High LDL Cholesterol on a Ketogenic Diet: What You Need to Know | William Cromwell, Dave Feldman

I'm not going to call anyone out but I'm going to say that there are a number of people I wrote to via email as I started developing this data but almost nobody was answering my my calls let me put it that way so Bill why answer those calls well it was novel The Usual way we think about lipids and lipoproteins is only over of months now here's Dave who comes along with his in of one experiment and says in a matter of days I could radically change my cholesterol we've we've not talked about that in

lipids because we'll be able to also see if there's a correlation between LDL levels especially apob and both incidents and progression apply so the soft push back I would have on that is that in today's episode I sit down with Dr William Cromwell or Bill and Dave Feldman to discuss how blood lipids affect our risk of cardiovascular disease Dr Cromwell is a lipidologist with over 35 years of experience Dave Feldman is a software engineer and citizen scientist who after adopting a ketogenic diet noticed that despite markers of metabolic Health improving his LDL cholesterol elevated severely

his question since then has been whether or not high LDL cholesterol is a problem in the background of optimal metabolic Health I've wanted to have this conversation with Dave for some time to better understand his views we've had private back and forth for I believe 6 to seven years at this point given lipidology is not my specialty I invited Dr Cromwell on for a balanced discussion it's a pretty nerdy Deep dive into lipids and atherosclerosis the buildup of plaque in Our arteries not for the faint-hearted but if you do love this topic like me then

I think you will find it incredibly interesting please enjoy Bill Dave thanks for doing this pleasure thanks really interested to hear perspectives from both of you today on a number of things lipid and heart disease related to kind of kick things off and get people up to speed let's just quickly go over kind of where both of you fit in here so Bill you're a lipidologist that's right what is a lipidologist and how have you kind of spent your career so far so lipidology is the science of cholesterol metabolism essentially it's a little bit more

than that it has to do with the particles that carry cholesterol cholesterol and triglyceride in their relationship to things like heart disease other diseases like the pancreas pancreatitis um so my uh journey in this area if you want to call it that started in the late 80s I was one of the first guys to have a private practice slipper clinic in 1988 right so at a point when nobody cared and nor should they really at that time because that time we really did not have our understanding uh of heart disease lipids we didn't have very

many therapies to even consider whether they would be reasonable or not uh we had a lot of epidemiology we had a lot of genetic uh understanding some experiments of nature uh but what was very clear to me was that uh we didn't have a lot of practical ways to move forward to blunt the scourge of heart disease and it seemed that lipoproteins and cholesterol metabolism was part of that so for the past 35 years I've worn many hats uh the clinical hat is I've had some form of a lipid practice since then I've been head

of a variety of divisions of aerosis lipoprotein disorders spent um 20 plus years in bench research um using NMR as an analytic platform to quantify lipoproteins Jim OS who originated that technology has been my research partner for 30 plus years um and then uh human research at various times in clinical trials so between clinical trials bench research and clinical practice that's where I've spent my three decades so we're in pretty good hands here well I did speak to Thomas dpring before organizing this and and he couldn't do it but he said Bill's your guy so

I feel like we're in good hands if he's saying that well I appreciate his over the 35 years in your clinical practice and even in your kind of research and just thinking about artherosclerosis have there been many things that you've kind of changed your mind on well absolutely um so this is a model really this is a disease model and and like any model it's just a matter of you know what's uh the new learning that informs the model how do we modify the model in a way that I hope Embraces all good outcome and

and findings uh so one of the things I think we have to at least explore during this conversation is the interface between the particles that carry cholesterol and how they contribute to vascular disease and cholesterol as a biomarker of those particles and that's really what the story is the story is not that cholesterol causes heart disease the story is not that there's good or bad cholesterol the story is that there are particles that carry cholesterol that can have punitive or protective characteristics right and here in terms of being potentially problematic we're talking about aob B

containing lipoproteins just to kind of there's some overlap here with previous conversations that I've had with with Thomas dpring right so the aob B pool is a a group of particles 90% of which are LDL about 10% are other things and there are various reasons why apob particles have the potential to be atherogenic okay so we'll come back to that right Dave you're a software engineer and a citizen scientist what what is a a citizen scientist I guess is that something that that you even refer to yourself as or is that something that other people

refer to you yeah you know it's fascinating because I I would argue that my life was entirely about software engineering um really up until about 8 years ago 9 years ago gosh 8 and a half years ago so basically November of 2015 was when my life changed after 7 months of being on a ketogenic diet I got a an eight and a half sheet of paper 8 and a half by 11 sheet of paper that changed my life forever because my cholesterol levels had gone through the roof I found that to be surprising because my

other first degree relatives who also started keto around the same time did not see their cholesterol levels rise substantially and so I became obsessed with trying to find out why and so as you probably heard I started doing a lot of self-experiments in of ones to eventually elucidate that actually my lipid levels changed quite rapidly depending on what I was eating in this ketogenic context and what I liked was coming from software engineering I work with networks all the time distributed objects that are interacting with each other and that's actually what the lipid system is

and so then I got a lot more interested kept doing more experiments eventually started uh blogging about it giving presentations on it and then connecting with a number of different people at higher and higher levels eventually you know got to the 10th level boss over here so you got you guys I mean we spoke off air but you have met before and and done podcasts and spent time with each other right yeah we it's it's fascinating because we we were just chatting about this we he was really the first lipidologist who Not only was able

to get some time chatting with but uh was good enough to provide you know an ear to Soundboard off of and what was your initial motivation to adopt the kenic diet actually to avoid um type two diabetes which is rampant in my my family did you have pre-diabetes yeah an A1C of 6.1 two years in a row and so it coming the second time in 2015 I was pretty admit about trying to figure out a way to not get it mhm and at that time it wasn't really keto it was lchf low carb high fat

uh but I found that the fors were chatting about it a lot and I remember distinctly at that time writing well wait a sec if I'm having a lot of cholesterol and saturated fat aren't I going to get a high LDL cholesterol and they said no no no that's it's actually pretty rare almost nobody gets high cholesterol after granted ketogenic diet and uh yeah that was the starting point so you make Bill Bill's I guess I kind of sort of just interrupted them but I think you were alluding to the fact he was for lack

of a better word uh one of the first lipidologists to kind of take you seriously or be interested in what you're doing I think so I mean I I'm not going to call anyone out but I'm going to say that there are a number of people I wrote to via email as I started developing ing not only this data but what I felt were the early beginnings of what we may be chatting about the lip energy model that I felt you know was fairly straightforward and how it explains why these lipid levels change as rapidly

as they do and could also have further relevance with regard to being on a ketogenic diet but almost nobody was answering my my calls let me put it that way so Bill why why answer those calls you know there's a number of people and again I'm not going to name names who I think just take the position that we understand what's causing atherosclerosis why entertain any of these ideas why have these conversations is it is it productive is it useful is it clarifying well it was novel um so the the usual we think about lipids

and lipoproteins is on the order of months you know we see people say every 3 months if we're doing something to improve their values we'll see them every 6 to 12 months if they're well controlled and we're just keeping a finger on the pulse now here's Dave who comes along with his in of one experiment and says in a matter of days I can radically change my cholesterol we've we've not talked about that in lipidology we we don't have models where we're uh looking at people on a daily weekly basis to see well how quickly

can we modify what are reasonably steady state levels for most people so just the fact that this was reproducible and the fact that as he was going through the this very methodically if I do this I get this if I go back to this I get that and let me tweak the system again so he had a very organized series of data which were very interesting because in that time frame a I would not have thought that values would have shifted that much in that shorter period of time and and B the fact that he

was able to begin to dial in uh a set of variables that uh he could almost call the ball you know if I do this I bet my levels will go to about this level and pretty close right so there's something to learn here that a we we don't usually think of that in lipidology and B the mechanisms that might drive that aren't your usual mechanisms uh that we have in the textbooks so part of it was was interest and what can I learn from this and then secondly um the question of what impact does

this have as far as risk is concerned because our model for risk for almost any risk factor is how bad for how long bad things for a long time increase risk so what would be the downside of having a super high LDL for a week two weeks two months two years how long does it have to be high to really Drive things in the wrong direction does it happen on day one probably not you can think smoking for example somebody who's smoking we think of pack years how many pack years have you been smoking if

you just picked up a pack of cigarettes today you don't have the same risk as somebody's been smoking for 20 years so this begins to bleed over into other thought processes of how do we ascribe risk to individuals what's the big picture and if somebody's looking at me and saying well should I be concerned How concerned should I be uh do I have to take a drug can I just modify my diet or lifestyle if that's what was responsible for a lot of this in the first place so there were a lot of practical edges

to this that I could see would be helpful to understand right so just just clarify something for me and the listeners so kind of bring everyone up to speed with with exact what we're talking about here da you're talking about you adopted a ketogenic diet which is it's high fat it's low carbohydrates you got your blood work done you saw extremely elevated LDL cholesterol what level was that at uh historically my total cholesterol was around 180 my LDL historically was around 120 to 130 which is right about the midpoint for a male my age when

I adopted the k diet I believe my total had gone up to something like 340 or 350 my LDL to something like 24250 something right and at at the same time your HDL was relatively high and triglycerides relatively low I'm presuming correct both of those moved in that direction right okay and was that like a new sort of cluster of lipids that you hadn't seen before I guess we I'm getting at is why look at that and think well that's that's interesting when you know I know that there's other lipidologists who I guess just look

at that and say well his LDL is elevated that's that's not optimal it can't be optimal so a couple of thoughts um I don't believe that people have high LDL for a long time with impunity um so I think you you will eventually have a consequential bridge to cross in most cases the higher the longer the worse now for the reasons that things are going up in lipidology we think of production and clearance whatever I have a lot of I made a lot I didn't get rid of it or both so if Dave is making

a diet modification as LDL almost doubles is that a production problem is that a clearance problem is that a combination of the two and when you think through those Pathways and it's happening in a matter of days that challenges some of our thinking as to why LDL is his ially high in people for example with a genetic problem where they can't clear their LDL clearance doesn't change that quickly in that shorter period of time necessarily so just the time frame of these fairly significant changes in a short period of time and then me as a

lipidologist thinking production clearance both what's going on here right so so your question is are those a containing lipoproteins behaving similarly in within that context to other contexts well two questions why they're high what mechanism is driving them and then um we really go back to the model that we most commonly see people in a an unfavorable lipoprotein State chronically and their chronically abnormal lipoproteins are contributory to their vascular risk um have we seen Series where people were otherwise fine for the majority of their life and then a switch was thrown and now we have

ldls in a level that would historically be very worrisome um is it stay there is that a new normal if it's that new normal then we have a different conversation well what happens after 3 four five 10 years of this right U maybe this is transient maybe what we're catching is a body adapting to some sort of major macromolecule uh change and it's going to Peak and it's going to come down and some people it does are you saying like so it's it Peaks and then it comes down back to a new kind of Baseline

over weeks or months where you're talking about throughout the day it's going up and coming back down so this was the the the interest right so Dave was the first person that could show me data where we could begin to ask those types of questions and so early on why would I take an interest because this type of time frame of change I hadn't seen before and there are a lot of questions of well how long does it take and how uh steady state is it once it gets there are there people for example who

are reasonably compliant with the same diet over time and the numbers go up to a new level and stay there in some cases for various reasons to they attenuate and begin to come back down the these were all things I was interested in trying to understand has your LDL cholesterol remained at that level I'm assuming that you've continued to sort of adopt this ketogenic diet yeah it has which also conforms to the model to the lipid energy model it per my expectation when I was coming into this space people did speculate that if you saw

your LDL increase it was probably going to come back down again and to be fair there is some context around that that's worth appreciating which is that indeed if you're actively losing fat Mass you are liberating more of the lipids that are inside your atopus tissue and if that's happening then sure there actually is a clear physiological reason for which you might have higher uh vldl being produced by the liver and th higher LDL but once weight's stable would you still see your LDL being higher and I would contend that generally speaking if you're metabolically

healthy and generally leaner it's more likely than not that not only will your LDL be higher but even at weight stability it's probably going to remain persistently higher especially the leaner you are this is more of a personal question um and I'm kind of asking you to speculate a little bit but why is it that you think some other lipidologists are not open to having these conversations with you you know I've actually I've had this conversation with uh Bill literally just in the last hour we we were chatting on our way here I really mean

this when I say it I genuinely think that a lot of um the lipid hypothesis not only is heavily entrenched but there is a sense that obstruction of that even as well intentioned as you may want to cast it can still be seen as harmful for their patient care so I think a lot of people who are detractors to my research are actually genuinely well-intentioned but to an extent um it's true a number of them have difficulty having this conversation because they're concerned it's platforming a kind of as is often you know referred to a

kind of denialist position or something along those lines all I can do is the best that I can to continue to try to engage as reason ably and as cordially as I can okay so I want to put a pin in the I guess the lipid hypothesis come back to that and clarify what your your view is I guess on whether you uh agree with some of it part of it whether you think it's totally wrong whether you think it just doesn't apply in certain context Etc so we will come back to that I just

came off a 7-Day diving trip in sakuro told you about my customs issues last night um and I I don't only have you do either of you scuba dive no I don't no okay so uh neither had I until like a few months ago I did my certification and I I think I had five Dives before I went and I was going there with this super experienced group of divers sakuro is like 600 km off the West Coast of Mexico Cabo and it's a spot where you can see Manta ra and hammerheads and dolphins and

incredible Wildlife but crazy currents and very Advanced and so I was lucky that the advanced divers I had really like we we went down quite slowly I'm thinking about this because I think um that was helpful for me I had a great experience and here we are sitting here and you guys are completely very experienced with lipids I want to make sure we don't just get straight down to the bottom so um let's try and hold everyone's hand like they held my hand and got me down without my e drums bursting um and I had

a lot of fun and hopefully the listeners get the same out of this conversation so if we kind of just descend slowly here Bill what is the kind of current model or lipid hypothesis as it stands today well I take you back um so the history of how we got here I think is important to answer that question so the history of how we got here was uh it was not uh lost on people that cholesterol was in plaques back in the late 1800s early 1900s now how it got there was a mystery was it

made was it transported it didn't appear to be made so it had to be transported and now you have to ask more questions how do you move cholesterol which is a fat and blood which is mostly water and people thought well maybe it hitches a ride with albumin or a plasma protein that sort of thing but the real work here came from two guys golfman at Lindon in the 1948 to 52 times spr and they they characterized human life of proteins they're the guys who figured out that we have these these particles they look like

tennis balls uh they're Hollow on the inside and inside which is a fat uh safe place the cholesterol and tri right get packed in the middle and these particles are the way that we move cholesterol around and so that was the beginning of what some people call the cholesterol hypothesis it was really how did cholesterol get into plaque and then what do we learn about the particles that carry cholesterol so in my world I'm I'm a little careful in the way that I discuss this because I don't think it is a lipid hypothesis I think

