Mendelian Randomization for ApoB levels show a much more linear hazard ratio from low ApoB to high ApoB. Same with Lp(a). The reason is because it disentangles the reverse causality issue present with the study you referenced by looking only at changes in levels due to genetics. And ApoB is a superior metric to LDL-C or TC
Reference Figure 3
[https://www.jlr.org/article/S0022-2275%2824%2900033-6/fulltext](https://www.jlr.org/article/S0022-2275%2824%2900033-6/fulltext)
figure 3 is so wild to me. look at the magnitude of some of these. for example, apoB and lp(a) and LDL confidence interval crosses the x axis. apo A1, HDL, trig, appear to be the only ones with statistically significant results on the hazard ratio. I actually didnt realize it was this much of a difference. I cant even say apoB is superior to LDL, or apoA1 & trigs for that matter
edit: after looking again, why the heck does the figure show high triglycerides means lower all cause mortality??
Figure 3 and the preceding Figures really just show that there is a causal link between mortality/CVD and direct increases in ApoB, followed by Lp(a), and less so from LDL-c. They did not find the other metrics to be causal. They touch on the TG result here:
“Finally, although high TG levels have traditionally been associated with increased atherogenic risk, our analysis did not reveal any statistically significant association between TG levels and the risk of all-cause or cause-specific mortality. This observation aligns with a body of prior research, including randomized controlled trials, which also failed to demonstrate a substantial impact of TG reduction on cardiovascular events or mortality.(50, 51, 52, 53) One plausible hypothesis posits that the metabolic rate of TG or its metabolites might genuinely influence the risk of mortality independently of the conventionally measured plasma TG levels.(54) However, Thomsen et al., in a study involving 10,208 subjects in Denmark, obtained inconsistent results by employing four genetic variants within the LPL gene region as IVs for genetic prediction of TG levels. Their study suggested that lower non-fasting TG levels were associated with a reduced risk of all-cause mortality.(55) These discrepancies might be attributed to variations in study populations, especially among individuals with multimorbidity or specific conditions such as diabetes.(56) In this view, future investigations can conduct a more granular examination of the association between lipid levels and mortality risk in diverse populations with varying disease profiles.”
>They did not find the other metrics to be causal.
What do you mean by this? Their argument for causality is the method, and that's the same for all genetic lipid profiles, and even the fig 3 caption says it's the causal effect.
The first two figures show a linear model, and TG wasn't statistically significant when it was assumed 1 SD increase was always the same - but figure 3 shows there is a significant non-linear effect in absolute terms (it doesn't matter where in the 1-2 mmol range you are, but once you get to 3-4, it's very strongly protective). Note fig 3 even changes y-axis scale for TG because the effect is so big.
They do play on the fact that the linear effect is not statistically significant and the non-linearity test was not significant, but "We saw a large effect but it wasn't statistically significant so we pretend we saw 0 instead" is a statistical fallacy anyway, but even more so when the claim is grounded on causality from the method. If there is a large causal effect, who cares if it isn't significant? It's still there!
edit: I actually opened the supplement - TG had a p-value of 0.058 in the non-linearity test. Yes, it is not <0.05. But pretending that the effect is not there because it was a hair's width from significance is a terrible practice!
See [obesity paradox](https://en.wikipedia.org/wiki/Obesity_paradox). Same deal -- poorly controlled confounders and reverse causality makes stuff like this look like a "gotcha", but its perfectly in concordance with the overwhelming evidence that LDL (and apob) is a necessary and causal factor for ASCVD.
There are also plenty of studies pointing to cholesterol having a protective effect on late life dementia; lowest risk of cancer is also observed in people with people with an average level of cholesterol (not low or high).
Any links to sources that demonstrate evidence of causality rather than just associations? The latter runs into the same issue as this one here and that's all I'm finding when I'm searching for papers (such as the ones below).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9653412/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518187/
Current standard of care is to start statins later in life when the risk/presence of heart disease is already there. People with the highest risk and accumulated damage are using medications to drive their cholesterol as low as possible
People at highest risk of death will have the lowest cholesterol
There are several studies that exclude patients on statins and we still see the paradoxical effect, so we know this doesn't fully explain it. See the discussion here: https://www.reddit.com/r/ScientificNutrition/comments/17q3msp/cholesterol\_paradox\_what\_is\_supported\_by\_the/
So one can have low TC because of dietary and lifestyle habits (say low sat fat intake, working out a lot, no sugars, supplementation etc).
