Claim: High LDL cholesterol is unhealthy.

Published January 2018: "LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature"

This lit review is a critique of 3 large reviews that had recently been published by statin advocates. The authors state, "our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality."

Some key takeaways:

-numerous studies have shown a lack of association between LDL-C (LDL cholesterol) and degree of atherosclerosis (plaque buildup inside arteries).

-there was one exception but association does not prove causation, for example, mental stress can both raise cholesterol and cause atherosclerosis by mechanisms other than an increase in LDL-C

-A study of 140,000 patients with acute myocardial infraction had lower than normal LDL-C at the time of admission to the hospital; this and other studies may signal inverse causation that explains the inverse association between mortality and LDL-C.

-healthy individuals with low LDL-C have a significantly increased risk of both infectious diseases and cancer

-multiple studies have found elderly people with high LDL-C live the longer than those with lower LDL-C or on statin treatment; numerous Japanese studies have shown high LDL-C not a risk factor for coronary heart disease mortality in women of any age.

-They critique statin trials, saying "If high LDL-C were the major cause of CVD (cardiovascular disease), the benefit from statin treatment should be better the more LDL-C is lowered" this is known as 'exposure-response." The authors state, "true exposure–response is based on a comparison between the degree of cholesterol lowering in each patient in a single trial and the absolute reduction of their risk. True exposure–response has only been calculated in three clinical statin trials, and it was absent in all three."

-One of the reviews they are critiquing was a meta-analysis that was trying to measure a therepeutic benefit of statin treatment lowering LDL-C. They note that 11 unsuccessful statin trials were excluded from the meta-analysis and state "there was a weak, positive association in the included trials, whereas the association was inverse in the ignored trials."

-A trial of a new cholesterol-lowering drug was stopped after 2.2 years when the results were showing that major vascular events were reduced with statistical significance but CVD (cardiovascular disease) mortality and total mortality had increased, though not with statistical significance. Authors suggest this is more proof of no exposure-response between LDL-C levels and CVD (cardiovascular disease) mortality.

The authors conclude, "The idea that high cholesterol levels in the blood are the main cause of CVD is impossible because people with low levels become just as atherosclerotic as people with high levels and their risk of suffering from CVD is the same or higher. The cholesterol hypothesis has been kept alive for decades by reviewers who have used misleading statistics, excluded the results from unsuccessful trials and ignored numerous contradictory observations."

Published May, 2022, this scientific article agrees that high LDL cholesterol is an important risk factor for atherosclerotic cardiovascular disease, but posits that lean people who adopt low-carbohydrate, high-fat diets may develop elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs) because of the Lipid Energy Model (LEM).

According to the authors, the LEM suggests an adaptive response that can facilitate efficient lipolysis of triglyceride-rich lipoprotein. In other words, (if I understand correctly), they're suggesting that it may be a process of converting fat to energy that may produce high LDL and HDL and low triglycerides in lean people who eat a low-carb, high fat diet.

I can't understand the very technical explanation for why, but the authors suggest that for lean people on this kind of diet, it may reduce the risk of atherosclerotic cardiovascular disease. They say the risk profile really needs to be studied so we really don't know for sure yet.

High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study

"the major potent lipid risk factor was HDL cholesterol, which had an inverse association with the incidence of coronary heart disease (p less than 0.001) in either men or women. This lipid was associated with each major manifestation of coronary heart disease. These associations were equally significant even when other lipids and other standard risk factors for coronary heart disease were taken into consideration. A weaker association with the incidence of coronary heart disease (p less than 0.05) was observed for LDL cholesterol. Triglycerides were associated with the incidence of coronary heart disease only in women and then only when the level of other lipids was not taken into account. At these ages total cholesterol was not associated with the risk of coronary heart disease."

A consensus statement from the European Atherosclerosis Society published August, 2017 states, "Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C (LDL cholesterol level) and the risk of ASCVD (atherosclerotic cardiovascular disease); and this effect appears to increase with increasing duration of exposure to LDL-C."

A second consensus statement published by the European Atherosclerosis Society in June 2020 states, "Extensive evidence from epidemiologic, genetic, and clinical intervention studies has indisputably shown that low-density lipoprotein (LDL) is causal" in atherosclerotic cardiovascular disease (aka heart disease), citing the first Consensus Statement published in 2017.

This second consensus statement adds that there are various kinds of LDL cholesterol, and they all increase risk of heart disease to some degree, but some kinds of LDL do so more than others. They specifically highlight small, dense LDL as potentially increasing the risk of coronary heart disease, stating that, "in several recent large prospective cohort studies, and the placebo group of a large statin trial, concentrations of small dense LDL but not large LDL predicted incident coronary heart disease independent of LDL cholesterol level."

They suggest some potential causes for this, including small dense LDL's "susceptibility to hydroperoxide formation under oxidative stress," a genetic variant associated with incident myocardial infarction that is "preferentially associated with increased levels of small dense LDL," the fact that small dense LDL stay in your plasma longer, and more.

More info about how LDL causes damage to arteries:

"Retention and subsequent accumulation of LDL in the artery wall triggers a number of events that initiate and propagate lesion development. Due to the local microenvironment of the subendothelial matrix, LDL particles are susceptible to oxidation by both enzymatic and non-enzymatic mechanisms, which leads to the generation of oxidized LDL (oxLDL) containing several bioactive molecules including oxidized phospholipids. Oxidized LDL, in turn, initiates a sterile inflammatory response by activating endothelial cells to up-regulate adhesion molecules and chemokines that trigger the recruitment of monocytes—typically inflammatory Ly6Chi monocytes—into the artery wall."

They note that genetics may influence the susceptibility of the artery wall to coronary disease, affect LDL concentration in the blood, and more.

"Although the evidence that treatments to reduce LDL-C lead to fewer ASCVD events is unequivocal, understanding of how the beneficial effects of lower circulating LDL levels translate to changes in the atherosclerotic plaque is less clear."

They make note that HDL (high-density lipoprotein) may have anti-oxidative and anti-inflammatory properties that slow plaque progression caused by LDL.

They make note of some outstanding questions, including:


"Do omega-3 fatty acids influence the mechanisms that underlie the atherogenicity of lipoproteins, including... LDL?"

One of the famous, initial studies that established the relationship between serum cholesterol and coronary heart disease was the Seven Countries Study by Ancel Keys, which began in 1958 and ended in 1999.

"It showed that serum cholesterol, blood pressure, diabetes and smoking are universal risk factors for coronary heart disease."