
Total cholesterol and all-cause mortality – a study among 13M adults - pizza
https://www.nature.com/articles/s41598-018-38461-y
======
carbocation
The study methods don't seem to indicate whether they adjusted for statins!

If they failed to account for statin use, then they will get the wrong answer
due to confounding by indication.

[https://twitter.com/skathire/status/1110909549811322880](https://twitter.com/skathire/status/1110909549811322880)

 _Edit: Found it - they are_ not _accounting for statin use! None of their
conclusions seem warranted._

~~~
tonfa
FYI this is discussed in the conclusion:

> First, the use of lipid-lowering medication was unaccounted for. The risk
> associated with high cholesterol might have been underestimated. However, in
> Korea, IHD mortality accounted for only approximately 5% of all-cause
> mortality, and only 10% of people with hypercholesterolemia received lipid-
> lowering therapy[39]. Therefore, the impact of not considering medication
> use is likely to be modest, and the TC levels in this study generally
> reflect levels without lipid-lowering medications

~~~
carbocation
And yet, if you look a the twitter thread I pointed out, it turns out that in
a large biobank of 500,000 people, their aspiration is refuted: if you fail to
account for treatment effects, the association results will be inverted.

~~~
candybar
But,

> only 10% of people with hypercholesterolemia received lipid-lowering therapy

Wouldn't this be much higher in the UK cohort? Also,

> The sex- and age- specific levels of TC in the current study of Koreans were
> lower than those reported in other high-income countries, including Japan,
> England, and the US

Which would reduce the effect (relative to what was found in the analysis of
UK data) even further.

I don't think it adds a whole lot to talk about the confounding variables of
this nature - it's an observational study, so of course it will have all sorts
of confounding variables. If you are going to make a strong case that
controlling for a specific confounding variable would reverse the relationship
though, you should quantify the impact. It's unclear to me that statin usage
would make a large difference, given that the study notes it wasn't a popular
treatment.

My general feeling is that these types of studies tend to end up measuring
overall health - given that most of the factors that lead to high cholesterol
level were controlled for (BMI, physical activity, smoking status, drinking,
etc) - and the average person in any population is relatively healthy and
well-adjusted to the common diet, any large deviation from the norm in any
direction statically makes it likely that the subject has some health issues.

What would be interesting to see in a meta-study is whether the optimal level
of cholesterol either was consistent across populations that had very
different averages or it tends to be near the median in each population. The
former would be evidence that it's an independently meaningful biomarker; the
latter would be evidence that it's just measuring how normal you are.

~~~
carbocation
You don’t think that talking about confounding by indication is important?
Confounding by indication inverts the entire discussion section of the
article.

~~~
candybar
Again, observational studies are going to have all kinds of confounding
variables - if you're going to make an argument that one of them is important
enough to reverse the conclusion, you should have some evidence and certainly
more than a just-so-story.

------
virtuallynathan
Cholesterol / lipid science is a mess. First it was LDL-C that was bad, then
that doesn’t actually correlate, then it’s LDL-P, oh wait, then it’s LDL size,
and then it’s ApoB that’s going to “clog your arteries”. Once you dive into
the “hard” science like pathology of atherosclerosis, you’ll find that the
lipid hypothesis makes no sense.

We have drugs (PKCS9 inhibitors:
[https://www.nejm.org/doi/full/10.1056/NEJMoa1615664](https://www.nejm.org/doi/full/10.1056/NEJMoa1615664),
bile acid sequesterants, CETP Inhibitors:
[https://www.nejm.org/doi/full/10.1056/NEJMoa1609581](https://www.nejm.org/doi/full/10.1056/NEJMoa1609581))
that can lower LDL to 10-20mg/dL — the later even increased HDL. No impact on
cardiovascular mortality. The studies all use composite endpoints.

What might cause Atherosclerosis?

\- Bacteria

\- Bacterial lipid byproducts

\- Endothelial damage from toxins (lead, mecury, etc)

\- Endothelial glycation from high blood sugar (Diabetics have a lot of CVD)

\- Bad genetics resulting in excess hemodynamic stress at coronary branch
points (fun fact: CVD only develops in a few specific spots)

\- Autoimmune conditions (higher rates of CVD in this population)

What most of these things have in common is they trigger the activation of the
immune system.

