brand new trial just came out looking at triglyceride lowering and it contains some
interesting lessons. it was a randomized clinical trial with a triglyceride-lowering drug compared
to a placebo, and it was double blind, meaning the participants don't know which one they're
taking and the doctors following them also don't know who's on what. obviously this is all recorded
somewhere, the people running the trial know who's on what, but the doctors directly interacting with
the patients don't know, so this removes a lot of the bias. and they had over 10,000 participants,
all with type 2 diabetes, high triglycerides and low HDL-cholesterol. most of them had a
history of heart disease and were already on a Statin or some form of lipid-lowering treatment
so their LDL-cholesterol was already pretty low, it was only their triglycerides that were very
high. so the 10,000 were split randomly, half on the drug, it's called a fibrate, and the other
half on the placebo, the inert pill with no drug, and then they were followed for three and a half
years. the fibrate reduced triglycerides by 26 percent compared to the placebo,
so that's expected, that's what the drug does, and HDL-cholesterol actually went up by a little bit,
five percent. bottom line, at the end of the three and a half years there was no significant
change to their risk of cardiovascular events like heart attacks, Strokes or death. okay,
why wasn't the risk reduced if triglycerides came down substantially? lipids like triglycerides
or cholesterol are carried in our bloodstream in little packages called lipoproteins, like LDLs or
VLDLs, those are two types of lipoprotein. VLDLs, which stand for very low density lipoprotein,
carry mostly triglycerides, while LDLs, which of course stand for low density lipoprotein,
carry mostly cholesterol. and in general what we see in cardiovascular research is that the risk
follows the number of these lipoproteins, not the lipid levels per se, so the lipid levels,
how much triglycerides or how much cholesterol is in our bloodstream, seems to be a marker,
an indicator, kind of like the check engine light on our dashboard. usually,
the higher the triglycerides or the higher the level of cholesterol in the blood, the more of
these carriers, the more lipoproteins there tend to be, but not a hundred percent of the time,
so the lipids are imperfect markers. okay, so if the lipoproteins, if the carriers are
the real determinants of risk, then we should be looking at lipoproteins, right? so what happened
to the lipoproteins in this trial? VLDLs and LDLs actually belong to the same family of
lipoproteins, they're kind of like cousins in a way. in fact, VLDLs can turn into LDLs. both of
them carry a protein called ApoB that serves as an identifier of this family. so ApoB, the total
number of this whole family of lipoproteins, actually went up slightly on the drug,
4.8 percent increase. so this makes sense based on everything we know, ApoB didn't come down so risk
didn't come down, regardless of what happens to triglycerides or cholesterol. by the way,
the drug actually raised LDL-cholesterol by 12% or so, but again, it's ApoB that's expected to
determine risk and ApoB barely changed, so... now, why didn't risk go up 4.8 percent like ApoB did?
risk actually went up by an estimated three percent but it wasn't statistically significant,
you normally don't expect to pick up a difference that small, so this depends on how the trial is
designed, the number of participants you have, how long you follow them for, how many heart attacks
occur, all of these factors are going to determine the statistical power of the trial, so this trial
was designed to have a statistical power to pick up a 18% or higher difference in Risk so it
makes sense that a three percent or five percent difference would not reach significance. what's
the take-home message from this study? the most likely interpretation for their findings is that
lack of efficacy of the drug despite triglyceride lowering may be largely due to a lack of overall
decrease in Apolipoprotein B. so ApoB didn't come down. in order for lipid-lowering therapy to show
an effect, a net reduction in apoB-containing lipoproteins is vital. now, when we look beyond
just the total number of apob lipoproteins, at the effect of the drug on specific subclasses,
like LDLs and VLDLs, the results are pretty interesting. this fibrate lowers VLDLs, so those
guys who carry mostly triglycerides. so that makes sense, both tend to come down, triglycerides and
their carriers. but this drug raises some of the LDLs, specifically the larger LDLs. so they think
the VLDLs are being reduced not by being destroyed or by being removed from circulation, but by being
converted to LDLs. the results were consistent with increased conversion of triglyceride-Rich
lipoproteins (that's mainly the VLDLs) to LDLs. so it's a lateral move, reducing triglycerides
by transforming one type of ApoB lipoprotein, the VLDLs, into another type of ApoB lipoprotein, the
LDLs, is not very helpful. on a side note, there's a common idea that only small LDLs are potentially
problematic and large LDLs are harmless, we've actually made a couple of videos on this before,
going pretty in depth on the evidence. the strongest data I've seen doesn't support this
idea and instead points to all of the members of this family being about equally atherogenic,
about equally risk-inducing particle for particle, whether it's VLDLs, large LDLs, small LDLs,
etc. there is one exception we've touched on before, lp(a), which is a type of LDL and it seems
to be nastier than most of its relatives, not because of size but because of its composition,
but in general all of the members of this family regardless of size seem to be about equally
problematic. so this trial generally aligns with this idea, the drug reduces VLDLs, which
pretty much everyone agrees can be atherogenic, but it does that by increasing the large LDLs,
and predictably, not much happens to risk. now, as always, we don't want to bet the farm on one
trial because maybe there's something weird with this drug, maybe the specific conditions of these
participants don't translate to other populations, maybe a billion things, right? so we always want
to look at balance of evidence, big picture, and these results align pretty well with everything we
know, for example other trials with different drugs have shown similar results, lowering
triglycerides without lowering Apob doesn't seem to provide much benefit as far as cardiovascular
risk, and from genetic studies we also see that triglyceride levels seem to play little if any
effect on cardiovascular risk when we account for ApoB. people often ask about HDL-cholesterol,
and the answer is generally similar, higher HDL-cholesterol either with drugs or determined
genetically don't seem to confer much protection, and genetic levels of both triglycerides and
HDL-cholesterol combined seem to play little if any role in cardiovascular risk when we account
for ApoB. also, people with good levels of both triglycerides and HDL-cholesterol, both in the
healthy range, can still have plaque in their arteries. so what does this all mean? well,
this trial makes some important points. first, a physiological parameter, one of these values
in your blood work, can be a good marker of risk in a population and yet not necessarily determine
risk. this concept can be a little confusing, a little counter-intuitive, but bear with me.
