Diet Doctor Podcast #9 — Dr. Ron Krauss

Welcome to the DietDoctor podcast
with Dr. Bret Scher. Today I’m joined by Dr. Ronald Krauss. Now Dr. Krauss is really a luminary
in the field of lipid research and he’s got a laundry list of accolades
with over 450 publications mostly in the field of lipidology. And he’s the director
of atherosclerosis research at the Children’s Hospital Oakland
research Institute, he’s a professor of medicine at UCSF,
professor of nutritional science at Berkeley, he’s been involved in development
of cholesterol guidelines, what was called the ATP program,
in the past, he was the founder
of the American Heart Association Council on nutrition, physical activity
and metabolism. He definitely has one foot firmly planted
in the cholesterol world and one foot firmly planted
in the lifestyle and nutrition world. And I think that’s one of the things that
makes his perspective so unique. Let’s be honest we can all kind of get
too entrenched in certain paradigms, one paradigm that all LDL is bad
no matter what, one paradigm that LDL
does not matter at all. And clearly I think neither one
is truly accurate into much more nuanced discussion and that’s what I really appreciate
Dr. Krauss’ approach to this and his knowledge. And let’s face it, I mean he was the pioneer in identifying the size and the density
in the different varieties of LDL cholesterol. So when it comes to understanding
the nuance and that not all LDL is the same, he is definitely the man to talk to. So we cover a lot of ground in this discussion
about LDL, about lipids in general and of course what it means to your lifestyle
and how your lifestyle impacts that. So sit back, get out a pen and paper,
there’s a lot to digest here, but I really hope you enjoy this interview
with Dr. Ronald Krauss. Dr. Ronald Krauss, thank you so much for
joining me on the DietDoctor podcast today. It’s a pleasure to be here. Now in the intro you’ve obviously been
around the world of lipids in lipid research and very proficient for a number of
decades. You’ve seen a number of changes
in the world of lipidology and the world of nutrition and lifestyle. And one of the things that I appreciate
most about you is that you were the founder
of the AHA Council on nutrition, physical activity
and metabolism and you’ve been very involved
in how nutrition affects lipidology. Give us if you can just a brief overview of how you’ve seen the sea of nutrition
and lipids in the interaction sort of change over the time
that you’ve been involved in this. Let me do that in the context of my role
with the American Heart Association. Early on I became involved with what was
called the Nutrition Committee that among other things set guidelines for heart disease prevention
with diet periodically. And one of my first exercises
was to update those guidelines when I became chair
of the Nutrition Committee. And I’d inherited a kind of a set of rules that were implemented over the years that emphasized reducing fat
and replacing the fat with carbohydrate. It was this low-fat method. This was not that long ago. Well, for me anyway, it was 20+ years ago. That was the prevailing recommendation. But at the same time I was doing research trying to understand the role of lipoprotein
metabolism in atherosclerosis as it’s affected by diet. And so one of the first studies
that I did to address that was to test the effect of the standard
low-fat high carbohydrate diet in a group of volunteers
who had a lipid profile that most of whom were normal
to start with. And it was really to see whether or not we
could improve certain features of a profile. We can talk about that
perhaps in a few moments. But what I found was to my surprise that
the standard low-fat high carbohydrate diet actually worsened the lipid profile
in a substantial subset of this population very strongly related to heart disease risk
outcomes, higher levels of LD particles and higher levels of triglycerides which is another risk factor
for heart disease. And it wasn’t a complete surprise
because looking back over the years others have shown that high carb diets
can induce a high triglyceride level and the effect on the LDL was really
what was quite surprising. And as a result of that
and further research that I engaged in to explore that mechanism further, I changed my views on what the proper diet
should be for heart disease prevention. One issue was individualizing
the approaches to people based on their metabolic profile. So there’s an issue of not everybody needs
the same diet. But for the overall recommendations I tried to move the Heart Association a little
bit further away from the low-fat approach and I wrote another set of dietary guidelines
five years later that reflected that. But that was like trying to move
a mountain, because the amount of investment
in that old message was so strong that there was resistance to doing that. Overtime I think with further research
if we can talk about, that approach I think has been challenged
by many others. And that change I think is now in play, although organizations
like the Heart Association and even the US dietary guidelines that are
charged with making public recommendations still up put a great deal of emphasis
on the facts out of the equation, beginning to be more concerned
about the carbohydrate trade-off. But I think it could be taken even further. Yeah, there’s a lot there and just in that
one statement that you made that these guidelines were already set
in place and believed to be true and yet you had research showing
not only was it maybe a neutral effect of what the guidelines were,
but a potentially deleterious effect. For a significant subset of population,
not for everyone, but enough people to be concerning. Right, and yet still they haven’t come
180, which you think they would
once the research came out, because once you’re entrenched
in the guideline like that, it’s hard to back out of that room
and change your tune. And then you have to look
at the overall evidence, not just about what happens to lipids
on various diets, but how do those diets relate
to heart disease outcomes. And I’ve been more engaged recently
evaluating the literature that addresses that. Some of this sure you’ve already