it is a lipoprotein conversation lipoproteins are the core of this conversation uh and this was actually what they thought would be the conversation beginning in the 50s uh but it's hard to measure lipoproteins especially back then but you can measure cholesterol much more easily so what you can measure easily becomes a surrogate for the rest of the story uh interestingly some Pioneers uh that were giants of the day in the 60s at NIH fried and Levi and Le talked about the facts that and they lamented this they said it's unfortunate that people are talking about

lipoproteins as a cholesterol problem really that's not the case cholesterol is just kind of getting caught up in this cholesterol is a neut fat that's stuck inside a particle the cholesterol in HDL is the same as the cholesterol in LDL one is not good one is not bad one is not protect you and does not hurt you it's the particles that have the potential for good or for bad and so what we think the model is today is if you have any number of problem problems or processes that give you lots of apob containing lipoproteins

and that stays high for a long period of time that is part of the process that fuels formation of plaque in the artery wall that can grow over time and under various circumstances lead to heart attacks and strokes is that independent of other factors you know one of the things that I was speaking to Tom dpring about when he was on my show was whether those lipoproteins I think you said there they have the potential to be good or bad are they inherently problematic or is a particular environment or concentration required yes and yes uh

so apob containing lipoprotein specifically LDL and Remnants are very atherogenic um there are lots of models where we can show that persistently high levels of these are directly related to development of plaque independent of anything else but like anything else in the body multiple contributors together have a different impact than just one so if you're a smoker hypertensive diabetic uh if there are other things going on that also set the table for atic risk and you add High apob to that that's a very different environment than just high apob right so yes you can amplify

the delarius effects of apob by other things but it is not true that you have to have other things for a to be delarius okay so you can be otherwise completely healthy but have an elevated apop B above some physiologic level and at that point those lipoproteins will be problematic so this is a concentration conversation the higher the longer the worse so there's not a step function or a threshold above which people are in Dire Straits but it is a Continuum of risk and as you escalate the number of particles to extremely high levels and

you leave them there for an extremely long period of time uh that would be one working example where you can say yes under those circumstances um absent some other thing we don't understand such as favorable genetics or other factors uh this is a setup for plaque formation in increased arotic risk so do you think that applies and will unpack the Triad the Lan Mass hyper respond but do you think that applies in this context of what's you know Dave's experience himself where otherwise you know metabolically healthy I'm assuming trigs High HDL perfect but his LDL

is high above that physiologic level I think it a great question and you just heed up a different conversation and that is that we we're not a system that has only one thing going on at a time so hu usually exist in the context of other things in this culture hob is usually uh part and parcel of insulin resistance part and parcel of metabolic syndrome part and parcel of pre-diabetes diabetes and so we have these other physiologic perturbances that are part of the fabric of AAL sclerosis in which apob is layered and so that's the

most common expression of hob related risk that we have another example is familial hypercholesterol emium or other genetic disorders where you just can't clear your particles well you don't have these other processes necessarily but you do unfortunately have a lifelong exposure to very high LDL very high apob and there's a consequence to that so we have these two different models one which is physiologically unhealthy the other which is genetically driven and in both cases high apob is contributory to AOS sclerosis but the magnitude and how much risk the individual has is more than just their

apob level it is a combination of all these other factors and so one of the challenges clinically when I see somebody if you were my patient I would seek to understand Simon what's the rest of your story are you insulin sensitive are you insulin resistant are you a smoker are you hypertensive are you diabetic what other comorbid conditions do you have what other things are important and the guidelines are now beginning to reflect this as well the guidelines has a whole list of things called risk enhancing factors that you're supposed to ask about that contribute

to potentially what your risk would be and then we layer on top of that things like apob lpla lipoproteins that are aogen right and so you would find out all that information because it may affect how aggressive you are or proactive you are with lowering my LDL cholesterol or apob or how worried you would be yeah I think the question you would have is if my apob is a bad number what's the rest of the story now we live in an age where we can do non-invasive Imaging and we can get an answer as to

using certain modalities do we see evidence of plaque already if I see that you have plaque and you want to talk to me about your apob that's a different conversation than somebody who is apparently physiologically healthy has no evidence of plaque has a high apob and my question is has it been that way for a long time is that a more recent phenomenon the these are important considerations and you know we can kind of unpack this as we go uh but there are combinations and permutations of this where in one extreme let's say you're 75

years old with a zero calcium score and a high LDL the guidelines would say statins are optional for those people at a younger age you tell me that you have plaque and you have a high apob or LDL I'm going to tell you that getting that down is the best solution at A lipoprotein level you have to stopping the growth of plaque regressing plaque decreasing LDL related risk and the term I just used there LDL related risk I think is a very important Nuance because it acknowledges on the one hand there is risk attributable to

bad or atherogenic lipoproteins but it's only one of many actors in the story of AOS sclerosis uh we have lots of data where people's LDL has been really well managed and yet they can go on to continue to have events so we just want to paint a a broader context a broader picture that as important as it is it's part of a bigger story I imagine some people might push back a little bit on that last part there and they might say well Bill you might still see events because you've intervened too late in life

and I know that there are certain people out there that it seems to me at least that there's this idea that that precautionary approach that you know is APO B the kind of is it the spark that sets off the flame and if so if you just get it down to a low level early in life are you going to help that person kind of avoid it you know we don't know 5 years 10 years out what this person's metabolic health is is going to look like why not just aggressively lower it and get it

to a safe level I agree with that so primodial prevention is don't let it happen in the first place we have experiments of nature uh you can look at people who genetically have low LDL for a lifetime and they have marketly reduced aosr risk irrespective whether they smoke or they're hypertensive or other things happen in their life because if if you kind of mechanistically look at this uh you could ask well what's the committed step of AOS sclerosis and the committed step is forming maccrage foam cells formation of maccrage foam cells is the committed step

of AOS sclerosis and what's a foam cell a foam cell is a maccrage that ate atherogenic lipoproteins so once you have begun that process uh you have turned on the switch right so that's an important caveat and just to underline something there that process can begin if a PO or LDL cholesterol is elevated without systemic inflammation without insulin resistance it can sort of instigate that it can Dave we're going to come to you we're going to bring you in uh diet enters this conversation because the foods we eat can affect lipids what's the the diet

hot hypothesis well that probably is something that each of us would have a different opinion about so that's great that's what we ha to do right I've heard a lot of different exp explanations of what the diet hypothesis is I I assume that we're saying that there are diets that for various reasons can contribute to atic risk as well is that where we're going with that I guess did you mean the lipid hypothesis because diet heart hypothesis usually wraps in saturated right so so we spoke about the fact that elevated APO B in the current

model of lipid hypothesis is I guess part of the explanation as to why people develop atherosclerosis and where I'm getting at now is why does Diet end up getting brought into this conversation and at least to my knowledge um a lot of that research yes focuses on the fact that saturated fats raise these apop containing lipoproteins relative to other types of fats yeah yeah for for me it's it's funny the diet the diet heart hypothesis the Anil Keys version as relates to saturated fat can increase serum cholesterol levels I feel like we're now at a

point where we can kind of almost set that aside and be like let's just focus on whether or not your LDL went up whatever diet you're on and if there's agreement that saturated fat can result in increased LDL and that in turn results in greater risk for cardiovascular disease it's almost like you can leave the diet heart as the older 40s 50s model and just jump ahead to the lipid hypothesis from the lipid standpoint unless there's unless there's a hypothesis that saturated fat absent raising LDL cholesterol can increase your risk the mediating factor is the

elevation in a I think that's what all sides at this point are arguing about right I mean unless there's another version I might have got this this wrong and I might be misrepresenting your view but are you of the view that the kind of underlying mechanism by which apob is elevated matters affects the degree to which these particles are arenic before I unpack that I want to emphasize something because this this is kind of important one thing I've become more sensitive to as my profile has grown is unfortunately people turning this into a false dichotomy

so I do have a distinction a difference between where you and Bill lie but it's more in that there's a greater confidence that apob b containing lipoproteins absent all other factors prove a causal directionality towards development of atherosclerosis and I'm not arguing the reverse of that and I want to put that up front first what I like to do is lay out the case for why I don't think that we know enough so there's a difference between I know it's atheros scerotic versus I know it's not atherosc cortic I'm not arguing in this case I

do feel that we don't I think have enough data to suggest confidently that we know the true causal directionality of apob containing lipo proteins absent these clusters of everything else and I can lay out the case for that but the catch is that I want to emphasize it's a hypothesis and that I don't want anyone to be instructed or to take anything I'm saying as medical advice yeah I think that you know if we go back to why some IND individuals might not want to have a conversation with you I I think that some of

them are of the view that people hear what you say and prematurely adopt a diet and Elevate their aob think thinking that they have no risk yeah and and again you can happily like turn this into a clip for the future I I don't want anything that I say nor would I want anything that I'm doing to become somebody's sole reason for um their decision-making you know as I've said a million times before I want people to work with their doctor to work with their family to uh understand as best they can what they need

to do now all of that said I I will emphasize that I do think that there's points that I bring to bear that I think are important to consider from a scientific examination standpoint and in the case of apob containing lipoproteins virtually all of the data that we have that show an association between apob and atheroslerosis come from populations that have some version of a cluster that include these confounders and I think that's very relevant so I can divide them into two buckets bucket number one you were touching on which is um it's pathological insulin

resistance I'm going to just kind of group it together and call it insulin resistance syndrome but it generally exhibits what's known as metabolic syndrome the big five that we're used to hearing um low HDL high triglycerides uh blood pressure uh waste to hip ratio and so in the case of these this manifestation to to simplify it because you'll appreciate this I'm going to use avatars because you like to do that right so let's say we have identical listening listening to the show Dave yes I have them I have them so we have identical twins one

is Abby one is Betty right and Abby and Betty are living their life and uh at age 20 Betty decides to take on a bad dietary lifestyle starts developing ultimately insulin resistance syndrome in her 40s she starts gaining weight she starts developing viseral fat the two things we can anticipate or likely is her HDL cholesterol goes down and her triglycerides go up compared to your twin and modestly her LDL cholesterol increases but modestly we also know what's also going on under the hood almost certainly her apob containing lipoproteins are also going up now I've drawn

a line to causal directionality her developing insulin resistance syndrome resulted in this change in her lipid profile now I think the three of us here would agree that the insulin resistance syndrome is independently causal at least in part towards her risk for cardiovascular disease we we agree on that right the question then is how much the change in the profile the lipid profile particularly the increase in a b containing lipoproteins are in addition independently causal towards her atheroslerosis now that's one bucket bucket number two is let's change it this time the identical twins are separated

by the fact that Betty is born with homozygous familial hypercholesterolemia hfh so she has extraordinar high levels of LDL cholesterol and apob containing lipoproteins from birth she develops aosc cortic cardiovascular disease at age three she has her first Mi at H6 but she does not have the symptoms typical of U metabolic syndrome of insulin resistance but there is a key difference that I would draw attention to it's not just that she has less clearance by her hepatocytes the liver which is where we're all typically focusing all her nucleated cells are different and that includes the

immune cells and that includes macrophases macrophases themselves and their capability in metabolizing lipoproteins I believe is to be very relevant in this larger story of the development of atherosclerosis I think that's also something that we see and how the manifestation of disease with those who have homozygous FH turn out one of your prior podcasts you refer to something that is near and dear to my heart for discussion on this larger topic which is cholesterol years often referred to as milligram years and there's a there's a great stud study on six children that uh include uh

CT and geography and the reason I like it so much is because we we rarely get modern science with children who have CT angiograms and of the six children it's heartbreaking but this is just the case with HH children four of the six have uh not only aosr cardiovascular disease as detected by the cctas but have it it m sites and this is very common place for those who have this disease when they're born with it is it's in multiple locations and develops it multiple locations it's not like say the runner um who might get

it in say just the L like they have an intense occlusion just in the LED and not hardly anywhere else throughout the coronary arteries so this is why all roads lead back to this research I realize we haven't talked about it yet but this study on folks like myself like on Nick norwitz like on Adrien sod who are on low carb diets who see some increase in abob containing lipoproteins along with LDL but outside of these two buckets outside of some form of dysfunction in lipid metabolism let's come back to that in a second I

have a few questions on on what you just went through um so my first one is on that on the genetic data that you were referring to and you said you you believe the macres might be implicated so the the the change in maccrage maccrage function might be explaining some of the heightened risk that we see in individuals who have genetically elevated LD my understanding is there's you know 4050 plus different LLS that result in LDL cholesterol being increased do we see different maccrage Behavior across the board well I can only speak to the study

that I was able to see where they cultured um macras of specifically hfh and they were able to see the expression of ldo receptors of course there's a whole family of Elo receptors um it's not just of course the main one that we hear about all the time so I can't speak as much to other variations of FH what I can say though is that there are genetic diseases that result in increased LDL and apob and even increased triglycerides but that aren't actually the ideology of them is not actually originating with um uh a dysfunction

in lipid metabolism it's a dysfunction elsewhere that's very relevant to the lipid energy model which is in glycogen stores so glycogen storage disease 1A for example results in a poor ability to to synthesize glycogen and the reason of course that's very relevant to us in the case of lean mass hyperresponders is that's kind of simulating in in a roundabout way what is it the the heart of our hypothesis which is that lower hepatic glycogen stores can induce this greater amount of lipid circulation what's interesting about that is glycogen storage disease 1A has this Downstream impact

but not due to poor lipid metabolism but does result in higher levels of LDL cholesterol in apob and yet they do not have the associated higher corresponding levels of aortic cardiovascular disease that's why there's been a lot of studies where they're trying to figure out exactly why the lipid energy model might explain why that's the case have you seen that bill well let me go back to a couple of things uh macras you know macras um in the context of AOS cardiovascular disease um are scavengers they have no off button uh they will Express scavenger

receptors in proportion to the things in their environment with which they're trying to clear if you put more LDL in the environment you will have more uptake in macras you get big maccrage foam cells and so they basically are the cleanup crew they're there trying to rid the environment of this uh steps we have not talked about that I believe interact with this idea of macrofagos and what's happening have to do with the fact that lipoproteins that are in the blood end up in the wall of the artery now how do they do that in

the past we thought they just kind of wiggled through the cells that line the blood vessel the endothelial cells and so these things have little Gap Junctions and they wiggle their way through uh what we now believe is that it's a much more active process transcytosis there they going through the cell no they're going through the cell right so they're transcytosing through the cell they're not trying to wiggle in between cells and that transcytotic process is something that in and of itself is very Dynamic it's very influenced by a variety of things and so the

fact that we have high apob on one uh part of the of the equation and it's getting into the suola space on the other part of the equation requires this transcytosis and transcytosis can be influenced in a variety of ways and this is where I believe there's a little bit of synergy taking place between the old uh injury model and the retention model the response to injury model back in the 70s was we injure our lining of our endothelium and that allows it to be more permeable to Lio smoking or high blood pressure right um

and another way to just kind of make that a little more relevant now is to say those things affect endothelial function they can affect transcytosis they can affect things that do impact the movement of apob it may not be because they're altering the Gap Junction so much as they're actually affecting transcytosis so we have that part of the conversation that's new so we've moved from thinking that these lipoproteins that carry cholesterol are moving between cells in the a well to now understanding that they're actually going through the cells correct they're being transported from one side

