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Comment by dnhz | Hacker News Reader

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.

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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.

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

because they had high cholesterol for decades and the damage is already done. Decreasing cholesterol helps them, but they are not as healthy as someone with naturally such low cholesterol.

But naturally low cholesterol was not associated with decreased mortality in Koreans?

This study doesn't tell us if these participants had naturally low cholesterol or artificially low cholesterol (i.e., from medications). So no such conclusion can be determined.

Agreed, yet that conclusion (that low cholesterol is somehow harmful) cannot be excluded either. I agree that it would be interesting to see how the results of the Korean study would change if statin-takers were excluded.

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

I agree with this conclusion.

Not all mortality risk operates through cholesterol-dependent mechanisms. And even for those that do, decades of exposure to high cholesterol can’t be totally reversed by medications.

That’s reasonable. Does that mean that another endpoint aside from cholesterol should be the target of control?

Ultimately you want a readout of CAD risk, and we know that only a portion of CAD risk is attributable to LDL. We're always on the lookout for better biomarkers, but right now there isn't a comprehensive CAD biomarker (aside, perhaps, from coronary calcium - but we can't go around exposing everyone to radiation every year just to observe disease progression).

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...

This is a mix of outdated and simply wrong information.

I’m unconvinced by your unsupported assertion.

True.

Also interesting: Current physician guidelines don't recommend treating to a specific number, like <200. When I trained (<5 years ago) we were taught to check cholesterol levels and if LDL > n then start a statin and increase the dose until LDL < n.

Now, its (almost) entirely risk assessment based: https://www.acc.org/latest-in-cardiology/ten-points-to-remem...

> "because statins have such a powerful effect on cholesterol"

They may lower cholesterol some amount, but in many populations this has almost 0 impact on morality. Watch out for those relative risk ratios.

Amusing typo (morality vs mortality)!

Bah, yea, seemingly can't edit it now.

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?

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.

Right, but I suppose the model for what's occurring then is: High cholesterol either is a marker of some otherwise unrelated health issue, or high cholesterol causes damage to accumulate over time. Beginning to take a statin would prevent the accumulation of further damage, but presumably not reverse that damage that has already occurred. Since I assume there is some benefit of statin intake in terms of actual outcomes, it would seem the latter model fits the data more closely. However, you could imagine a world where statin intake is actually just correlated with "being concerned enough about your health to visit a doctor and follow their instructions", which may be correlated with a turn towards a healthier lifestyle, etc.

It doesn't look like they directly test for this kind of thing, but they do address it:

Reverse causality has been suggested as an explanation of higher mortality associated with low cholesterol levels. However, a long term follow-up study in a Japanese-American population showed that individuals with low cholesterol levels maintained over a 20-year period had the worst all-cause mortality, and concluded that reverse causality was unlikely to account for the higher mortality associated with low cholesterol entirely14.

My reading of "reverse causality" here is that people with high TC have more cardiovascular disease and take more statins that lower their cholesterol. I haven't read the referenced study.

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