11 ms·

Total cholesterol and all-cause mortality – a study among 13M adults

167 points by pizza 7y ago

leptoniscool 7y ago
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.html https://medlineplus.gov/cholesterollevelswhatyouneedtoknow.h...
- new299 7y ago
  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 7y ago
    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.
  - chiefalchemist 7y ago
    Odd? Odd because we've been taught what are amounting to myths[1] about cholesterol. Afaik, humans - especially the human brain - need a healthy supply of cholesterol. You literally can't think straight without it. And how many people are being pumped with statins? [1] https://www.nytimes.com/2016/09/13/well/eat/how-the-sugar-industry-shifted-blame-to-fat.html https://www.nytimes.com/2016/09/13/well/eat/how-the-sugar-in...
  - carbocation 7y ago
    When you do your study without accounting for treatments that are given to people with high risk of disease and which reduce cholesterol, you will find that lower cholesterol corresponds with disease due to those treatments. In other words, they have performed a large study that is likely to be confounded by indication.
  - scns 7y ago
    People brought into mental hospitals after trying to commit suicide have been diagnosed with very low cholesterol levels. The body sythesizes sexual hormones from cholesterol.
  - dhimes 7y ago
    I remember back in the 1980s that the Japanese researchers, whose population has (had?) very low cholesterol, were arguing with the US researchers, saying that cholesterol too low was bad as it led to (perhaps allowed for) strokes- which was one of their young-people-killers.
  - mathgeek 7y ago
    Like most things which your body needs (or produces from other materials), moderation is likely better than an outright deficit or abstinence.
- baxtr 7y ago
  I read it as: 200 is the lowest point of the U curve they found. Below 200 mortality decreases as TC increases, and above 200 mortality increases as TC increases, meaning anything close to TC seems to be the value with the lowest mortality rate. > U-curve associations were found. In the TC ranges of 50–199 and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI:23%,24%) and 7% higher (6%,7%) mortality, respectively. In the age groups of 18–34, 35–44, 45–54, 55–64, 65–74, and 75–99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group).
- deleted 7y ago
  [deleted]
- tim333 7y ago
  Cholesterol research is a mess of unproven cause and effect and conflicting results. I'd try to live a healthy life and not worry too much about it.
  - ses1984 7y ago
    What does healthy even mean?
    - deleted 7y ago
      [deleted]
    - chiefalchemist 7y ago
      Exercise. Avoid sugar. Lean towards nutrient dense foods (i.e., not too many simple carbs). Low / no alcohol. Etc.
    - makeszerosense3 7y ago
      Organic, ripe, in season fruits and veggies. Raw as much as possible. No animals foods of any kind.
      - Broken_Hippo 7y ago
        This is certainly not correct. One does not need to eat organic foods to be healthy. I'll add that not everyone has in season fruits around. I live in Norway. Do you know what is in season during January in Norway? Nothing. Absolutely nothing. Doubly so if you aren't eating animal products. I'll add that avoiding all animal products has its own perils, namely the sort that results in vitamin deficiencies. And while a diet filled with whole grains and mostly plant-based foods is considered healthy, we simply don't know enough about nutrition to have one way or another. Or even to get vitamin doses right. I say all this while eating mostly vegetarian myself. I eat fish about once a week. I don't like it so much, but it is healthy.
      - vbtemp 7y ago
        Username checks out
keymone 7y ago
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 7y ago
  "much more important metric is particle count" That is really interesting, do you have a source you can recommend for reading further?
  - keymone 7y ago
    There is plenty of research, but here’s more consumable version: https://peterattiamd.com/the-straight-dope-on-cholesterol-part-iv/ https://peterattiamd.com/the-straight-dope-on-cholesterol-pa... The whole series is a gold mine tbh
  - virtuallynathan 7y ago
    I think Lipidology has now moved on from LDL-P, now it's all about ApoB containing lipoproteins and lifetime burden of exposure.
carbocation 7y ago
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.
- avsteele 7y ago
  (caveat:I'm not an expert) Why would you need to account for it? Trying to understand the logic here. The study goes to showing the association between high cholesterol and all-cause mortality (which is what we really care about right?) is weak. This would seem to diminish the benefits of statin use, all other things being equal.
  - carbocation 7y ago
    In the tweet that I linked to, we noted that failure to account for statin use can invert the causal relationship between cholesterol and mortality. With regard to the point of the study, they start by saying, "It is unclear whether associations between total cholesterol (TC) levels and all-cause mortality and the optimal TC ranges for lowest mortality vary by sex and age." So, interpreting their statement, I would say that their goal with this study was to investigate whether the relationship between total cholesterol and mortality was consistent across age and sex. That is a different point from assessing the strength of the relationship between cholesterol and mortality. I do agree, however, that there is no single biomarker aside from age that is a particularly powerful predictor of mortality in the general population.
    - fauigerzigerk 7y ago
      I don't understand why it matters for the conclusion whether lower cholesterol (or specifically LDL) is caused by diet or statins or something else altogether (if the assumption is that high LDL affects mortality). [Edit] I just read another one of your comments that answers my question, and I think you're right: https://news.ycombinator.com/item?id=20138685 https://news.ycombinator.com/item?id=20138685
dnhz 7y ago
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 7y ago
  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.
  - darawk 7y ago
    Hmm...but doesn't this suggest then that cholesterol levels are merely a biomarker of something else that causes the mortality, and not a direct cause of it?
    - carbocation 7y ago
      That is a good question. These results tell you that statins don't take your risk to zero. If you were totally protected from CAD as soon as you took a statin, then I agree that confounding by indication would not be a thing. But, across all fields of medicine, we know that confounding by indication is a problem. Preventive medicines, by and large, are not sufficiently powerful to reduce risk to zero.
      - darawk 7y ago
virtuallynathan 7y ago
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.
- village-idiot 7y ago
  For the life of me I really don’t understand why the regulators haven’t clamped down on statins. Sure, it lowers your cholesterol, but unless if you’re in a very specific population it doesn’t move your all cause mortality risk one iota. All while costing the patient money and causing some pretty nasty side effects too.
  - viraptor 7y ago
    > but unless if you’re in a very specific population it doesn’t move your all cause mortality risk one iota Have you got a link to some relevant research?
    - village-idiot 7y ago
      Sure do! I typically defer to Mark Sisson for this kind of stuff, who’s very good at linking in relevant research. https://www.marksdailyapple.com/the-evidence-continues-to-mount-against-statins/ https://www.marksdailyapple.com/the-evidence-continues-to-mo...
astura 7y ago
Why use total cholesterol instead of LDL?
- alecco 7y ago
  Probably because it was the only available measurement for such a large sample (12.8M).
  - pkaye 7y ago
    Isn't LDL and HDL measured with TC all as part of the same test?
matonias 7y ago
Is it irony its posted by 'pizza'
tmaly 7y ago
What is the TLDR?
danbmil99 7y ago
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 7y ago
  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 7y ago
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 7y ago
  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.
petilon 7y ago
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-e7d9d8eea983 https://medium.com/@petilon/cholesterol-and-statins-e7d9d8ee...

