HDL, the "good cholesterol". where does HDL stand in predicting overall risk, right?
so we mentioned that high LDL-c, high ApoB, more or less causal in cardiovascular disease risk,
but for those who have a high LDL-c, they might mention that, well, my good cholesterol
my HDL-c, is also extremely high, so that must mitigate risk to some degree, right?
how would you respond to someone who puts that forth? i would follow the same logic
we've already followed like two or three times in this conversation. you basically have to look
at the evidence, the totality of the evidence, you look at the observational evidence,
you don't dismiss that, it has value, but then you also look at everything else that we know, all
the causal tests, and then you put everything together and you see what the total
landscape is likely to be. so, similar to the particle size, it's understandable that people
rely on or believe that hdl-cholesterol might be protective, because the associations are there
very clearly, all the way back to framingham you see an inverse correlation, very strong, you see
people who have lower hdl-cholesterol levels tend to have higher risk and that's a
powerful correlation, you see it consistently in epidemiology. the problem is... and that created
a lot of excitement, people in the field were very excited about it, hdl-cholesterol, that's where
"good cholesterol, bad cholesterol" came from, fortunes were invested in coming up with drugs
that raised hdl-cholesterol, that hopefully would be protective, dozens of randomized control
trials were run, hundreds of millions of dollars per trial, we're talking massive,
colossal endeavors trying to test this and no doubt rooting for it to work. the problem is, causal
tests have consistently been a dud, so the clinical trials, the randomized controlled trials, there's been
at least 39 that i know of, there's a meta-analysis that looks at 39 randomized controlled trials,
several different drugs, at least three classes of drugs, three different drugs that do effectively
raise hdl-cholesterol but you don't see an improvement of risk, the risk doesn't come down
and then the genetics, same thing, when you look at hdl in isolation you do see a correlation,
an inverse correlation with risk which would appear to be protective, but then when you bring in
apoB and these other metrics, that effect goes away, so it's completely abrogated. so when you put
everything together, what it's very consistently telling us is that it's a marker, it can be
predictive in a population setting. that's why this is confusing and it's hard to explain,
because you can point to the studies and say "look,
you have a better correlation with hdl -cholesterol in this population study then
even ldl-cholesterol so how can you say that this isn't protective, isn't causal?"
and it's not intuitive, it's tough for us to
see this, but you can have correlations with things that are really strong but then do not
have a causal link, i mean one analogy would be if we're trying to figure
out what causes lung cancer and let's say we don't know yet and maybe we suspect that
it has something to do with smoking but we're not quite sure and so we go into people's houses we
do an inventory of their lives and then we follow them and we see who gets lung cancer we find out
that there's a strong correlation between people who own ashtrays and people who get lung cancer
20 years later. so now you tell me: "man, you're smoking a lot, aren't you worried? and
i say: no, but i gave away all my ashtrays, so i'm protected, i'm no longer at high risk."
it seems silly in this setting but what i'm doing is i'm taking a correlation that is really strong
and i'm extrapolating causality. if the causal links are not clear in our heads
it's not hard to make that mistake and that is what's being done in general with HDL-
cholesterol when we assume that it's causal and having it high is going to be protective
now, i think it's reasonable to say as well that although the evidence is very consistent
in pointing against the causality there, first of all, we're talking about major cardiovascular,
atherosclerotic cardiovascular disease. i'm not ruling out that that HDL-cholesterol could have
a protective effect or a positive effect in immune function, maybe in peripheral
artery disease, there's some indication that that might be the case, but not with these
events, not with heart disease, not with myocardial infarction, with
ischemic strokes, these major things that we're worried about
and so to posit that having high ldl-cholesterol, or even worse, high apoB,
that that would be somehow mitigated by having high hdl-cholesterol,
it's just incredibly difficult to justify that based on the totality of evidence
the other thing to say is that we are talking about hdl-cholesterol, we're not ruling out that
the particle itself, HDL, might have a protective effect, it hasn't been studied as much, there have
been some experiments, there are some mimetics that people have used where it's kind of an
artificial lipoprotein that's made synthetically and then it's injected into people and they
showed that it does sort of replicate the reverse cholesterol transport function of HDL
but then when you inject it into people it doesn't lower risk
so the function of HDL having some protective effect hasn't been ruled out
but this simple idea that just raising HDL-cholesterol is going to protect me
and make up for high LDL-cholesterol or high apoB, i would highly discourage people from
thinking that way, i wouldn't encourage anyone i cared about to go along those
lines, it's just really dangerous, and i also see incredible agreement on this
when i interact with on twitter with these leading experts and they're
actually more categorical than i am when they talk about this, tom dayspring or sam tsimikas,
they are so clear on this, they say "we don't even look at HDL-cholesterol anymore", and by the way,
they extend this logic to the ratios. almost not a day goes by that somebody doesn't
ask me if triglycerides over HDL-cholesterol is not a better metric than ldl-cholesterol
what you do when you take a a metric that isn't reliable, that isn't
causal, and you throw it in a ratio, you end up with an unreliable ratio, and it's
not hard to see that if my hdl-cholesterol shoots up through whatever lifestyle change but nothing
else changes, that ratio is going to look better but i've done nothing causally to protect myself
so i see these people being incredibly categorical and clear about the fact that they don't
even pay attention to hdl-cholesterol anymore. again, i would say follow apoB