talked about in other contexts, but it’s clear that the evidence
that was thought to exist linking saturated fat in particular
to heart disease risk didn’t hold up very well when we looked
at the actual literature. There are issues about what one substitutes
for saturated fat potentially being an important factor. And there’s now more of us,
generally women, that the substitution of carbohydrate
for saturated fat, which was really what was a consequence
of the earlier guidelines… People were encouraged
to drop saturated fat and many times they were eating the wrong
kinds of carbs in considerable amounts. That approach I think has been shown to be
a factor in increasing heart disease risk– Increasing heart disease. So this amount of research
has really converged I think with a broader look at heart disease risk
and its relationship to diet, giving us a little more latitude
on the fat side. I think it still could go higher. And more attention
to the carbohydrate side with particular emphasis
on simple sugars. The total carbohydrate load
is still a matter for discussion as to how deliver recommendations for overall carbohydrate intake
to the population. There are so many nuances, I mean there’s the issue
of reducing carb itself overall, there’s the issue of using carbs
that are really whole grain and whole grain itself is something that
many people don’t even quite understand. The whole grain that works
is where the kernels of the grains like brown rice or whole kernel rye,
where you haven’t grounded up, that’s fiber rich source that is probably okay
for a number of health outcomes. But that’s not
what most people understand and they wind up just going
overboard on carbs and the one way of dealing with that
is just to tell them to drop the total carbs. I tried to get into what kinds of carbs. Right, the quality of carbs matters. It does matter. It’s very hard to convey that information
in a way that the public can implement. The food industry has not been
particularly helpful– I wonder why. Well, they were initially on board
with the low-fat message. That’s in fact what took us down… Took my predecessors down the path of
making incorrect public health recommendations and the food industry
was helping that along by providing high sugar low-fat products
like SnackWell’s and that was the classic example
of going the wrong way on the carb story to kind of educate people and the food industry trying to provide
the healthful form of something that food industry could market
is very difficult since most of what we are now trying
to promote in the current approach which meshes with some of the aspects
of the dietary guidelines is to think about foods and as much
as possible to think about foods that you don’t necessarily have to get
in the box. Because once the food industry gets involved
with packaging and processing things change and there isn’t a strong
advocacy on the marketing side for the kinds of foods
that carry a lot of health, the whole grain products, products that have the kinds of things
that you get from the vegetables and fruits, everybody talks about that. But when you go to get your food
in the supermarket and you get it in a box, it doesn’t necessarily have
the same qualities. But yet those boxes can sometimes say
heart healthy or gluten-free and low-fat. It’s very confusing. So talking about carbohydrates,
proteins and fats we should be talking about foods,
like you’re saying, they should come from the ground
like a vegetable, should come from an animal,
should not come from a box. And simple messages like that
sort of get lost. Yeah, and I think there’s more and more
recognition of that approach. But it’s very hard to deliver that
to the public in an actionable way, given our current distribution of food,
you know, where the supermarkets are and who can buy the groceries
and who can afford to buy for example fish, which is another thing that you think
adds value in the diet. These are all kinds of approaches
that are not always easy to implement for social and economic reasons. And it doesn’t help that age-old subsidies that have been helping promote
sort of the wrong types of foods and not the right types of foods
and that’s a whole another battle. That’s right, absolutely. I want to focus a little bit more
on the LDL. So you mentioned a study that you did
to help sort of change the tune of the AHA and the big concepts are –
are we following the right markers? Because anybody goes to their regular
doctor even their cardiologist and the first thing they want to talk about
is the LDL-C. Is that the right marker to follow? Well, it’s not the best marker. LDL-C stands for LDL cholesterol and that is the portion of the cholesterol
in the blood that is carried around in the blood
on particles which are LDL particles. So LDL-C is potentially a marker
for the numbers of those particles, but it doesn’t fully reflect
the numbers of those particles and it’s in numbers of the LDL particles
more than the cholesterol content that determines atherosclerosis risk. So traditionally over the years LDL-C has served as being
an easily measured laboratory test. I was involved when I was at NIH
for a number of years at the time that the LDL-C test
was actually developed. Most labs actually calculate it,
it’s not a super accurate measurement, that’s another issue, but it took hold because people were able
to use it in large population studies and in clinical trials and in the literature therefore is heavily
weighted towards LDL-C as sort of be-all and the end-all. Yet it’s the particles that matter and there are a huge number of situations
in the clinic, particularly in individuals
who have metabolic syndrome, which is a constellation of risk factors
that include high triglyceride and low HDL where LDL cholesterol
does not really reflect the true atherogenic potential,
the true cardiovascular risk, because in that syndrome there can be
an increased number of LDL particles, but they are small particles
which have less cholesterol and that’s really been the focus
of my research. It was identifying those particles and
showing that they are predictor of risk even when LDL cholesterol was normal. And so that’s a significant percentage
of population where LDL cholesterol
