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What if I told you that having extremely high
cholesterol levels doesn't always mean you're
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at high risk for heart disease. It sounds crazy
right? Well data from a brand new study published
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by our research team has just dropped and the
results... well they rub up against one of the
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biggest beliefs in modern cardiology. In this
video I'll explain what these one-of-a-kind
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groundbreaking new data mean, and what they don't,
why I am so excited, and what's to come. But if
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you want my upfront opinion on whether this
study could revolutionize modern cardiology,
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well I do, i really do. Now let me make that case
and at the end you can judge for yourself. Now,
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for context colleagues and I have spent the last
several years studying what happens to cholesterol
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levels in people who adopt a very low carbohydrate
diet, often called ketogenic diets because they
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put the body into a state of ketosis. Now most
people do not see increases in cholesterol
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on a ketogenic diet many even see decreases.
However, some specific people see their LDL bad
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cholesterol increase so high most doctors think
it's inconceivable. These special individuals are
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termed lean mass hyper-responders because they are
as a population generally lean and metabolically
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healthy, insulin sensitive. In fact our prior
meta-analysis of 41 human randomized control
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trials showed that the leaner a person is the
higher their LDL cholesterol tends to rise on a
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low carbohydrate diet. This prior meta analysis
also showed that having a BMI under 25 was five
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times as powerful as being in the top quartile of
saturated fat intake for predicting LDL change.
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So this is certainly far more interesting than
a blame the butter story. But that's a tangent
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back to the topic at hand in the current study
we followed 100 lean mass hyper-responders and
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near lean mass hyper-responders having a mean and
average BMI of around 22.5 kg per meter squared
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and a mean LDL cholesterol of 254 mg per deciliter
we followed them with coronary CT angiography and
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prospectively over one year to see whether and to
what degree plaque accumulated in their hearts'
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arteries of these individuals with exorbitantly
high LDL cholesterol remember the 254 that was
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just the average. Now the data I'm about to report
I know the suspense is killing you just hang in
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there they build upon a prior publication
where we compared the baseline coronary
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plaque scores of this lean mass hyper-responder
population with a matched population and found,
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in the prior report, strikingly that even after
having LDL cholesterol levels between two and 600
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for almost 5 years the lean mass hyper-responder
keto folk did not exhibit any greater total plaque
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score compared to a match control population
people with much much lower LDL cholesterol
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and in this prior report we also found
no association between LDL cholesterol
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and plaque score. But in this study that I'm
talking about now we report on the prospective
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data i.e. when we follow these individuals does
plaque accumulate in their arteries. And, if so,
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what predicts plaque accumulation finally the
results? The vast majority of participants
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exhibited no or minimal increase of coronary
artery disease and I'm sure this will capture
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headlines six participants showed decreases
in total plaque scores over the one year.
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You heard that right some participants appeared
to show regression. that said the median change
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in percent atheroma volume which is a measure of
how much of the coronary artery surface is covered
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in plaque was 0.8% pretty small number. This
reflects a level of progression that is expected
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with aging and is comparable to that observed
in other cohorts. So to be crystal clear if you
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ask the question are lean mass hyper-responders
on a ketogenic diet with very high cholesterol
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completely protected against heart disease the
answer is "no, of course not." But we must then
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ask what predicts progression of plaque is it the
LDL cholesterol or the associated bio marker ApoB.
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No, neither LDL cholesterol nor ApoB, I'll repeat
neither LDL cholesterol nor ApoB, were associated
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with plaque changes by contrast baseline coronary
artery calcium CAC score was positively associated
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predictive of changes in cardiovascular plaque.
And I cannot overemphasize how important this is.
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While some people did see plaque advanced what
predicted this advancement had nothing to do
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with cholesterol but rather whether they had
plaque at baseline. So simply put in a phrase:
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in this population plaque begets plaque but
cholesterol and ApoB does not. This finding
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will ruffle some feathers maybe even the whole
bird but these are the data. Now I want to delve
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even deeper into what this means in a nuanced
and hopefully responsible manner. While both
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LDL cholesterol and ApoB are independent risk
factors for aththerosclerosis the absolute risk
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associated with high LDL cholesterol or high ApoB
is context dependent including consideration of
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the ideology the underlying physiologic cause of
the elevations in these biomarkers LDL and ApoB as
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well as interactions with other risk markers like
markers of insulin resistance thus these data are
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consistent with the observation that high LDL and
ApoB among metabolically healthy populations has
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a different cardiovascular risk implication than
high LDL among those with metabolic dysfunction
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overweight, obesity, type 2 diabetes. And
it's worth emphasizing that the population
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at hand here lean mass hyper-responders and near
lean mass hyper-responders on a ketogenic diet,
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this population is distinct from any previously
studied population in several critical ways.
