk and they should consider it and part of the information they need to know is how much do i gain now how much is gained now versus how much is lost by waiting and that's that that's why these Methodologies of calculating benefit are so important do you have a sense ellen of what fraction of the population has relatively normal apob relatively normal triglycerides and yet has accelerated atherosclerosis through some combination of yet to be identified polygenic risk factors

so you see atherosclerosis that runs in families and they There's not an obvious cause right they don't have fh they don't have lp little a and frankly their apo b is harboring around the 20th or sort of called the 50th percentile of the population but they disproportionately uh get afflicted young so they're all having first events before 60. and i i think i don't know i think that's where that's where research needs to be done and i would look at factors that affect The trapping of the apob particle within the arterial wall i think kevin

john williams from from philadelphia they've done amazing job amazing job in putting this all together and wouldn't that factor into our decision-making then i mean would we if we if we had two people that had the who were both say 40 and they both had the same let's just say they were identical in Terms of lipids and lipoproteins they both had the same blood pressure they birthed they were both not smokers etc but one had that family history the other did not are you treating them different pro i would i would it would factor into

my decision okay um if if the apope is actually low i'd be Less inclined to let it influence let's say they're both at the 50th percentile if they're if they're 50 60th percentile i get that makes me more antsy okay the higher they are the more antsy i get and a lot of these decisions at the individual level actually aren't that difficult when you're speaking to a particular patient because they have their own objectives and goals and we get if we give people medications Our medications have risks associated with them i don't think we fully

understand the relationship of statins and diabetes we just i don't think we do um so statin therapy is like amazing but it's not at no cost so but when you talk to a individual human Being at least at this stage of my career it's been easier to make clinical decisions individually than to write rules for groups yeah and there's no question about that um let's now look at yet another predictive tool um which is the coronary artery calcium score So um maybe tell folks what what a cac is i suspect the number of people listening

to this will have had it but enough will not have so it's worth explaining what the test is coronary calcium is a an important step forward in cardiovascular imaging and it's a process where you can accurately and And pretty safely determine using x-ray techniques whether there's calcium bone in the coronary arteries and calcification is part is a feature of advanced atherosclerosis and so there are there's Very strong evidence that people who have coronary calcification are at higher risk of a heart attack or stroke than people who do not have coronary calcification and and that's a

that's an important piece of information but there's several facts you also have to appreciate First the the frequency of a positive cornea calcium goes up as we age and so does the risk of disease so by the time a man is 60 all american men are at high risk according to your current guidelines women are five to ten years later so at the point where the test is most Commonly positive i don't even need it because that person we were talking a while back about the natural history and stereo and stuff that stuff is for

real okay our arteries in [Music] the majority of us have become substantially transformed in Bad ways by the time we're 60. now in people who are younger than 60 can this give you extra information if you're on the cusp of saying should you be treated or not and i think the answer is yes if you or the patient says i want more information i'm not convinced that i personally are In a situation where i should be taking medications and you have a positive coronary calcium i think that can be extremely helpful it's the it's it's

what's taken as the corollary that if your coronary calcium is negative you're okay and that's the problem for me from my Knowledge and interpretation of literature and the pathological studies coronary calcification is a advanced side disease means advanced disease is present when people have a heart attack they don't just have one little area of their arteries that are abnormal but that's the area where the plaque broke or the endothelium eroded But the the arteries diseased and and there there's a chance of an event a sonometer down or a sonometer closer so if somebody has a

high apob the fact that their coronary calcium is negative doesn't mean they don't have a lot of disease and that the disease isn't developing at a rapid rate it could well be there So there's an argument saying well if your coronary calcium is negative nothing's going to happen to you in the next 5 or 10 years and maybe but the disease is going to develop and we can't make the disease go away we can modify the effects of the disease modify the consequences but when we talk about i mean ldl Cholesterol and apob levels are

now so low but but you still have an artery that's destroyed you're going to have a substantial number of events and there's a paper john wilkins and don lloyd jones from northwestern they have a paper in jaw and it's a it's a terrible paper to read but because it's so complicated and i wish they hadn't presented it in as complex form as they did They're friends of mine so i can criticize them but within it are the observations that starting to treat waiting for coronary calcium is a bad idea so i'm a conservative physician it

may not be my politics but as in that i want to protect patients give them the option because it's the Patient's choice of course it is give them the option to have the best outcome possible when it's they appear to be in danger so i wouldn't use a negative coronary calcium to change my clinical decision when i have a high apob or another cause of vascular disease present so i think it's a good test but relatively limited utility for me Yeah the way i've sort of talked about it maybe even on the podcast but certainly

the way i talk about it with patients every day it would seem is i describe it as a two by two matrix so we think about how this test is helpful in people who are young and people who are old now i usually use 50 as the cutoff it sounds like you use 60 as the over under but let's just say it's somewhere in That sixth decade and then is it zero or is it non-zero um and i i i agree with what i'm hearing is your assessment which is in the older patient the positive