does not truly reflect the risk. And it can sometimes
over-represent the risk because there are a set of particles
on the other side of the spectrum that are large LDL
that actually have more cholesterol, but their association with heart disease risk
is really quite low. In fact there are a number of studies
which… People still don’t really register that there is really no obvious relationship
of those particles to risk. So some would argue
if you cancel that out by accounting for the number of particles
then the size has less of an impact. But I think you would disagree with that. Well, it’s how you frame the question. The numbers of LDL particles is a desirable
metric for heart disease risk and when the particle number
is elevated in general, that tends to be correlated with increased
levels of small LDL particles. The number of individuals in the population
who have high LDL particles based on the larger LDL is a minority. So when one measures LDL particles and
says the size isn’t important, well it is because those are small LDL
particles you are measuring, but what matters is not so much the size,
but the numbers of those particles. So people confuse those concepts
and to me it’s a relatively simple notion to say that the total number of LDL particles
is what one should be concerned about and that when the particle count is elevated
more often that represents his small LDL. When it’s elevated and they’re
predominantly the larger LDL is that usually
in the metabolically healthy person who has elevated LDL for some reason but not because they have insulin resistance
or diabetes or metabolic syndrome? Well, there is a category
in the population that fits the criteria
that you’ve just described and who not only have
a health metabolic profile in general, insulin sensitivity,
normal triglyceride levels, HDL levels are high, that’s another marker
of lower heart disease risk… that constellation can be associated
with increased levels of larger LDL particles. But here’s where it gets a little thorny because there are people out there
who have genetic disorders that cause their LDL levels to skyrocket. And that’s because the LDL is not being
taken out of the blood stream effectively. And those people can have
large LDL particles, but they are hanging around too long. And in fact the theme
that I’ve been trying to promote is an underlying concept to help people
grapple with these distinctions is atherosclerosis which is the basic
phenomenon that leads to vascular disease and heart events and strokes is built on the accumulation of LDL particles
in the artery wall. And if the particles in the blood
are circulating long enough, there’s going to be a greater tendency
of those particles to wind up in the wrong place. So it’s what we call the residence time. And the smaller particles have a long
residence time by virtue of their structure. And we don’t have to go
into the reasons for that, but it’s been well-established that they are cleared much less effectively
than larger particles, they hang around longer and that’s clearly I think in my view
and those of others a basis for understanding
why are they associated with risk. Well, if you have a defect
in the receiving end of liver– So the LDL receptors. The receptors are defective that can also
lead to increased circulation time and there are the LDL particle number
still is important, but they could well be larger particles. Because the defect is not in the particles,
it’s in the receptor. So that’s why I do what I do. Cardiologists such as yourself
interested in this field have a great role in helping
to elevate recognition of prevention through LDL and other lipid modification. Use of statins for example
was greatly enhanced by the involvement of the cardiologists
in clinical trials. The lipidologists can go
into a little more detail than is usually possible
in other clinical settings. Basically in part using the right kind of tests
that can distinguish these different particles and making clinical recommendations
on an individual basis. I see patients and I can make
generalizations and we’ve made some here
about large and small LDL. But I see patients who have large LDL
and I worry about them sometimes because of other factors… genetic– So if they have familial
hypercholesterolemia… Yeah, a family history of heart disease or if they have other known risk factors
I tend to take them more seriously and hedge one’s bets
and I say, “Don’t worry about this”. And in fact in the low-carb community,
your listeners, a significant subset of people would like
to think that LDL is not harmful at all, because after all the benefits
of low-carb diet are so strong even when LDL goes up which sometimes can go up rather high
in some of these patients, that that must be okay
because the people are healthy and their metabolic profile is good
and their insulin sensitivity is good, they don’t have any coronary calcium. So there’s this tension about extrapolating the kind of work that I’ve done
to an extreme saying that if you have this high LDL,
particularly if they’re large LDL particles, you don’t have to worry about it and I’m a little nervous about making
that recommendation to every patient I see. Sure, and that’s understandable and as a cardiologist I get nervous
into that setting as well. And a lot of it is just what we’ve been told
for decades and decades. But I think to be fair this population
is really underrepresented by the current literature
that’s out there. And we really don’t know that the LDL studies
have looked at standard American diets, have looked at low-fat diets,
have looked at general population, haven’t looked at this specific subset. And I think that would be so interesting, that’s the information we need
to say is it safe or is it not. Now until then we still have to decide
what to do that patient sitting across from us and that’s when we have to incorporate
the whole profile; their metabolic health,
the size and density of the LDL, their HDL, the triglycerides and
the other benefits they get from the diet and then make an individualized decision. But can’t say, “No, LDL doesn’t matter
forget about it”. And in the same token can’t say,
“Any elevated LDL needs a statin right now”. It’s more nuanced than that. You framed that perfectly.