167 points by pizza 7y ago

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.html https://medlineplus.gov/cholesterollevelswhatyouneedtoknow.h...

new299 7y ago
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 7y ago
  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.
- chiefalchemist 7y ago
  Odd? Odd because we've been taught what are amounting to myths[1] about cholesterol. Afaik, humans - especially the human brain - need a healthy supply of cholesterol. You literally can't think straight without it. And how many people are being pumped with statins? [1] https://www.nytimes.com/2016/09/13/well/eat/how-the-sugar-industry-shifted-blame-to-fat.html https://www.nytimes.com/2016/09/13/well/eat/how-the-sugar-in...
- carbocation 7y ago
  When you do your study without accounting for treatments that are given to people with high risk of disease and which reduce cholesterol, you will find that lower cholesterol corresponds with disease due to those treatments. In other words, they have performed a large study that is likely to be confounded by indication.
- scns 7y ago
  People brought into mental hospitals after trying to commit suicide have been diagnosed with very low cholesterol levels. The body sythesizes sexual hormones from cholesterol.
- dhimes 7y ago
  I remember back in the 1980s that the Japanese researchers, whose population has (had?) very low cholesterol, were arguing with the US researchers, saying that cholesterol too low was bad as it led to (perhaps allowed for) strokes- which was one of their young-people-killers.
- mathgeek 7y ago
  Like most things which your body needs (or produces from other materials), moderation is likely better than an outright deficit or abstinence.
baxtr 7y ago
I read it as: 200 is the lowest point of the U curve they found. Below 200 mortality decreases as TC increases, and above 200 mortality increases as TC increases, meaning anything close to TC seems to be the value with the lowest mortality rate. > U-curve associations were found. In the TC ranges of 50–199 and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI:23%,24%) and 7% higher (6%,7%) mortality, respectively. In the age groups of 18–34, 35–44, 45–54, 55–64, 65–74, and 75–99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group).
deleted 7y ago
[deleted]
tim333 7y ago
Cholesterol research is a mess of unproven cause and effect and conflicting results. I'd try to live a healthy life and not worry too much about it.
- ses1984 7y ago
  What does healthy even mean?
  - deleted 7y ago
    [deleted]
  - chiefalchemist 7y ago
    Exercise. Avoid sugar. Lean towards nutrient dense foods (i.e., not too many simple carbs). Low / no alcohol. Etc.
  - makeszerosense3 7y ago
    Organic, ripe, in season fruits and veggies. Raw as much as possible. No animals foods of any kind.
    - Broken_Hippo 7y ago
      This is certainly not correct. One does not need to eat organic foods to be healthy. I'll add that not everyone has in season fruits around. I live in Norway. Do you know what is in season during January in Norway? Nothing. Absolutely nothing. Doubly so if you aren't eating animal products. I'll add that avoiding all animal products has its own perils, namely the sort that results in vitamin deficiencies. And while a diet filled with whole grains and mostly plant-based foods is considered healthy, we simply don't know enough about nutrition to have one way or another. Or even to get vitamin doses right. I say all this while eating mostly vegetarian myself. I eat fish about once a week. I don't like it so much, but it is healthy.
    - vbtemp 7y ago
      Username checks out