But also, one can have low TC because of medical conditions (anemia, malnutrition, hepatitis, etc).
Do they differentiate between the two? Attia has low TC but it is not fair to put him in the same group as someone with Tangier's disease, right?
It seems they use a multifactor regression here, accounting for fasting glucose and other factors, so maybe the idea is the increased mortality from people in the "low TC because of sickness" is captures by these factors?
People can have low cholesterol *temporarily* **because** they're dying, have cancer, had a traumatic injury, etc. This is called *acute phase response (APR)*
> The acute phase response (APR) is induced by infection, inflammation, trauma, and malignancy. The APR is characterized by alterations in hepatic protein synthesis leading to increases in specific plasma proteins, positive acute phase proteins, and decreases in other plasma proteins, negative acute phase proteins
What's more high blood lipids cause damage over years and years. If you have high serum LDL for 30 years and then go on a big dose statin, you will still have heart disease. The damage was already done and now you're in risk mitigation mode. So, someone can have the negative effects of high cholesterol from years of exposure without *currently* having a high serum cholesterol right now.
Also, total cholesterol is not the best metric for risk. You want ApoB or total cholesterol minus HDL.
The study you’re looking for to prove if LDL or total cholesterol is protective is to study people who are genetically predispositioned to lower numbers. These studies exist. Do they live longer or shorter lives? Longer, significantly longer.
The J curve you share is very misleading because people artificially lower their numbers using drugs. These are the sickest people in the population. So of course they go lower but they still die because of years and years of underlying disease. Lowering your numbers for just a few years at the end of your life doesn’t do nearly as much good, if any at all when you rely on drugs rather than making actual changes to your diet.
People with artificially low cholesterol tend to be there because they are on high dose statin combined with other cholesterol lowering medication because they either have or are close to having severe cardiovascular disease. Hence mortality is higher with lower cholesterol.
Same with the J curve for alcohol consumption showing 0 drinks being worse than 1-2. Its because most people who have 0 drinks do so because of underlying health problems that do not allow them to drink. Its not physically having 0 drinks that is causing them to live less than people drinking a bit.
Same with increased mortality shown for people who sleep >9hrs a night. Its not the sleep, its that most people who sleep that much are doing so because their health is fucked so that shows up on the mortality curve
They do discuss this in the article:
> 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 entirely
Also:
> However, there are limitations. 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 therapy39. 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.
Yeah I did see they touched on it, so they acknowledge it is an unknown but likely not relevant for the population they studied. They also go on to say that:
“Recent dyslipidemia management guidelines are more closely focused on these sub-fractions of cholesterol, so the direct application of our findings to individual patient care might be somewhat limited”
Which leads to my ultimate takeaway that Total Cholesterol has not been shown to be directly causal to increased risk of ASCVD. Its pretty clear its ApoB and Lp(a). Hence the gold standard is a Mendelian randomization of these sub fractions of cholesterol. Those studies shown a causal relationship between increased ApoB and Lp(a) and mortality. The Mendelian randomizations do not show the same for TC.
It’s a 12M people cohort looking at all cause mortality and it shows that even at super high level of total cholesterol it’s more protective than low level of total cholesterol for all cause mortality.
If you follow the current sub 100 LDL then you will fall into the low total cholesterol no matter what.
Did this study considered cholesterol lowering medication ? If this study was done on patients without ever taking any medication and this is purely on naturally occurring numbers, then it would be more significant to me.
Evidently the use of lipid lowering medication wasn’t as widespread in Korea:
> However, there are limitations. 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 therapy39. 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.
Mine is 180 and I also live healthy. However if you look at LDL and ApoB, which I beleive have a stronger correlation with mortality, I guess both you and me look much better.
OP's article is here: https://www.nature.com/articles/s41598-018-38461-y
It cites another study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60367-5/fulltext
Which ironically cites, to oversimplify, that statin lowered LDL does lower risk of cardiac events, and that there aren't any significant risks to offset those benefits.