I completely agree with that. That’s exactly the right approach. Are there other ways and things we can
do to try and get an idea of residence time in someone who doesn’t have–
or even in someone who does have FH? Because when you look at the FH subset,
you know, it’s not 100%, not everybody gets coronary disease
in their 40s and 50s and there’s some data suggest if you don’t,
you might live even a little longer. So how do we get a better sense
of residence time? The short answer is we don’t have
a good test for that specifically. In fact I’ve been talking to colleagues
who do studies of metabolic signatures using metabolomics on the aspect. We’re interested in identifying molecules
and the particles that might reflect their residence time and in principle I think there’s a reasonable
shot at being able to do that, but we’re way far away from even initiating
those kinds of studies. And so we are left
with at least for the small LDL individual. There I think the data are sufficiently
compelling to me that having an increased level
of small particles does implicate residence time as a factor. Now does small LDL tend to be a proxy
for insulin resistance and pre-diabetes, or can you see them also separated
from that? That’s another very good question. I hang out a lot with people who are
interested in insulin resistance, I’m actually an endocrinologist
by training, and I was very close
with the late Gerry Reaven who was the endocrinologist at Stanford,
who put that on the map, so insulin resistance does play
a central role in many of the manifestations
of the lipid disorders that we see; nitroglycerin high triglycerides,
low LDL, and it does contribute
to the small LDL trait. Having said that,
the overlap is not by any means complete because I tend to see a lot of patients in whom I can characterize
all these metabolic features. I can speak at least
based on that experience to the fact that there are people
whose insulin sensitivity is really very good but they have a genetic predisposition
to a small LDL trait itself, that there’s something
affecting lipoprotein metabolism that doesn’t come
through insulin resistance. In fact there is a larger proportion
of population I think who have the dyslipidemia. Those without insulin resistance in total, than those who are at risk because
they have some insulin resistance alone. This is metabolic fate, with small LDL
is really prevalent. We just did a study in healthy
but somewhat overweight and obese men and the prevalence of the phenotype that is
just they have mainly small vs large LDL was almost 50%. So as one deals with populations that are more representative unfortunately
of the average American in terms of body fat, waist circumference, these kinds of things
that predispose to insulin resistance. We’re exposing more
of the small LDL phenotype, but then in many of those individuals
when one tries to reverse it, and this is something we’ll be talking about
more in the talk I’m giving at this meeting, we can reverse that phenotype by reducing
carbohydrate or reducing weight or both. But there remains
a residual group of people who appear to be genetically hardwired. Fortunately it’s a minority. So the answer is
for the most part there’s an overlap, but there still are people who have an
independent lipid trait that needs attention. And is there any difference in outcome
between the two as you’re aware of? No, we don’t know, because we don’t have good integration
of detailed metabolic measurements with the kinds of clinical data
that are coming from outcome studies. The outcome studies rely on the high
throughput inexpensive kinds of tests and it’s even been hard to generate
enthusiasm for another test, which I think has a role in clinical practices
and it’s Apo protein B, which is a marker
in a number of number particles. That’s a pretty simple test to do and I’ve been an advocate
for at least taking that step if not going further into measuring
different particles themselves, but a lot of studies
don’t even have that measurement. And if they do
sometimes they don’t publish the results. So it seems that consensus is starting
to change certainly in the field of lipidology and hopefully in the field of cardiology, that LDL-P, ApoB are better markers
than LDL-C and that knowing the size and density
of your LDL particles is certainly helpful
to inform lifestyle changes. But yet it seems like most people
have to fight with their doctors to get those measured…
Why the disconnect? Part of the problem and I’ve been
indirectly responsible for this problem is the methodology and the nomenclature
that has been used in the clinical laboratory, because I actually introduced
the first clinical testing for this, which was electrophoresis procedure which was really
not completely quantitative. It was a way of getting
a semi quantitative assessment, but we’re talking about different kinds
of LDL in that measurement. But then there were a couple of new methods
including another one that I developed much further in terms of being able
to quantitate the numbers of particles. But they use different principles,
these methods. One of them is NMR, spectroscopy, my method uses something called Ion Mobility and we haven’t yet joined forces. So clinicians from the clinical laboratories
can be confused as to what is they should be measuring, we don’t quite know
what the targets should be because there haven’t been
really extensive studies to establish anything like targets, although now the guidelines for cholesterol
are an abandoned cargo anyway, so maybe they’re not needed,
which I tend to disagree with. Subsidiary books are confused in part
by the methodology and it’s also a little bit daunting to see the information that comes through
with these tests, because the way the reports are annotated
while they attempt to be helpful, the clinicians I think still leave
a lot of questions as to what this means. So what I’ve been doing is an N of 1
and others have been doing it more broadly but whenever possible as you keep people
in these tests. And once they get a feel for it, I think
it becomes much more attractive to them. In fact when I first discovered
that the worthy subclasses– it’s been now 30 years ago actually, I face a tremendous amount
of assistance among my colleagues. It took about 10 or 15 years,
believe it or not, of hammering away that this even exists, because people were not able to see it
in their own laboratories. I had this very, what they call “esoteric”
at the time. Some people still call it esoteric
methodology and they weren’t doing it themselves. What happened was as the methods
became more accessible and other people started to adopt them,
