Does LDL CAUSE Atherosclerotic Cardiovascular Disease?
Number One Cause of Death
Think for a moment about what the top cause of death is worldwide. One may assume it to be murder or automobile accidents.
Perhaps it is starving children, war, or cancer. However, all of these answers would be incorrect. As it so happens, even with the summation of all these figures together, it still would not reach the enormous death toll that is heart disease and stroke. According to the World Health Organization (2019, WHO), of the 56.9 million deaths globally in 2016, 15.2 million (26%) were due to heart disease and stroke. In contrast, a mere 1.4 million (2.4%) were due to road injuries.
What Does Mainstream Science Think Causes It?
With death and cardiovascular disease on the rise in the 1950s, research was undertaken to determine the best course of preventive action. It was discovered that a fatty molecule in the blood called cholesterol appeared to increase plaque formation. The more of it one seemed to have, the higher their risk of the disease. Today, and thirteen Nobel Prizes later, there is a near-unanimous scientific agreement on the role of cholesterol in heart disease (Ference et al., 2017). There is high-quality evidence that demonstrates this, and medications such as statins and PCSK9 inhibitors have been created with the intent of saving lives and preventing the disease (Libby, 2008). However, on the internet, the role of social media influencers has instilled doubt into the public eye and confusion around this issue. According to them, the experts have gotten it completely wrong, and the conventional wisdom on cholesterol is misplaced. Many people are choosing to abandon prescribed LDL lowering statin drugs to patients at risk, or who have heart disease. My view is that this is anti-science and unacceptable. Ultimately, anyone can believe whatever they wish, so long as it is not harmful to others. In this article, I will show beyond any reasonable doubt why cholesterol causes heart disease, as well as analyze the various lines of argumentation used to deny this link, to see if they stand to the weight of scientific evidence.
What is Cholesterol?
To begin, it is imperative to understand what cholesterol is. Cholesterol is an organic molecule produced by the liver that serves a critical role in steroid and hormone production, as well as cellular membranes (Ference et al., 2017, p. 2461). Cholesterol is a carrier of what are called lipoproteins, of which there are five main types: high-density lipoproteins (HDL), low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), Intermediate density lipoproteins (IDL), and Lipoprotein a (LPa). However, this article will focus on LDL because of its clinical significance to heart disease risk. According to a paper published by the European Heart Journal (2017),
"In most people, LDL particles constitute ∼90% of circulating apoB-containing lipoproteins in fasting blood (Figure 1)"
(Ference et al., 2017, p. 2461).
However, Ference et al (2017). posits that in clinical practice, a better metric than merely looking at the amount of LDL in the blood, is to assess the total amount of cholesterol contained within these LDL particles; going forward, this will be referred to as LDL-C (p. 2461).
LDL vs HDL
Despite cholesterol being an aforementioned integral component of organic systems, the worry from various health authorities is having too much of it within the blood over a prolonged period, which is a disorder known as hypercholesterolemia. While all lipoproteins may play a role in atherosclerosis (heart disease), the most studied are LDL and HDL. To put simply, LDL is known as the "bad" cholesterol, and HDL can be thought of as the "good" cholesterol. HDL carries cholesterol back to the liver, while LDL carries it out where it can be deposited inside the coronary arteries (American Heart Association (AHA), 2017). A simplified explanation of the view is to imagine a pipe being slowly clogged and restricting flow, in this case, blood, to vital organs, eventually leading to death. The problem occurs when there is too much LDL per HDL such that the cholesterol begins to deposit along the inner lining of the artery walls (AHA, 2017).
Cholesterol Denialism & Skepticism
People who do not accept or downplay the role of cholesterol in heart disease are not taken seriously by the scientific community and are sometimes referred to by experts as "cholesterol denialists" (Boseley, 2018). The most significant critics of the lipid hypothesis, or cholesterol as a cause of heart disease, are the International Network of Cholesterol Skeptics (TINCS), who often rail against the use of statin medications. Professor Rory Collins (2018) of Oxford University has criticized many of these individuals, especially when they espouse pseudoscientific claims against the use of life-saving statin medications. He has said this is no different to denying smoking:
When the director of TINCS Uffe Ravonskov was asked why he believes this, he said that the experts only say cholesterol is damaging to heart health because"The claims that blood LDL cholesterol levels are not causally related to cardiovascular disease (which is really in the same realm as claiming that smoking does not cause cancer) are factually false," (Rory Collins The Guardian, n.p).