score is not very informative so when i have a 70 year old patient whose calcium score is 50 it's sort of like so what like you're you're normal it that doesn't tell me much um And conversely when i have uh an older patient whose score is zero and they're adamant about not getting treatment it becomes an easier decision to accept because you can say well gosh you're pretty fortunate to be 73 years old and despite having an apo b of you know 140 milligrams per deciliter Your your your your calcium score is zero there must

be some other protective mechanisms in you yeah our our the bounds of our knowledge are really quite limited and it's important that we admit that to ourselves as and and to our patients as well uh i look at it maybe a bit differently i say yes i would say the same thing and i would Say yeah but even so well yes to me there's an asymmetry which i want to come to in a moment on the flip side of things the young patient who has a positive calcium score really that's a four alarm fire regardless

of the apob right so if you're if you're under 50 and you have a spec of calcium in your coronary arteries even if it's a low enough spec that it would predict a 10-year risk of Four percent that's still utterly unacceptable oh no if if it's if it's positive it's positive and it's going to it's only going to go up exactly and more to your point it's what it says about the milieu of the entire system so yeah that might be the one area in the middle of your left anterior descending artery Where you're at

such an advanced stage that you've already laid calcium there um but you know it's sort of like looking at the concrete that's been poured over chernobyl and trying to infer what's going on in the 10 miles around chernobyl it's all bad yeah that's correct Where i find the most challenge is in the the there's there's the there's the group think that says if a person's calcium score is zero no treatment is needed um and this kind of gets back to your your paper from jama i think 2018 maybe 2017 looking at the the 30-year risk

the causal model which i want to come back to you you mentioned it very Briefly at the outset but it's so important that i want to now use this as a as a jumping point to go to go there which is you take that 45 year old person who you expect their calcium score to be zero it is zero but their apo b is higher than it should be or you would like it to be that calcium score of zero hasn't really added much information to my decision Making no because your time horizon is different

and and i and i think that that's what those studies are we use 20 30 years okay i think the 10-year if you're 45 you want to get to further than 55. your career your children your your enjoyment of things surely you're not just planning to age 55. and you should be thinking well what am i going to be like at 65 or 75 that's reasonable and it's also by taking it out to that you can get to numbers that are really meaningful when somebody's at a thirty percent chance like one in three that's a

that's a number most people can understand and it starts to become a Truly individually meaningful a meaningful number for an individual when somebody's at 7.8 percent risk i you know that's that's that's tough to absorb in you know in a in any way that means something so when you're in one of these higher risk groups it doesn't mean you're doomed But you're in company with a lot of folks who are and and we can say that absolutely accurately and yes it's limited it may not be you make your bet but but you know it's funny

allen i would i would even i'm i'm maybe a bit more of a of a what's the word i might even be more risk afraid so you're saying that if a person's 10-year risk is 5 How can you get somebody excited about a five percent event in the next decade if somebody's 50 so somebody's 50 and you say you've got a 5 event risk by 60 and you're saying well the two things that are wrong with that are one you shouldn't just be thinking about being 60 you should be thinking about being 80 which i

completely agree with you we expect you to live a minimum of 30 more years if not more Um and secondly you're saying well five percent's not that much to get excited about well let me turn the table i want you to pretend you're 50 allen and i say to you alan there is a 5 chance that in the next decade you will die on a commercial plane how would you change your behavior as a result of that i don't think i would you wouldn't stop Flying no because there's a 95 chance i won't okay so

i mean i think 5 is a bigger risk than people realize i get it it's bigger than one in a thousand okay well not only that but in the in the case that i just gave you the treatment would be don't fly for 10 years which is a real impediment to your lifestyle versus the treatment to lower lipids Which is far less of a burden and the risks of it can be yeah let me come back to you what are the confidence intervals on that number of five percent well that's a good question yeah no

that's a good question excuse me excuse me i'm gonna let's let's say i can tell you it's plus or minus two percent how do you tell me that where's that Number have you ever seen that number at the population level let's pretend i'm able to tell you that at the population level no you've never seen it i've never seen well we can't do it at the individual level of course no no no no i'm saying what are the confidence intervals for that prediction have you ever seen them published and the answer is Nope okay and

and as i'm not sure how much of your audience does confidence intervals and this kind of thing but as scientists for any result we get the result and we get the range of possible results then we know how accurate the prediction is if the confidence let's say it's five Percent the confidence interval is 4.5 to 5.5 well you're there if the confidence interval is 0 to 70 which it could be by the way maybe it isn't so i'm saying we got an industry that captured clinical care that doesn't include error well why is that that

seems now that you mention it Almost impossible to believe well but but it's true please please reassure your audience i'm telling the truth because we've become less critical this this process of forming opinion in in medical care that's that's that's that's that's appeared over the last 30 or 40 years has damped down the essential Element of science which is challenge different viewpoints um the contention of ideas the the creation of an experiment to say this is the right way or the the someone with a different view creates a different experiment science is a democratic activity