of Cy right in other words it's a very controlled manner whereas it's not mediated by concentration gradient like it's getting pushed into it in a passive manner It's actually an active manner which raises a lot of questions as to what's the function of that carry the thread on a little bit before we get there all right so uh LDL particles that are in the sub space don't always stay there they exocytose they they they actually pass back and forth like a waiter in the restaurant they take your order and they go back to the kitchen

and they get your food and they bring it back to you and they go back to the kitchen right so lipoproteins move back and forth across this IND thelium much more than people would ever expect it's the ones that get trapped that are where the story occurs so retention of lipoproteins in the wall of the artery are the particles that are then subject to add additional steps that make them the things that maccrage want to eat right so you first have to get in then you have to get stuck and once you've retained the particles

in some cases they're already atherogenic remnants in other cases they need to be oxidized or post-translationally modified so they become identified as and that's a problem and when macras begin to clear the environment of these retained injurious atherogenic lipo proteins the maccrage once it's ingesting these becomes an activated foam cell and they begin to secrete a number of chemicals which increase inflammation there are chemoattracted substances that bring more monocytes and macras into the area adhesion cell molecules so the the activated foam cell is that guy who starts stirring the pot of inflammation and a variety

of processes which result in AOS sclerosis so we've just gently touched on holding your hand diving down a little bit not blowing your drums out I appreciate that we're we're just touching on these on these additional processes which are an important part of the story of how it go from my blood number is this my plaque is or isn't here there are steps in between that are important that are still being elucidated now having said that I can still go back back to at a at a macro level uh using your your avatar I I

can go back to that and say uh what happens if I don't have this protein that is one of the more recent targets of medical therapy pcsk9 people may never heard of that what the heck is a pcsk9 It's A protein that limits how many times the LDL receptor goes up and grabs a particle and comes back in the cell for people who genetically don't have that protein they have lifelong low ldls and an 85 to 90% reduction in anotic Risk independent of anything else so they're very good at clearing they they they don't have

particles in their blood that are making their way into the wall of the artery now why is that because the there is a gradient there and the number of particles that are in the blood are low and that is a direct attenuation of particle entry if I have a low number in the blood there is much less entry into the wall of artery that's why LDL lowering apob lowering has several potential benefits one is you don't continue to transport apob into the wall of the arteries so you begin to blunt the circus of more and

more maccrage foam cell formation um you also with aggressive LDL lowering stabilize plaques we know with a variety of techniques from CTA to Optimal tomography um you can get to the point where plaques are regressing in size so on the one hand apob can be shown in a variety of context to be directly acting in the formation or not of plaque lowering apob directly stabilizing plaque and decreasing events but even if you are on a pcsk9 inhibitor and you have a median LDL cholesterol of 26 and you stay that way for years that's a pretty

good LDL lowering people are still having events why why would people still have events if we've largely taking apob off the table is it because they already have enough pla that can be problematic under the wrong environment that plaque's being stabilized that plaque is no longer as active we're not contributing to new plaque we're stabilizing existing plaque the plaque that is there is not inflamed and contributing I would argue it's because there are other parts of the process that direct LDL reduction does not always touch for example um there's a compound called EPA EPA is

part of fish oil the active ingredients of fish oil are EPA and DHA um there is a purified form of EPA that was studied in a trial looking at 8,000 individuals with vascular disease or diabetes all managed to a good LD level and the addition of purified EPA versus placebo significantly reduced events and had nothing to do with the apop level had nothing to do but what did it do well by virtue of its physical chemical properties it's decreasing inflammation in the wall of the artery it's decreasing oxidation of lipoproteins which needs to happen before

they're going to take up by macrofagos it decreases foam cell form it decreases plaque rupture it decreases clots on top of plaques so here's a whole another mechanism that is additive and beneficial on top of whatever the LDL reduction is doing and it's been shown in many different series to be helpful on top of aggressive ldol reduction so I just use that as an example that this is a complex process there is LDL related risk and there's aosr risk that may not be LDL related and that what you're talking about there is that are we

really talking about secondary prevention so that's once people have been exposed to an elevated level of apop for decades maybe they've had one event and then we're intervening you're saying if you just get their LDL apop down to 20 milligrams per deiler you're not guaranteeing that that person no longer has events you'll marketly reduce their events yeah you'll marketly reduce but but you cannot say that that is sufficient to mate all of the risk that they have sure yeah I think most people can understand that at trying to be fair right trying to be fair

with with the whole apob story because as you know there there are people who um look at the data and we'll come to different conclusions and and one of the things I want to do is let the totality of the data teach me right uh so I think uh as we're having this conversation part of it is we get into unique combinations of what does that mean that we need more data to help answer the question yeah there seems to be quite a bit of sort of binary thinking in this area where it's like it's

just that that's actually what I want to push back against though that's that's the main issue is that it's with respect to any any side that's presenting it as just that simple and I think that's actually something the three of us agree on I I don't think that there for example I think a lot of your colleagues would disagree with you on not treating apob as the central determinant the I as one lipidologist put it that's a straight line that apob is a straight line from how much you have all the way up until your

cardiovascular death which kind of brings it back to kind of the cholesterol years as being a commonality well I I'm of that school of thought I'm of the school of thought that uh you know hiob for a protracted period of time is problematic unless you have data to indicate to the otherwise okay so you're saying essentially just to be really clear the earlier in life you can get it down low to a physiologic level the better yes got you uh so can I draw some distinctions I I am I am curious because I'm not actually

sure exactly where we both mutually stand on this I think that there's two questions of enormous interest the first is is apob containing lipoproteins are they participants in the process of atherosclerosis as I regularly State often I believe that they are I believe they absolutely are a major component to the process of aosc closis the question for me is how much does that provide information getting back to the macras story is you know there have been for example trials that take action against the immune response that can have a benefit towards reduction in cardiovascular disease

but there's usually a tradeoff in place there is of course an understandable trade-off if you're if you're impairing the response those who have pcsk9 loss of function they do have lower cardiovascular risk full stop it gets substantially dropped but with lifelong super low levels of LDL and apob do they live longer do they have a benefit in longevity such that they have lower all CA mortality if there's no tradeoff that's actually what we should observe right because if there's nothing say an increase in some other non-cardiovascular disease we should actually see that they would live

longer than those in their same region in cohort so I'm going to put a pin on that one that's a great question but that's going to take us down a rabbit hole uh and and the rabbit hole is going to take us down and you know the answer to this because I just presented this at your conference and that is that all cause mortality is a very special endpoint and one which is hotly debated as to whether it should or should not be significantly improved by apob reduction there there are reasons to believe that it

should if if it's true that aerosis and cardiovascular disease is number one cause of death if apob is critical to that process if I lower apob and I lower cardiovascular events I should Visa get an improvement of mortality that seems logical unless mortality is driven by something else MH is so if there's a tradeoff and then but if mortality is driven by metabolic vulnerability and inflammation which have nothing to do with apob then we're we're actually setting this up as a straw man to fail you're asking apob to solve a problem that it's not causing

in the first place apob is not the reason that people would die if you're looking at newer data that say it's metabolic vulnerability and inflammation that set people up from Death from any cause and these are data that I presented today's conference where whether it's cardiovascular disease or cancer or chronic kidney disease or heart failure or COPD or fill in the blank the people who are or people who are metabolically vulnerable and have high inflammation right so this is almost a similar argument to I guess some people in the ketogenic camp that say you can't

just look at people with high LDL that have poor metabolic health and assume that LDL their risk of atherosclerosis is the same in someone who has good metabolic Health what you're saying here is in people with genetically low apob if we're looking at their total mortality but we're looking at people who have poor metabolic Health it's not the same as looking at someone who gets apob down very early in life and doesn't have inflammation or insulin resistance close um I think what you're saying is part of it but I'm I'm zooming back and saying that

uh mortality is a function of metabolic vulnerability and inflammation irrespective of anything else that is the setup for increased mortality now what we can say is that there is data that would show that in certain situations LDL lowering improves mortality but it's not in all cases in all data sets that have been looked at and and I think that some people look at the expectation of mortality Improvement as being a universal response to LDL lowering uh if you don't show me better mortality I'm not going to believe the story of AP contributing to aerosis and

reducing events which incidentally is not my position just to emphasize like this is why I brought a pcsk9 loss of function because now we're talking both lifelong and an extraordinary shift in in exposure I mean if you can maintain a 35 milligram per deciliter LDL throughout your life and you've got a whole bunch of other people along with you that are being looked at and it's the number one killer like we're not talking about luk Garrick's disease or something rare for which we wouldn't expect a signal of change we're talking about the number one killer

in the western world if we were to go to Africa for example right now and we could reduce the incidence of death by malaria 80% 85% I would expect that the population at large would live longer on average I don't think that there would be another disease state that might jump up right away so that they're now dying of cancer just as quickly or something along those lines and so that in in that sense when we're talking about lifelong this is this is why I like it is it's strong signal especially against pcsk9 loss of

function wasn't there in 2015 when I started this once those studies became available I got excited because I was like this answers both questions really well the first question is is there a strong association between apob containing lipoproteins and the development of atherosclerosis right and certainly I've known many people in the low carb Community who would say the two have nothing to do with each other right I Point to P C sk9 loss of function as a great example but conversely on the other side I would say but again ascvd is the number one killer

I don't you you're not going to find an easy way to convince me if you go to any region any country if we were to go back in time 200 years ago with Penicillin that we wouldn't whatever country we took it to we wouldn't see a longer lifespan for those people who we got involved if we could find ways that isn't a what you're talking about acute conditions versus chronic though but okay sure but let's take let's take a pill that cures cancer let's say I found a pill that cures cancer would you expect in

trials that were lifelong that the population that I could apply this to that they would actually see a net longevity benefit what I would argue is it depends on why they're dying and this is what you're you're not looping back to so um I've made the statement that metabolic vulnerability and inflammation are the drivers of death um what I can show you in populations otherwise healthy individuals they're healthy they don't have chronic disease it is their metabolic V ability and inflammation which is their distinguishing characteristic for death independent of age independent so so what I'm

suggesting is whether you're young or whether you're old whether you're healthy or whether you have diabetes whether you have chronic kidney disease whether you have cardiovascular disease whether you have cancer all of those people share one thing it is their metabolic vulnerability and inflammation which significantly distinguishes who lives and who dies actually got an idea and that and that is independent and the reason that's important is because if that is true then this conversation is a is connecting two things a story about asbd and apob and mortality which is a separate story if if we

did a subset analysis is on those who do have pcsk9 loss of function intentionally for metabolic Health would you think that there would be a longevity benefit I can tell you what the data show the data show that if you have lifelong apob you live a long and healthy life now whether you live longer than the general population has to do with what's happening in the general population or what's happening in those people this is metabolic vulnerability and inflammation so I keep going back to this think of it in terms of of infectious disease um

100 years ago when I was in medical school uh when people were doing infectious disease uh uh rounds we have two people same age same organism same side of infection one lives one dies they're both given the same antibiotic why did one person live and one person die we could say the host the person who was the better host had the better survival why because an antibiotic can be thought of like a stick I hand you a stick you're going to go beat away the the bacteria you have a chance to survive this but what

if you're too weak to wield to stick what if you're such a frail host such a vulnerable host that the antibiotic is not as effective under those conditions as it would be in a more uh whatever healthy individual or a better host okay so I just want to make sure I'm understanding everything here cuz I think Dave's point about pcsk9 loss of function is is interesting would I be right in saying that in that context so that population who has lost the function of pcsk9 Gene who has very low apop where in the studies that

Dave's talking about there's no total mortality benefit they're not living longer you're of the view that it's not a PO B that's killing people in that population it's it's poor metabolic health I'm saying they're living as long as anybody else there's no are dying less or more so DA's point is shouldn't they be getting extra years added to their life if you're taking away the causal Factor uh to atherosclerosis which is you're not taking away the causal factor for their mortality their causal factor for the mortality is their metabolic vulnerability and their inflammation and if

that is what is driving their mortality the fact that they've had a long and wonderful life with decreased ascvd risk and they're living as long as anybody else is to be expected they're having a wonderful Health span with decreased events and they're living a long and healthy life but when the time comes to understand why these people are dying it is metabolic vulnerability and inflammation which are the rest of that story and just to double click on that and it could take us down a massive rabbit hole but what do you think is causing that

metabolic vulnerability ah so the the the multimarker that I am alluding to that we haven't unpacked is called mvx and mvx is a multimarker that we developed uh some years ago to mirror uh metabolic health and then gly a and small HDL particle number which mirrors inflammation this multimarker cons consisting of six individual elements is unusually robust as I said you can look at Mesa you can look at cathen you can look at any number of data sets and it is eerily good at segregating actual mortality independent of age independent of comorbidity Etc so the

fact that that is there is the point I'm making now why would it be there what would cause the metabolic vulnerability that's a whole different conversation and there are many chronic diseases that have what are called this reverse epidemiology chronic kidney disease the people who die aren't the obese people they're the lean people the people who die don't have the high cholesterol they have the low cholesterol the people who die don't have the high blood pressure they have the low blood pressure so what's this reverse epidemiology all about it's their physiology they have a physiology

which is CTIC these are CTIC individuals and as they become CTIC they are demonstrating lower cholesterol all lower body weight lower blood pressure and yet if you look at certain studies which are very interesting and they say okay what's the relationship of APO and mortality and you sometimes see kind of a U-shaped curve right people use that often to say hey lowering AP or LDL is not great for mortality what happens if you adjust for malnutrition and um metabolic vulnerability guess what happens it's a straight line lower is less mortality higher is more mortality and

the u- shape goes away if you adjust for metabolic vulnerability I have to I have to draw a distinction here there's again this is less making it the case for the opposite than is making the case for us not knowing as much as I think is the confidence right now so I think that there's I think that there's a lot of confidence that we can through the use of statistics iCal instruments like sensitivity analyses determine the degree with which there are these other impacts of causality such that we know what the remainder is and that

is I certainly one difference that I may have with the two of you is that's exactly why I want to do studies like the lmhr study because I don't share that confidence that sensitivity analyses have determined the degree with which each of those are independently causal towards atheroslerosis so that we can feel confident we know how much a independently contributes that's the catch do you think low serum cholesterol is problematic or could be problematic I think it's possible part of part of the challenge is that we need to have so I'll make the case for

you both in that I do believe that if you're looking at data sets for which there's say two or 3 years or less low LDL can be associated with greater mortality due to there being a common cause of both that's the reverse causality now let's say we're looking at 10 years 15 years 20 years is there a latent disease State that's reducing the LDL that's not being acted on prognostically by you know doctors that's a tougher cell to me because now now what you're saying is in any population where we see the low LDL and

we're seeing the higher uh all cause mortality at like a decade or more so we're censoring out everybody who's died in less than a decade and looking only at those people who've died a decade from now or more and that's still holding up reverse causality should have an expiration there should be a threshold where it flips where instead low LDL is going to associate with longer lifespan if indeed it's only pathogenic if indeed there is no benefit I I think the Steelman position I think even uh folks who study familial hypercholesterolemia the Steelman position is

