people with low cholesterol have a higher chance of dying. this confuses a ton of people
on social media including doctors but the explanation is not that complicated and it
teaches us a lot about cholesterol and about how to make sense of these contradictions in
general so let's crack this. a recent study looked at a large population in Denmark
and found that people with very high cholesterol levels have higher risk of dying
and interestingly people with low or normal cholesterol also have higher risk of death
the lowest mortality was at 140 milligrams per deciliter of ldl-cholesterol which is quite high
the normal range is usually under 100. so this is what's called a u-shaped curve
because it kind of looks like the letter u. now, of course on social media this study unleashed panic
with people saying low and normal cholesterol is lethal and we want it high but not way too high so
let's take an objective look at the evidence and what it means. first, is this an isolated result?
is this study a fluke? no. in fact this u-shaped pattern has been shown many times, it even
has a catchy name: the cholesterol paradox. here's another study, in a korean population
almost 13 million people, massive, and they found a u-shaped curve between cholesterol and mortality
there it is. mortality goes up for very high cholesterol and also goes up for low or normal
cholesterol. okay so if this is reproducible, it's a legit phenomenon, what does it mean? low cholesterol
could cause death as many people on social media assumed. what's wrong with that conclusion?
why can't we just assume that and case closed? because of the type of study we're looking at
some of you are familiar with the three bags of scientific evidence, bag one is lab experiments in
test tubes or mice. bag two are population studies like the two studies we just looked at in Denmark
and korea, you look at a given population in a city or a country and you look for parameters
that tend to coincide, that tend to co-occur in the same people, in this case low cholesterol and
death. these are also called observational studies because we're just watching what happens, we're not
intervening, we're not causing any change. but the catch is that many things can vary because
this isn't a controlled lab experiment, it's an established population living its normal life
with an entire history. people with low cholesterol could eat different diets, have different
lifestyles, different diseases, a million things. same is true with high cholesterol, by the way
we can't jump to a conclusion there either from this type of evidence alone, we covered the high
cholesterol side before, with the different levels of stronger evidence. so these observational, bag 2
studies tell us that low cholesterol and death tend to co-occur, tend to happen in the same people
but these studies can't establish what causes what, the causality, the chain of cause and effect
is unclear. low cholesterol could cause death directly as we said, that's one possibility, or
something else, some other variable could cause both low cholesterol and death. okay, that sounds
kind of far-fetched. some random thing is gonna lower cholesterol and separately causes death? how
convenient. but actually it's well known that for example people with some types of cancer
often have lower cholesterol levels. it seems tumor cells suck up a lot of cholesterol. they've
even shown that after chemotherapy when cancer goes into remission cholesterol goes back up and
it's not just cancer, people with gastrointestinal diseases like inflammatory bowel or with chronic
liver disease can have lower cholesterol as well, so in several chronic disease states
it's common to see lower cholesterol levels so we got our two basic models herem we're going to try
to figure out this mystery, maybe low cholesterol is really bad, unhealthy and causes death
or maybe low cholesterol happens to be there in the same people at risk of dying
but doesn't actually cause death per se, very different implications so how do we figure out
which one is true? how do we figure out who's the killer? one way is to look at
people on cholesterol lowering medication like statins. if low cholesterol is itself the killer
then any means of lowering it will cause death so these poor bastards having their cholesterol
pushed down by medication should die more but if low cholesterol is just an innocent bystander
caused by disease, maybe, then artificially lowering it with medication should not cause death. the
recent study from denmark looked at exactly this question. people on statins did not die more
even when they had lower cholesterol levels, they did not show that characteristic
u-curve unlike the general population and unlike people who were not on statins so low cholesterol
itself is not the cause, it has to be a specific context. okay, time out. how do you know i'm not just
making this all up, why would you just trust me on this? well, you don't have to because the authors
of the study say it themselves: "our findings indicate a non-causal association", meaning it
doesn't seem low cholesterol itself causes death, and "it would be incorrect to use our data as
argument against lipid lowering treatment in prevention of cardiovascular disease
and mortality" and finally "our findings support the hypothesis of a decrease in cholesterol because of
debilitation and illness" so they're arguing for the innocent bystander model, that cholesterol
goes down because of some underlying disease and it's that disease presumably that causes death,
not low cholesterol. you'd be surprised how often this happens, there's a media storm and panic
over a new study and all we got to do is actually read it and the authors themselves often explain
the misunderstandings. okay but this so far is just suggestive, it's circumstantial evidence so
let's keep investigating. here's another way to test the two models: if this innocent bystander
scenario is correct and cholesterol drops in some people because of some underlying chronic disease
like cancer, then we should see that drop over time and those people could be in trouble but
people who have always had low cholesterol because of genetics or lifestyle, they should be fine, they
should not be at higher risk of death. on the other hand, if this innocent bystander model is wrong
and low cholesterol is itself the killer then it shouldn't matter, whether you dropped to low or
were always low either way you're in trouble. that's exactly what this study looked at, they
found that people who started out with higher cholesterol and dropped the low levels over
the years, that group also coincided with higher risk of cancer and liver disease
and more death but people who always had low cholesterol didn't have those problems so the
problem isn't having low cholesterol, it's specific to the drop and it's not any drop because we saw
in the other study dropping with medication is not a problem. the issue are drops that are unexplained
and that could potentially be caused by underlying disease. as the authors explain, "our results support
the hypothesis that low total cholesterol appears to be a manifestation of tumor activity or the
consequence of chronic liver disease". alright, very interesting but it still feels a little
slippery, it doesn't nail it and that's because everything so far is still from bag 2,
observational studies. we're still just looking at associations and inferring. so this is where
bag three comes in, clinical trials. we recruit volunteers and split them randomly and change
only one factor between the groups. that is how we test causality. so which factor should we play with?