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First their elevations in LDL cholesterol and
ApoB are dynamic and a result from a metabolic
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response to carbohydrate restriction rather than
as a function of a genetic defect. These people
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aren't born with high LDL it is a response to
carbohydrate restriction having to do with energy
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flux through the body. Also these people are of
normal healthy weight a BMI under 25 generally,
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and metabolically healthy as a population rather
than living with obesity, pre-diabetes, or type 2
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diabetes or other insulin resistance disorders.
This is really important metabolic context and
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again the high LDL in ApoB in this phenotype, it
emerges as part of a lipid triad also inclusive
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of high HDL cholesterol and low triglycerides
representing a metabolic signature a metabolic
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fingerprint of a distinct physiologic state having
to do with fuel flux around the body. These points
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are worth emphasizing because unique populations
require independent study to properly characterize
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the risk associated with their metabolic profiles
furthermore this is the first and only population
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in which LDL cholesterol is independently elevated
without any clear underlying congenital genetic
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defect and outside the context of any
other notable metabolic dysfunction.
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Therefore the lean mass hyper-responder
population constitutes a unique and important
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natural experiment for evaluating the lipid
heart hypothesis in an unprecedented manner
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these data presented herein are consistent with
the notion that elevated ApoB even at extreme
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levels elevated ApoB and LDL cholesterol does
not drive aththerosclerosis in a dose-dependent
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manner in this population of metabolically healthy
individuals with carbohydrate restricted induced
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elevations in LDL cholesterol and ApoB I know
that's a mouthful listen back to it that is a
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critical critical point. However this doesn't mean
that the lean mass hyper-responder population is
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without risk and it should be emphasized that
this risk includes a diversity a heterogeneity
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in progression and even regression quite
astonishingly across the population however
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again the question that should follow is what
explains this heterogeneity in plaque progression
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and here we found that LDL and apple exposure was
not a significant predictor of changes in plaque
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whereas all baseline plaque metrics, including a
CAC score, were significant predictors of changes
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in plaque at this time we can only speculate
about the lack of association between ApoB,
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LDL, and plaque progression, and the mechanisms
driving progression in this population. Possible
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explanations include diet and health related
differences in lipoprotein lipid quality,
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and changes in kinetics, insulin sensitivity or
inflammation profiles as compared to the general
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population. Future studies will absolutely have to
be directed to assess these questions and compare
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these potential mechanisms but these insights
they can facilitate personalized treatment and
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risk mitigation strategies based on modern cost
effective cardiac imaging you have questions get
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an image of your own heart for instance despite
profound elevations in LDL cholesterol in Ap B
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based on these data lean mass hyper-responder
subjects with a CAC of 0 at baseline,
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which was a majority of participants constitutes
a low risk group for plaque progression even as
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compared to other cohorts with far far lower
LDL and apple. But by contrast those subjects
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with elevated baseline CAC scores possibly from
a history of metabolic damage and dysfunction
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prior to adopting a ketogenic diet they appear
to constitute a relatively higher risk group
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even where their LDL cholesterol and apple be
equal to their CAC 0 counterparts. So again the
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practical takeaway for you for me is don't guess
about your risk profile based on your lipids get
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imaging that makes the most sense the finding that
in this study plaque begets plaque could result
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from underlying susceptibilities in those with
greater amounts of pre-existing plaque or could
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result more directly from the pro-inflammatory
state associated with the coronary artery
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disease pre-existing. And more research will be
needed to identify the pathophysiology driving
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the progression of atherosclerosis in people
with higher levels of baseline plaque. There's
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always more to the story it's really interesting
story if I do say so myself. But what does all
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this mean. Well after following 100 people with
sky-high LDL on a ketogenic diet, we found no
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association between LDL or ApoB and plaque buildup
instead baseline plaque predicted future risk,
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not ApoB or cholesterol levels, supporting the
notion that in this population plaque begets
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plaque but cholesterol and ApoB do not. And if
you want my CTA no no not that CTA I mean my
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call to action although my coronary CT angiogram
actually does look pretty great anyway my CTA call
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to action is to encourage you to share this video
and the associated paper linked below widely share
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it to your social media link the video or paper
in an original post with your take your two cents
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and tag members of the research team myself,
Dave, Adrian leave a comment help us push for
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more deep discussions that transcend diet dogma.