triglycerides associate well with risk at population level in observational studies,
so in general people with higher triglycerides have higher cardiovascular risk and vice versa,
so it's a good marker of risk in a population, and yet lowering triglycerides doesn't necessarily
lower risk. this is a very important distinction and that's why randomized trials and genetic
studies can be important data. now, some people may not be surprised by any of this,
in fact in the reaction to this trial coming out I saw several people on social media basically
saying "duh, triglycerides are a marker of the problem, they're not the problem itself".
and I think that's generally accurate, triglyceride levels reflect things like obesity,
overweight, diabetes Etc. so going in and changing triglycerides directly doesn't necessarily do much
by itself, at least for cardiovascular risk. the best analogy is probably the lighter,
people who carry a lighter with them everywhere tend to have more lung cancer,
but obviously it's not the lighter that causes cancer, it's just a marker of the real problem,
so we could use lighter-carrying as a marker of risk in a population and it would probably track
pretty well with risk of lung cancer, and yet individually it would fall apart if we over rely
on it. maybe I carry a lighter with me to light candles or something and I don't smoke, or maybe
I do smoke but I use matches instead, right? so losing perspective and over relying on a marker
at individual level can cause us to misestimate risk. kind of similar for cardiovascular disease,
lots of factors are markers and reflect causes and track pretty well with risk in a population
setting but don't actually cause the problem themselves. triglycerides are one example,
particle size seems to be another, whether the LDLs are large or small.
HDL-cholesterol is another as we saw, tracks pretty well with risk in a population setting
but when you go in and you change HDL-cholesterol directly, it doesn't seem to do much to risk.
by the way, LDL-cholesterol is another example, it's a marker at the end of the day of the number
of carriers, of the number of LDL lipoproteins, but LDL-cholesterol level is not what determines
risk. this also helps explain why a lot of these ratios, total cholesterol over HDL-cholesterol,
triglycerides over HDL-cholesterol, a lot of these different ratios that people ask about
can be a little misleading at an individual level even though they track risk well at population
level, because they reflect a number of risk factors, they reflect obesity and diabetes and
alcohol intake etc etc, but individually I could have high HDL-cholesterol determined genetically,
which makes those ratios look a lot better but it doesn't do anything to my actual risk of a
cardiovascular event like a heart attack or a stroke which is what we really care about. or
as we saw in the trial, triglycerides can come down, even by a respectable margin,
which makes the ratios look a lot better and yet the risk can stay the same, that's possible,
so we just want to be a little cautious with these markers, always bearing in mind we're looking at
imperfect Reflections, we're not looking directly at the actual causes, right? so the two can
sometimes mismatch, that's the caveat. we're not saying these numbers are 100% useless all the time
and Let's ignore our high triglycerides! if I have high triglycerides, chances are I'm overweight or
obese or diabetic or have some lipid condition, and if my triglycerides come down because I lost
a bunch of weight then they are reflecting that positive change. also important to note that there
are other reasons besides heart disease that very high triglyceride levels can be bad news,
like risk of pancreatitis or fatty liver. in fact, in this trial this drug that lowered triglycerides
lowered the risk of fatty liver. so you don't want to ignore your high triglyceride levels,
alright? that's not what we're saying, we're talking about what they do and don't tell us.
we can't assume that lower triglycerides necessarily means, automatically means lower
cardiovascular risk. I also can't assume that because my triglycerides are in the healthy range,
that automatically means I'm safe, I could still have some actual determinants of risk that are out
of whack, like high blood pressure or high ApoB. alright? I hope that makes sense. in other words,
triglyceride-lowering without decreases in ApoB will probably not suffice to produce meaningful
decreases in risk of cardiovascular disease. and I would extrapolate that to any of these causal
determinants, blood pressure or diabetes or weight loss. and that's the other very important lesson
from this trial, probably the most important takeaway, these metrics don't work in a vacuum,
lowering a parameter isn't necessarily an improvement, depends on what else changes,
the drug lowered triglycerides, it even lowered actual VLDLs, which in general is a good move,
and yet risk didn't improve because of what else changed. so always very important to keep in mind
big picture and not get lost in treating one value and playing this game of gerrymandering metabolism
where we're just going to optimize this corner over here and we're going to forget
this thing exists. not a good approach. how do we optimize all aspects of Health at the
same time? maintaining a healthy body weight, not smoking, managing stress, good sleep and eating
a healthy diet, meaning easy on ultraprocessed foods, favoring sources of unsaturated fats and
fiber and not going crazy on added sugar, salt or alcohol. many ways to tailor that pattern to your
individual preferences and circumstances, it's not a one size fits-all. I know lipids and heart
disease is a tough topic, it´s complicated, and this question of the markers versus the makers,
the indicators versus the actual causes, is one of the hardest things to approach and to explain
well, I've been working on better ways to explain this for a long time now, I don't know if we're
there yet, you tell me if this makes sense, if it's not clear yet we'll just keep working on it,
alright? thanks for watching, let me know your thoughts, take care, I'll catch you next week