~~~
carbocation
Just so other readers are aware, this view of cholesterol and lipidology is
far outside the mainstream medical understanding of the topic.

LDL-c is bad. LDL-p (the particle number), LDL size, and ApoB (which is the
protein part of LDL) are all very well correlated with LDL-c. So, while some
people prefer one measurement or another, they're all proxies for one another.

We have lifelong exposure to our genetics-and-diet-induced cholesterol levels,
whereas clinical trials run for a few years. The long-term follow up of the
statin trials show mortality reduction. PCSK9 inhibitors reduce all-cause
mortality, and the long-term follow-up of the PCSK9 trials may or may not show
the same for cardiovascular specific mortality. However, everyone in the field
thinks they will, because those with loss-of-function PCSK9 variants live
longer with less cardiovascular disease. Also, adjudicating the cause of death
is hard - autopsy, if done, overturns the diagnosis nearly 60% of the time[1].

Cholesterol isn't the only risk factor for cardiovascular disease, so other
things (like autoimmune conditions) will contribute to risk as well, but this
isn't an either/or phenomenon.

1 =
[https://www.ncbi.nlm.nih.gov/pubmed/12913844](https://www.ncbi.nlm.nih.gov/pubmed/12913844)

~~~
virtuallynathan
> "PCSK9 inhibitors reduce all-cause mortality, and the long-term follow-up of
> the PCSK9 trials may or may not show the same for cardiovascular specific
> mortality."

Check the evalocumab trial I posted, ACM was actually slightly worse in the
PCSK9 side of the trial.

> "LDL-c is bad. LDL-p (the particle number), LDL size, and ApoB (which is the
> protein part of LDL) are all very well correlated with LDL-c. So, while some
> people prefer one measurement or another, they're all proxies for one
> another."

Yes, this tends to be true, however discordance between them is possible - and
generally not a good thing.

> "Cholesterol isn't the only risk factor for cardiovascular disease"

Sure, but I think the whole of the field has rabbit-holed on lipids for too
long, ignoring actual causal factors.

~~~
carbocation
> "Sure, but I think the whole of the field has rabbit-holed on lipids for too
> long, ignoring actual causal factors."

LDL cholesterol is by far the best established causal risk factor for coronary
artery disease.

> "Check the evalocumab trial I posted, ACM was actually slightly worse in the
> PCSK9 side of the trial."

All cause mortality was significantly lower in Odyssey:
[https://www.nejm.org/doi/full/10.1056/NEJMoa1801174](https://www.nejm.org/doi/full/10.1056/NEJMoa1801174)

~~~
virtuallynathan
> LDL cholesterol is by far the best established causal risk factor for
> coronary artery disease.

Is it causal, or is it a risk factor? I'd say at best it is "necessary but not
sufficient". CVD risk calculators don't even take LDL-C into account, that's
how good of a marker it is.

------
dnhz
My question is that whether the U-shaped curve found here is caused by similar
phenomena as the J-shaped curve previously found for alcohol. That is, for
alcohol, individuals who drank no alcohol tended to have disease or be
recovering alcoholics, and so that association made it seem that drinking no
alcohol was less healthy than drinking some alcohol. Here too, is it possible
that having low cholesterol is associated with individuals with disease? We
don't know what caused different individuals to have low TC here.

~~~
carbocation
Absolutely. In fact, because statins have such a powerful effect on
cholesterol, there is a good chance that a bunch of the people in the low
cholesterol strata are taking statins. So, at the risk of being a broken
record in this thread, these results are likely to be confounded by
indication. That is, the low-cholesterol groups are enriched for people who
have low cholesterol because they are taking statins. And they are taking
statins because a physician has deemed them to be at elevated risk of disease
(or already have disease), and are thus more likely to die.

~~~
someguydave
If moving “high risk” patients to lower cholesterol levels does not decrease
mortality, why bother with statins?