where differing views That are legitimate have have a chance to contend i'm not saying every crazy theory has equal well so so that's exactly what i was going to come back and ask you alan is who is the arbitrator of what's a legitimate differing hypothesis in science it's called the experiment that's what's different about science an experiment is done to test a hypothesis if the hypothesis is sustained you can continue to hold the hypothesis If the hypothesis falls then you must reframe your understanding and we do experiments to gain understanding it's our tool but it's

not as easy as it sounds the methods could become complicated the methods we use to analyze them statistically can become complicated are complicated and the conclusions we draw from them may or may not be correct error is occurs When i was a medical student the major medical meeting of the year was in atlantic city and the big professors would contend the elephants you know and there are different views and they would argue them out and it was a contentious open battle evidence-based medicine came along which has lots of pluses in which it says You know

we should use randomized clinical trials as part of our knowledge base but we developed the belief that it was easy to assess knowledge and it's not it's not easy to assess experiments all the time some of them are straightforward most of them actually aren't most of them there's uncertainty Involved and it's important that we acknowledge the uncertainty and say well maybe there's another way of looking at this that's even better but we developed tools like statins that we that we there's very good evidence can save lives so this process of consensus came along saying look

this is too complicated for regular Doctors and it is they don't have the time to analyze all the evidence so we'll analyze the evidence for them and write it out in a way that tells them what's the best we can do now and and there's a lot of good in that but there's potential weakness and i think where a lot of the Weakness is happening because you get a view that becomes the conventional view and it hangs on longer than it should science is about change if we're still saying the same things we said 30

years ago could be a problem because we should have learned how to say it better More accurately and a consensus you could get in these consensus conferences i don't know if your listeners appreciate the recommendations are unanimous the supreme court isn't unanimous often there's a majority view the minority says this that and the other thing and it can turn out that the minority over time we see the wisdom in the Minority any process that has unanimous recommendations has a weakness any process where the decisions become larger than the individuals who who propose them has a

weakness like the recommendations are the american college of cardiology american heart association blah blah and about 30 other groups there are actually a hundred people you know they're good people but there's only whatever number it is a Hundred of them but by cloaking it in the the the anonymity of the group they become impervious to criticism even when there's obvious inadequacies and that's not science if if you write a paper i could do an experiment and try and overturn your paper or confirm it but when you have the guidelines they're The judgment that's cast in

stone to the next group of guidelines and and depending on which people write them it can influence what you see i mean i i i completely agree with that um i would add even more complexity to it which is if you go through what the critical steps are in the elucidation of Knowledge the first presumably would be the formation of a hypothesis the second might be designing an experiment to test that hypothesis then conducting that experiment analyzing the results of that experiment and interpreting it again i'm oversimplifying a little bit but these are quite discreet

steps and as you pointed out any one of these steps offers Infinite ways to do it wrong in a relatively few rate ways to do it right i'll give you an example that's near and dear to both of our hearts so just yesterday i was having an email debate with a friend um i forget what spawned it oh he he had sent me an article about um something lipid related and it somehow led to a discussion about the The fourier trial which for listeners is the trial that looked at one of the two pcsk9 inhibitors

this was repatha and it demonstrated that on patients who were on a very low or on a very high level of statins and had a very low ldlc i think their average ldlc was in the neighborhood of 70 milligrams per deciliter over a five-year period they had a reduction in cardiac revascularization but no change in Mortality am i getting that right i think that's the gist of the 48 trial as it was first published um his point was how can these drugs be you know tolerated how is it that we live in a society where

insurance companies are paying for these drugs or people are using these drugs and doctors are prescribing these drugs where they Didn't even demonstrate a reduction in mortality all they demonstrated was a reduction in revascularization i can't remember if there was a reduction in events uh because i sometimes confuse odyssey and fourier um to which i said well it's really interesting um because the time course of that disease was the time course of that study was so short in a group of patients who were already so heavily Statinized that it's my interpretation of that study when

it came out which is probably six years ago it's actually a miracle that showed anything at all because if these patients are walking around with an ldlc that's at the fifth percentile of the population and then you give them another agent that lowers ldlc to you know the first percentile of the population and we're talking about a disease that takes At least four decades to take hold and you study them for just five years would you really expect to see an event difference which by the way you did see in odyssey probably because using a

very similar drug those patients were started out at a higher level of ldlc so you saw potentially a greater risk reduction so here you could have two relatively smart People looking at the same presumably well done experiment with the same reasonably legitimate statistics but we have a different lens for what the disease is and therefore draw a completely different conclusion is your point that no consensus can ever basically resolve that and the way that medicine has to progress is that each of us needs to progress on the basis of our own understanding or how would