Your contribution really does make a difference
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really in fact this entire clinical study was
crowdfunded by you which is a massive testament to
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the enthusiasm and power of the metabolic health
movement but before we part let me just say that
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science is a team sport. In fact it's only been
through the tremendous collective efforts of
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multiple teams including my friends Dave and
Adrian the generosity and support of Baszucki
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Group and Metabolic Mind and of course the team
at UCLA in the Lundquist Institute overseen
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by the principal investigator of this study and
cardiac imaging expert Professor Matthew Buddoff
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that this pivotal project was completed and now I
want to give you the chance to hear from my team
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members so here are some words from Dave Adrian
and Professor Buddoff. Stay Curious and thanks
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so much. Hi I just wanted to highlight from a
clinician's point of view why these results are
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so relevant because it can really be harmful if we
are confused about what causes black progression
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in a group of patients if we don't get this simple
question right we may chase the wrong mechanisms
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and implement the wrong treatments at the same
time when we think we already found an answer
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we stop looking and this could prevent us from
finding the real culprits of the problems in our
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body imagine someone who is coughing a lot and
we believe their cough is caused by an infection
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when in reality is caused by an allergy well we
may prescribe antibiotics and expose them to the
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potential adverse effects of a medication that has
no chance to help them at all ask any clinician
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not getting right your causes and your treatments
for an allergy is problematic but getting them
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wrong for cardiovascular disease is much much
worse another point I wanted to make is that we
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are confident about the associations we saw and
equally confident about the associations we did
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not see because as you know not because you didn't
see something means it doesn't exist sometimes
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scientific studies don't see statistically
meaningful differences because there was not
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enough statistical power but this is not the case
we are confident that neither ApoB nor LDL were
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associated with plaque progression and let me be
perfectly clear about this point because we did
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see plaque progression in some participants the
thing is that no matter how we sliced it neither
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ApoB nor LDL explained this plaque progression and
as a teaser let me tell you that we have another
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study in the making that will reinforce how it
can be problematic to rely in ApoB or LDL for
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assessing cardiovascular risk in patients with an
element phenotype i also wanted to highlight that
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the only thing we saw predicts plaque progression
is how much plaque there was in the first place
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and this is clinically relevant because it
emphasizes how important it is to assess
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cardiovascular risk in patients with an element
phenotype using modern imaging tools finally I
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just wanted to say how cool it is that a group of
curious patients and citizen scientists found the
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meanings and paid in blood for very clinically
relevant insights to everyone who made this
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study possible thank you and congratulations stay
tuned because as happens frequently in science
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the process of answering a question brings more
questions to answer and the amazing data that has
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already been collected has much more to give stay
tuned starting with an idea from a crazy engineer
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bolstered by a one-of-a-kind crowdfunded study
and finally rocket powered by a passionate team
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of innovators we finally reached the finish line
if you followed me from the beginning you know how
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long I had been asking even begging conventional
researchers to study lean mass hyper-responders
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and indeed this phenotype I identified 8 years
ago continues to defy expectations now these new
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data support it is defying the largest one of all
the expectation of high risk at a population level
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these new data show no correlation between
coronary plaque progression and LDL cholesterol
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even for those at the very highest levels is this
the end of the discussion no there's still so much
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to do we need to continue building on these data
with our coming study which is in development
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right now but with that said is this a giant leap
forward i think many will agree it is especially
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for low carb doctors and patients who will rely
on these data to better assess individual care
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make no mistake this victory is as grassroots as
it gets and I couldn't be happier that cameras
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were there to catch all the ups and downs of
the study as it happened in real time for our
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coming documentary The Cholesterol Code lastly
thank you to every single person who contributed
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their time money and effort to share and advance
this research we we couldn't have done it without
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your support in lean metabolically healthy people
on a ketogenic diet neither total exposure nor
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changes in baseline levels of either ApoB or LDL
cholesterol were associated with changes in plaque
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conversely baseline plaque was associated with
plaque progression supporting the notion that
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in this population plaque begets plaque but ApoB
does not i think it's important for patients to
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know whether or not they have underlying plaque
as if they do we might treat them differently
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for those patients with KD as compared to
those who have clean coronary arteries.