~~~
ArturSoler
It could be that it reduces mortality, but it's still above average.

~~~
village-idiot
Last time I’d read into it, statins didn’t move mortality numbers for most
members of the population.

Edit: they do decrease your risk of a heart attack a bit, but the increased
incidence of cancer and diabetes actually eliminates the benefit for most
users. The only people who showed any measurable reduction in mortality were
non-elderly patients with a history of cardiovascular disease.

[https://www.marksdailyapple.com/the-evidence-continues-to-
mo...](https://www.marksdailyapple.com/the-evidence-continues-to-mount-
against-statins/)

~~~
carbocation
This is a mix of outdated and simply wrong information.

~~~
village-idiot
I’m unconvinced by your unsupported assertion.

------
keymone
I find it strange that research of this scale is looking exclusively at a
compound metric. TC is HDL (apo A-I), LDL, VLDL, IDL (apo B) and few more
things. Its different proportions of these things that define how healthy your
cardiovascular system is, not the total sum. To complicate even more - those
things are usually measured as concentrations (mass/volume) while much more
important metric is particle count, but that’s not easy/cheap to measure.

Considering how complex this system is, measuring TC is like measuring average
body temperature in the hospital.

It’s cool that they found a U-shape but this approach just makes patients(and
doctors) hack the TC number without understanding how that affects lipoprotein
composition and, subsequently, patient’s health.

~~~
salty_biscuits
"much more important metric is particle count"

That is really interesting, do you have a source you can recommend for reading
further?

~~~
keymone
There is plenty of research, but here’s more consumable version:
[https://peterattiamd.com/the-straight-dope-on-cholesterol-
pa...](https://peterattiamd.com/the-straight-dope-on-cholesterol-part-iv/)

The whole series is a gold mine tbh

------
leptoniscool
Current recommended 'healthy' level is below 200, while it looks like the
study found 200-240 is the best range. Is this accurate? Should people that
have under 200 get it up to the 200-240 range? Or does it depend on family
history of heart disease?

[https://medlineplus.gov/cholesterollevelswhatyouneedtoknow.h...](https://medlineplus.gov/cholesterollevelswhatyouneedtoknow.html)

~~~
new299
In fact it looks like below 200 mortality increased? And it was worse to have
low cholesterol than high in most cases... very odd.

~~~
azeotropic
Animals need cholesterol for their cell membranes; particularly for neurons.
It's a precursor for Vitamin D, testosterone, and estrogen and is needed in
the blood to help transport fat-soluble vitamins (A, D, E, K).

It doesn't seem at all strange that there should be an optimum level that is
non-zero.

------
petilon
So if I am understanding the results correctly, lowering cholesterol beyond a
certain limit can increase morbidity. The results are not at all surprising.
The science behind cholesterol and statin drugs is not settled science. Drug
companies are making 100s of billions of dollars selling statin drugs, and
this money flows to researchers too, so the truth is very hard to know. “It’s
almost impossible to find someone who believes strongly in statins who does
not get a lot of money from industry,” says Dr. Rodney A. Hayward, professor
of internal medicine at the University of Michigan Medical School. Read more
here: [https://medium.com/@petilon/cholesterol-and-
statins-e7d9d8ee...](https://medium.com/@petilon/cholesterol-and-
statins-e7d9d8eea983)

------
danbmil99
As a somewhat overweight male approaching 60 with elevated cholesterol who has
been on and off statins for years, the ridiculously inconclusive state of this
research is very depressing.

I finally decided to stop taking them as they have annoying side effects and
the cynic in me believes the science may have been pushed a bit off center by
monetary incentives to the makers of these patented treatments.

~~~
x3n0ph3n3
I have absurdly high LDL levels, but can't tolerate them because they make all
of my muscles stiff -- which consequently lead to a foot injury. My doctor
considers me allergic to them, but I haven't been able to get my insurance to
pay for another other treatments since they require that I also be on statins.

------
mikorym
12m adults in the study of which 600k died in the following 10 years—is that
normal or was it a high risk group?

~~~
candybar
600K / 12M = 0.05 or 5% over 10 years. This means roughly 500 deaths / 100,000
annually. According to CDC
([https://www.cdc.gov/nchs/fastats/deaths.htm](https://www.cdc.gov/nchs/fastats/deaths.htm))
the death rate in the US is 850 deaths / 100,000. These aren't exactly apples
to apples but that seems enough to say this doesn't look especially high-risk.

------
astura
Why use total cholesterol instead of LDL?

~~~
alecco
Probably because it was the only available measurement for such a large sample
(12.8M).

~~~
pkaye
Isn't LDL and HDL measured with TC all as part of the same test?

------
tmaly
What is the TLDR?

------
matonias
Is it irony its posted by 'pizza'