you Sort of referee the debate between my friend and i the i i think we can only understand as individuals there is no such thing as a group understanding we we we can't get beyond ourselves really it's it's not it's not possible and when you talk about thinking I can't think about every issue that's out there that's important either in medicine or my car or my woodworking i have to delegate a lot i'm writing a paper now about familial hypercholesterolemia and there's a study that's that's the core study For um demonstrating that the patients with

familial hypercholesterolemia and whomever you can demonstrate a genetic abnormality are at much much much much higher risk than people with similar ldl cholesterols but without the genetic abnormality now that study's been accepted by everybody as being well done And decisive and um and i mean by everybody everybody just to make sure i understand what you said you can have two patients who are phenotypically identical but the one who has the genetic abnormality of fh which is simply a phenotypic disease by the way it's not a genetic it's a it's a the disease is defined by

the phenotype You're saying they carry a residual risk that's not present in the wild type that's correct three to five times that risk 300 percent that's that's unbelievable i thought so too and so i i read the study and i read it again and i reread it because i kept i couldn't understand it so then it dawned on me after A lot of re-readings i think they made a mistake in their methodology i think they made it a great school error now maybe i'm wrong okay because i'm writing this up i'll subject it to review

and criticism and i'm given that i'm saying every authority in the field is wrong i'll chances are coming out on positive and this are pretty slim but but but the error in the methodology That i think is present is so simple it's decisive and and i'm just putting maybe i'm wrong but my bet is i'm actually right is that thinking is damn difficult and we have to continue to think and discuss with ourselves hdl cholesterol everybody believed it till they didn't okay I mean how many dissenters were there until everybody said it was obvious there

was nothing there and we're human beings we we search for validation but science isn't about that it's real science and and it turns out that real science the world is a very s slippery thing to get your Mind around i i gave the example at the beginning of this talk about risk now if i said if i asked you what risk was i wouldn't do that to you because you're the you're the boss of this podcast uh but risk is the number of events per standard number of people over a defined period of time We

leave out the standard number of people when we say your risk is five percent we say well that's one in 20 well it's per standard group of people that's why i said risk is low if you're under 60. the number of events per 100 people is Low but the number of hundred people is a lot larger than over 60. that's why the absolute number of events is so high so a difference of words tremendous difference in action because it means i don't use the 10-year risk model okay and even though that has been published And

even though that has been reproduced by other investigators that has not changed the guidelines and that's wrong when i look at the guidelines and i have enormous respect for people who serve on them i can look at the literature on an issue i can tell you who wrote the guideline there was a recent guideline from europe that Was negative about apob one paper cited one paper and that became the guideline so i'm not talking about throwing out the process the process of reviewing knowledge in a group is positive i'm saying that we better watch out

for the process and we we need to do much more to ensure that the process includes A multiplicity of views so we don't wind up with bad decisions and if you don't think we can't make bad decisions just look at all the bad decisions the politicians and the business guys make we're no different so if you did what you're suggesting alan if you brought in a more heterogeneous group of views and greater diversity of priors by definition you could probably never Arrive at a unanimous decision so what's wrong with that nothing's wrong with that my

question is well is everything right with that yeah exactly my question is i mean how often what does the guideline look like so now let's take it back to the doctor who has to see 40 patients in a day will never listen to this podcast let alone read the show notes of this podcast Which are probably going to be 150 pages of the backup of everything we've talked about in every city that every study that's been cited et cetera et cetera they literally just want to know what to do in the moment with the person

sitting in front of them and currently they look to the guidelines which are unanimous expert run and you know revised often enough that It gives you the feeling that hey they're keeping up with the science right every five to ten years i'll get a new one of these now it's going to be this complicated legal document that's like reading the dissents and reading the in favors and how would they well i mean again i'm not saying that we shouldn't be doing this but how does it translate to the uh to the field how do the

guidelines read now oh they're pretty miserable no mistake About it they're they're not pretty miserable they're totally miserable i mean you talked about legal documents no doctor or i shouldn't say no doctor that's me being uh talking for too long uh no you they're not but there's a summary and that's what the doctors typically read right the doctors will read the one page executive summary that basically says and and that gets hammered home And do you know what that says about and that's i get this rebuttal all the time we've got to do this because

the doctor who sees 40 patients isn't going to do anything unless we dumb this down i don't think most doctors are dumb i think they're caring i think doctors want to do good jobs i think we need to learn more about how we present information I don't think we should ever compromise on truth because when you do you say i've got to do this in order to get to here and i don't want to use your political history in the united states negatively but but afghanistan i can't think of anybody right left or center who

thinks that the process getting in and throughout it Represents the best efforts of the minds of america it doesn't you guys are really smart wonderful people but it's what happens when you boil the options down to two and you've got to get it down to a one-liner and life isn't a one-liner not real life and if we're going to learn to make decisions that are to present information to our patients We're going to have to learn how to deal with doubt that's what it's all about it's it's it's funny just as you said that i

