# cholesterol

Structural formula
General
Surname cholesterol
other names
• Cholesterol
• Cholest-5-en-3 β -ol
• 5-cholesten-3 β -ol
Molecular formula C 27 H 46 O
Brief description

white odorless solid

External identifiers / databases
 CAS number 57-88-5 EC number 200-353-2 ECHA InfoCard 100,000,321 PubChem 5997 ChemSpider 5775 DrugBank DB04540 Wikidata Q43656
properties
Molar mass 386.67 g mol −1
Physical state

firmly

density

1.07 g cm −3 (20 ° C)

Melting point

147-150 ° C

boiling point

Decomposition at> 200 ° C

solubility

practically insoluble in water

safety instructions
GHS labeling of hazardous substances
 no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Pure cholesterol is a white solid

The cholesterol , also more accurate cholesterol ( Greek χολή cholé , German , Galle ' and στερεός stereos , German , solid, hard, hardened' ), is a occurring in all animal cells crystalline, fat-like natural substance . The name coined by the chemist Michael Eugène Chevreul in 1824 is derived from the fact that cholesterol was found in gallstones as early as the 18th century . Aside from bile, the cholesterol produced in the liver is also abundant in the brain, nerves and blood. Cholesterol plays a role in the stabilization of cell membranes and nerve function, is important for the production of sex hormones and other processes.

Cholesterol was also found in small amounts in plant cells ( potato tops , pollen , isolated chloroplasts ) and in bacteria . As particularly cholesterol vegetable oils were corn oil (55 mg per kg), rapeseed oil (53 mg per kg) and cottonseed oil (45 mg per kg) identified. Typical sources of cholesterol of animal origin contain many times this level. For butter , for example, a cholesterol content of 2340 mg per kg was found.

## function

Cholesterol is a vital sterol and an important part of the cell membrane . It increases the stability of the membrane and, together with proteins, helps smuggle signal substances into and out of the cell membrane. The human body contains around 140 g of cholesterol, over 95% of the cholesterol is within the cells and cell membranes. In order to be able to supply the cells with cholesterol, which is lipophilic (fat-soluble) and hydrophobic (insoluble in water), via the blood , it is bound to lipoproteins for transport . These can be of different density and are divided into chylomicrons , VLDL , IDL , LDL , HDL and lipoprotein a according to their behavior during centrifugation or in electrophoresis .

Numbering of the carbon atoms and the designation of the rings in the steroid structure, which is also the basis for cholesterol.

In the body, cholesterol serves, among other things, as a precursor for steroid hormones and bile acids . For the formation of hormones, the cholesterol side chain separating enzyme converts cholesterol to pregnenolone . This is the starting compound from which the body builds the sex hormones testosterone , estradiol and progesterone and adrenal hormones ( corticoids ) such as cortisol and aldosterone . Bile acids such as cholic acid and glycolic acid are also based on the starting substance cholesterol.

An intermediate product of cholesterol biosynthesis, 7-dehydrocholesterol , is the provitamin for the formation of vitamin D through UV light.

New research also shows that the body uses cholesterol to biosynthesize cardiac glycosides . The significance of these endogenously synthesized glycosides is still largely unknown.

On the basis of sediment finds with chemical cholesterol relatives ( sterols ) it is assumed by some researchers that the cholesterol molecule, if it never appeared otherwise than in living matter, must be very old in evolutionary terms. However, the biosynthesis of the molecule can only function once oxygen has been present in the atmosphere. For this reason, hardly any cholesterol is found in bacteria and the membranes of mitochondria ; Plants and mushrooms also contain no cholesterol, but other, structurally similar sterols.

## Chemical classification

Cholesterol is a polycyclic alcohol . Traditionally it is counted as a steroid belonging to the group of sterols (sterols) to the lipids . However, contrary to popular confusion, it is not fat . The steroids belong to the isoprenoids , which, unlike the fats, are not esters of fatty acids and alcohol, but can have hydrophilic poles as diverse patterns in their hydrophobic basic structure.

