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Cholesterol and mortality: Evidence of a U-shape Relationship

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Re: Cholesterol and mortality: Evidence of a U-shape Relationship

#31

Post by lvass »

sooheon wrote: post #30
lvass wrote: post #29

Earlier quoted context omitted.

Please enlighten us how you know statin health effects are 100% related to the fact their usage happen to reduce TC measurements, as your entire post assumes that. Alternative hypothesis: high cholesterol is correlated (a small part of TC is from eating) with some adverse medical condition that statins are effective against. From this cohort, statin users measure lower cholesterol and die less. That lower cholesterol…

I don't know 100%. I'm not a lipidologist or god. However, logically my post does not entirely rely on knowing the precise in vivo mechanism of statins and their causal health effects. We only need to see that in RCTs, lowered cholesterol doesn't cause increased mortality as these observational studies would suggest. That is a pretty direct test of the null hypothesis. edit re your alternative hypothesis: what is thi…

If you don't assume we don't know nearly anything, you're bound to jump into some early and bad conclusions. I have no idea what such condition may be. Heck, a year ago we thought the human body had a different number of bones than we do now. We definitely do not understand how cholesterol in the diet or otherwise affects health, and using statin studies is a really long shot.

Re: Cholesterol and mortality: Evidence of a U-shape Relationship

#32

Post by sooheon »

lvass wrote: post #31
sooheon wrote: post #30

Earlier quoted context omitted.

I don't know 100%. I'm not a lipidologist or god. However, logically my post does not entirely rely on knowing the precise in vivo mechanism of statins and their causal health effects. We only need to see that in RCTs, lowered cholesterol doesn't cause increased mortality as these observational studies would suggest. That is a pretty direct test of the null hypothesis. edit re your alternative hypothesis: what is thi…

If you don't assume we don't know nearly anything, you're bound to jump into some early and bad conclusions. I have no idea what such condition may be. Heck, a year ago we thought the human body had a different number of bones than we do now. We definitely do not understand how cholesterol in the diet or otherwise affects health, and using statin studies is a really long shot.

I assume we know nothing, but multiple RCTs with tens of thousands of participants in agreement tend to be the strongest forms of evidence we have in clinical matters: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...

I think you have an axe to grind re: dietary cholesterol, which I have made no statements on one way or the other. Don't read more into my post than what's there.

Re: Cholesterol and mortality: Evidence of a U-shape Relationship

#34

Post by darawk »

sooheon wrote: post #30
lvass wrote: post #29

Earlier quoted context omitted.

Please enlighten us how you know statin health effects are 100% related to the fact their usage happen to reduce TC measurements, as your entire post assumes that. Alternative hypothesis: high cholesterol is correlated (a small part of TC is from eating) with some adverse medical condition that statins are effective against. From this cohort, statin users measure lower cholesterol and die less. That lower cholesterol…

I don't know 100%. I'm not a lipidologist or god. However, logically my post does not entirely rely on knowing the precise in vivo mechanism of statins and their causal health effects. We only need to see that in RCTs, lowered cholesterol doesn't cause increased mortality as these observational studies would suggest. That is a pretty direct test of the null hypothesis. edit re your alternative hypothesis: what is thi…

> However, logically my post does not entirely rely on knowing the precise in vivo mechanism of statins and their causal health effects. We only need to see that in RCTs, lowered cholesterol doesn't cause increased mortality as these observational studies would suggest. That is a pretty direct test of the null hypothesis.

It doesn't quite prove that, though. It proves that statins do not increase mortality risk on net. But it doesn't prove that reducing cholesterol by other means wouldn't increase mortality risk. It's possible, for instance, that lower cholesterol does increase mortality, but that statins are offsetting that increase in some other way.

Re: Cholesterol and mortality: Evidence of a U-shape Relationship

#35

Post by radford-neal »

sooheon wrote: post #14

This is not a new finding. It's common enough to have a name: the cholesterol paradox ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374572/ ). Also replicated in a more recent n=100k Denmark study: https://www.bmj.com/content/371/bmj.m4266 These are all observational studies, meaning cause and effect is not established. It's relevant that people with some cancers will have very low cholesterol (the cancer apparentl…

"...there are no strong theories for the diseases caused by low cholesterol..."

Well, the body has a whole mechanism for manufacturing cholesterol, so it must be good for something. It seems obvious that there's some level at which low cholesterol must cause death. A U-shaped cholesterol-mortality curve is pretty much guaranteed to exist. The only question is where the minimum is.