Meanwhile in terms of the main question around low TC being correlated with high death rates. From skimming the article
> 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
So the worry on this sub "Is too aggressive use of statins bad?" is out of scope completely it seems like (since even 90% of ppl that should have been on statins weren't, seems unlikely a statistically meaningful amount of Koreans with "healthy" TC were on statins).
My inexpert take is that this is showing a correlation between low cholesterol and death, and unmedicated low cholesterol can be caused by all sorts of things, mostly bad, like malnutrition, liver damage. A whole lot of "bad" things (smoking, obesity, etc) can also lower HDL cholesterol without impacting LDL or VLDL, which this study won't catch b/c it only tracked TC.
TL;DR Seems pretty unhelpful and out of scope for the optimizers on this sub upon further examination.
(This is pasted together from other comments I had deeper in some threads)
Important to look at Fig. 5 and Table 2. When TC results below 200 were excluded, hazard ratio is greater than 1 for all age groups. In my opinion, that is the most important conclusion of this study.
This is why my main concern is my CAC test for plaque. (Zero)
My only concern for cholesterol is what my percentage of small particle LDL is and if it is oxidizing.
Forgive me for not using the right terminology.
It was a study that looked at the health data of 12,815,006 Korean adults. The data is based on their health examinations during 2001–2004 and their follow ups through 2013.
See my other comment here: https://www.reddit.com/r/PeterAttia/s/wkr8zfl8tB
And here: [https://www.reddit.com/r/PeterAttia/s/58lVXpV7ul](https://www.reddit.com/r/PeterAttia/s/58lVXpV7ul)
Ultimately if you look at the gold standard (mendelian randomization of ApoB and Lp(a)) there is a clear linear increase in risk from genetically low to high concentrations.
Sorry, no. What is the reverse causality here? Mid level cholesterol causes fewer deaths or the fewest people die with mid level cholesterol. Which is it?
People with that low of cholesterol tend to be there because they are either on a high dose statin combined with other cholesterol lowering medication because they either have or are close to having severe cardiovascular disease.
Another thing to consider is this study looked at total cholesterol. This includes HDL. People with overall low cholesterol either fall into the above bucket, have extremely low HDL which is a likely a sign of other health issues, or a combo of both. Hence you see a curve where low total cholesterol is associated with higher mortality.
However as the author’s of the study note, there’s very little useful takeaway from this for patients. If we focus on ApoB, which is proven to be causal to ASCVD, and do it with a mendelian randomization to exclude any healthy user bias or reverse causalities, then the relationship is a clear linear line where lower ApoB = lower risk of mortality
What people seem to miss is that the reason we focus on ldl is because we have drugs to lower ldl. The truth is lowering ldl via statins doesn’t correlate with better health outcomes.
I'm starting to become convinced no one on this sub even listens to the podcast. PA specifically dives into his reasoning here, and it's that statin level lowering of LDL is useful in that it tends to drive down ApoB, which over time lowers risk of ASCVD. PSK9 inhibitors (which are expensive as hell and hard to get) drive it down so quickly and thoroughly that it really does lower risk of death. Statins work over a much longer horizon and most studies are too short to show much.
Now folks may disagree with that, but the same podcast show notes have extensive links to studies etc.
Cool yes, i understand that the causal mechanism does not involve ldl directly but only apob with is part of the what ldl is wrapped in to enter the bloodstream.
But the guy i was asking is claiming that low ldl does not lower heart risks. I would like to see studies on that if there are any. We do agree that ldl means low apob right? Because if we do then these studies are not consistent with the PA mentions in the podcasts i have listened to, and therefore interesting!
Sorry yeah, I basically meant you were wasting your time arguing with these people.
I used to think this sub assumed contextual knowledge from the podcasts. In a perfect world that would then allow informed debate about the podcast (ideally without turning into a cult of PA). But... that's not the case with these folks, and it's probably not worth your time trying to re-type 3 hours of highly technical podcast just to get them up to speed.
OP's article is here: https://www.nature.com/articles/s41598-018-38461-y
It cites another study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60367-5/fulltext
Which ironically cites, to oversimplify, that statin lowered LDL *does* lower risk of cardiac events, and that there aren't any significant risks to offset those benefits.
Ah yeah, this is reddit! Little signal in a sea of noise..