they said, “Wow, this is obvious.” Right. And now it’s in the textbooks
and I didn’t even get a credit for this. You fought the battle for a decade. I fought very hard for this and I feel that
I have at least gotten the small LDL trait as part of metabolic syndrome
and insulin resistance some and established that now is in the Bible. I guess one of the other arguments
is someone say it’s an added cost without a clear added benefit
beyond non-HDL cholesterol. Because you’re talking
about the whole population and there’s probably a subset
where that may be true, but it seems like there’s a huge subset
where that still is not true, that people just don’t recognize. Well, again it’s hard to talk
about the population as a whole based on my experience
or anything even in the literature, because in my case I see people whom these other measurements
don’t adequately define risk and on the science side I sometimes have to deal with people who make all their clinical recommendations
based on the list patient they saw or anecdotal evidence
and I think there are problems there. However my anecdotal evidence
which I would give more credit to is that there are people come in
and I just saw one last week whose father had an early heart attack,
his lipid profile was small LDL and the lipids were perfectly normal. And in fact it’s been very difficult
to reverse that trait without medication. So that’s an example which I think is not
uncommon of a genetic underpinning that’s messed by standard lipid levels. And there are people out there like that
picked up at a standard lipid test and who should be intervened on. Family history can be helpful but not everybody
has an informative family history. It’s not the greatest clinical test. But there’s another test by the way
which I think deserves mentioned, that is part of this overall assessment,
called Lipoprotein (a) or LP(a) which is another form
of LDL type particle in the blood that has a very strong genetic
determining factor. And what we found
is a combination of people who have a role to the high level of this
LPA. And we think may be
as much as a third of the population that has levels that potentially
would increase risk of heart disease. If that’s coupled with small LDL
and there is any kind family history at all, people are dropping dead of heart attacks
in their 50s. But these are not picked up
by the standard lipids– Not picked up
by a standard LDL-C or LDL-P, but this informs you a little bit more
about the type of LDL that’s there. Well, LDL-P can help, but it’s still not
as specific as the small LDL measurement. Right, so LP(a) tends to be a little
more pro-thrombotic potentially, pro-inflammatory and– does it also have
a higher residence time as well? Yes, it is very slow clearance
by the LDL receptor and it tends to get oxidized easily which is one of things
that happens to small LDL as well that makes them more toxic
to the arteries. So a very important test to measure. Now the traditional teaching
is you measure it once and there’s really not much to do about it
in terms of treatment. Now of course there’s research been done
with these antisense RNAs, but for the time being
do we have much to address it? Not much. One of the treatments that is currently
out of fashion, nicotinic acid, can lower LP(a), but the argument against it is we don’t have evidence
of lowering LP(a) with that is beneficial. Some of the new approaches,
this anti-PCSK9 antibody that is used in high risk patients
can lower the LP(a). It’s one of the more attractive features although you can’t get insurance people
to cover it for LP(a) lowering, it’s not a bona fide indication. But you’re right, without exception for the most part LP(a)
is relatively fixed genetically. The value of it and I believe there is value
at this meeting is to give a broader picture
of the overall risk particularly in the context of situations
where you’re not sure whether one should be
aggressively lowering LDL for example. So this brings in the concept which– I will take a few seconds to emphasize this
absolute risk versus relative risk. So LPA increases the risk of heart attacks
when it’s elevated by as much as a factor of threefold,
but it’s pretty powerful. That’s relative risk. But you’re multiplying that relative risk
by the absolute risk overall. And so if the absolute risk based
on every other measurement is very low multiplying that by three
is still going to give you a low number. If it were zero, it would be zero. So what we do I think justifiably is to be more aggressive in lipid management
and risk management in general to lower the absolute risk in patients who have high LPA
and a strong family history. In my experience again
I’ve been doing this a long time and I have patients whose siblings
dropped dead or had a stroke in her 40s who had high LP(a) and I’ve been treating
them and they are now in their 70s. I think we have found a way
to overcome that genetic risk. That’s a great point to bring up
the relative versus absolute risk reduction because that’s something that confuses
people and confuses clinicians as well. Partly driven by Big Pharma I would say. Absolute. They love to promote relative risk,
it’s a sexier number, a more catchy number. A 50% reduction in risk…
isn’t that great? If the risk is here,
that 50% is small. So it doesn’t just apply to drugs,
it applies to lipid markers as well. Now interestingly,
I have to throw this out there… Up until a couple of weeks ago I thought LP(a) was something
you could not change with lifestyle, because it was genetically set. I don’t know if you’re familiar
with Dave Feldman at and his colleague Siobhan Huggins. She did an N of one experiment, which take it for what it is,
an N of one experiment, where just changing
her dietary consumption she was able to see a huge swing
in her LP(a) which was shocking to me and I hope there’s more
coming on this topic because it’s traditionally been taught
you can’t affect it with lifestyle, but here we have some evidence
that maybe you can. So there are two features of that…
I wasn’t familiar with that particular story but there are two components there
that I think are relevant. One is– in fact I published on this… a way back to the traditional
low fat high carbohydrate diet which was supposed to be good. It can raise LP(a). So LP(a) can go up with high carb
so the converse can be true as well, there can be some reduction. It tends to be relatively fixed
i.e. the changes in general are small, but they are in the direction that if you go
on this kind of diet with dropping carbs, that you may have some benefit. But the second component is genetics because there’s at least