they would say no there are some benefit benefits there are some immune benefits to LDL but that really came more in the days when infection was a bigger concern and that's why it got conserved to the degree that it did so that what is that why you think there is that active transcytosis occurring where ldls move from serum into the arterior wall well yeah so okay if we're gonna we're going to go back to that we should go back to that because here's the thing I'm actually quite obsessed with transcytosis and since the door got

opened I do want to get into a little bit of the geek Zone on that because from the moment we moved to what is I'd say the modern I like to call it lipid hypothesis 2.0 we're at about 40 40 foot of depth make sure we don't just jump down to a 100 foot oh he's close yeah well but but this is an exciting moment that a lot of people missed this big dotted line we crossed which is brown and Goldstein in really the last what four and a half decades has been this passive version

of LDL particles including guests you've had on your on your show including conversations we've had as far as this being this concentration gradient in the Lumen driving passively this push towards the subintimal space going through the endothelium so the point at which there was just broad acknowledgement in the world of lipidology that no we're now pretty sure it is transcytosis the engineer and me got really excited because that's very testable it's a very testable hypothesis because that's an active process it's and not just a little active it's not like it's not like it can just

drop in the surface and manage to get to the other side you have receptors that have to be transcribed and you have to have uh ATP extended you have to have chaperone proteins there are we now know that there are many different routes by which there can be the transcytosis of course uh there's srb1 which is probably the most common one uh the intro the use of uh Cav 1 for cavolle and creating the vesicles there's a actin um actin induced folding which actually is less selective right all of these are ways by which there's

not just endocytosis but potentially the transcytosis now why is there a designed process in of all places IND thelial cells I believe it's absolutely engineering but more importantly if the concentration gradient is the driver and that still is the what's being thought of is the primary means by which it's entering the subintimal space we should actually see that reflected in the endothelial cells themselves you should be able to go into the endothelial cells and find all the clues I just described you should be able to see more of the uh receptors themselves present you should

see more of the chaperon proteins you should be able to see the vesicles themselves now I know I'm making it sound relatively easy but you have to do all kinds of stain and there's a lot of processes that are involved to accomplish that but that said you should be able to see those those processes being driven with endothelial cells but important thing to add to this is that per what uh Dr Cromwell said yes there's already a lot of transcytosis that happens quote unquote naturally we can get into that later I think it's part of

structural demand I think there's actually a lot more to the story than is assumed that that they're just going in and out as like just passengers I think actually getting made use of but importantly endothelial cells and are in a state of inflammation are transcytosing more that means they have a designed process where they are quite literally expressing more for non-modified LDL particles to transcytose them into the sumal space I think that's also an a crucially important clue so you think that is part of the immune response yes and I've speculated on this for five

six years I believe iial cells are participants in the immune response and I believe it's part of the larger Arc of hemostasis could it not be that some yes some Flux Of AO containing lipoproteins into the subintimal space is normal and beneficial at a certain concentration but then can become detrimental at a higher concentration purely because there's just more of them hanging around and therefore there's more chance of them becoming retained that's absolutely possible but it's also testable right so a concentration gradient that's higher in say an area for which endothelial cells do not typically

develop plaque is something that you could check right now for example you could you could check this postmortem right actually this might be something that's more your domain as to what we can actually detect and what we can't but the bottom line is the clues of Greater effort towards transcytosis by endothelial cells is a is completely testable now the the version of passive filtration was harder to look for but endothelial cells participating in this process of transcytosis that's absolutely viewable what do you think about that bill well several things um so it is being looked

at it is being tested it's it's not something that people have observed and then said well I don't know what to do next because I mean this is actively being looked at um I want to finish this then I want to go back to the question you had about low cholesterol and and potentially whether that's problematic or not um I think what we are appreciating is that um transcytosis is critical to entry of apob and on the one hand you have to have enough apob particles to make the transcytotic journey more or less and that

is a gradient driven process how effective efficient and quick transcytosis occurs is what I hear you speaking to and that is absolutely correct that we can modulate transcytosis and we can modulate it under various conditions uh in conditions of endothelial dysfunction broad statement it will trans cyose differently than a healthy normal functioning endothelium that that is true as well and so it's an important Nuance because it gets us back to this idea that there are physiologic States which in addition to your apob level are together part of the story it also is this cumulative exposure

over time the longer that you're having trans cytosis and the more maccrage foam cells you're making the more you're accelerating AOS sclerosis now there's a little bit of a black box in the middle of that and the and the black box is how long and under what conditions does apob B need to be elevated in order to change the natural history of this process and that's a little bit of a black box but but one of the questions that I thought was interesting is is there a low cholesterol and if so is it a problem

we can answer this question differently there are experiments of nature where people have either low or no LDL AA lipoproteinemia no APO containing lipoproteins one in a million I have one of these patients most lipidologists never have a patient and that's that's Z milligrams per de serum cholesterol cells are still chol they have zero apob containing lipoproteins but the cells throughout the body every cell with a nucleus makes its own cholesterol right but in this case they are not able to traffic with vldl and apob containing lipoproteins so this brings me back to my discussion

with Tom dpring if I recall correctly his view is that cholesterol's role in the lipoproteins or its main role was to help create structure which then allows you to package in the triglycerides they can now flow freely in this lipoprotein which they otherwise wouldn't be able to dissolve into and then can be taken to cells and used as an energy substrate well before that even you have to have the structure of APO B so APO is the structureal it's a scaffolding around which you create a lipoprotein particle if you don't have the scaffolding you can't

make a vldl particle You Can't Make A lipoprotein right so the the point is that if you have essentially no apob then you are not going to have the ability to traffic fat soluble vitamins and other critical elements because these things aren't being made and in that setting it's a horrible disease these folks go blind they have long trck neurologic findings they die a horrible miserable early death so is there a an example where you can have very low cholesterol and it' be absolutely problematic yes a beta lipoproteinemia well one step remov from that is

hypoa lipoproteinemia I make apob just not a lot of it and they largely Escape that demise because they have enough apob containing lipoproteins to traffic fat soluble vitamins when you say enough what average level are we talking about so LDL cholesterol 30 40 right um so these individuals have hypoa now their consequence can be for example if you have a lot of triglyceride synthesis in the liver what do you do with that triglyceride well you either export it you burn it beta oxidation or it becomes part of the liver steatosis if I need apob to

export it and I in the insulin resistance state for example am over producing a lot of triglyceride in my liver and I can't export it these people become steatotic and they go on to nafl Nash Stato hepatitis right so there's a consequence in that setting but hypoa patients have very low rates of AOS sclerosis because they have very low circulating levels of apob so that's all production and do they have any issues with hormone production no because that's done primarily by the cells that are nucleated to make their own cholesterol now that's the production side

of the house why we're making AP then there's the clearance side of the house pcsk 9 deficiency uh without pcsk9 my LDL receptors work overtime and I clear great so I have a low level not because I'm not making but because I'm clearing tremendously well is there a consequence to that not that we know of if we look at clinical trials and and one of the big caveats here is we only know about the amount of time that people were studied in the clinical trials so we can't extrapolate 20 30 40 years we can't do

that but we can say within the life of the study if we draw LDL cholesterol to a median of 26 with a Statin and a pcsk9 together both of which are clearance exercises we haven't found a significant consequence to those people compared to individuals at 50 70 100 that could be just because it's a short-term phenomenology we didn't have 20 or 30 years to watch them maybe we would learn something if we watched for a longer period of time but the point I'm making is that really low cholesterol can be a production question or a

clearance question and our best data that there can be a consequence is when it's not produced not when it's cleared significantly gotcha it's it's important for it to get into circulation is basically what it comes down to and and that's why he mentioned a number that's comparable he said uh AAL lipoprotein or rather hypoa lipoproteinemia say 30 we just got done talking about loss of function having 35 right so these are like right next to each other but in this case it's not not entering circulation in this case it's coming out of circulation faster that's

that's the key distinction can I can we return to transcytosis just because I do want to put a pen in I want to I want to button up the the distinction I was drawing that I do think is relevant if transcytosis is increased at a sight of inflammation it becomes a challenge for us to confirm that a healthy endothelium is in fact accumulating LDL particles via noninflamed transcytosis that's part of the challenge well I think we go back to FH as the working example there it but that's because that's normal endothelium it's not starting inflame

there's don't we have other studies like the pacis pesis study and Cadia where there's people with high LDL if I recall correctly but have low cardio other cardiovascular disease risk factors that developing PL is my understanding with p is that they do adjustments against the existing lipids such as HDL and triglycerides if if Pisa has open data like if we can do an examination on it I would be interested but the but the challenge is that we're we're still getting back to the mechanistic aspect of it if we can see in normal lipid metabolism people

who don't have homozygous FH or who don't have some form of dysfunction in their lipid metabolism that the increased levels of apob demonstrate that likewise development of plaque that that's why the lean mass Hypes study I think will be advantageous because we'll be able to also see if there's a correlation between LDL levels especially apob and both incidence and progression of black so the soft push back I would have on that is that their endothelium is fine their physiology is fine for homo sure they are absolutely fine been studied because well I'll tell you they

gentle push back push back okay let's let okay go ahead go ahead sorry I I will tell you that in FH what you have is one of a number of defects that results in poor clearance of LDL particles that is your defect period it's not the only defect though it's also their macroasia I I'll give you the site no no I I would I would push back on that but let me finish and then I'll bet you $1 sorry go ahead macras respond to their environment macras are sitting there saying my general role is to

consume things that I need to rid my environment of the more things that are there the more I adapt to my environment the more I will Express various scavenger receptors Etc because my environment is changed my macro is changing in response to my environment the maccrage is not different in and of itself absent the apob which is present in large quantity requiring it to change so you can't say because my apob is high which forces my macroad to then adjust that an adjusted maccrage is inherently an independent problem independent of the apob that's not the

way it works if the apob is high and driven into and retained in the arterial wall the maccrage adjusts and has the characteristics that you talk about not because it is natively that way but because it is adapting to its environment and doing its job I I've got the study on my computer I will pass off the study we'll we'll leave it at that if you like but but I I will I'll just I'll just say per the in vure study there literally is a difference in the expression of receptors um I don't know them

off the top of my head I need to have my computer in front of me to show you but it's it was part of what I coupled into the transcytosis talk I did because I was that curious about that component because it literally is part of the scene of the crime macroasia and how they function I think is very relevant but the macro phases and how they function in this context of genetically elevated a b are you saying that there is evidence that they're functioning differently to how macres would function let's say if if someone

doesn't have genetically elevated apop but adopts a diet where their apob goes up to the exact same level and the maccrage is adapt you're saying that in those two contexts macres are behaving differently it's not just that they're behaving differently they're physically different the macroasia of somebody who has a home who has monogenetic homozygous FH per this and vitro study for example they physically different from say the macras is you you or I have now again I'll reemphasize this is a hypothesis and I'm not suggesting that I know for sure that that's exactly what's going

on and I'm not saying that I don't know it's combinatorial it could be but are they physically different I would I would bet because of the increased apob they're different that's the point I would make it's because of the increas apob B it's because of the environment in which they are in if if you did not have homozygous FH and you did not have increased numbers of aob contained lipoproteins and there is not increased movement into the subendothelial space so if if we were if we were to take macras of some of a lean mass

Hypes with likewise levels of apob and culture them they would look identical to those of those who have monogenetic FH well that's a different argument but that's what I that's what but that's not the same argument that's a different argument clarify that bill because it because seems like where I was trying what I'm saying is when you when you have homozygous FH you are born from birth with extremely high apob levels and we're talking about a child not an adult with growing tissues and all the physiologic demands that a newborn has and under those conditions

from the jump from the get-go the mon the maccrage is going to have to be reacting to a very different milu than someone who at a later point in their life has a high uh apob or high LDL I'm just saying that if what I understood you to say is that the maccrage in an FH patient is uniquely different and I'm saying the difference is because they are reacting to the AP in their environment it's not that they are a genetically different monoy maccrage system it is a monoy maccrage system which has been insulted from

the time the first breath has been drawn and therefore is reacting as it would under those circumstances that's that's the point I was making let's just separate the two I would agree the circumstances are different but I would also press that there's physically a difference that the that macras of somebody with FH is physically different if you culture the macras side you'll see differences in how the uh re ctors are expressed and that's that's the again if I had the study from you let me agree with you by saying it backwards if I take a

perturbed maccrage and culture it it's going to be perturbed you're telling me that you have a perturbed maccrage and but you're saying it's environmental only I'm saying that if it did not have a high apob it would not be as you have described it and I'm not disagreeing with the environment being different I'm just saying physical it's its DNA is in fact different you're you're saying that depending on the context that sort of underpins the elevation of AP B if I'm hearing this correctly the maccrage is behaving or looking differently no no no I'm saying

I'm not disagreeing with there being an environment that can change a macras for sure an environment can change a macras but I'm also saying it's genetics or different it's again I'll just have to I'll either be right or I'll be wrong that macras in somebody who FH regardless of environment is in fact physically different but it seems to be an important point because this is this why you believe in the context of a lean mass hyper responder that APO B may not carry as much risk I'm saying I believe it's possible that why there's greater

risk in somebody who has homozygous FH is because there's broken lipid metabolis potentially in cells like macro fases that may be very relevant so if you're if I send you a car from my factory and it comes without an engine right and it comes without a you know passenger door or something like that and you say I can't drive this car they say but it is a car you can say but how you manufactured it is improper and therefore I can't make use of it to you know take my girlfriend to the hospital I think

that's a relevant clue that's kind of important and that's that's kind of my larger point with the macro fish is again I'm not asserting that I know for sure that that's what it is but I do think it's something that you've got to look into or at least at a minimum help to eliminate to be able to look at the independent Association of causality Define Lane Mass hyper responder we've said it quite a few times and and we kind of have defined it but let's just be really clear yes so per the original article in