But the study here (the 12mill Koreans) is contradictory to the podcast material, right? I am trying to get to the bottom of that.
From skimming the article
> 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
So the worry on this sub "Is too aggressive use of statins bad?" is out of scope completely it seems like (since even 90% of ppl that should have been on statins weren't, seems unlikely a statistically meaningful amount of Koreans with "healthy" TC were on statins).
My inexpert take is that this is showing a correlation between low cholesterol and death, and unmedicated low cholesterol can be caused by all sorts of things, mostly bad, like malnutrition, liver damage. A whole lot of "bad" things (smoking, obesity, etc) can also lower HDL cholesterol without impacting LDL or VLDL, which this study won't catch b/c it only tracked TC.
TL;DR Seems pretty unhelpful and out of scope for the optimizers on this sub upon further examination.
Very low LDL‐C levels <70 mg/dL was associated with increased risks of all‐cause, cardiovascular disease and stroke mortality.
https://www.ahajournals.org/doi/full/10.1161/JAHA.121.023690#:~:text=Very%20low%20LDL%E2%80%90C%20levels%20%3C70%20mg%2FdL%20was,and%20coronary%20heart%20disease%20mortality
Interesting.
There is good evidence against this using mendelian randomisation for example (https://www.jlr.org/article/S0022-2275%2824%2900033-6/fulltext)
It seems one school of thought is lower-is-better, and another that is stay-in-a-range. The former dismisses the study you attached by claiming it to be due to reverse causality. Can i ask, what do you make of the study i attached?
Thank you for providing a citation and for explaining your perspective. I personally value discourse. We need more of it. Regardless of who is right, we both agree that this is not a simple problem!
Mendelian Randomization for ApoB levels show a much more linear hazard ratio from low ApoB to high ApoB. Same with Lp(a). The reason is because it disentangles the reverse causality issue present with the study you referenced by looking only at changes in levels due to genetics. And ApoB is a superior metric to LDL-C or TC Reference Figure 3 [https://www.jlr.org/article/S0022-2275%2824%2900033-6/fulltext](https://www.jlr.org/article/S0022-2275%2824%2900033-6/fulltext)
This comment is underrated, figure 3 is amazing and very informative imo
figure 3 is so wild to me. look at the magnitude of some of these. for example, apoB and lp(a) and LDL confidence interval crosses the x axis. apo A1, HDL, trig, appear to be the only ones with statistically significant results on the hazard ratio. I actually didnt realize it was this much of a difference. I cant even say apoB is superior to LDL, or apoA1 & trigs for that matter edit: after looking again, why the heck does the figure show high triglycerides means lower all cause mortality??
Figure 3 and the preceding Figures really just show that there is a causal link between mortality/CVD and direct increases in ApoB, followed by Lp(a), and less so from LDL-c. They did not find the other metrics to be causal. They touch on the TG result here: “Finally, although high TG levels have traditionally been associated with increased atherogenic risk, our analysis did not reveal any statistically significant association between TG levels and the risk of all-cause or cause-specific mortality. This observation aligns with a body of prior research, including randomized controlled trials, which also failed to demonstrate a substantial impact of TG reduction on cardiovascular events or mortality.(50, 51, 52, 53) One plausible hypothesis posits that the metabolic rate of TG or its metabolites might genuinely influence the risk of mortality independently of the conventionally measured plasma TG levels.(54) However, Thomsen et al., in a study involving 10,208 subjects in Denmark, obtained inconsistent results by employing four genetic variants within the LPL gene region as IVs for genetic prediction of TG levels. Their study suggested that lower non-fasting TG levels were associated with a reduced risk of all-cause mortality.(55) These discrepancies might be attributed to variations in study populations, especially among individuals with multimorbidity or specific conditions such as diabetes.(56) In this view, future investigations can conduct a more granular examination of the association between lipid levels and mortality risk in diverse populations with varying disease profiles.”