50 different genetic subtypes of LP(a) and there are some
that are more responsive to X and others that are unresponsive. There are some that we follow over time
and they go like this and they go up-and-down and there are others that are rock-solid. So there’s a genetic component. It’s one of the keys, one of the prime examples
of a complex genetic trait that is very difficult to dissect
on an individual basis. We don’t have ways of knowing
who has which genetic markers and how is that going to respond to that, but this may be part of the story
for that N of 1. Good point. So one other marker I wanted to bring up… Or I guess more than just a marker,
is ratios. Because we talk a lot
about individual markers and there’s also an importance of ratio. So I talked to Prof. Andrew Mente
with the PURE study and one of the most interesting things
about the PURE study was– again it showed LDL-C is not
a very good marker for cardiovascular outcomes and a better marker was
to ApoB to ApoA ratio. And that was really the best one, but again
not one that gets measured very often. So how do you see the role
of ApoB to ApoA ratio? I think it has a lot of merit, because the numerator is a measure
of number of LDL particles. In fact overall, not just LDL, but all
of the atherogenic ApoB containing particles. That’s good. The denominator is reflecting a protein
that is responsible mechanistically for the benefit that has been attributed
to HDL and heart disease risk. We can get into ApoA
versus HDL cholesterol… It’s another example where the HDL
cholesterol it’s taking us down the path where that marker is not so informative because it’s not necessarily
reflecting something that can be reflected by ApoA1 specifically. So the ratio of ApoB to ApoA1 I think
has merit as a risk assessment tool. In fact the ratio of HDL cholesterol
also works pretty well as a risk marker. The problem is that we can’t necessarily
translate that risk marker to a target of treatment. If you start treating a ratio you get into some potentially
very inappropriate outcomes trying to resample raise the HDL
has been shown… HDL cholesterol has been shown to be
relatively… in fact completely ineffective. Completely ineffective. Despite the fact that low HDL
is a risk factor. Well we don’t have the same confidence
in ApoA1 as a measurement in ratio. It’s reducing that ratio by raising ApoA,
is that going to be beneficial? One would like think so,
but we don’t have the evidence for that. So I would put those ratios
in the category of good markers for risk, but not necessarily using them,
the ratios themselves as targets. And that’s another great point
to bring up to differentiate targets on treatment
versus targets with lifestyle changes. Because there does seem to be
a significant difference. You can target the HDL with CETP inhibitors which have either increased risk
or being totally neutral. So clearly the drug manipulation of HDL
is not beneficial, but the nutritional manipulation
and the lifestyle manipulation theoretically should have
a different impact. Well you are doing the right things to risk
by a proper lifestyle intervention, and that could be reflected by these ratios,
by measurements approving, absolutely, whether they are markers
or whether they are actually involved in delivering the benefits
of those interventions, we don’t know, but they go along with the territory. For example we showed years ago one of the earliest studies that was able
to show changes in HDL was looking at the effects
of physical exercise. Peter Wood at Stanford
was the pioneer of that work and we were collaborating with him. In fact when he learned
that exercise could raise HDL levels he convinced me to go out and start running. I was actually very sedentary
up until that time. And I decided,
“This is going to raise my HDL.” And of course in retrospect it’s probably the running and
that raise of the HDL that was beneficial. But no, you’re right, that axis of working on a metabolically
healthy nutritional lifestyle intervention, when it causes changes in these markers, I think it’s more or less a reflection
of the benefits of those changes. Yeah, because one of the changes
is increase in fat in the diet and specifically saturated fat can
dramatically improve the ApoB to ApoA1 ratio. Yeah, you have to be careful. Yes, one can do that or can keep
the ratio high if it’s high to begin with and that has also been shown in people that you can raise the ApoB
and the ApoA1 together. Our studies, when I look in the literature,
would suggest that’s probably benign, but we don’t know for sure
if that’s true for everyone. So we touched on HDL here a little bit
so I want to talk a little bit more about HDL. So when people have an elevated HDL level
whether it’s, you know, 70 to 120 and it’s naturally elevated,
not on any drugs, would you count that as a beneficial effect or would you say we need to know
more about it? Do you want to know
if it’s the specific HDL too, or do you want to know
what their ApoA1 is or some greater assessment
of HDL function rather than the absolute number? Well, there can be a measurement, there is actually a management
of HDL function that does appear to reflect its benefit on cardiovascular risk,
atherosclerosis development and that is the ability of HDL to promote
the efflux removal of cholesterol from tissues and particularly
the cells and macrophages that would lead
to plaque development and progression and there are tests that are being
developed and a lot of that have to be measured, those you’re not clinically out there,
they are more for research purposes. And what we’ve been trying to do, what many people have tried to do,
including myself, is to try to identify a particular
measurement that we can do in the blood of a more standardized nature that
doesn’t involve having to go into the lab and use cells and culture. And it hasn’t been a clear match,
so making a shorter answer, we really don’t have a particle
that we can identify. Having said that I will take credit
for one other thing that was sort of lost in the literature. I was never convinced that HDL
had a beneficial role at all. I felt that what we were seeing
and in fact this is still largely true, people who have low HDL also have
small HDL, triglycerides, insulin resistance and I thought low HDL was a marker
and not causal. Well, this was an era where we were just
starting to make transgenic mouse models and my colleague E.M. Rubin and I
took a mouse model of atherosclerosis and expressed the human ApoA1 gene. So were able to jack up the A1 levels
and make human like HDL. And guess what?
