Thank you. Excellent observations, excellent points.
it is impossible to make an in depth decision on this, unless you have some degree in this and even then there is so much disagreement between MDās and other people with credentials. for me it comes down who do I trust, and I tend to follow Saladino (carnivoreMD) on this which would not ever recommend statins.
One last question: what levels define ānormalā and āhigh cholesterolā? Is it defined by what is average and above average based on modern people on modern diets. Or is it something else?
From reading some of the early papers on the paleo diet, I recall claims to the effect that hunter gatherers following traditional diets typically have TC in the 110-130 range, with LDC-c in the 50-70 range. I think most cardiologists would love these numbers, and large numbers of people on western diets would struggle to get to these levels without medication.
Likewise, I wonder then about people on carnivore or keto diets who have super high TC and LDL? Perhaps those high numbers are telling them their diets are not as concordant with their biology as they would like to believe?
As I understand it, the American College of Cardiology and the American Heart Association pow-wow and come up with adjusted numbers every so often, based on experience, opinion, and possibly bird droppings. Same goes for desirable blood pressure ranges. Same goes for optimal blood sugar readings and the American Diabetes Association.
As far as the keto and carnivore people and high TC, there is evidence ā not universally accepted, though ā that high saturated fat intake lead to high TC.
TC,
I love that you call them ācontrariansā rather than ādeniers.ā Some may be driven simply by a dogmatic anti-establishment mindset, but there are many brilliant, sincere, respected scholars who still find enough evidence to reject the cholesterol-heart disease theory. I donāt blame them, but I do disagree.
When evaluating the evidence they present, itās helpful to keep in mind a few principles:
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The atherogenic lipoproteins in the blood include LDL, VLDL, IDL, and Lp(a), all of which have an apolipoprotein B attached on their surface. The number of these particles in the blood, rather than the amount of cholesterol they contain, is what correlates with vascular disease. Apo B tells us precisely how many particles are present and is therefore the best measure of risk. LDL-C, however, is used in most studies, and itās a good surrogate. Total cholesterol is only roughly useful.
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The mountain of research confirming a link between LDL-C to heart disease is massive. For example, that Lancet article you referenced from 2007 is a meta-analysis of 61 studies including nearly a million people. Few relationships have been evaluated more thoroughly, and ā at the risk of committing an āappeal to authorityā fallacy ā few subjects have such widespread agreement among the experts who study it. The handful of studies failing to show a connection cannot be dismissed, but they must be viewed against this context.
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Such studies (cited by contrarians) are usually snapshots in time. These are unhelpful because the atherogenicity of LDL-C is, like any potential toxin, dependent on both dose and duration of exposure, and this can only be captured longitudinally.
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People with known CV disease are likely to be on cholesterol-lowering medication, yet their current LDL-C level ā which may be quite low ā says nothing about their cumulative lifetime exposure, which was probably much higher.
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Serum lipids decline naturally during advanced illness, toward the end of life (explaining the lack of association in old people), and acutely following myocardial infarction. LDL-C remains about 30% suppressed for a week following MI. Studies looking at patientsā cholesterol levels during hospitalization or at the time of a cardiac event thus do not accurately represent their lifetime exposure to elevated apo B-bearing lipoproteins.
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Mendelian randomization studies, however, do. These show an unambiguous, dose-dependent link between LDL-C and cardiovascular disease ā in both directions ā just as we would expect in a causal relationship. Genetic mutations causing high LDL-C consistently result in higher rates of premature CV disease. Conversely, the lucky souls with mutations like PCSK9 defects have super-low levels of LDL-C and virtually never get heart disease. (And they suffer no ill effects so far as we can tell.)
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Familial hypercholesterolemia confers a massive increased risk of coronary disease far earlier than the general population. Those who survive past age 60 tend to have mortality rates similar to background, but prior to that the risk of death from CHD is ā100-fold in young adults aged 20-39 years, and about 4-fold for patients 40-59 years.ā Patients with homozygous FH have an average lifespan of 33 years according to one study. Patients with undiagnosed FH die 16 years earlier according to another. In other words, FH is quite deadly over about 5 decades, but if it hasnāt killed you by then, youāll probably be fine.
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To further establish causation, dozens of randomized clinical trials demonstrate reduction in CV events when LDL-C is lowered. This relationship, like that seen in Mendelian randomization, is monotonic ā the lower your LDL-C, the lower your risk. Even more importantly, these studies show the effect of time ā the longer your apo B has been low, the lower your risk.
To summarize, LDL exposure does cause atherosclerotic cardiovascular disease. It would be a mistake, however, to say that it causes it in everyone (Iāve seen people in their late 70ās with high LDL-C and coronary calcium scores of zero), or to say that LDL-C is the cause. Plaque formation is a complex process that may involve any combination of factors, including smoking, obesity, inactivity, hypertension, systemic inflammation, hyperglycemia, hyperinsulinemia, stress, and processed food. But in every case, it must include a minimum blood lipid level. Any one of these other factors may contribute to endothelial damage, but only dyslipidemia is necessary for plaque formation. In other words, you cannot build plaque without an adequate supply of atherogenic particles in your blood. If this is true, then driving LDL-C below a certain threshold ought to prevent atherosclerosis.