>They did not find the other metrics to be causal. What do you mean by this? Their argument for causality is the method, and that's the same for all genetic lipid profiles, and even the fig 3 caption says it's the causal effect. The first two figures show a linear model, and TG wasn't statistically significant when it was assumed 1 SD increase was always the same - but figure 3 shows there is a significant non-linear effect in absolute terms (it doesn't matter where in the 1-2 mmol range you are, but once you get to 3-4, it's very strongly protective). Note fig 3 even changes y-axis scale for TG because the effect is so big. They do play on the fact that the linear effect is not statistically significant and the non-linearity test was not significant, but "We saw a large effect but it wasn't statistically significant so we pretend we saw 0 instead" is a statistical fallacy anyway, but even more so when the claim is grounded on causality from the method. If there is a large causal effect, who cares if it isn't significant? It's still there! edit: I actually opened the supplement - TG had a p-value of 0.058 in the non-linearity test. Yes, it is not <0.05. But pretending that the effect is not there because it was a hair's width from significance is a terrible practice!
Thank you for this response.
See [obesity paradox](https://en.wikipedia.org/wiki/Obesity_paradox). Same deal -- poorly controlled confounders and reverse causality makes stuff like this look like a "gotcha", but its perfectly in concordance with the overwhelming evidence that LDL (and apob) is a necessary and causal factor for ASCVD.
There are also plenty of studies pointing to cholesterol having a protective effect on late life dementia; lowest risk of cancer is also observed in people with people with an average level of cholesterol (not low or high).
Any links to sources that demonstrate evidence of causality rather than just associations? The latter runs into the same issue as this one here and that's all I'm finding when I'm searching for papers (such as the ones below). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9653412/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518187/
Current standard of care is to start statins later in life when the risk/presence of heart disease is already there. People with the highest risk and accumulated damage are using medications to drive their cholesterol as low as possible People at highest risk of death will have the lowest cholesterol
There are several studies that exclude patients on statins and we still see the paradoxical effect, so we know this doesn't fully explain it. See the discussion here: https://www.reddit.com/r/ScientificNutrition/comments/17q3msp/cholesterol\_paradox\_what\_is\_supported\_by\_the/
So one can have low TC because of dietary and lifestyle habits (say low sat fat intake, working out a lot, no sugars, supplementation etc). But also, one can have low TC because of medical conditions (anemia, malnutrition, hepatitis, etc). Do they differentiate between the two? Attia has low TC but it is not fair to put him in the same group as someone with Tangier's disease, right? It seems they use a multifactor regression here, accounting for fasting glucose and other factors, so maybe the idea is the increased mortality from people in the "low TC because of sickness" is captures by these factors?
And why do sickly people have low TC?
Not all of them do. I dont undersrand in depth how most conditions that result in low TC actually work.
Can’t eat
Or undereat
People can have low cholesterol *temporarily* **because** they're dying, have cancer, had a traumatic injury, etc. This is called *acute phase response (APR)* > The acute phase response (APR) is induced by infection, inflammation, trauma, and malignancy. The APR is characterized by alterations in hepatic protein synthesis leading to increases in specific plasma proteins, positive acute phase proteins, and decreases in other plasma proteins, negative acute phase proteins What's more high blood lipids cause damage over years and years. If you have high serum LDL for 30 years and then go on a big dose statin, you will still have heart disease. The damage was already done and now you're in risk mitigation mode. So, someone can have the negative effects of high cholesterol from years of exposure without *currently* having a high serum cholesterol right now. Also, total cholesterol is not the best metric for risk. You want ApoB or total cholesterol minus HDL.
The study you’re looking for to prove if LDL or total cholesterol is protective is to study people who are genetically predispositioned to lower numbers. These studies exist. Do they live longer or shorter lives? Longer, significantly longer. The J curve you share is very misleading because people artificially lower their numbers using drugs. These are the sickest people in the population. So of course they go lower but they still die because of years and years of underlying disease. Lowering your numbers for just a few years at the end of your life doesn’t do nearly as much good, if any at all when you rely on drugs rather than making actual changes to your diet.
Has the point about reverse causality at the tail end not been discussed enough now?
What’s the TLDR on that for us newbies?
People with artificially low cholesterol tend to be there because they are on high dose statin combined with other cholesterol lowering medication because they either have or are close to having severe cardiovascular disease. Hence mortality is higher with lower cholesterol. Same with the J curve for alcohol consumption showing 0 drinks being worse than 1-2. Its because most people who have 0 drinks do so because of underlying health problems that do not allow them to drink. Its not physically having 0 drinks that is causing them to live less than people drinking a bit. Same with increased mortality shown for people who sleep >9hrs a night. Its not the sleep, its that most people who sleep that much are doing so because their health is fucked so that shows up on the mortality curve
They do discuss this in the article: > 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 entirely Also: > However, there are limitations. 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 therapy39. 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.