was about to say the real problem here alan is we are not trained to be comfortable with uncertainty i think we are i think that's what medicine's all about i think it is for Things that can't be measured and i think it's not i think there's a false degree of confidence that comes from things that can be measured so you're absolutely right in the olden days when um a surgeon went down to the er to evaluate somebody for appendicitis so this was long before the days when every one of those patients had a ct scan

right this is this is based on the books that i used To read from the the great surgeons of the 50s and 60s where this was a purely clinical diagnosis so you know seven percent of people in their lifetime are going to have appendicitis and you know that the pre-test probability on this person is a heck of a lot higher than seven percent because they're sitting here right in front of you presenting with these signs or that signs But you also know that there's an asymmetry in your decision in other words there's two wrong decisions

that can be made here operating on the person without appendicitis and not operating on the person with appendicitis and you also understand that you have to calibrate your decision-making around that uncertainty so that one mistake is more likely than the other And so i think you're absolutely right i think most physicians are very good at doing that somehow that doesn't translate into the type of uncertainty that i think is necessary to do what you want to be able to do which is rather than give people a sort of unanimously agreed upon consensus that is so

distilled down to simplicity that it's it borders on being incorrect You'd like to be able to give them the range of thoughts on a subject acknowledging that you can't tell them which one is correct yeah it's it's a i think that for example even we talk they're different audiences there's the practicing doctor the surprising family doctor there's a practicing internist There's the academic internist there are the experts in the field i think at a minimum you've got to have a range of opinion in the experts in the field and i don't think we meet that

minimum and i think that when there's doubt you ought to be able to write i'm not sure about this Which we do when we have weak recommendations but they're also always unanimous what what happens when you put five people in a room doctors experts are no different the one with the loudest voice can carry the day the one who claims the greatest expertise in the area can carry the day um so these these And then we wind up with documents that are very difficult to read and and and read like you know 20 years ago

with minor modifications you can't say anything was wrong well good gracious we learned it was okay what's our problem who are we here for ourselves or our patients and the truth And so i i think you can write clearly and and people can read and make informed choices in the end of the day what this is saying is that people are too stupid to make a real choice and i don't believe that i believe that when we tell people i mean heaven when when i've treated patients and made recommendations were they always the Right ones

of course not they were what i thought was best to advise but i can't claim they were always right and in knowing i could be wrong then i calibrate the safest way through for my patient that's what keeps me that's what makes me if i was good that's what helped me was saying i if i'm wrong about this how can i set up something to catch it How can i how can i hedge my bet here or i got to go a little stronger here because i could be missing this that's what medicine is medicine

is algorithms help us of course they do but when we treat algorithms just by algorithms then that isn't what's called clinical medicine or clinical surgery that's that's algorithms and and and we Have good health care professionals who are more driven by algorithms and and more advanced healthcare professionals who can take the algorithms and and work within them and around them and and everybody's doing a good job but we got to respect the fact that our understanding is limited and that science requires Different views to contend equally and that we need to write the truth i

mean do you think that we've seen an acceleration of the kind of forcing function around a uniform voice i mean it seems to me that the past 18 months with kovid has really Amplified what you're describing um i think there are you know lots of dissenting views out there for how kovid could be managed what the potential efficacy is for repurposed drugs and truthfully i've struggled to wade through the literature on this stuff um and you know you'll always find somebody Who's made it their you know it's their mission to understand how this drug or

that drug or this intervention or that intervention is the is the is the solution to the problem um but there's no denying that that such people have been you know pretty roundly silenced uh for for this and it begs the question That you know should we be paying more attention to these views and when do these views become so fringe and marginal that they're actually harmful yeah it's it's it's they're because they can be they can be and and we've got to be uh but that's why i think when the the first level of discussion

is is should be amongst experts Where you can call out views that are um so divorced from experimental uh evidence that they're not serious views i do think we can separate out as i mean covet cover's a great example i heard good people express Somewhat different views at different times on different issues not the same person but one person had a view and you say gee that's got a good point and the other person had a view that's a good point but but they were all within a channel that was um that made sense to

me as a physician not an infectious disease expert so I'm not talking about legitimizing any possible view because it's a possible view i am saying that people were saying we're pointing out different aspects of a complex problem and they might put a little more emphasis here and a little but the result would be oh i i i understand more clearly That there is a uh a series of choices involved and and and it's challenging to go through them in in canada the government we had much longer periods between the first and second vaccination so more

people got their first dose before the second so i get that that's a that's a decision in real time that's a real challenge That it's that you can't be sure that you got it right at the moment you're making it but you're the responsible person you gotta deal with it but it was in the open so you know what was being done so i'm good with that process because i know what happened and we can assess The the the outcomes i i'm not good with someone just shrieking uh and and i think it's it's the