Does Low LDL Cause Cancer and Higher All-Cause Mortality?"the vast majority are paid generously by the drug companies." (qtd. In Bosely, 2018. n.p).
Among the more credible claims that the TINCS make, is to point out that high LDL cholesterol in old age has a longevity advantage, while low LDL shortens lifespan. Ravonskov's finding is not novel. The 30-year follow up of the Framingham Heart Project found that for people over the age of 50, high cholesterol was protective, (Anderson et al., 1987). In 2016, The Center for Evidence-Based Medicine (CEBM) responded to Ravonskov's claims of high LDL being protective. They pointed out that it is privy to extreme bias, such as reverse causation, meaning that it might not be that low LDL causes illness, but that illness causes low LDL (CEBM, 2016). The evidence shows that this is indeed the case. RCTs have shown that interventional LDL lowering treatments reduce CVD without, leading to increased cancer risk (Strandberg et al, 2004). Furthermore, a genetic study in the elderly also refutes Ravonskov's claim, as those over 60 with genetically high LDL had a high risk, and those with genetically low LDL had a lower risk, as expected (Postmus et al. 2015).
The Importance of Genetic and Interventional Data in the Assessment of Causation
Other problems are not looking at the duration of exposure and survivor bias. This highlights the unreliability of cross-sectional and other population studies like Ravonskov's and the importance of randomized genetic research for addressing cholesterol and whether or not it causes heart disease. In this respect, one may ask how scientists know cholesterol causes heart disease. In science, it is often stated that correlation does not equal causation. Meaning, just because a variable is associated with another, does not mean one variable caused the other. For instance, it could be the case that those who live near telephone wires have a higher risk of heart disease; however, this is not a demonstration that telephone wires cause heart disease. The way to separate correlation from causation when it comes to cholesterol is by looking at genetic research.
Some of the most transformative work in this regard came from Mike Brown and Joe Goldstein, who had been performing various experiments on cholesterol metabolism. Brown and Goldstein found that those with a genetic condition characterized by elevated LDL-cholesterol (familial hypercholesterolemia) had LDL that would not bind to the rate-controlling enzyme of cholesterol synthesis known as, HMG-CoA reductase (A. G. Motulsky,. 1986). HMG-CoA reductase is the main target of the class of cholesterol controlling statin medication used today. Ultimately, their work lead to the discovery of the LDL receptor, earning them the Nobel Prize in Physiology and Medicine in 1985 (A. G. Motulsky,. 1986). Brown and Goldstein paved the way and were paramount in understanding cholesterol in the following years.
How Do We Know LDL-c Causes Atherosclerotic Cardiovascular Disease?
In 2017, the European Society of Cardiology released a massive consensus paper concluding that LDL-c causes atherosclerotic cardiovascular disease (ASCVD). The analysis found the following:
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 and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. (Ference et al., 2017, p. 2460)
Above we see various criteria for causation of LDL on ASCVD from table 1 of the paper.
Genetic Evidence Provides Strong Evidence For Causation
Furthermore, they concluded that
As explained on page 2463, a mendelian randomization study is a genetic study in which participants are naturally randomized based on if they have an LDL-c raising or lowering genetic mutation. This allows an unbiased estimate that separates cholesterol from other confounding factors such as smoking. As mentioned, familial hypercholesterolemia (FH) is a genetic condition where a loss of function of the LDL receptor leads to markedly increased levels of LDL-c. As it turns out, these individuals have a significantly elevated lifetime risk of the disease and, in some instances, may die in their teens and twenties of heart disease (Ference et al., 2017, p. 2462). Furthermore, those who inherit the FH mutation as compared to unaffected siblings provide substantial grounds for a causative effect; the authors explain,"Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD." (Ference et al., 2017, p. 2460).
Contrastingly, genes that lower LDL-c, also correspondingly lower the lifetime risk of CVD (Ference et al., 2017, p. 2462) (Libby, 2018). The fact that Ravonskov and colleagues choose to ignore this data highlights their bias and tarnishes their credibility.“The fact that siblings who inherit an FH mutation have markedly elevated plasma LDL-C levels and a corresponding dose-dependent markedly elevated lifetime risk of ASCVD as compared to their unaffected siblings provides powerful evidence that LDL causes ASCVD” (Ference et al., 2017, p. 2462).