They had less atherosclerosis. So that actually convinced me
that there is potentially an important role for this pathway if you are increasing
ApoA1 availability. That’s probably the best way to reduce risk
from the standpoint of HDL raising and maybe measuring ApoA1
is a good reflection of that, but it’s really the dynamics,
it’s the production. So that’s been a holy Grail in the Pharma which has not yet yielded a drug
that has that effect. So it’s still I think kind of undeveloped
as a potential path to be able to pinpoint
what it is that reflects that quality. It’s doable,
we just haven’t gotten the answer yet. So it seems like it’s clear that a low level
is an increased risk factor based on Framingham data,
based on all the observational data we have that actually a low level of HDL
is a better predictor than a high level of LDL but maybe the higher level of HDL, there’s some sort of subset and
differentiation we still need to make. Yeah, but a low level of HDL
is a risk factor, I’ll come back to the point, that when you start introducing
measurements of small LDL for example, remnant lipoproteins, which is another class
of triglyceride particles that are atherogenic, high levels of those particles tend to travel
with low levels of HDL. So again we don’t know how much
of the risk that is attributed to low HDL is due specifically to low HDL,
something probably is, but a lot of it may be related
to the co-conspirators that are part of this syndrome,
the metabolic syndrome. Which brings us back
to these low-carb hyperresponders with naturally high HDLs
in the 80s and 90s, naturally low triglycerides
in the 40s, 50s and 60s and then the LDL cholesterol above 200,
the LDL-Ps in the 2000 range and… it is unchartered territory with, you know,
things coming from both sides. If we have a conversation
maybe two years from now, maybe we will have completed a study
that I’ve been really anxious to do and in fact I am talking about developing, where we at least look
at the cause of that hyper response. Is it production, is it clearance? This is in fact the residence time in which these particles are just sailing
through and causing problems. Maybe they’re going the other way,
maybe they’re coming back. Right. But these are all kinds of questions
that have been out there which had been more or less pure fantasy
because we don’t have the data. So I think it’s one of the more interesting
questions that I’d like to address. But having said that,
I think as we talked about a moment ago, there is a subset of individuals
who have this trait who for all intents and purposes look like
they’re not going to develop coronary disease at least over the short-term data, no family history,
there’s nothing else genetically going on… And this high LDL-P response may be benign
in a subset of those individuals. We just need to know they are. Right. One thing that’s so interesting is a number
of physicians when they see these people they want to label them as having familial
hypercholesterolemia and throw them on a statin right away. And that shows the failings of just
wanting to hang your hat on one biomarker instead of realizing FH is a is a constellation
of symptoms, diagnosis, family history and physical exam findings. That’s one interesting feature. If you have one of the FH genes,
if you’re heterozygous for FH, you may go through life with high LDLs
and never have any problems at all. There are families like that. And so it’s not always
a marker for high risk. Homozygous FH, where you have two genes
and you have super high LDLs, that I think is a different category. But there are people who– It gets back to your point,
just based on the LDL alone, even in those patients may not be sufficient
for assessing the risk. So how else would you assess the risk? Would you use calcium scores, CMT…
what other tools do you have in your toolbox? Well, calcium scores I do use
in situations like that. I don’t use them a lot routinely, but if there’s any question
that a patient presents, either genetically or on a low-carb diet
with a high LDL-P and with what looks
like an otherwise metabolic profile, I do use a calcium score as a way
of helping me to stratify risk, because sometimes there’s some people
who do have some calcium, in those I go after it. If they don’t, it doesn’t necessarily give
them a clean bill, because after all the calcium score
is just measuring the outcome of a plaque that may have already healed. It’s not measuring the cholesterol
in other parts of vessels that are parts of plaques
that could become inflamed and rupture. So it is not a perfect test in that regard. But if there is a negative family history and you can look at triglyceride
and HDL small particles, if none of those things apply, it gives me much more confidence to agree
with a patient who usually is coming in saying, “I don’t want to take a statin.” They come in and say,
“I’m ready to take a statin. I’m interested in taking a statin.” I usually don’t argue against that, honestly because I can’t be convinced that is safe
that they don’t need something. But if I feel that I could support the patients
to avoid statins– Particularly, for example in young women
whose absolute risk is so low to start with, I just worry about that
because one of the things, and I don’t want to over emphasize this because
it sometimes can be blown out of proportion, but my major NIH grant right now is to address the basis
for adverse effects of statins. So we’re studying the mechanisms by which
statins can promote muscle damage, myopathy, as well as increased blood sugar levels
and increase insulin sensitivity and diabetes. These effects tend to be written off
by many cardiologists who say, “The benefit is so great that
this effects are not worth worrying about.” But if you take an individual
whose risk is already low and who is not necessarily likely
to get a huge benefit of statin, like again a young woman and we know that the risk of developing
diabetes is actually higher in women than men we may be tipping that person into a worse
metabolic state by prescribing statins. I don’t want to over emphasize that
because people are scared of statins. This is still a minority of the population, but we like to find ways of identifying
people who are susceptible to those effects so we can advise them in advance. That’s another goal that eventually could lead
to better personalize medicine. Yeah, such an important statement about
weighing the risks and the benefits and you made a comment
that so many physicians say, “The benefits are so great
you should just take it.” Well, are the benefits that great? Because that’s when we get
into the relative versus absolute and what baseline risk
are we starting at? That’s right, the patient population
matters a lot. I think there’s no doubt that for patients
who have had cardiovascular events that the clinical trials strongly support
the benefit of statins use. It’s this sort of intermediate group that looks like they may be at high risk
or borderline risk, who have not yet had
any cardiovascular events, that create the quandary for deciding is it going good be more or less harmful
to prescribe statins? That’s where this CVD risk calculator
comes into play, where you type in their age,
whether they have hypertension, diabetes and what their LDL and HDL are
and it spits out a number and based on that number
you’re supposed to treat. But it doesn’t involve inflammatory
markers, it doesn’t involve any of the more advanced
testing you talked about, whether ApoB or small density or LP(a). It doesn’t involve any of that.