what i'm against is saying because we can't have somebody shrieking we can't have any debate that's wrong that's totally wrong because it winds up then we make mistakes where we we don't have To make mistakes and and and the responsibilities we have to make recommendations to our patients are so awesome that we our humility we need to we need to be humble and say okay give me your best shot i'll give you my best shot and we're colleagues we're not enemies i mean i disagree with lots of people because i Have a scientific viewpoint but

they're not my enemies and we have ways of discussing this and if i'm in the room i can say hey you said that you show i'll show you line 26 in your paper which contradicts you and he has to respond in front of other people that's what i believe in is the testing of the argument in a in a in a jury of your peers is that culture being watered down In science is it the same today as it was 30 years ago no i think that's the weakness i think that's the i think that's

the crucial weakness i think inside the room that's what's not occurring as i judge that by the product that comes out and why do you think that why has this process become diluted because of the the the part is that People get attached to views i think people select view because this emphasis on consensus and unanimity you don't want schneiderman in the room because he's going to argue for apob you can deal with me i'm not hard to deal with you can say okay i heard you but here's what's wrong with you your argument not

me personally here's what's wrong with your argument But has something changed to make it that ideas are more personal like what what is the factor that has led to or factors that have led to that i think people are invested in what came up came out in a way they're no longer speaking as individuals no i mean i think people used to become known for their own science now if you're on the guidelines that's your science that's your that's your you're very prominent because You're on the guidelines not that you did the science you're only

you're on the guidelines and and we have so much science that's done like the clinical trials i mean i think clinical trials are wonderful but they're limited tools and i'm not sure [Music] i i think the composition of the committees needs to be Re-examined and i think you ought to be able to criticize what comes out like i've written critiques of the apob's my thing okay so i wrote a critique of the 2018 american guidelines how many references were there on the comparison of apob and and ldl cholesterol and non-hdl clusters in the guideline yeah

i don't know five there were four two from a group opposed and two from me And mine weren't even correctly cited now that's one issue they dealt with a whole bunch of issues but that's not adequate that wouldn't get you a passing grade in school and we're not limited now by space in dealing with issues we can we can put anything out on the internet for anybody who wants to read it and what that represented to me was that I can't tell what happened inside the room was there wasn't a full discussion and that and

we didn't have these processes when i was young contending ideas could could contend more easily i mean i i think it will be i don't think it's going to happen and i don't think it's going to happen because not because there is some value But i think there were a group of people who just weren't interested and that's sad and you think that ultimately there are still that many physicians who are going to defer to the guidelines because i don't look i don't think you need the guidelines for i mean reimbursement's not an issue right

apob bills your insurance company four bucks and its cash pay is two dollars and fifty cents i mean it's this is not a Cost issue this is really an awareness issue on the part of physicians that's that's really all it comes down to at this point well the guidelines presented as a cost issue that's the argument against apob right but the guidelines must have failed to actually look at the cost then that's correct that's correct i know that okay but but i can't say that Okay because the guidelines are the guidelines of course you can

say that that's what we're talking about here i mean why is i mean that might be your next paper is do a survey of the laboratory cost of apob and the average medicare reimbursement rate on it across the united states or something to that effect and and in canada i mean it's it's such a again i think it's it's Those are those are valuable exercises right i i think they are and they we did a cost analysis on apob i think using a charge of 10 and looking at the cost of care and i think

it contributed 0.01 to the cost of care something like that okay i mean the cut the concept that a 10 test really changes the cost of care Well furthermore the whole thing is so idiotic right the last time i looked in the united states and admittedly we're spending infinitely more than we should and infinitely more than anybody else so this is ten-year-old data so it you know it's probably closer to 10 000 now but 10 years ago in the united states our health care spending was 7 000 per person per year that's 10 years ago

so again i don't see How it's less than ten thousand dollars per person per year in the united states today so if the apo b test cost a hundred dollars which again is like 20 times more than it actually costs so what atherosclerosis when last i checked is the number one killer of men and women it kills women At a rate that is more than 10 times that of breast cancer what i mean are we missing something here is there some part of this that you haven't told me that's that's my frustration that's my that's

my sadness is because you're absolutely correct this is pennywise pound foolish where it's lives That are being lost and we've calculated the number of lives and heart attacks it could be avoided live saved heart attacks avoided if we switched to apob the american college of clinical chemistry the european clinical chemists they have a series of reports saying apob can be measured more accurately than ldl cholesterol or non-hdl Cholesterol no question is that in any of the guidelines accuracy of measurement no that's where that's where that's what's so hard to deal with when you say you're

criticizing the guidelines maybe it's just you you're uh who are you you're a nobody which is true but i'm saying look it's a laboratory test Surely the quality of the measurement is something that should be mentioned not not the diagnosis of type 3 can't be done without april b so any hydro hypertriglyce needs an apob not done not mentioned type three so Um i can't beat on you with sadness and stuff but it it's it's uh i've been incredibly privileged uh to have the opportunity to um try and understand the world around me i mean