July of 2017 and has since been published in I think nine or 10 papers by this point it is specifically the combination of three markers an LDL cholesterol of 200 Mig per deciliter or higher HDO cholesterol of 80 milligrams per deciliter higher and 70 and triglycerides of 70 milligrams per de or lower I was writing about it because at the time in 2017 I saw the emergence of what what I was regularly just calling the Triad which is just not cut points but just a the combination of high LDL High HDL low triglycerides that seem

to be more common in folks who were particularly metabolically healthy like the the thing that was surprising to myself and to many others is normally you associate having higher levels of LDL cholesterol being part of poor metabolic Health whereas the highest levels of LDL cholesterol that we were seeing through the community were people like myself and it seemed to be conversely those people who had better and better metabolic Health what percentage of of a group of people that adopt a ketogenic diet are going to end up as a lean mass hyperr they're meeting that those

three criteria of LDL over two 200 or higher HDL 80 or higher was it and triglyceride 70 or lower well it used to be hardly anyone and the reason I say used to is because For the Longest Time those people who would adopt this diet were just in a crisis situation they were typically folks who were mobely obese and they were just trying any diet so they heard of Atkins would try Atkins but athletic folks were not choosing to adopt Atkins they were already lean they were already metabolically healthy and as the rise of Keto

the ketogenic diet as it became a lot more popular that's when there seemed to be a higher and higher proportion of folks like myself like Nick norwitz like Adrien soda we saw our LDL cholesterol go up as we found benefit in the ketogenic diet but then that also brought around this new question why weren't there more people like us that were seeing this you know Sky High all your current hypothesis I think you use the language cautiously optimistic is that right yeah although to be fair I I now almost never use the term because people

still take it too too liberally yeah so so there's liberal interpretations of it what what is your uh definition or what do you mean when you say cautiously optimistic yeah so so I used to say I was optimistic in the scenario where somebody sees like me high LDL cholesterol as a result of metabolic fat adaptation I know that's a m mouthful but in other words why the LDL is High may be relevant as my profile grew more and more people were starting to just take that and run with it and so I'd say cautious cautiously

optimistic and then eventually I just I couldn't even count on the cautious so I just I just stopped saying it I now just regularly say things like I don't know work with your doctor we're getting data okay but if you were to hypothesize do you think these people are at increased risk of atherosclerosis and developing plaque compared to someone who is all else equal but has a lower apop LDL oh actually I would hypothesize that if somebody were a lean mass hyperr and they took every step possible to lower their LDL and apob they would

likely have a lower outcome chance of um of say dying of cardiovascular disease right so in other words if what I wanted to do was to be less likely to die of cardiovascular disease I would take steps to lower my LDL and apob as much as possible but obviously I'm phrasing it that way on purpose because they don't know if there's not a tradeoff that in fact I'm increasing my chances of cancer or infection of other things that are associated with low LDL again emphasizing that I'm not asserting that that is the case only that

I do believe that AP B containing lipoproteins and as as Dr cromo was going through in this podcast I do believe that if you take very strong steps to reduce them as much as possible that particular outcome you will affect so you don't think that you can get the kind of best of both both worlds here where you you take these people that have that are Lan Mass Hy responders they're improving their metabolic health and you say hey that's great let's maintain that metabolic health and also optimize AP at the same time I genuinely don't

know the the thing I love about the research we're doing right now is we at least answering that question at a m at a high magnitude level it's hard to be able to answer that question at a low magnitude level so your sort of core belief here is that you're definitely not discounting the research on AP and disease it sounds like you're on board with a lot of that you're just unsure whether there is a total mortality benefit up for grabs if you lower APO when you say disease are you saying if you lower apob

you'll get less disease period atherosclerosis so cardiovascular disease right so take for example the what um Dr cromo brought up with AA lipoproteinemia I've seen the research for sure there's nearly no uh plaque that builds up with AA lipoproteinemia they seem to be like almost like superum and that they don't develop it the hypos hypo hypo hypoa Lio prmia um however they have a whole bunch of issues that come with it so there's a tradeoff right and certainly not quality of life enhancing per se I think a better example and certainly one I would like

to get the data on are PCS G and loss of function not just with lifespan which we just talked about at length but with health span for example I would love to see the UK biobank on those who have pcsk9 loss of function and for example hospital visits right compared to those otherwise who do not have pcsk anoco function part of what I said was an idea that I didn't get a chance to to expand on earlier when Dr cromo was bringing it up is literally this idea occurred to me while we were chatting is

I'd love to take like say the top metabolically healthy cortile of those who have pcsk9 loss of function and then match them with a metabolically healthy of the you know again of the surrounding cohort because presumably then we would actually see a signal of of Health span right with the pcsk9 loss of function because now we're looking at healthy versus healthy but as you said with the benefit of low LDL that should show us a signal of longevity not just with health not just with health span but also with um or sorry not just with

lifespan but also with healthspan would that be a fair hypothesis I think healthspan is is the question that is easier to answer right so if you're saying a lifetime a fewer events heart attack stroke than the pcsk9 not just that like also all of it that that's what I'm calling dementia right yeah exactly and we have you know so interestingly a little backstory you may know this uh the way pcsk9 came to be was they were looking at families that were long lived and absent of cardiovascular disease and they haven't have really low LDL I

said well isn't that interesting they're living long they're healthy they they don't have chronic diseases they don't have cancer they're looking really good they have low LDL what's up with that PCS can9 deficiency so the context in which this was identified was exactly the context you're talking about these are best of all worlds these people are looking really good I'd like to know why they're that way pcsk9 deficiency came up as the genetic marker that they identified now there could be other things but that's what they identified and having identified that that led to a

development program saying well would it be the case that we could make this a target of therapy we could come up with say a monoclonal antibody that would mimic a genetic situation where we take it out and then we would ask what would happen to these people well in the short term because these are just short-term studies there's a significant reduction in plaque stabilization of existing plaque significant reduction in events significant reduction in stroke without over the short span a significant risk signal so so that's kind of the backstory they were looking at these really

you know very healthy long-lived individuals without ascvd and with low LDL and so what's up with that PCS can deficiency so you know as the story has kind of come to us as we've identified it that's where you're talking about extending the data which would be great but what we do know currently is that that's the what characterized these people when they were first identified so I mean this is this is this is what I like about my origin with regard to science is I like asking these questions before the data are in hand could

all of us and I'm this is not at all a trick question could all of us agree that that idea at least sounds like an interesting one to examine with like say the UK biobank or Copenhagen because I'm going to pursue this data you and I have had some DM conversations if you don't mind my mentioning where I've stated it a priority right where I've said I would like to find any genetic abnormality that results in 70 milligrams per deer lifelong and I'm going to State this in advance before before we get the all cause

mortality data but if you have some ideas on for example what would be a good quality of life marker before I get the data that's the best way to do it because and I would add one thing to that as we're kind of a priori laying things out I want mvx in that as well okay because what I know is that mortality in healthy individuals is a function of mvx with nothing else on the table so if mvx is significantly segregating mortality risk independent of any chronic disease and otherwise healthy individuals then that needs to

be part of the analysis to ask the question is the longevity signal as we might expect it to be improved by lifelong low apob is there an mvx signal that superimposes on that that's also part of the story so if they had uh so we can make it a 2 by two we have favorable low mvx and we have high m VX and we have pcsk9 deficiency and wouldn't it be interesting if long life was attenuated by high mvx and long life was as expected in the setting of low mvx that's another hypothesis to kind

of put in here because it it's a new learning that might help us to better understand the data look for our paper in one year we we started it here yeah get cracking gents we can break in vain and and unpack it I I'll one one critique that I have that I think is a valid one a lot of people in low carp Community have is that a lot of these data are first acquired with an expectation in mind and then analysis is applied and I myself I wish that there was more of an effort

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up for a $1 per month trial period at shopify.com prooof that's shopify.com prooof all in lowercase okay so let's come back to your interest in lean mass hyperresponders and the questions that you have how do you plan on answering them you know with what is your hypothesis essentially and how are you going to test that so it's there's really two questions there's two questions of enormous interest the first one is the nerdy one which is the mechanistic explanation for this Triad particularly for this phenotype that's at the center of the research that one's quite complex

been working with a lot of folks including many that you're going to be interviewing ultimately but uh that's really not the one that probably most people are watching as closely or even understand as well the second one is what everyone's interested in the question of risk are lean mass hyperresponders at an increased risk for cardiovascular disease now this is the thing that I think um is great because we'll be able to get around to something both Dr crl and I have enormous overlap with which is that apob and LDL are certainly very interesting they're very

interesting metabolic health is probably one of the most gigantic blind spots you can imagine in healthcare today even for as much as it's getting talked about it's not getting talked about enough it's not getting focused on enough right okay but bringing it back to ldla apob I think that even a lot of non low carb physicians in the scenario of a lean mass outrageous today I'm actually surprised at how many people clinicians outside of the low carp Community have gotten surprisingly a little bit more permissive about that if everything else looks great but then you

get to somebody who has an ldal of 400 or 500 or 600 now we're talking Brown and goldstein's children who were developing atherosclerosis at an extremely rapid rate why would anybody leave their LDL at 500 600 Etc especially when we've already published papers leveraging the lipiner regy model showing just a very modest reintroduction of carbs which we won't get into the mechanisms here can bring that down to the levels we just now talked about like 200 which again still seems outrageous but to many would still be more permissible than being at the 500 600 and

so forth well some folks have truly diseases like say epilepsy where they really do need to keep their carbs that low some that we've interviewed for the documentary we're doing uh are treating say bipolar need to be that low we also interviewed a prominent low carb doctor in the UK who uses it to manage her food addiction which is quite severe and so those three examples that I've just mentioned it's not uncommon for them to come from the perspective that you just we couldn't know what a difference in the quality of life is for them

and what the risks are for the converse so we need to get this data not just for those that have even mildly elevated LDL but those who have it at those levels to at least see if it's not just an increase of cardiovascular disease but it's that high magnitude of change that should come through in the data that we're getting right now particularly with CT angiography earlier I think you kind of emphasized that at least with the genetic data the pcsk9 lost the function you're not convinced there's an improvement in mortality uh but I think

you accept that they have less atherosclerotic cardiovascular disease right yes again I don't know if there's some version of a tradeoff I just don't know right so why is it in this context of lean mass hyper responder and it I might have this wrong but it would kind of follows that your hypothesis would be they might have they they'll probably have increased PL progression but they're going to have lower risk of some other disease and their total mortality is not going to be different this gets us back to the magnitude question so the the magnitude

question is let's say I were to tell you you have an increased risk of of dying of a heart attack at age 95 but but if you take steps a through z you'll have a reduced risk to where you'll be more likely to die of cardiovascular disease at age 100 obviously I'm using hyperbole to illustrate a point that the risk level relatively speaking seems to be seems to be low even though I'm talking about a difference of 5 years but it's because of the time Horizon is so different from what we're discussing and if I

throw in there well there's a tradeoff the trade-off is if you don't die of cardiovascular disease you're more likely to die of cancer and for whatever reason I have absolute knowledge that that's what the trade-off and risk is but how are you going to ascertain that in a very short term study where you're looking at pla with with plat formation with CT Ang geography yeah how are you going to really ascain whether there is that tradeoff long oh that's that's very difficult to determine but we can determine if there's rapid plaque progression shortterm to at

least determine if there's uh that pronounced increase in Risk that's why I keep bringing it back to magnitude see I'm actually making a key consession here that's very important for those people who are going to be looking at this research that we're doing right now and they may want to make a categorical claim I would already be pushing back on it that we don't know if what you just said isn't true true that for example somebody who exhibits a lean mass Hypes phenotype has an LDL of 200 even wouldn't be better off having a sweet

potato a day and bringing their LDL to let's say 130 over 25 years right because the magnitude of change is so small that it'd be difficult to pick up and say the study that we have do you have any thoughts on that bill well I would look at it a little differently uh and that is that most lipid just think of exposure over time as they've saying and because we encounter people who are high when we get them we really don't know how long they've been that way in some cases people have medical records a

lot of times we don't know right so you come to me and for whatever reason your LDL is high and I say first question I always ask my patients how long has it been that way I have no idea so now we're left with a fill-in the blank has it been a long time has it not been a long time one way to try to answer that question is noninvasive Imaging and if we see plaque we assume something is going on that has turned a process on that we would like to turn off and part

of understanding that is what else is going on and LDL related risk turning that down now in this case we have people who were doing fine apparently they they didn't have high LDL they are metabolically not unhealthy they seem to be metabolically healthy at least to first impression but didn't you say earlier and I'm not trying to catch you out that you had pre-diabetes correct right so it wasn't as though you were starting with someone who had perfect metabolic Health right they adopted the diet they they may have had or um not non-optimal metabolic health

and then become right it's an important distinction because again if we're looking at the big picture I I don't know who these folks are prior to their identification as and I adopted keto and this happened to me I I don't know what their uh history was to that point so once they have now had this LDL response what I would be very concerned about is it being high for a long time that's my concern because the models of disease that we have say there's a consequence that we expect is likely for people who have high

apob for a long period of time and especially if you could adjust your macronutrient intake reintroduce carbohydrates and bring that down to a more acceptable level that would seem like a very reasonable thing to consider especially if you have any evidence of of plaque right but if you have a zero uh evidence of plaque either by CAC score or CTA you're zbo even if someone's younger like in their 20s or 30s let's say you're zero Okay so we've looked and you're zerbo and the point I'm trying to get to is if you have a high

LDL that is new in the setting of no known disease what is the time frame for that to assert itself into plaque I don't know the answer to that I think if you give them 20 or 30 years the expectation is it will drive AOS sclerosis over some period of probable time is that 5 years is that 10 years is that two years that time window is what it back to the magnitude question right that brings it back to we we need to study these people sequentially to be able to answer that question yeah like

you could you could tell me given what I've come to understand is the total plaque score you could tell me I know for a fact Dave that um your LDL concentration does mean something that it's not an unknown in this hypothetical but it is a known you will add one total plaque score to your total plaque score over 50 years I would say oh okay well then that's that's an easy answer right because we've intentionally I've intentionally created hyperbole for a 50-year Time Horizon to add one total plaque score but now let's shift it up

say no in 5 years you'll add 20 to your total plaque score out of a total score of 45 that's hyperbole in the opposite direction right the the question that's difficult for us to answer and has been this entire time is how do you disentangle these clusters of the issues that we're talking about from the apob that's embedded within them right and for metabolic syndrome that's that's very difficult the Catalyst event that we were chatting about earlier and is still very present to all of us is the work of brown and Goldstein with those who

have homozygous FH that is why we're so interested in lean mass hyperresponders at those super high levels at 400 500 600 are they going to look comparable to those who have homozygous FH that's what we're Gathering data on in terms of progression of PLA and events yeah yes both correct plot they correlate of course extremely close so the presentation and progression of plaque if apob is the central driver should be what we would observe you both Mass hyp are you interested in looking at that in subjects who have no plaque at the onset of adopting

a ketogenic diet when they sort of shift their phenotype to this Lan Mass hyperr phenotype well of course because that's again getting back to the children of brown and Goldstein there was the the study that I mentioned that had the six children who were who had homozygous FH I did the math on their milligram years so on the cholesterol years they don't have it in front of me but I think I remember this from memory I think it's they had 14 I think the latest of the children that had not yet developed plaque I think

it was 1400 milligram years and I think the earliest for which they did have plaque was 1,800 milligram years and theistic that um I've seen you use as a graphic as well as many others has and it's a heuristic so it's not something you have to be held to exactly is like around 5,000 milligram years is kind of like this red line right and it's a great it's it's great as an illustration for the amount over time because the faster upward you're going right presumably the faster you're going to show both the uh presence of

plaque and be at risk for an event and it becomes cumulative right it keeps doubling with each I think 1250 milligram years well those children are getting it much much earlier than 5,000 which goes to a Dr cromwell's point and that it is a different context but already saying it's a different context is a little bit controversial because that is a Cornerstone of the lipid hypothesis to begin with that their levels are indicative of what the risk velocity is for cholesterol years but I already know myself a number of folks who are and have been