It doesn’t even involve triglycerides. Yeah, and it has
a wide margin around it. So again this is the product of the role
of epidemiology and public health which likes to look at population data and
give numbers that apply to populations, but that population-based risk assessment
has a wide variation around it and if you’re dealing with smaller
and smaller numbers of individuals and if you go doing an N of 1,
you don’t know where you are on that. So I am not a huge fan… I mean I endorsed
thinking about absolute risk, but I try to integrate more
than just the standard test. Yeah, it makes sense. Dr. Krauss, I think I can speak with you
for hours about lipids, this is fantastic, if I knew I have to get you downstairs here. So tell us what’s on the horizon for you and where can people learn more
about you and your work? I do have a website which is reachable
through Children’s Hospital research Institute at UCSF actually
I have an appointment there. So people can find what my laboratory does and the kinds of papers
that I’ve been involved with. That’s probably the best way. I get people who hear about me
through the social media and they find me and my web,
so that works pretty well. Okay, very good. Thank you for taking the time today,
it’s been a pleasure.

17 Replies to “Diet Doctor Podcast #9 — Dr. Ron Krauss”

  1. Dr. Krauss any declaration of conflict interest and who is financing your studies….look at your abdominal adiposity before your tell people to consume complex carbohydrates which still spike the insulin and get people to get this abdominal adiposity. If you really believe in your research your fat belly should be gone…..

  2. At approximately the 25 min mark Dr Krauss mentions that the subset of people with the phenotype of numerous sdLDL that are healthy without metabolic syndrome outnumber those with numerous sdLDL with insulin resistance. I find that hard to believe. As I listen to this I hear Dr Joseph Kraft asking how this can be since over 50% of adults have the phenotype that overproduce insulin to control blood glucose. I am wondering if Dr Krauss might have that reference to the work he is quoting? It would be interesting to see if there was an overlap in the population he is referencing that just might be hyperinsulinemic and not identified as such. It reminds me of Dr Phinneys work in that he established that any study that doesn't allow for keto-adaptation is not a fair representation. It seems studies that decide that a study population has high sdLDL but are healthy and not insulin resistant cannot be considered as such without a kraft test to rule out that they truly are healthy and not closet diabetics.

  3. With so much genetic testing available.. is there a benefit to know if one has a single (hetero) or two (homo) copies of the familial hypercholesterolemia (FH) gene variation?

    I understand small LDL particles and lp(a) tend to have longer residence-time, and so measuring the number of particles (either by LDL-P or APO(b)) is a better CVD metric since small particles are usually the ones proliferating.. however, what does a good lipid panel look like? For example, what does Dr. Krauss like to see for ApoB/ApoA1?

    Also, would have loved to have heard his thoughts on niacin. it seems to move all the numbers in the right direction.. preferentially lowering small LDL particles, lp(a), and triglycerides, while raising HDL-C.. yet is it actually effective in reducing CVD mortality? For example, perhaps its raising HDL without using APOA1? And unlike PCSK9 inhibitors that inhibit the PCSK9 protein from killing the livers LDL uptake receptors, perhaps Niacin lowers LDL via some other mechanism?
    (BTW, there's an interesting Niacin book that talks about the work by Abram Hoffer.. suggesting niacin can help with everything from CVD to bipolar and schizophrenia disorders!)

    What about the role of Vitamin K2? Does calcification happen independent of cholesterol oxidation/inflammation/rupture.. i.e does adequate K2 levels only prevent atherosclerosis that was caused by calcium deposits.. not by cholesterol deposits?

    Finally, regarding the balancing act of whether or not to prescribe statins due to its upside in high risk patients, versus the side effects (muscle damage, diabetes) for those not in high-risk.. what about dementia? Isn't there also a danger in reducing ApoB and lp(a) so low that you block (Bloch pathway) in the Cerebral Spinal Fluid that converts desmosterol into cholesterol?

  4. Spoke of a result of a N=1 result where someone was able to dramatically effect Lp(a) with lifestyle intervention. What was the intervention ? Diet? Please specify?

  5. Dr Krauss is a Giant in the field of sorting out all the confusion and misinformation surrounding the risk of Cholesterol. He pioneered the techniques that enable us to measure lipoprotein number, size and character, taught us all what really causes heart disease (Particle count and size distribution) and he deserves a Nobel Prize. You can take what this incredible physician says to the bank. You'll live longer if you do. Thank you Dr. Krauss!!!!

  6. I'm surprised that, at the time of this podcast being uploaded (Dec. 2018), Dr. Krauss is still referring to "whole" grains (whole-schmole or otherwise) as a healthier form of carbohydrate. We, as humans, have no business consuming the seeds of grasses. Grains/wheat, etc. are extremely inflammatory to our bodies, and thanks to Big Food and Agribiz, there is virtually no such thing as a naturally occurring "whole grain" left on the planet, anyway. Additionally, in some cases, their conversion to glucose in our blood is as high, or higher, than table sugar. WARNING: Eat grains at your own risk!

  7. I love the information and expertise of Dr K but what a dichotomy. Obese expert guest, lean healthy host. Makes me scratch my head a bit. Physician heal thyself.

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