i my background is not a would have led you would have normally led someone like me to have that chance nor to work with the quality Of people that that i've had the privilege of working with and and i've been able to write and record the images of the world that that that looked real to me and and how few human beings ever get that um that privilege um [Music] and [Music] i'm just sad that it it it won't help it won't help people i'm sad about that and i and i'm sad that the um

you go so far in the thinking and then somebody can take it to the next step it's not like i've done that much somebody can see this and say oh wow if that's so let's go there and And it's not going to happen i i don't i don't agree on two levels the the first is i don't and i'm going to call you out on this allen for a guy who understands uncertainty and probability and risk you're using awfully black and light white language right now it's not going to happen with what certainty can you

say that no i mean it it's October i'll be 80. okay um so you're right you're right and it and it and it and it's and it's self-pity and it's not attractive to me either okay yeah no no and i'm not saying that to to sort of uh to belittle the point of view what i'm really saying is you know i forget the the the there's a there's a beautiful you know story about the guy that's hitting the stone right The mason who's who's hammering away on the stone for 10 000 strikes and on the

ten thousand and first strike when he hits the stone it finally fractures now to the person watching it it was that ten thousand and first strike that fractured the stone but of course the stone mason knows that it was that strike plus the 10 000 the the 10 000 that came before it and so i i i think You just have to accept the non-linearity of the advancement of knowledge and it's it's it's embarrassing that i would even attempt to try to say that to you because you know that's so much better than i do

of course but maybe in this one situation alan you're just closer to it than i am and therefore you you're just too close to kind of the the political environment of it right because at the end of the day These these these these these um consensus statements are largely political um they're they're they're far more based on who you are and who you know and how long you've been on the committee than than the strength of the evidence but i i just i wouldn't bet against the truth i i think that in the end um

[Music] the truth generally wins in science not always um but it also depends on your time course and it wouldn't so yeah it just wouldn't surprise me if in 10 years 20 years we're going to look back at this just as we are looking back today at htlc i mean that was not that long ago alan that people thought hdlc was everything And today thanks to the ctep trials the mrs we now know hdlc is a much more complicated than we ever thought and b probably not something we should be trying to manipulate in an

effort to improve outcomes no i i hope you know what i at the end at the end of it all that's what i'll hope for You know uh and uh you need to pick yourself up and keep keep fighting we have we have new a new observation that we think is even different more startling than anything you've heard and we'll try uh It's it's it's um and it's it's to to quit is wrong to admit because then your part of this is for yourself just to see can you understand the k what looks like chaos

is there any is there any pattern to what looks like there's no pattern how do How does blood sugar and lipids and how do they how do they combine to to hurt us so just to have the privilege of you know looking at those questions and to write down your thoughts in a manuscript and to publish the manuscript is That's so few people ever have that privilege i mean i've i've just been extraordinarily you know rewarded for for the very little bit that i've been able to achieve so um it just I have a short

fuse and it annoys me stupidity annoys me ignorance annoys me and um and pretentiousness annoys me deeply look i think those are all things worth being annoyed at um i think you know another one of your strengths alan that i've observed over the i don't know 10 years that we've known each other maybe longer Is you're you're you have an insatiable curiosity about things that are theoretically or you know in quotes theoretically outside of your lane and we've probably exchanged as many emails on the mechanisms of insulin resistance as we have on everything that's related

to to lipids so um i think that That's a very important part of your success which you've been very modest in downplaying is the breadth to which you think about this problem and i think that i i think that's why you've been able to sort of spot patterns that are not obvious to others before we wrap there's one thing i want to go back to because we spoke about it quite briefly but i think it is so important and when we spoke about it at The outset we hadn't given the listener the full landscape of

the disease but now that we have i think they will understand more what you mean when you talk about the causal model of risk this 30-year causal model versus just a risk calculator so let's go back to that you you go to a framingham risk calculator and you plug in a few Variables right i'm this old i do smoke or i don't smoke my hdl cholesterol is this my blood pressure is this what is my 10-year risk and you hit click on the button and a number comes up and most of the guidelines say if

that number is below something and a typical response would be if the 10-year risk is below five percent there is no need to treat Carry on as normal i'm exaggerating a little bit but that's that's the gist of it i practice medicine a very different way because i have a very different goal right i have a i have an objective for how long a person might be able to live disease free and i also tend to be influenced by people like you Who have taught me how long it takes for this disease to take hold

so the analogy i would use is imagine there was a calculator that told you you know how much money you should be saving for retirement but it could only predict 10 years into the future it wouldn't be a very useful tool because a 30 year old isn't going to be retired in 10 years So how has your thinking which has influenced me greatly how did you come to the 30-year model that is based on the causal relationship and what what are the types of yields that we see there part part of it is utilitarian 30