Re: Cholesterol and mortality: Evidence of a U-shape Relationship

#36

Post by staticassertion »

radford-neal wrote: post #35
sooheon wrote: post #14

This is not a new finding. It's common enough to have a name: the cholesterol paradox ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374572/ ). Also replicated in a more recent n=100k Denmark study: https://www.bmj.com/content/371/bmj.m4266 These are all observational studies, meaning cause and effect is not established. It's relevant that people with some cancers will have very low cholesterol (the cancer apparentl…

"...there are no strong theories for the diseases caused by low cholesterol..." Well, the body has a whole mechanism for manufacturing cholesterol, so it must be good for something. It seems obvious that there's some level at which low cholesterol must cause death. A U-shaped cholesterol-mortality curve is pretty much guaranteed to exist. The only question is where the minimum is.

> Well, the body has a whole mechanism for manufacturing cholesterol, so it must be good for something.

It's good for all sorts of things, for example building cells - cell membranes are made of cholesterol, which is why our body produces a shitload of it.

Re: Cholesterol and mortality: Evidence of a U-shape Relationship

#37

Post by c54 »

radford-neal wrote: post #35
sooheon wrote: post #14

This is not a new finding. It's common enough to have a name: the cholesterol paradox ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374572/ ). Also replicated in a more recent n=100k Denmark study: https://www.bmj.com/content/371/bmj.m4266 These are all observational studies, meaning cause and effect is not established. It's relevant that people with some cancers will have very low cholesterol (the cancer apparentl…

"...there are no strong theories for the diseases caused by low cholesterol..." Well, the body has a whole mechanism for manufacturing cholesterol, so it must be good for something. It seems obvious that there's some level at which low cholesterol must cause death. A U-shaped cholesterol-mortality curve is pretty much guaranteed to exist. The only question is where the minimum is.

Cell membranes (remember the “lipid bilayer”?) include cholesterol molecules floating around within the phospholipid matrix to help the cell membrane stay flexible and flowy. This is the case for all cell membranes in the body, afaik.

Re: Cholesterol and mortality: Evidence of a U-shape Relationship

#39

Post by sooheon »

darawk wrote: post #34
sooheon wrote: post #30

Earlier quoted context omitted.

I don't know 100%. I'm not a lipidologist or god. However, logically my post does not entirely rely on knowing the precise in vivo mechanism of statins and their causal health effects. We only need to see that in RCTs, lowered cholesterol doesn't cause increased mortality as these observational studies would suggest. That is a pretty direct test of the null hypothesis. edit re your alternative hypothesis: what is thi…

> However, logically my post does not entirely rely on knowing the precise in vivo mechanism of statins and their causal health effects. We only need to see that in RCTs, lowered cholesterol doesn't cause increased mortality as these observational studies would suggest. That is a pretty direct test of the null hypothesis. It doesn't quite prove that, though. It proves that statins do not increase mortality risk on ne…

> it doesn't prove that reducing cholesterol by other means wouldn't increase mortality risk. It's possible, for instance, that lower cholesterol does increase mortality, but that statins are offsetting that increase in some other way.

It's within the realm of possibility, but very unlikely given the state of the evidence.

Ok, ignore statins because that seems to be a trigger. Another way to test this hypothesis is to look at people with polymorphisms in their lipid regulation genes that cause different cholesterol levels, ranging from familial hypercholesterolemia to the opposite, lifelong low cholesterol. Drugs don't come into this, so it's not an intervention trial or RCT, but it's called a Mendelian randomization trial. Here's one: https://www.jacc.org/doi/full/10.1016/j.jacc.2012.09.017

> All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I2 = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10−19).

Re: Cholesterol and mortality: Evidence of a U-shape Relationship

#40

Post by sooheon »

radford-neal wrote: post #35
sooheon wrote: post #14

This is not a new finding. It's common enough to have a name: the cholesterol paradox ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374572/ ). Also replicated in a more recent n=100k Denmark study: https://www.bmj.com/content/371/bmj.m4266 These are all observational studies, meaning cause and effect is not established. It's relevant that people with some cancers will have very low cholesterol (the cancer apparentl…

"...there are no strong theories for the diseases caused by low cholesterol..." Well, the body has a whole mechanism for manufacturing cholesterol, so it must be good for something. It seems obvious that there's some level at which low cholesterol must cause death. A U-shaped cholesterol-mortality curve is pretty much guaranteed to exist. The only question is where the minimum is.

Yeah good point. The point is not that lower serum cholesterol must be monotonically better down to 0, just that observational studies like this overestimate the the minimum due to confounders like underlying disease.
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