What is the Optimal Range For LDL?
Evidence from (Fernández-Friera et al., 2017) and (O'Keefe et al., 2004) show that when LDL is above 50-70mg/dL plaques form, and below this, the disease does not occur.
What Increases Serum Cholesterol Within The Diet?
Now that I have established that LDL cholesterol does indeed cause heart disease, it is essential to know what increases cholesterol in the blood as this is controversial online. The three main factors that increase LDL are dietary cholesterol, saturated fat, and trans- fat.
Dietary Cholesterol: Does it Raise Serum Cholesterol?
Eating cholesterol from food (dietary cholesterol) increases cholesterol in the blood (serum cholesterol). In scientific research, this is usually done with egg feeding as they contain a high amount of dietary cholesterol. However, most cholesterol feeding studies have found either a weak or no correlation, or only an association in specific individuals. Often these individuals are deemed "hyper-responders." This variability has led many to conclude that the relationship is weak or non-existent. With countless blogs and videos all over the internet, including some experts mistakenly concluding dietary cholesterol does not affect serum cholesterol.
One of the proponents of this misinformation is Chris Kressor, an acupuncturist, and an online blogger. Kressor references a 2005 study looking at cholesterol feeding that found eggs raised cholesterol in insulin sensitive, but not in the diabetic or obese participants (Tannock et al., 2005). However, upon further investigation of the subject characteristics table, those that had low baseline serum cholesterol had an increase, while those who had a high baseline did not find an increase. In other words, the higher the baseline cholesterol, the less of an impact eating more had. In addition, a meta-analysis of forty studies from the American Journal of Clinical Nutrition found a similar finding; dietary cholesterol only raised serum cholesterol in those with a dietary intake under 900mg/dL (Berger et al., 2015).
Hegsted Equations and Meta-Regression Analyses
Interestingly, this is predicted by a mathematical equation called the Hegsted equation. The Hegsted equation is a way to predict the expected change in serum cholesterol from added dietary cholesterol and is remarkably consistent (Postmus et al. 2015, p 1063). The relationship between dietary and serum cholesterol is a non-linear hyperbolic curve, as shown in the figure below by Postmus et al. (2015) meaning it would be expected to level off.
Simply, the higher the starting cholesterol is, the less of an impact eating more will have. Importantly, for this reason, decreasing dietary cholesterol would have a stronger impact.
LDL: HDL Ratio Negates Negative Effects?
Skeptics like Kressor and others may claim that cholesterol feeding increases HDL, and therefore the risk is attenuated. This is also a false claim as cholesterol feeding has been shown to increase the HDL to LDL ratio in an unfavorable direction (Weggemans et al., 2001)
Large Boyent LDL particles are benign?
Further claims by cholesterol skeptics such as Kressor are that saturated fat/dietary cholesterol only increases a large "fluffy" type of LDL, which is harmless. This claim is also false as large LDL increases heart disease risk by 44%, while small LDL increases risk by 63% (Samia et al. 2009).
How Do We Know Saturated Fat Raises Cholesterol?
395 separate metabolic ward studies, or controlled feeding experiments, confirm that saturated fat also raises LDL cholesterol. It has a much more substantial impact than that of dietary cholesterol (Clarke et al., 1997). Change in cholesterol from saturated fat can be predicted with the Keys and Mensink equations. Prediction of serum cholesterol with both types of equations together produces the most robust predictive capability, effectively removing ∼80% of the variability. Therefore, it is difficult to argue against this data.
The first figure is from (Hegsted et al., 1993), showing predicted change in cholesterol versus the observed change, while the second figure uses the Mensink equations to show predictions for saturated fat on raising cholesterol.
With these data, we can conclude that the variability excuse does not pan out.
Does The LDL Raising Ability of Saturated Fat Actually Result In Worse Outcome?
based on 47 systematic reviews and meta-analyses of randomized controlled trials and prospective cohort studies from the Scientific Advisory Committee (2019), saturated fat increases the risk of CVD outcomes, the replacement of saturated fat with polyunsaturated fat reduces this risk, and percentage of calories from saturated fatty acids should not exceed 10% of calories and there is no reason to change these recommendations (SACN, 2019).
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Philosophical vegan said the same thing.