years was the longest stretch we had reliable data for and And part of it was that the the the period of uncertainty is greatest between age 30 and i'm saying 60 but 55 whatever that's where the tenure falls down and and we originally did these models based on 10-year risk and and you could say look You're right we're not we're not we're going to miss most premature disease let's just lower the the risk instead of 5 we'll make it 2.5 and you could do that the problem is it's not cost effective because you're multiplying the

number you treat need to treat more than you would need if you start off with a cause now let's say i i categorize you by your Apob or your non-hdl cholesterol let's say you have a high apob so you're in this group of about 25 of the population because i i use 25 75 to get you there so that group has over 30 years a 30 event rate it's a lot it's not just the apob that's doing it age is still a big driver age is a driver but they'll be fatter at The start their

blood pressure will be a little higher at the start it's not that the other things are being left out you're catching them you're just selecting differently and i would submit you're selecting more accurately because i can measure apo b or non-hdl cholesterol with much less error than i can measure Your risk the variables that we know michael pincinis calculated we were account for about 20 percent of the variance in risk okay that's about it that's not such a that's not such a large number that's a it's a small number so from a utilitarian perspective By

stretching out the thing and using the idea of cause and and and precision of measurement i i group you and then i can present a patient with their with the with the what we know about the group and they can make their decision and i there are people who say thank you i'll pass they come back in Six months a year we could have the same discussion again i didn't lose anything they didn't they might they've lost some and we can show that but but these aren't decisions that you can't revisit if you if someone

starts on therapy they can decide to stop it patients are free agents i mean i respect that and it's up to us to present our Arguments and continue to present them as we frame them to their what we think is their best interest and the best we can do so i i i i like to maintain contact with my patients to who are in this sort of thing to make sure that they know they can change their mind but i can also show them progress If if their apo b started at 120 and we're down

to 60. hey i know they're taking the medication i really do okay otherwise it would be 120 and they can see and appreciate the extent of change that's occurred and i for me and for the patients i've cared for that tends to work one of the things that i find very helpful to explain this because it's non-linear and I think non-linearity is not innate to us i don't i don't think evolution needed us to be able to think non-linearly i think linear thought was good enough and that included linearity with time and and chance but

this problem doesn't lend itself to that and therefore i think it's not intuitive to somebody who hasn't filled with numbers a lot or hasn't spent time looking at things that compound That even if you were just to look at a risk-based model that was short-term there's a significant benefit to reducing risk from four percent to two percent over a decade because even though that might only mean there's a two percent risk reduction over the next decade the amount that that amplifies over two three and four decades is amazingly counterintuitive Just in the way it is

if you think about saving for retirement if you're 40 years old or hopefully younger when you start saving for retirement if you're 30 years old when you really start an earnest to saving for retirement and you have one option that's going to generate a return of seven percent and another that generates a return of ten percent or nine percent there's a two percentage point Difference that's not going to yield an enormous difference by the time you're 40. but by the time you're 70 it does i've done the math on these and you can easily show

how you can it can literally double the nest egg just based on relatively small changes up front so i think that's also part of the issue here is just understanding what compounding does and how it works in your benefit when You're talking about investing but understanding how it works against you when you're talking about a disease like atherosclerosis and we've we've done some of these calculations and you're right uh starting early pays off later and and when you start later what you're doing essentially is to try and modify the disease that's Already present when you're

starting early what you're actually doing is starting stopping disease from developing and if you can stop a lesion developing that's a 100 percent success trying to treat modify through one process a complex set of outcomes at this end much less likely to succeed So stopping disease is perfect prevention treating disease is partial prevention and it has to be partial can't be more yeah i think that's a very important point because although we haven't stated it explicitly the undertone of everything we've said is not only that apob is causal but that it's a necessary but not

sufficient driver of atherosclerosis and i think that's important because Necessary but not sufficient creates a lot of confusion in medicine doesn't it right necessary means you have to have an apob particle traffic a lipid into an artery wall if that doesn't happen you don't get atherosclerosis sufficient means if that's the only thing that happens do you necessarily get disease no you don't we can each of us could rattle off tons of patients who somehow make it into Their 90s with high apob and don't have disease but from a prevention standpoint it's much easier to go

after something that's necessary because you only have to block that versus once the disease has already taken hold you're advancing something that's multifactorial so i think that's a very important point you raise and i i don't think it's i don't think it gets made Enough well alan um i'm glad you i know you you were you were a little reluctant to sit down you you didn't see the the value in doing a podcast but i'm glad we twisted your arm a little bit and uh i i uh it's funny i didn't realize until a little

while ago that you were you were 80. i you always come across as so much younger to me so there's uh that that explains to me why you've got lots of lots of miles left In terms of the the apob work and the crusade here so i'm i'm very optimistic thank you it was nice to dinner would be even nicer but this was nice to speak with you again well we'll make that dinner happen again at some point so now thanks so much you're very welcome thank you for listening to this week's episode of the

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