Interestingly, several trials over the past 6-7 years have suggested that an LDL-C level below 50-60 mg/dL is incompatible with plaque growth and may even induce plaque regression. You referenced one such study of 1779 participants. The incidence of atherosclerosis in anyone with an LDL below 60 mg/dL in that study was zero, while the incidence for any level above that increased linearly. This is why many experts are recommending more aggressive lipid lowering goals. If statins were āin the drinking water,ā the entire population would have much lower LDL-C exposure over a lifetime, and CV disease rates would ā in theory ā plummet.
But statins are not harmless for everyone. Myalgias are a very real and underreported side effect. Muscle pain stops when the med is stopped, fortunately. The increased risk in diabetes is even more concerning and deserves more scrutiny. Nevertheless, statins are powerful tools in our arsenal against cardiovascular disease. They consistently show reductions in both CV events and mortality that correlate with the degree of LDL-C lowering they induce ā slight reductions in LDL-C over a short time cause slight reductions in CV events; larger reductions over longer times cause greater reductions in CV events.
(I might add that in the 20 years Iāve been prescribing them, no one has ever offered me any type of financial incentive to do so. Iāve always been puzzled by the claim that doctors make money by writing for certain drugs.)
PCSK9 inhibitors show even more promise with a cleaner profile and impressive outcomes. Gene therapy to alter PCSK9 expression, mimicking the genetic mutation, may be a reality someday, too. But already, today in 2023, we have the knowledge and tools available to dethrone cardiovascular disease from its ignominious reign as the top killer of humans.
The lipid rabbit hole is deep and confusing, honestly. I feel like Iām only beginning to understand it. Thereās so much more to say, but this is already way too long, and at some point I gotta get to bed. Iāve enjoyed your writing for years, TC, and appreciated your open-minded expression of confusion about this issue. Hope this helps a little.
Here are some of my references. Iām too tired to annotate or order them ā please forgive me.
Recent Developments in Gene Therapy for Homozygous Familial Hypercholesterolemia - PMC (nih.gov)
Statins for the primary prevention of cardiovascular disease - Taylor, F - 2013 | Cochrane Library
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Very much. Thank you. From the bottom of whats left of my heart. 
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First, Thank you for such a detailed post. I recently had some lab work done which has me very concerned. I would love to hear your thoughts. Iām a 40 year old female, mostly live off of grilled chicken, salmon and veggies, donāt smoke or drink, exercise 5 times/week. How is it possible to have a vldl of 8, triglycerides 40, Hdl 119, and an apoe B of 101? Should I be worried?
And thatās WITH treatment!
Some with homozygous FH absent of treatment die in their teens.
Good question. Your triglyceride and HDL-C levels imply excellent metabolic health. Iād be curious what your LDL-C is, although I canāt imagine itās very high given your VLDL. So my guess would be an elevated Lp(a). If you havenāt checked that, you might want to.
Beautiful! Thanks!!
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I was going to write more about Lp(a), but then I discovered you had already written about it.
I also found this interesting:
https://www.ahajournals.org/doi/10.1161/ATV.0000000000000147
Itās been a few years since I went through it, but for all cause mortality, the scope of statins helping people live longer was extremely limited. Itās like middle aged men whoāve already had a cardiovascular event. Very interestingly, at that time there was no evidence for effectiveness in any cohort of women. Did you find other (maybe new) studies showing prolonged life in other groups?
Not really. This study seems to confirm what you wrote:
Yeah, this is the stuff that always makes me skeptical of usage.
āno data suggest a mortality benefit.ā And yet itās somehow justification for wide scale use.
Iām dealing with the same thing with my wife and thyroid cancer. The doctors only ever look at treatment risks and rewards in isolation to what they are treating. In thyroid cancer, they will adjust hormones and almost purposely make the patient gain 50 pounds. Why? Those levels reduce future thyroid risk. They literally never seem to care or consider what 50 pounds of adipose tissue does to all other risk factors. Arthritis?, oh well. Breast cancer?, ops. CHD?, thereās another pill for that. Itās infuriating.
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Statins were initially meant for people with serious hereditary diseases (predominantly FH, or those with very unfavourable cardiometabolic risk profiles)
The idea that every second adult needs a statin is a new (and predominantly American) concept.
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(Mark Sisson is just a (rich!) blogger, and he himself proclaims that heās ānot a doctorā in that video, ānot a doctorā translating to heās never actually treated anyone)
(James OāKeefe MD, not the āpolitical activistā one)
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Hereās a current interview with a cardiologist explaining his view on the matter. British medical journal is a journal known to have the guts to publish studies that go against the mainstream.
You are a pharmacist
Surely you agree that high cholesterol caused by INHERITED dyslipidemia should be treated
The consensus is unequivocal. Familial hypercholesterolemia (heterozygous or homozygous) = vastly increased risk of CVD.
Thatās why I take a MINISCULE dose of a statin.
Strong family history, both parents have absolutely wack lipidsā¦ I have shit lipids. Grandfather had a stroke and died in his 40s. My fathers sister had a total cholesterol of around 400 despite being very petite. My grandmother lived til 98.
Thereās like a 50/50 split on both sides of my family. Either you have atrocious lipidsā¦ or you have PERFECT lipids. My twin has good lipidsā¦ and he doesnāt have ehlers danlos syndrome. Though he does have his own set of difficulties owed to being born 3 months premature.
5-10mg rosuvastatin takes my HDL/LDL ratio from like 5-1 to 2-1 or less and brings my trigs down to normal range.
Statinās were initially synthesised to treat hereditary dyslipidemia. Not āhe eats too much kfc and has slightly elevated LDLā
Cholesterol (and statins) are bullshit. it was a scam from day 1 and a big pharma opportunity