we can't kill half our subjects just to see what happens. pretty hard to get that study approved... but
we can manipulate cholesterol, of course. we saw in the bag two studies that people on statins
did not die more but we know those studies have confounders. maybe people taking statins in the
general population are also more health conscious and also exercise more. so we want a more rigorous
test, a randomized clinical trial with a placebo control where the drug is the only variable. if
low cholesterol is our killer then lowering it with meds will cause death, if it's just
an innocent bystander they'll be fine. lucky for us this type of study has been done many times
here's one such trial. they lowered ldl cholesterol by 30% and deaths did not go up. this one lowered
ldl cholesterol by 35%. death actually went down. 30% less mortality with cholesterol lowering. here is
a large analysis combining 26 cholesterol lowering trials. total mortality was reduced. 10 percent less
death per unit of cholesterol drop. so depending on the total number of people and the specifics
of the population we either see no change in death or less death with cholesterol lowering
so the opposite direction of the u-shaped curve. and it's not some weird fluke of one drug
different cholesterol-lowering drugs of different classes show a similar effect. people who have low
cholesterol because of genetics or dietary change, in all those cases we see a similar picture, total
death tends to stay the same or go down, not up. so as usual we get confused if we're only shown
a pocket of data, that's why headlines tend to throw people off but in science it's absolutely
crucial to look at everything we know about a topic in order to try to make sense of it
of course that's much harder to do but that's the goal and when we look at all of the evidence
together, the picture that emerges is that it depends why your cholesterol goes down. if you
actively lower it with medication, with healthy lifestyle choices or if you have the lucky genes,
that's beneficial. it lowers your cardiovascular disease risk, it may even lower your overall risk
of dying, certainly doesn't raise it. but if cholesterol starts dropping spontaneously,
unexplained, especially in someone living a typical western lifestyle: eating poorly,
not exercising, overweight, they didn't change anything and yet their cholesterol starts creeping
down over the years, yeah, that could be a red flag, there could be a chronic disease developing.
now, as we were literally sitting down to shoot, something remarkable happened. remember the recent
observational study from denmark with the u-curve and how it was widely misrepresented on social
media? well the authors of that study just posted a letter addressing all of this. here it is. "we are
saddened to learn about the mischievous misuse of our observational study, a potential misuse
we discussed thoroughly before publication and even considered whether we should publish this
data. it is important to understand that our results are observational, they say nothing
about the causal role of cholesterol in the development of cardiovascular disease or mortality
or the effect of cholesterol lowering therapy. for that, we have abundance of experimental, genetic,
and clinical trial evidence. so this is really special, out of pure happenstance we have in real
time the authors of the study explaining how the interpretation of their work that's going around
is misleading. welcome to the internet. if they had posted this a week earlier they would have saved
us the trouble of making the video because that sums it up perfectly. okay, here's even more context
this cholesterol paradox, this u-curve, this is nothing unique, we see this pattern in many
other areas of health. BMI, for example, body mass index. in bag two studies, obesity is associated
with higher mortality but so is normal body weight, a u-shaped curve, with mortality going up
at very high bmi but also going up with low and even normal bmi, and the lowest mortality point
actually sitting in the overweight range. you know what they call this phenomenon? the obesity paradox
and the explanation is similar, it's not the normal body weight that kills people, it's probably
an innocent bystander because several factors that cause weight loss, like smoking and chronic
disease, also raise risk of death. so you see how misguided it would be to look at this u-curve
for bmi and conclude i shouldn't exercise or try to eat better, i should try to be overweight
because of this mortality pattern. it's confusing association with causality. the u-curve
doesn't mean normal bmi is bad, it means that in the general population many people who lose weight
and drop to the normal range lose it for the wrong reasons, like underlying disease. the exact same is
true with cholesterol. by the way, we see the same trend with salt. higher mortality at very high salt
intake and higher mortality at low salt intake and this confuses a ton of people who then jump to the
conclusion that we shouldn't moderate salt intake because of this association, this u-shaped pattern
but we now understand the association doesn't necessarily reflect causality. we'll look at the
salt confusion in more detail another day, for now take home message is we see these u-shaped patterns
because the norm in our society is to be a bit unhealthy. a bit overweight, a
bit hypercholesterolemic, a bit too much salt. so the average is high and for many people who drop
down to the normal range, that happens because of underlying disease, not because of healthy choices
it's a very sobering view of our society but on the flip side it shows us that it's in our hands
to have normal cholesterol, normal body weight and low mortality all at the same time, it's
not a trade-off, we don't need to compromise, we can have it all. bottom line: be a little
skeptical of these u curves. and bag 2 studies, observational studies, they're important evidence
but we have to interpret them in context, we can't jump to a conclusion. and if you're motivated to
lower cholesterol, don't be confused. the evidence tells us it's overwhelmingly beneficial and for
most of us, very doable with lifestyle changes and it can be as quick as a few days. i want to help
more people achieve their cholesterol goals so we're going to start sharing the best tips and
tricks for cholesterol optimization every week completely free. go to this url to sign up and
you can click the link in the description below. and we have several videos explaining in detail
what foods raise your cholesterol and what foods lower it so check them out and let's crush this
peace