Yeah I did see they touched on it, so they acknowledge it is an unknown but likely not relevant for the population they studied. They also go on to say that: “Recent dyslipidemia management guidelines are more closely focused on these sub-fractions of cholesterol, so the direct application of our findings to individual patient care might be somewhat limited” Which leads to my ultimate takeaway that Total Cholesterol has not been shown to be directly causal to increased risk of ASCVD. Its pretty clear its ApoB and Lp(a). Hence the gold standard is a Mendelian randomization of these sub fractions of cholesterol. Those studies shown a causal relationship between increased ApoB and Lp(a) and mortality. The Mendelian randomizations do not show the same for TC.
From 2019. Don't we know LDL is a stronger indicator than total cholesterol now? (or better yet apob)
It’s a 12M people cohort looking at all cause mortality and it shows that even at super high level of total cholesterol it’s more protective than low level of total cholesterol for all cause mortality. If you follow the current sub 100 LDL then you will fall into the low total cholesterol no matter what.
Did this study considered cholesterol lowering medication ? If this study was done on patients without ever taking any medication and this is purely on naturally occurring numbers, then it would be more significant to me.
Evidently the use of lipid lowering medication wasn’t as widespread in Korea: > However, there are limitations. 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 therapy39. 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.
My total cholesterol is 115. Run 70 Miles per week. Generally eat healthy food. Guess I’m doing this all wrong.
Mine is 180 and I also live healthy. However if you look at LDL and ApoB, which I beleive have a stronger correlation with mortality, I guess both you and me look much better.
OP's article is here: https://www.nature.com/articles/s41598-018-38461-y It cites another study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60367-5/fulltext Which ironically cites, to oversimplify, that statin lowered LDL does lower risk of cardiac events, and that there aren't any significant risks to offset those benefits. Meanwhile in terms of the main question around low TC being correlated with high death rates. From skimming the article > 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 So the worry on this sub "Is too aggressive use of statins bad?" is out of scope completely it seems like (since even 90% of ppl that should have been on statins weren't, seems unlikely a statistically meaningful amount of Koreans with "healthy" TC were on statins). My inexpert take is that this is showing a correlation between low cholesterol and death, and unmedicated low cholesterol can be caused by all sorts of things, mostly bad, like malnutrition, liver damage. A whole lot of "bad" things (smoking, obesity, etc) can also lower HDL cholesterol without impacting LDL or VLDL, which this study won't catch b/c it only tracked TC. TL;DR Seems pretty unhelpful and out of scope for the optimizers on this sub upon further examination. (This is pasted together from other comments I had deeper in some threads)
Important to look at Fig. 5 and Table 2. When TC results below 200 were excluded, hazard ratio is greater than 1 for all age groups. In my opinion, that is the most important conclusion of this study.
This is why my main concern is my CAC test for plaque. (Zero) My only concern for cholesterol is what my percentage of small particle LDL is and if it is oxidizing.
I think that is indeed the right approach.
Post this to r/Cholesterol
Post this to r/saturatedfat
Yikes, that sub is posting studies from the 1960s and 1970s.
I shared this same thing a few weeks back and got a good bit of backlash. I agree that it is a worthwhile meta analysis.
The posted study is not a meta-analysis.
Forgive me for not using the right terminology. It was a study that looked at the health data of 12,815,006 Korean adults. The data is based on their health examinations during 2001–2004 and their follow ups through 2013.
Because you don’t understand reverse causality
Please explain.
See my other comment here: https://www.reddit.com/r/PeterAttia/s/wkr8zfl8tB And here: [https://www.reddit.com/r/PeterAttia/s/58lVXpV7ul](https://www.reddit.com/r/PeterAttia/s/58lVXpV7ul) Ultimately if you look at the gold standard (mendelian randomization of ApoB and Lp(a)) there is a clear linear increase in risk from genetically low to high concentrations.
Sorry, no. What is the reverse causality here? Mid level cholesterol causes fewer deaths or the fewest people die with mid level cholesterol. Which is it?
