Reddit reviews Fat and Cholesterol Don’t Cause Heart Attacks and Statins Are Not The Solution

As already discussed, this review has a lot of shortcomings.

I'll reproduce my own comment down below.

Looking at table one, it appears they completely disregard the high likelyhood reverse causality.

The authors state:

>Older subgroups general populations exhibit no positive associations, but often inverse associations between LDL and ASCVD.

and

>All-cause mortality is the most important endpoint for cholesterol-related health issues. In many propesctive cohort studies, high LDL levels are associated with low all-cause mortality due to low rates of cancer, stroke and infectious disease, and high LDL-C is a predictor of longevity.

They completely fail to mention this:

1 Check out Figure 2. Cholesterol concentrations in populations with higher average cholesterol drop in later life. Not in populations with lower avg cholesterol. Obviously we shouldn't over interpret this graph. However, it indicated that disease might cause lower LDL-C and not the other way around.

There are two interesting studies about a man2 and his relatives3 with familial Hypobetalipoproteinemia. The man has LDL-C of 4-8 mg/dl, low HDL and normal-ish Triglycerides. He's healthy overall, even though he has a slight fat mal-absorbtion.

The relatives are healthy, have LDL-C down to 1 mg/dl and have no heart disease. Lifelong LDL-C doesn't appear to be a problem.

However, Hypobetalipoproteinemia is a disease with many faces.4

This study describes children having neurological disorders among other problems. However, their TAG were unusually low. That indicates a larger problem of fat transport in the blood.

Anyways, you can't get your LDL-C this low with diet or normal statin dosage.

The most interesting and important paper, the authors of OPs paper completely disregard.

Cancer, patients often have low cholesterol scores. However, this appears to be because of the cancer and not the other way around.5 By the way the study is great, i'd recommend a read.

>Our results indicate a strong time-dependent association of TSC with overall cancer incidence and several site-specific malignancies in both men and women, with a significant risk excess in the lowest TSC tertile for malignancies diagnosed shortly after baseline TSC measurement. While further research is needed to shed light on the underlying pathophysiological mechanisms, the pattern of association seen in the present study supports the hypothesis that the inverse association of high TSC levels with cancer risk may largely be attributable to reverse causation due to preclinical malignancies.

Neglecting these pieces of evidence sheds doubt on the paper imo.

And u/shlevon's comment.

This paper is honestly pretty weird, looking at it. Besides what u/AcceptableCause pointed out, there are lots of little baffling things strewn throughout.

For instance, in the mendelian randomization section, they lead off with:

>We are relatively new to the field of Mendelian randomization studies and would find it challenging to evaluate the methodology and results in detail.

That's kind of an odd thing to disclaimer, and begs the question of how they're in a position to evaluate this evidence. Not exactly confidence inspiring.

Within their critique of the mendelian randomization studies, the authors keep noting (over and over) throughout this section that the risk reductions seen with the various LDL receptor mutations involve far more risk reduction than statins.

E.g.:

>Analysis of the data in Table 2 revealed that increased LDL-C was highly positively associated with increased MI risk, with a regression coefficient of 0.89 and a 10-mg/dL decrease in LDL-C corresponding to a 48\% decrease in MI risk. An association of this strength has never been reported for cholesterol-lowering medications.

Uh...yah, because risk reduction in statins is usually over compressed timeframes in already-sick populations, and risk reduction with genetic mutations are, by definition, lifelong, acting over decades before these diseases have already manifested. The fact that they're pointing this out as suspicious is pretty odd.

Further, they're kind of ignoring the central point of the mendelian randomization studies presented in the paper they're attempting to critique, which is that the mendelian randomization studies involve many dozens of different mutations all occurring through different biochemical pathways. Despite this, they converge in effect that's directly proportional to the reduction in LDL seen in each of these ~50 different mutations. If what they were suggesting is true (that somehow, despite these being LDL receptor mutations, that their impact on ASCVD is being mediated by incidental non-LDL factors), this would apparently be the world's biggest coincidence.

I also can't help but notice that they don't even attempt to critique one of the cornerstone pieces of evidence used in the European paper, which is that literally every mammal tested to date (including close primate relatives like chimpanzees) can have atherosclerosis induced via elevating their endogenous LDL. In any discussion of LDL's causal role in ASCVD it seems odd not to at least address the many mammalian models of induced atherosclerosis.

You'll also note repeated citation of #10 in their list throughout this paper. I haven't counted but while reading I saw it cited so much I had to look. What is it?

A book co-authored by a lead author in this paper. Citing secondary works like this rather than primary research is generally considered poor form. Citing secondary works that you co-authored even more so.

The book was also co-authored by Uffe Ravnskov, notorious author of the "Cholesterol myth" books. All in all, some pretty big red flags imo.

This paper is honestly pretty weird, looking at it. Besides what u/AcceptableCause pointed out, there are lots of little baffling things strewn throughout.

For instance, in the mendelian randomization section, they lead off with:

> We are relatively new to the field of Mendelian randomization studies and would find it challenging to evaluate the methodology and results in detail.

That's kind of an odd thing to disclaimer, and begs the question of how they're in a position to evaluate this evidence. Not exactly confidence inspiring.

Within their critique of the mendelian randomization studies, the authors keep noting (over and over) throughout this section that the risk reductions seen with the various LDL receptor mutations involve far more risk reduction than statins.

E.g.:

> Analysis of the data in Table 2 revealed that increased LDL-C was highly positively associated with increased MI risk, with a regression coefficient of 0.89 and a 10-mg/dL decrease in LDL-C corresponding to a 48% decrease in MI risk. An association of this strength has never been reported for cholesterol-lowering medications.

Uh...yah, because risk reduction in statins is usually over compressed timeframes in already-sick populations, and risk reduction with genetic mutations are, by definition, lifelong, acting over decades before these diseases have already manifested. The fact that they're pointing this out as suspicious is pretty odd.

Further, they're kind of ignoring the central point of the mendelian randomization studies presented in the paper they're attempting to critique, which is that the mendelian randomization studies involve many dozens of different mutations all occurring through different biochemical pathways. Despite this, they converge in effect that's directly proportional to the reduction in LDL seen in each of these ~50 different mutations. If what they were suggesting is true (that somehow, despite these being LDL receptor mutations, that their impact on ASCVD is being mediated by incidental non-LDL factors), this would apparently be the world's biggest coincidence.

I also can't help but notice that they don't even attempt to critique one of the cornerstone pieces of evidence used in the European paper, which is that literally every mammal tested to date (including close primate relatives like chimpanzees) can have atherosclerosis induced via elevating their endogenous LDL. In any discussion of LDL's causal role in ASCVD it seems odd not to at least address the many mammalian models of induced atherosclerosis.

You'll also note repeated citation of #10 in their list throughout this paper. I haven't counted but while reading I saw it cited so much I had to look. What is it?

A book co-authored by a lead author in this paper. Citing secondary works like this rather than primary research is generally considered poor form. Citing secondary works that you co-authored even more so.

The book was also co-authored by Uffe Ravnskov, notorious author of the "Cholesterol myth" books. All in all, some pretty big red flags imo.