at those levels again for medical reasons typically because they're trying to treat some other disease and um you know while I say every anything I say is not medical advice I will tell you that folks I work with like say Dr budoff uh kuram nir they would be very much a fan of Imaging so even if you're not in our study it's not the worst idea if you could at least know how much disease you already have question for you Bill let's say someone in their mid-30s presents to you they've adopted a ketogenic diet they

have an LDL cholesterol of 600 but otherwise healthy great insulin sensitivity metabolic Health looks good they have zero plaque no family history of cardiovascular disease and they don't have elevated LP little a what's what are you thinking in that context with regards to the management or uh attention that you give to LDL cholesterol I wouldn't want them to stay there I would not want them to stay there they're 30 years old the longer they stay there the more cumulative exposure risk they have so number one is I'm not aware of an advantage of them staying

there I don't think they're benefiting themselves by a 300 cholesterol so if I could adjust their macros and I could bring their LDL down decidedly as uh Nick and Dave and others have shown you can adjust your Macros and attenuate that increase that would be my first step and so you may be taking keto for a lot of great reasons um I would wonder if you can continue to get those benefits by making a gentle adjustment in your car carbohydrate intake taking the pressure off that drove you to a 600 let's get you down to

something much more reasonable see if you're getting the keto benefits you're looking for and then we can have our next step conversation from there and if they push back and said look doc I understand what you're saying but my symptoms say they have bipolar are better than they've ever been before I'm not changing my diet or they've tried that and it didn't work and I'm not familiar with the bipolar dietary intervention studies that are out there so I can't off the top of my head you know tell you if there are other diets that are

equally as beneficial or it's been studied at all but this is hypothetical I push back I say look my nal1 anecdotal experience uh is important to me MH I feel significantly better in my relationships with myself and others mood quality of life I'm not going to change the foods I'm eating is that are you recommend medications I'm saying that I have no data in hand to suggest that a 600 LDL cholesterol doesn't have a negative consequence down the road there is no data to show me that sustaining that level of LDL for an extended period

of time is anything but risky so I would knock that down with some type of a lipid lowering drug in that context if I was open to it I I would say that the the hard conversation is we have to do one of three things number one we leave you the way you are and we follow you with some sort of Imaging modality and wait for something bad to happen aerosis and then attack it once we detect it so one one option is to say if I ever find that I have disease I'll revisit this

conversation but until I have disease I'm not going to revisit this conversation for the reasons that you just said that's one thing that a patient could do a second thing a patient could do is they could say uh I'm willing to make subtle changes in my diet so long as I don't have uh loss of benefit in the ways that you just described and if by changing my diet subtly by just reintroducing some carbs knocks me down 200 points my LDL it's not perfect but it's better than it was I'm still getting the benefit that

I'm looking for and under those conditions I will wait until I have a plaque and do something that's a second U modification the third is to say um we don't want to expose you to an LDL of 600 needlessly and if we have to have the keto diet as is currently practiced for the benefit that you're getting out of it then I would strongly suggest treating that LDL pharmacologically if we can't agree on some sort of therapeutic lifestyle change dietary change in order to lessen the impact of high LDL over time and if I have

questions about the safety of statins I would look at the Statin safety task force data which is probably the best repository of worldwide Statin data and the liid associations in this twice oh the good and bad of Statin is they've been around for a long time there is there are millions of patient years of exposure worldwide um so we have lots and lots of real data to look at frequency so the challenge here is frequency uh I don't doubt that there are people who have had horrific stories on statins the problem is that with the

ability of that message to be Amplified it's hard for the average person to understand how frequently that occurs right so if somebody has a terrible Statin Associated effect but the frequency in large data sets is extremely low that's part of the conversation versus I know somebody who can you guarantee me that that won't be me I can't guarantee you that won't be you I can tell you the frequency of adverse effects is best understood in the context of the large exposure risk that has taken place and how frequently these signals occur and I think that's

a good conversation to have is what what are the fre frequency of these adverse signals and how do we mitigate them what is the frequency it depends on what you're talking about in the population so give you an example back in the day when we started with statins we had mevacor followed by zokor and pricol those were our first three statens these are all considered moderate intensity statens the high intensity are Lipitor and Crestor so these were moderate intensity statins that were used at moderate dosages so the number of individuals who are having significant problems

like mygas that were limiting their lifestyle diabetic signals Etc were very very low why because we were using modest doses of a moderate intensity Statin when we started coming up with lots of adverse event signals whereas when we used high-intensity high does statin therapy and a lot of this was driven number one by the apparent tolerance of statins as first used and secondly by data such as the miracle trial miracle was a study of people with acute coronary syndromes who received 80 milligrams of aorist Statin and their 30 60 90day uh morbidity mortality was significantly

benefited by being on high do statens in the setting of an acute coronary syndrome this gave apparent cover to the idea well maybe we should just use that dose in everybody now if statins have been well tolerated and this has a good effect in ACS let's give 80 of atorva in high-risk individuals from the get-go and by starting with that dose we precipitated a lot of Adverse Events and that was a different way of taking statins than what our first exposure had been when these drugs were coming to Market so I think two things can

be true at the same time highd dose high-intensity statins can absolutely uh press the adverse event profile but that doesn't need to be the way we start everybody at the same time and so for individuals who are Staten reluctant and I like that term they're very reluctant for a good reason I think we have to first make the case why would you need a Statin in the first place and remember the guidelines beginning in 2013 in my opinion made a good step toward saying it's not for everybody we should be selective in who we discuss

stattin therapy with do you have ascvd do you have LDL cholesterol one night or hire on a regular basis are you a diabetic 40 to 75 years of age do you have high risk as inferred by a validated calculator these are all candidates for Statin therapy right that's not everybody and then the guidelines in 2018 and the ESC guidelines other guidelines took it a step further and that is well let's not just look at your categories let's look at your risk more broadly well you could use the pulled cohort equation you could calculate 10e risk

or lifetime risk but what about all the risk enhancing factors LP littlea chronic kidney disease metabolic syndrome women with premature menopause women with preeclampsia inflammatory disease a whole list of risk enhancing factors if that's who you are then the opportunity for LDL lowering takes a little step up and then the next step is well okay given all this are you old enough that a non-invasive imaging test would adequately visualize what could be plaque in your vessels now if we look at Cor artery calcium score it's just calcified lesions we see not all lesions if you're

a younger person under 40 a zero means nothing it doesn't mean you have disease or don't have disease it can only rule you in it can't rule you out but incorporating some type of Imaging is the next step the guidelines would say okay if you have Imaging evidence of disease we probably ought to talk about the the treatment with statins to lower that risk stabilized plaques so so that discussion I think is the better discussion is is um am I worried about a Statin I think risk and benefit always have to be balanced right and

if there's no likelihood of benefit then any risk is outsized if there's a high likelihood for benefit then a small amount of risk so you have to put that into into context what percentage of the side effects and not to downplay them and suggest that they're not real because they are real they are real experience that people go through but what percentages are are attributed could be attributed to the fact that there's a lot of negative stigma and so people go into taking it thinking they're going to get side effects yeah the negative bias is

real uh one data set that speaks to that is gaus 3 they took people who were self- declared Statin intolerant they randomized them to receive Statin versus placebo and a third of them re uh exposed to Statin with no adverse effects so that is I believe an indication that people who are concerned about having adverse effects going in are potentially going to read into experiences a Statin uh consequence which may or may not be reproducible uh the other thing I tell people is a lot of the referrals I get are for Statin intolerance right so

high risk can't take a stat and go see the lipidologist well things I'd like to know what's your vitamin D what's your thyroid status if you have vitamin D less than 30 and your hypothyroid that's poorly controlled these will set you up for Statin Associated mygas no doubt about it have you ever tried Q10 what are other mitigating St factors have you tried one Statin two Statin several statins some statins in individuals are better tolerated than others have you ever started with a lowd does statin atypically dose like every third day and gradually increased to

a point where you're on a daily Statin or did you just start with a highd dose high-intensity Statin and the first shot over the bow was a bad one the these are all strategies to better understand what could I do if LDL lowering needs to be considered another strategy don't start with a Statin do bidic acid or something yeah you can use benoic acid you could use a zomi and and get to the Statin as a second step right but bino acid as you know Works two steps up from where a Statin works and it's

not active in muscles therefore it's much better tolerated at at that level and without come proven benefit in the clear outcome study so so some of the the factors around the stat and conversation with patients are you know what their experience has been what agents they were on um what contributing factors might predispose them to issues that that's one part of it what nonstatin LDL lowering therapy has been proven to have Al benefit that's another part of the conversation right uh and then the the other part is and what is the risk that we're trying

to mitigate here do you have disease are you in one of those four categories do you have a lot of risk-enhancing factors um this is why um with the company as our Precision Health reports we want to put that context in front of people so they have the full field of view from non-invasive Imaging clinical history risk-enhancing factors biomarkers Biometrics what is my story story and and how much of this should I you know consider as I need to do something and stattin may be part of that conversation Dave I appreciate this is slightly out

of your whe wheelhouse or the things that you spend a lot of your time thinking about uh and I want to come back to this the study or studies that you're involved in but just quickly what do you think about the strategy someone who is a lan Mass Hypes uh lowering there aob down to you know a level that we would say is optimal whilst waiting for data I would say work with your doctor work with your family learn what you can no I I uh I have kind of a stock answer now because any

more I want to keep repeating and emphasizing that even when people are saying Dave you're somebody I trust you seem to be smart you seem to you know have some advice that I could probably follow I say I've actually worked really hard at linguistically removing as much as I can any hinting of advice because I'm really trying to be just a researcher trying to just go get this data and then bring it back and the more I can do that the more I can emphasize that what you do about your high LDL that's really the

cart the horse is what's going on what's is this a problem is is what I'm most interested in now I will say this I found an answer that seems to help get me out of the feedback loop which is that I now defer to Dr budoff and Dr crom nir Who by the way have a lot of overlap with Dr Cromwell with regard to if somebody goes on a ketogenic diet they see their LDL go high they are very interested in doing Imaging next if they do imaging and they're satisfied they're at low risk then

they're interested in letting it be a decision for the patient past that point whatever it is their their next choices but to continue monitoring but what do they say if the patient says okay I have no plaque but am I at increased risk of laying down plaque I I've only just adopted this diet like I want to kind of know what's going to happen in the next five 10 years I think most every doctor that I'm aware of outside of the low context at least at those at those levels would say oh well if you're

just asking me then I'm not comfortable with it they would they would sound like Dr Cromwell generally speaking now again this isn't me giving advice this is me telling you what people tell me obviously uh Nick norwitz and myself we get asked this a lot because we have untreated higher levels of LDL but I immediately follow up by saying we also have CT Ang geography he's gotten a CT Ang gram once I've gotten it twice and I emphasize that this is Uncharted Territory that's exactly why we have to do this research do you think some

people I really I appreciate your position and I think previously I've I can put my hand up I've probably misunderstood you or and maybe even misrepresented um so I feel like I'm I'm understanding you more which is good that was one of my goals but do you think some people hear that and think Dave's an incredibly intelligent guy you know and he's happy with it so I'm just gonna I'm just going to follow suit and perhaps ahead of the data you know just continue to adopt this diet where they're able to be super elevated and

take on some risk that they're unaware of well to that extent I said what I said right after I mentioned where Dr budoff and Dr uh nir are in that I meet that first context they described if I have Imaging and I'm low risk if Nick norwitz has had Imaging he's at low risk at least with regard to the plaque that's present currently right and we're actively monitoring it then to that extent we kind of meet what it is that their position would be in the first place uh I will say that um Nick I

believe and I don't mean to put words in his mouth but I think he'd be fine with me mentioning this he said that he might feel differently if he had gotten you know CT angiogram and it turned out that he did have rapidly progressing plaque then he might take other steps and you're making that choice based on the fact that you don't seem to have had plaque progression um but is there any I know you're working on a few studies is there any outcome data at all that looks at this phenotype in my opinion currently

the data that show metabolic Health as Associates to cardiovascular disease outcome seems to suggest all else considered it Associates with lower risk at a population level but the key to emphasize here is population level so if you're talking to a clinician and they're saying wait a sec you as my patient got hung up in a group of people who feel confident that they're safe because a lot of their friends seem to be safe and by the way this isn't just in a low carb group as I'm sure you're aware there's many people who are on

plant-based diets who might for example feel that they're at low risk strictly because they're on a plant-based diet right and because they have friends who doubt highly their cardiovascular health being on a plant-based diet decide that that's good enough for them and don't pursue further Avenues when they uniquely seem to be an in an unusual circumstance and that's why I bring that context to bear I think the difference though is there is quite a lot of outcome data supporting that dietry pattern for long-term risk reduction at a population level at a population level that's that's

why I'm driving into that is I think you and I agree I'm certainly betting that Dr Cromwell agrees it's all populations until it's a patient then when a patient it's their specific context and then you've got to care a lot more but I guess it's a game of probability even a population level right it's like you know I it's possible I'm not going to have that because I'm an individual I'm not going to have the average response that you see in a study it's possible but if I'm you know playing probability then I'm likely to

have that outcome yeah and you you should care about probability more likely to have that outcome I should say you should care about the probability of the studies that you see for the spectrum of data that you have that applies to you in the population that you're in until you can get more distinctive data that's literally the origin which brings us back to you and your position saying there's a lack of data looking at this phenotype correct and that and that's that's why like it's it's such a challenge to walk this line because I genuinely