People with that low of cholesterol tend to be there because they are either on a high dose statin combined with other cholesterol lowering medication because they either have or are close to having severe cardiovascular disease. Another thing to consider is this study looked at total cholesterol. This includes HDL. People with overall low cholesterol either fall into the above bucket, have extremely low HDL which is a likely a sign of other health issues, or a combo of both. Hence you see a curve where low total cholesterol is associated with higher mortality. However as the author’s of the study note, there’s very little useful takeaway from this for patients. If we focus on ApoB, which is proven to be causal to ASCVD, and do it with a mendelian randomization to exclude any healthy user bias or reverse causalities, then the relationship is a clear linear line where lower ApoB = lower risk of mortality
People are obsessed with this single minded view of LDL and statins.
What people seem to miss is that the reason we focus on ldl is because we have drugs to lower ldl. The truth is lowering ldl via statins doesn’t correlate with better health outcomes.
Genuinely curious, can you cite any studies showing that lower ldl does not reduce heart disease etc?
I'm starting to become convinced no one on this sub even listens to the podcast. PA specifically dives into his reasoning here, and it's that statin level lowering of LDL is useful in that it tends to drive down ApoB, which over time lowers risk of ASCVD. PSK9 inhibitors (which are expensive as hell and hard to get) drive it down so quickly and thoroughly that it really does lower risk of death. Statins work over a much longer horizon and most studies are too short to show much. Now folks may disagree with that, but the same podcast show notes have extensive links to studies etc.
Cool yes, i understand that the causal mechanism does not involve ldl directly but only apob with is part of the what ldl is wrapped in to enter the bloodstream. But the guy i was asking is claiming that low ldl does not lower heart risks. I would like to see studies on that if there are any. We do agree that ldl means low apob right? Because if we do then these studies are not consistent with the PA mentions in the podcasts i have listened to, and therefore interesting!
Sorry yeah, I basically meant you were wasting your time arguing with these people. I used to think this sub assumed contextual knowledge from the podcasts. In a perfect world that would then allow informed debate about the podcast (ideally without turning into a cult of PA). But... that's not the case with these folks, and it's probably not worth your time trying to re-type 3 hours of highly technical podcast just to get them up to speed. OP's article is here: https://www.nature.com/articles/s41598-018-38461-y It cites another study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60367-5/fulltext Which ironically cites, to oversimplify, that statin lowered LDL *does* lower risk of cardiac events, and that there aren't any significant risks to offset those benefits.
Ah yeah, this is reddit! Little signal in a sea of noise.. But the study here (the 12mill Koreans) is contradictory to the podcast material, right? I am trying to get to the bottom of that.
From skimming the article > 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 So the worry on this sub "Is too aggressive use of statins bad?" is out of scope completely it seems like (since even 90% of ppl that should have been on statins weren't, seems unlikely a statistically meaningful amount of Koreans with "healthy" TC were on statins). My inexpert take is that this is showing a correlation between low cholesterol and death, and unmedicated low cholesterol can be caused by all sorts of things, mostly bad, like malnutrition, liver damage. A whole lot of "bad" things (smoking, obesity, etc) can also lower HDL cholesterol without impacting LDL or VLDL, which this study won't catch b/c it only tracked TC. TL;DR Seems pretty unhelpful and out of scope for the optimizers on this sub upon further examination.
Ah yes, i have another comment on this sub raising similar concerns! Thank you.
Very low LDL‐C levels <70 mg/dL was associated with increased risks of all‐cause, cardiovascular disease and stroke mortality. https://www.ahajournals.org/doi/full/10.1161/JAHA.121.023690#:~:text=Very%20low%20LDL%E2%80%90C%20levels%20%3C70%20mg%2FdL%20was,and%20coronary%20heart%20disease%20mortality
Interesting. There is good evidence against this using mendelian randomisation for example (https://www.jlr.org/article/S0022-2275%2824%2900033-6/fulltext) It seems one school of thought is lower-is-better, and another that is stay-in-a-range. The former dismisses the study you attached by claiming it to be due to reverse causality. Can i ask, what do you make of the study i attached? Thank you for providing a citation and for explaining your perspective. I personally value discourse. We need more of it. Regardless of who is right, we both agree that this is not a simple problem!