keymone 7y ago

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 7y ago
"much more important metric is particle count" That is really interesting, do you have a source you can recommend for reading further?
- keymone 7y ago
  There is plenty of research, but here’s more consumable version: https://peterattiamd.com/the-straight-dope-on-cholesterol-part-iv/ https://peterattiamd.com/the-straight-dope-on-cholesterol-pa... The whole series is a gold mine tbh
- virtuallynathan 7y ago
  I think Lipidology has now moved on from LDL-P, now it's all about ApoB containing lipoproteins and lifetime burden of exposure.

carbocation 7y ago

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.

avsteele 7y ago
(caveat:I'm not an expert) Why would you need to account for it? Trying to understand the logic here. The study goes to showing the association between high cholesterol and all-cause mortality (which is what we really care about right?) is weak. This would seem to diminish the benefits of statin use, all other things being equal.
- carbocation 7y ago
  In the tweet that I linked to, we noted that failure to account for statin use can invert the causal relationship between cholesterol and mortality. With regard to the point of the study, they start by saying, "It is unclear whether associations between total cholesterol (TC) levels and all-cause mortality and the optimal TC ranges for lowest mortality vary by sex and age." So, interpreting their statement, I would say that their goal with this study was to investigate whether the relationship between total cholesterol and mortality was consistent across age and sex. That is a different point from assessing the strength of the relationship between cholesterol and mortality. I do agree, however, that there is no single biomarker aside from age that is a particularly powerful predictor of mortality in the general population.
  - fauigerzigerk 7y ago
    I don't understand why it matters for the conclusion whether lower cholesterol (or specifically LDL) is caused by diet or statins or something else altogether (if the assumption is that high LDL affects mortality). [Edit] I just read another one of your comments that answers my question, and I think you're right: https://news.ycombinator.com/item?id=20138685 https://news.ycombinator.com/item?id=20138685

dnhz 7y ago

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 7y ago
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.
- darawk 7y ago
  Hmm...but doesn't this suggest then that cholesterol levels are merely a biomarker of something else that causes the mortality, and not a direct cause of it?
  - carbocation 7y ago
    That is a good question. These results tell you that statins don't take your risk to zero. If you were totally protected from CAD as soon as you took a statin, then I agree that confounding by indication would not be a thing. But, across all fields of medicine, we know that confounding by indication is a problem. Preventive medicines, by and large, are not sufficiently powerful to reduce risk to zero.
    - darawk 7y ago

virtuallynathan 7y ago

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.

village-idiot 7y ago
For the life of me I really don’t understand why the regulators haven’t clamped down on statins. Sure, it lowers your cholesterol, but unless if you’re in a very specific population it doesn’t move your all cause mortality risk one iota. All while costing the patient money and causing some pretty nasty side effects too.
- viraptor 7y ago
  > but unless if you’re in a very specific population it doesn’t move your all cause mortality risk one iota Have you got a link to some relevant research?
  - village-idiot 7y ago
    Sure do! I typically defer to Mark Sisson for this kind of stuff, who’s very good at linking in relevant research. https://www.marksdailyapple.com/the-evidence-continues-to-mount-against-statins/ https://www.marksdailyapple.com/the-evidence-continues-to-mo...

astura 7y ago

Why use total cholesterol instead of LDL?

alecco 7y ago
Probably because it was the only available measurement for such a large sample (12.8M).
- pkaye 7y ago
  Isn't LDL and HDL measured with TC all as part of the same test?

matonias 7y ago

Is it irony its posted by 'pizza'

tmaly 7y ago

What is the TLDR?

danbmil99 7y ago

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 7y ago
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 7y ago

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 7y ago
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.

petilon 7y ago

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-e7d9d8eea983 https://medium.com/@petilon/cholesterol-and-statins-e7d9d8ee...