I genuinely want to get through to folks like yourself and say look this does not have to fall into this false dichotomy between different camps if you will that have these these different opinions yeah I really don't want to be partt of a camp yeah I've decided that it's not that fun so here's a a thought for you uh there was there was a study out of pen pen heart study and they were interested in trying to tease apart something that you mentioned earlier and that is the interrelationship between things like insulin resistance APO B

and is one more important than the other or they're just part of the same old thing so what they did was they used coronary artery calcium score as an indication of disease all right and um if you took a look at H IR a validated index of insulin resistance in apob what they found was that if you adjust for all the usual confounders um each one individually was significantly predictive of the presence of disease okay that's good now let's start with h ir and add apob those H IR still significantly predict yes let's start with

apob b and add home IR does APO B still predict yes all right let's do another step let's say that I start with APO B and add home IR does apop significantly add predictive value yes and the vice versa is true and what they concluded was both significantly independent of each other and after multivariable adjustment were significantly predictive of subclinical disease that means that if your IR is normal and your apob is up that is significantly productive disease after multivariant adjustment and vice versa if APO B was not up and IR was it was predictive

so what we're saying is that again uh these things are embedded and overlap and sometimes I think people kind of U stress test the system to say okay where does it fall down where does this Association lose steam is can it still stand all these additional adjustments and what I can say is uh the purpose of doing so is to come up with a sense of the uh contribution to risk of the punitive biomarker in question and if apob for example survives all these adjustments then then is a significant player that should be considered I

think sometimes people stress test this to find a place where uh the biomarker of of Interest fails and says see I told you it it wasn't as bad as you thought it was it just failed there I'm not going to believe it anymore so so that's not what we're doing here but I see people doing that I see people kind of playing this game of I'm going to force it to fail and a forced failure model when it fails it's no longer a a topic of interest and and so we just have to you know

be aware that some of that is out there and because people do that we have to kind of remind them as we have today uh we're not trying to declare a winner or a loser we're not trying to declare the uh end all be all is this versus that it is the disease as we understand it contributed by all of these things including metabolic health and if you've got plaque you've got a disease that's turned on do you want to turn it off I I tell my patients you know what plaque means your house is

on fire now it may be in your bedroom but your house is on fire are you going to let your House burn down or you can do something about it plaque me your house is on fire and we should do something about it but there is a distinction which I was kind of mentioning from earlier pretend there's a a confidence meter right the confidence meter is very high you would and there there's this isn't rhetorical you both would feel that existing modeling existing adjusting even even in the course of when you were soliciting uh questions

for this podcast I forget who it was who brought up it might have been Eric Rogers he was bringing up something and then you you brought up now wait was this data looked at did it have the proper adjustments I think I even I had that here oh you even had it here perfect perfect it was something that well I mean it was a tweet from Nick so you can rate Nick's tweet okay perfect that accompanied that right so so this this is coming from engineering and especially with an interest in modeling uh we're doing

modeling of of a different kind for example take cell phone coverage right so I want to sell you my cell phone service for my business and I say it's 99.9% coverage and then you go to your house and it turns out you don't have coverage you have no signal and I say oh sorry uh we were adjusting for weather at the time that we were testing I guess it turns out that doesn't work you're going to be upset with me because you got the impression that you would have had the coverage in the case of

adjusting for something we cannot actually yet test independently so you're making adjustments with things like sensitivity analyses you are in fact making causal claims with that which you cannot disentangle yet until you can test its predictive power outside of that that's why we need studies like the Mass Hypes study we've not been able to independently test specifically High apob outside of some form of dysfunction or disease we've needed to get a population likely in mass hyperresponders that otherwise have low cardiovascular risk factors and seemingly we propose a functional metabolic uh lipid metabolism specifically and again

it's not that I'm saying I know for sure that that won't be accounted for for it very well could be which is what we should be able to see in the data as it emerges yeah I think the the point that I made on this which I've seen others make is that you know Nick was sharing this and many people have have shared it to kind of highlight that the hazard ratio for type 2 diabetes insulin resistance is much greater than LDL cholesterol right in this particular study but it's not just that it affects the

lipid profile directly so it affects yeah so you're saying because it affects lipids directly you shouldn't be adjusting for them it's I'm saying it's difficult to adjust for something that is part of the milu of what's getting affected by the common cause how do you feel about that bill so this goes back to the study that I just mentioned to you so two two problems with this number one cholesterol is not LDL and LDL is not cholesterol ldol is a particle that carries cholesterol and the amount of cholesterol in the particle is highly variable when

you serve me this it had more water it has less if I say this glass holds 300 MLS of water if I have 300 MLS how many glasses do I have one if it's full two if it's half full so on so using LDL cholesterol As the metric of A lipoprotein that we may or may not be interested in suffers from an analytic fatal flaw to begin with so the correct question is to what degree do arthrogenic lipoproteins have something to account now that would be apob B and then what would we do in an

entangled situation you would have to do these adjusted analyses sequentially in the way that I just did for example in the pin heart study and that is if insulin resistance and apob B are part of a similar path of physiology and I adjust one for the other and vice versa and put them in the same model now when you put them in the same model if they're telling you the same story neither one of them is significantly predictive M if I put APO B in the model and it's predictive and then I add H ir

and it's no longer predictive I just learn something MH but if I put it in the model and I add home ir and it continues to be predictive and if I start with home ir and I add apob and it adds significant predictive value that tells me while they're related this is independent and that's the way that you test the question of Independence does this independently contribute even after I adjust for these if you do that type of analysis you'll come up with a different potential answer than the way this was done right and so

you're of the view that they are independent based on that data so if you think about the lean mass hyperresponders and the studies that Dave's involved in you would expect to see plaque progression over time over time even though they are metabolically Health now what I don't know is because the time question is if I were not metabolically healthy with a similar apob versus metabolically healthy with the same apob would you expect them to track similarly over time or would you expect that there would be an amplification of aerosis by being metabolically unhealthy with a

high apob versus a blunting by being metabolically healthy with aob that's what I would expect and I would expect that if given enough time you would see in my my opinion plaque developing in the context of high iob but not necessarily at the same rate with a higher rate in those who are metabolically unhealthy when you say over time you would expect to see PL progression what does overtime mean that's what we need to know is it 10 years is it 20 years why is huh why isn't it right away hold on so you're saying

that there is no plaque progression right away we haven't really I guess double clicked on the studies you're doing oh no no no no I'm I'm saying why would there be a delay in plaque Maybe here's a better way of asking it how long does it take LDL to affect plaque so it's a great question and it's a hard question to answer for a variety of reasons uh I don't think you can look at pediatric cases of FH and say this is the expectation so if I have a newborn with HH and a LDL cholesterol

of 600 and they have a certain rate of plaque progression say okay that's the Baseline rate of plaque progression for anybody who has that LDL that to me is is not the same physiology as you or I as adults who have now had a change in our LDL level so you you first I think uh can can I ask why though because the yeah because you're you're growing as a child and you're not a child is not a little adult right that's what you're assuming is a child is a little adult and this little adult

acts like an adult does they just happen to be smaller and because this little adult has a 600 LDL and they change over this period of time an adult would be the same thing so so kids in in a growing state are a very different creature than an adult I right the only reason I ask and I'm not trying to catch you out on this if there is a physiological difference that can be applied back to lipid hypothesis to explain why it's different for them than it would be for us in a way that can

wrap in the lipid hypothesis I'm interested to know like what that would be like growth growth I definitely think part of me being obsessed with endocytosis is I believe that part of why it is for example that there's lower LDL particle count particularly in people who are growing rapidly so I think there's actually greater endocytosis for use for cell growth uh for tissue uh expansion right but as far as as far as the lipid hypothesis goes if greater transcytosis on net at a dose response level is resulting in Greater amounts that appear in the subintimal

space every single one is like a lottery ticket that you don't want to win right it's kind of like you're playing it over and over again what's is do we know what's different about homozygous FH children other than for example the things I was bringing up with their physiology several things first of all having the same LDL cholesterol level doesn't mean that a lean mass hyperr at 500 is a homozy f age patient that's not the same all right so you can't equate two similar LDL levels and say oh this person is just like a

homozygous of that's not true they may have a similar LDL cholesterol level at that point in time but a homozygous FH person has the inability to clear LDL because of a an AB barent LDL receptor axis it's an LDL receptor axis disorder and as an LDL receptor axis disorder that is a different physiology than saying if the uh lipid energy model would be the explanation for their high LDL we're overproducing we don't have a clearance defect we have a production issue that's a different physiology than I can't clear once I make so again I would

caution You by saying just because you have a similar LDL cholesterol you can't conflate One path of physiology with they're different Pathways but they they kind of converge at the same point in terms of if you stay that way and if you stay that way over years I would expect there to be black if you have a 600 LDL cholesterol and it's that way for a year and you were to go back down would I expect plaque in a year I don't think we have enough data to is that dat looking at uh you like

babies that are 2 three years old that have FH and whether they have plock progression so we can say that without FH you can look at pday study where children killed in car accidents who were autopsied had evidence of aerosis at at H2 they didn't have FH they were just normal 2-year-old so depending on what you're using as your metric for is there plaque or is there not we are we going to look at uh tissue under a microscope and say I see plaque because of tissue under a microscope versus I'm going to look at

plaque with an imaging technology now I need a much greater plaque burden to be detectable by CTA or even a much greater plaque burden than that if it's a calcified plaque with CAC right so so this disease process is one that takes a long time to show up in a macro level that we are detecting with some of these non-invasive Imaging Technologies so it's it's a sensitivity issue for detection in part how are you planning to kind of navigate that with your study protocols study designs well and that and that's part of it is that

I'm I'm I'm wanting to understand as best as I can the critique on the outside and and that's if you've watched me over the last eight nine years I'm I'm constantly planting Flags along the way it's almost like breadcrumbs if you will where I'm trying to be sure that we all have in mind what the go posts that we agree on are right now I actually agree that homozygous FH is a different context that's kind of the case I was making from earlier I think it is a physically different context and that it won't turn

out to be comparable to lean mass hyperresponders the scenario that I've wanted to drill into especially now that the data that um uh Dr budoff has presented on on December 8th with regard to um what we've already seen is that there is a lack of correlation between LDL and corresponding total plaque score that was quite stunning when I was seeing it because I was especially interested uh particularly for those who had extraordinar high levels of is that cross-sectional or you're following paper this was with the match control so it is cross-sectional we do have longitudinal

data that's coming next but the cross-sectional and I'll reinforce what I've been saying I don't know 100 times everyone should expect at a population level that we will see a plaque progression the question has always been whether or not we'll see a rapid plaque progression as would be expected if you compared it to homozygous FH but the the goalpost is in a different place now than when it started because if you were to go back 8 n years ago and I was to tell you we're going to be looking at a cohort whose average LDL

is 272 and whose mean age is 55.5 that's mostly male and we're going to have Baseline 4.7 years at those levels at eight nine years ago everybody would have taken the bet that we would see a rapid progression of plaque at least at a population level now I feel that there's a little bit of a difference and again this is not my saying that I believe the goalpost is moved to where people expect there's not going to be any difference or that there's or that uh this population is safe per se it's whether or not

again we're going back to the high magnitude of risk versus suboptimal which is the case that you were making from earlier but even so 272 just 8 n years ago would sound unfathomable the fact that our average in our population for this match analysis was 272 that's in the top 10% of the top 1% of the population it's extremely high levels of LDL explain that study a little more the cross-sectional study so and this is something um Dr cromwell's got a chance to see and we had we hadn't had a chance to by the way

this is peer reviewed but it's not published yet correct yeah so it'll it'll be coming out shortly but basically I just described the cohort so let me let me take a step back here's the lean mass hypers sponder study as it as it began we wanted to do a longitudinal study with 100 uh participants not quite lean mass hyperpc points but very close LDL of 190 or higher which is by the way the guidelines that at 190 or higher you should be on the maxim maximally tolerated dose of Statin HDL cholesterol of 60 or higher

triglycerides of 80 or lower and then a number of other uh cardiovascular risk factors were identified to be excluded so pretty much a healthy population but with the expectation that they're probably going to have sky LDL and apob which they do we didn't know for sure how recruitment would go and then finally we're getting around to the point where the first scans were completed in February of last year and thank goodness for Dr crom nir Who I mentioned earlier he is the principal investigator for the Miami Heart study the Miami Heart study I didn't know

about at the time that we were starting our study and it's the only other study that actually is looking at asymptomatic uh participants and therefore already had a huge pool of people who might have metabolic Health that we could do a matched control with because our group does not have a control group so matched control is um once we knew that we could be matching against Miami Hart we found that there were 80 in our pool of 100 with that initial uh scan data the initial CT and geography um sorry I didn't mention that part

all the longitudinal data is CT angiograms so all of them had gotten scanned all of those hundred scans had been completed in February from that we were able to find that there were 80 and by we I mean list because uh they've got the status stue it does all this uh that 80 of the 100 fit within the age range of uh Miami Hart and then from that went to do the match and the match then determines a group that has averages that match all of the averages as closely as possible to the cohort that

we had now unsurprisingly the one thing that stood out outside of the lipids was a BMI getting back to the lipid AR model which I didn't go into in depth here but other people can look it up we're probably going to not have enough time to hit it but we believe the higher levels of lipids are related to how lean you are which we discussed and so I think our average BMI was 22.5 but in the Miami Heart cohort even though all the other things were matched up up the average BMI I want to say

was 25.8 however their lipid profile was very comparable and that they also had very high HDL if memory serves around 60s uh and triglycerides under 100 so probably somebody like your what's your BMI if you don't mind my asking gosh put me on the spot here I think it's actually 24 25 maybe 25 oh really 25 okay anyway so yeah Pro but regardless outside of that age was matched 55.5 um ethnicity was perfectly matched risk factors were Incredibly Close A1C was nearly identical blood pressure was nearly identical uh C reactive protein all all were just

phenomenally close our group had an average LDL as I mentioned of 272 Mig per diler the match had 123 migs per Le so again right down toward the average right and interestingly our group before they gone on the ketogenic diet had almost identically the same LDL as this group had 122 what was the average in your group uh 272 so they had more than twice the LDL of this group and then here's the kicker how long had they been at these levels well our eligibility was at least 2 years the average in this group was

um 4.7 years nearly half a decade half a decade so getting back to the cholesterol years how is that verified how was it verified that 4.7 years yeah like each person just voluntarily says how long they've been eating that way or well that and they have to prove to us with their uh past cholesterol records their lipid tests so part of the eligibility for them to get into our study is they had to prove they had a hyper response so they had to have had an LDL below 160 before and it had to have changed

to at least 190 or higher so you rule out that it's genetic we also had genetic tests that help um confirm that they don't have monogenetic FH we did have one person excused because they did test positive for monogenetic FH but that's one out of a 100 so um they do the match and the match showed uh two important findings one is that there was no statis IAL significance between plaque across multiple metrics total plaque score let me unpack that a little bit how they do total plaque score is uh the reader goes through their

coronary arteries at 15 predetermined points and there are 15 points that typically accumulate plaque such as bifurcations and other bends of sheer stress Etc and give it a score between zero and three zero being no no Vis visual plaque of known quantity um one being mild two being medium three being um extreme and with that with as much as three in 15 points of interest the maximum score could be 45 uh This was done with both our cohort and with the other cohort so the total plaque score for our cohort was statistically non-significant and actually

trending toward it better there was actually less total plaque um in this group versus the other but I immediately follow up when I say that to still statistically insignificant so I don't want people to assume for sure that this group was doing better than this group just that if this was trending higher probably many people would say oh well maybe they are going really slow in plaque progression but probably they're getting closer to breaking out and heading in the other direction the other metrics um are not I believe presented by Dr budoff but he did

mention them is talk so I know it's public information other metrics such as total stenosis score segment involvement score and I forget what the fourth one is there's like four different metrics um they were all comparable to the to the total plaque score the other major finding is LDL how much did the LDL associate with the total plaque score there is no association with either group so you can actually see the sorted level average age average age was 55.5 what do you think about that bill is that because they the that group who adopted the

ketogenic diet they've done so was it four or five years uh 4.7 years trying to think what's the the if you look over a lifetime exposure area under the curve is there a significant difference between the the two well couple of additional things um so some of the individuals in Miami heartt are on statens about a third MH so about a third of those people in miam Mi heart are on Statin therapy so that is another factor to consider as to what their their numbers look like um in addition to the data that Dave mentioned

55% of the people in the keto group had a zero coronary artery calcium score 45% had a nonzero score so half of the people round numbers zero half people round numbers number higher than zero what I would be interested in longitudinally is for individuals that demonstrated some evidence of plaque versus individuals who demonstrated no evidence of plaque would those two groups behave differently with persistent exposure of LDL in the uh range that you said I think that could be a very interesting learning that goes back to what we were talking about before and that is

if we think that it's a combination of factors that affects an individual's trajectory in plaque progression then if you had nothing to begin with or you had something to begin with you might be uh moving at a different rate because what we we do know is that aerosis is not a linear process it doesn't just have a a single rate of change over time uh the initial rates of change are are a while in the coming and then as you have uh wall inflammation and other factors that are contributing to the progression of AOS sclerosis

it it very rapidly picks up steam in some cases so I think in addition to the data as presented it will be interesting to watch people over time and see if meaningful subsets behave similarly or different over time was there any thought of removing the people in the Miami Miami study that had were on lipid lowering drugs because they they were you know I'm assuming they were exposed to high LDL earlier in life higher relative LDL but yeah um couple things one my preference just in general would be to always exclude anybody on cholesterol loing

medication although there is a catch in that that also creates another potential confounder so for example let's say that let's say that I I was able to make that choice and I'll explain in a moment that I didn't have the ability to make that choice um if I could have said hey only pull from the pool people who did not adopt cholesterol loing medication there is potentially another kind of confounder that troduces which is non-adherence right so one critique that a lot of people put forward is that we have metabolically healthy break break that down

for me what do you mean so so non-adherence as in they're not listening to their doctor's advice because they know taking a Staten but but you have their average LDL in that group which wasn't that high you're talk you're talking in Miami Heart Miami yeah right but the point Dr crell is making is that it could be that their average LDL cholester draw was higher pre Statin as to what uh initiated their doctor giving them advice to take on Statin now you have this interesting issue which is that okay unfortunately there's now a healthy user

bias on those people who would choose to be on Staten if you exclude people who choose who would turn down their doctor's advice anyway then we might be pulling in people might other otherwise have bad habits does that make sense well I don't know to me it sounds like what you're saying is you'd be pulling in people who were perhaps advised to take statins and didn't take them and then I would expect to see that the average LDL cholesterol of that group now is higher than the 130 that you said yes but not only that

it might be that by doing that we could have skewed our Miami Heart population toward people who don't like to follow doctor's advice and therefore might have other bad habits involved but setting that aside what would have been interesting though just sort of to cut in is to remove the people that were taking the lipid lowering drugs and see what happens to the average LDL cholesterol and the people that it remain I agree but but a rightly so as the funer I don't get to go into their statistician and be like now I want it

done this way okay now do it this way now change this over this way we understandably have a limited amount of me being the representative of the citizen Science Foundation I have a limited amount of push post Hawk and again appropriately so I shouldn't be able to keep playing with the levers after the fact right um that said I myself am perfectly comfortable acknowledging all limitations I wish we all did on all these data right so in the case of it's possible that the lipid lowering therapy started them that they would have been higher possibly

earlier than that occurred 100% I don't want anyone to take the 123 at face value um directly but what I can say with some degree of confidence is this is actually a really good early set of data for what is the general population of what would otherwise be a decent match on metabolic health and what's commonplace for Staten use already that was part of what Dr budoff told me when I first saw this is I went hey why do we have you know a third of people using statins is like have you seen 55y olds

today that's actually extremely common in fact if anything um it's lower than the average for the general population probably because so many of them were in good metabolic health so Bill does I'm assuming not but does that being a cross-sectional study does that in any way change the way that you're treating now or are you interested by it and you know I guess paying attention to other studies that can be done to kind of answer some of those questions well I think it's good to collect data doesn't change the way I'm managing my patients talk

to us about the longitudinal study that you're doing well first of all I don't actually know that's that's being analyzed right now they have it out to a um they have it out to capture uh with I'm not sure if I'm able to say who the company is there's a company that does the analysis and I'm concerned I may tread into ground that I'm not supposed to discuss I'll just say that that analysis hasn't come back and I've had no internal preview or anything of of the sort again I want to manage everyone's expectations to

say what I've already said 100 times before at least which is expect that there's going to be an increase in plaque because any group of 55 year olds especially mostly male 55y olds even if they're in good metabolic Health are likely going to show at a population level an increase in pla there's no control in that study no because there's no longitudinal data on metabolically healthy people which I'm quite upset about Simon I wish that there was just I wish we just did that more often and it's unethical to randomize someone at this point like

would would any Ethics Committee approve a randomized control trial where you randomize some people to a ketogenic diet some to a higher carbohydrate diet look at the you know do a sub analysis on those that are lean mass hypers respond with full expectation you're going to turn some group into lean mass Hy responders or that they already were lean mass Hy responders you're going to turn a certain percentage of theman mass Hy responders like if you're Maybe I'm Wrong you think I don't think they would I mean because that's that's kind of the would you

say that's the perfect study to kind of set up it would be the perfect study because even even a scenario where we RCT let's say that I've got a lot of PLL with the community and I do have some right it's it's hard right now for me to talk them into an RCT on various lipid lowering drugs I mean after all that's kind of uh but let's just say we even did that the challenge then is the scrutiny on the whether or not the lipid lowering drug um that brought it down brought it down enough

for example and whether or not the community would adhere to it in the first place uh that said there is some discussion on that and that's a possibility that we might do something like that but I only want to do it if it can be truly double blind I I don't I kind of don't want to do an RCT where the population of our cohort is clearly and obviously aware of whether they're in the intervention group or the placebo group um and I've been kind of open about that what do you think about that study

design I I think it would be very difficult in the context of a randomized double blind Placebo control trial to try to get to a study design that would test that hypothesis I you're not going to get there yeah it's stuff yeah so what's it going to take then if we can't do that what's it going to take for clinicians to look at a lean mass hyperr and be I guess a little more certain in in what's happening under the hood can I sorry I not to cut you off but this is relevant you know

that we're working on a sister study though too we're setting up a second study that's going to be for this one which might be relevant to what your answer is but is important for me to mention here um but yeah so so literally uh Dr Cromwell was just now at a conference that we held to fund raise for the second study the sister study and it'll probably be a bit more relaxed criteria so we may actually get people who are already at uh moderately higher risk we haven't determined that criteria yet and it will have

an attached control group the catch is I doubt we can do an RCT but that'll at least provide a bit more data and with a moderately higher risk group in comparison to our current study so I guess is what the person's outstanding question is as to what my answer would be if your outstanding question is uh I'm not sure that high LDL is a causal factor for AOS sclerosis I'm not sure that if I'm metabolically healthy a high LDL is going to be a problem for me I choose not to want to lower my LDL

and I'm looking for data to suggest that people who have high LDL metabolically healthy do not develop athal sclerosis and therefore I'm good and I can have my high LDL I I think that's one group of people out there who have a question and and they're trying to get that addressed uh another group I think are people who are asking the question of over time what is the impact of high LDL in the context as Dave described it and what does it do in individuals who started out with a zero score or the presence of

disease and how do these two groups behave with longitudinal exposure to high LDL over time I think that could be an interesting set of data to help people better understand what is the natural history of the disease under these conditions because uh again two ways of looking at it if you have plaque you have disease if you have active disease you either shut it down or you let go I'm a clinician with 35 years of experience in this field and my heavy bias is I want to shut it down before it shuts you down I

I am and this is something Dave and I have talked about many many times I carry the burden of not wanting to incite harm first Do no harm is a critical tenant of clinical medicine if there is the potential for me to do harm because every data set I have in my hand says high LDL over over time has increased atic risk associated with it then I'm going to use that bias as a as a major selling point for not staying there now would the data support me well this is why we're collecting data but

in the absence of data to the contrary persistent exposure to high LDL and high apob is with consequence it is not inconsequential and just to clarify the data that you collecting at thus far is on healthy subjects that do not have a history of cardiovascular disease uh correct as in the eligibility criteria is I believe no prior diagnosis of aosc gratic cardiovascular I make that point and it kind of is me agreeing with your other point before where you were saying it's difficult to look at a study on General Public and then sort of generalize

that to yourself if you don't reflect the general public same sort of thing happening here I'm imagining if someone has a history of cardiovascular disease is thinking about adopting a ketogenic diet the data that you collect in your results are not necessarily generalizable to them which I'm up front of which I literally stated at the beginning of of the discussion look I'll make this I'll make this super easy right we've already published papers literally our very first paper uh includes a case Series where people titrate in a modest amount of carbohydrates in order to lose

lower their LDL right so if you are not metabolically healthy you have a BMI of let's say 26 and above let's let's go even higher let's say you have a BMI of 35 and above we just published a meta analyses that your lipid Levels by all the criteria Dr Cromwell would be interested in improve all of them the HDL go up the triglycerides go down and importantly the LDL goes down if your BMI is 35 or higher probably given our meta analysis this is a meta analysis of rcts 41 rcts now if it's BMI between

25 and 35 probably it moves marginally but almost certainly not by a a ridiculous amount in One Direction or the other right if you're below 25 BMI first of all you're probably more likely than not metabolically healthy more likely than not if you are metabolically healthy and you don't have some illness something for which you're using a ketogenic diet to treat it you're just you're just in on the trend but you're not comfortable with your high LDL our first paper published says hey here you go if you want to just bring back some of those

carbs use the principles of lip energy model and you'll see your LDL drop all right I think right now I've just covered about 97 98% of everybody considering a ketogenic diet we all agree on that right the one or 2% that's left over those are the ones that keep me up at night they're the one they're the it's the person who I'm I give uh you see how much I give caveats in this podcast imagine when I'm talking to somebody who has an LDL of 700 and they're saying I watch all of your talks I

listen to everything you say imagine what I say to that person I say this is Uncharted Territory just so you know there's uh existing like 99% of clinicians probably more 99.9 would say you need to take steps to lower this but they're likely telling me something like I have severe epilepsy it's so bad and I find that all these other medications are not working for me I want to take my chances I'm going okay we need to get this next study out just as fast when you say all these other medications you mean like with

bidic acid stattin lipid in medications that's what you're talking about yes although again this is where the conversation always turns to where I'm saying okay please consider chatting with Specialists please consider and and you have to understand I do still want to maintain my objectivity and not and not presenting a push in One Direction or the other the people I work with are more comfortable with nudging and that's because most of them are clinicians like Dr Cromwell so I'll repeat what I say over and over again here to them which is look my job is

just to get the data before it's worth your story definitely makes me more motivated to get it faster so I'm doing the best that I can I think the three of us can probably also agree that you know I hope that your study doesn't show increased progression or events because we need as many dietry options as possible for people and if there people are out there genuinely feeling better they're reducing their symptoms of whether it's bipolar or um alterative colitis it would be amazing that this is an option that isn't increasing their risk of cardiovascular

disease it's just that that's about that's a a lottery like bet I I wouldn't I shouldn't go that far but I'll just put it this way you randomly grab any hundred people of metabolic health and I don't I don't even care if they have super low levels of LDL the age is a big factor I'm sure you know this you just get up there into the middle age and you have a population that already has existing plaque I'm sorry if if almost half of them do probably there's going to be at a population level an

increase in plaque even if they are taking lots of steps individual level that's different an individual can seemingly arrest but it's it's you know it's Hit or Miss sometimes it's working sometimes it's not working working but I hope we can find some middle ground with people um and so I would not want somebody who has terrible epilepsy to have seizures right I I I wouldn't want that for them I wouldn't want somebody who has a very symptomatic bipolar to have uh a consequence that would make that worse at the same time I I would hope

that they would consider slight adjustments in carb intake for the purpose of blunting LDL that might be really really really high and see you know is there a way that we can have both at the same time the benefit of Keto without having the high LDL simply by reintroducing carbs or you know Nick is is very fasile with this he has lots of ideas of what you can do to you know kind of tweak the system and maros yeah well that's not I say more like pffas and things and things that that he has in

his toolkit that would you know blunt the LDL response but the idea of I have to stay on this diet with an LDL cholesterol a very high number whatever the number is and any reintroduction of carbs will undermine the benefit of my ketogenic diet I I don't know that that's true I I would be sensitive to the idea that just a little bit of reintroduction let's just give it a consideration yeah I think that's the pragmatic approach here yeah and and to be open to that as a possibility just a possibility be open to trying

it right uh in the absence of data that suggests that you know having that level of LDL cholesterol in that certain context is not problematic well to be fair again because they find me I am in regular discussions with a lot of these folks because I'm like this is this is another thing that just to get a little bit meta it shouldn't be me only it's actually very odd to me that we're starting up the sister study and we don't yet have another major study that's getting started yet by another team I I feel like

this is such a novel phenotype and really can provide us a lot of useful data around not just the development of atheroslerosis in this context but on lipid physiology overall and that's that's part of the challenge part of the challenge is it's slower than I would like although it's funny I talked to other researchers and they feel like it's going super fast um but getting back to these folks like in the case of Nick norwitz I knew him earlier on and I've seen how much this diet's actually helped him uh specifically that I get it

he had a very difficult time with I know that he he likes to pitch the you know the exciting aspects of the yor experiment but he had a very difficult time maintaining that for two weeks given what he has to what he has to put up with that the six weeks of the Statin even with the um the myalgia um was like a cakewalk compared to the Oreos and there are a lot of folks who found like a new lease on life and keto so I get it I get why from their perspective it's just

non-c compromisable it's been super interesting thank you very much um Dave is there anything that you want to add here before we close it out or build on or something that you wanted to say that we didn't get a chance to cover no I would I would say it's an exciting time I'm I'm very uh thank you for the opportunity to chat with you about this I really love that I was able to appear with Dr Cromwell I it's I'll share this I've shared it on my own channel before but it's been a delight to

me to see someone of his stature um really grock the lipid energy model because I feel like it's it's a direction to come and I'm looking forward to getting tested with stronger experiments ahead but um yeah I'm I'm also excited for what data we may be talking about in a year from now Bill anything from your end you know I think we we still need to think much more broadly about risk than just apob and LDL as important as is and I I'm a an apob card carrying lipidologist I'm not giving that up anytime soon

but I do think that uh as the guidelines have evolved there's a lot more emphasis on thinking about the individual who has the high LDL do you have plaque non-invasive Imaging what comorbidities do you have what risk enhancing factors do you have and I think that's just a nod to the fact that um we we need to be thoughtful about who the individual is we need to uh have a different conversation with people who have plaque versus no plaque we have to have a different conversation with somebody who's already had an event certainly uh and

as we're doing that I think we also need data to help us better understand what is the natural history of these individuals such as in Dave's cohort that are being followed because we don't have that data hand as we accumulate this data it helps us have a more informed conversation it really is I we've gotten to that point now where our patients deserve an informed conversation and we should have that with them well I think my goal has been achieved for the day you know I wanted to really wanted to better understand Dave's position and

I kind of wanted to facilitate a conversation in a responsible way have someone who's very esteemed in this area contribute and help unpack these things so I think we got there thank you very much for for coming thank you thanks for having us there you have it friends I hope you enjoyed this episode if you did and want to stay up to date with future episodes be sure to hit that subscribe button on YouTube and follow on Apple or Spotify finally thank you for showing up and the effort that you're making to take control of

your health I look forward to hanging out with you again in the next episode