Like many substances, cholesterol is sensitive to oxidants . Autoxidation processes can lead to many reaction products. To date, over eighty such substances are known, which often have considerable physiological effects. The oxidation products are isolated and purified by chromatographic methods . Your secure identification takes place z. B. by spectroscopic or spectrometric methods such as mass spectrometry . A comprehensive description of these cholesterol oxidation products is given in the work of Leland L. Smith: Cholesterol Autoxidation .

## physiology

Cholesterol is a zoosterol that is essential for humans and animals . In humans, cholesterol is largely (90%) produced ( synthesized ) in the body , in adults in an amount of 1 to 2 g per day, and only a small part of it can be ingested with food. The cholesterol absorption is on average 0.1 to 0.3 g per day, and may be at most 0.5 g to be increased per day.

All animals synthesize cholesterol. Starting from “activated acetic acid”, acetyl-CoA , isopentenyl diphosphate is produced in four steps via mevalonic acid . Another three reaction steps lead to squalene . After the ring closure to lanosterol, around a dozen enzymatic reactions follow, which can also run in parallel until cholesterol is finally formed. This last section is not known in full, but the enzymes involved have been identified.

Cholesterol is excreted in the liver by being secreted into the intestines in the form of bile acids via the biliary tract (around 500 mg per day). Bile acids are necessary for the absorption of water-insoluble food components, including cholesterol. Cholesterol is emulsified by bile acids and absorbed in the small intestine . Since around 90% of the bile acids are reabsorbed, the excretion of cholesterol is correspondingly ineffective. Cholesterol excretion can be increased by drugs such as cholestyramine , which bind bile acids and thus make their re-absorption more difficult. However, the lowering of the cholesterol level is then compensated for by an increase in the density of LDL receptors on liver cells and the resulting increased absorption of cholesterol from the blood into the liver, partly also by increased new synthesis.

### biosynthesis

The biosynthesis of cholesterol, which was elucidated in particular by the work of Konrad Bloch , Feodor Lynen , George Joseph Popják and John W. Cornforth , starts from the end products of the mevalonate biosynthetic pathway , from dimethylallyl pyrophosphate and isopentenyl pyrophosphate , and requires 13 further reactions. In humans, the liver and the intestinal lining are the main sites of cholesterol synthesis.

### regulation

The balance between required, self-produced cholesterol and cholesterol ingested through food is maintained through a variety of mechanisms. The inhibition of HMG-CoA reductase , the most important enzyme in cholesterol biosynthesis, by cholesterol (HMG-CoA reductase is even more strongly inhibited by lanosterol , a precursor of cholesterol) can be considered important. Products of this metabolic pathway (cholesterol synthesis) inhibit “their” enzyme; this is a typical example of negative feedback . In addition, the half-life of HMG-CoA reductase is greatly reduced when the lanosterol level is increased, as it then binds more to the proteins Insig-1 and Insig-2 , which ultimately leads to their degradation in the proteasome . There are many other, less direct regulatory mechanisms that operate at the transcriptional level. The proteins SCAP , Insig-1 and Insig-2 are important here. In the presence of cholesterol, for which they have a binding site, they regulate the activity of a large number of genes via the proteolytic activation of SREBPs . Also, insulin plays a role here as it u. a. increases the transcription of SREBP1c.

HMG-CoA reductase, the key enzyme in cholesterol biosynthesis, can be specifically and effectively inhibited by various substances (for example statins , which, as HMG-CoA reductase inhibitors, represent a certain class of drugs). Uptake into the cell is activated via the LDL receptor .

The level of cholesterol depends primarily on the body's own production and only secondarily on the intake from food. There are also a number of genetically caused hypercholesterolemia . The cholesterol level can also be increased as a result of other diseases (for example, due to hypothyroidism , kidney failure or metabolic syndrome ).

### Cholesterol transport (lipoproteins)

Lipid logistics: transport of triglycerides and cholesterol in organisms in the form of lipoproteins as chylomicrons, VLDL, LDL, IDL, HDL.

Since cholesterol is insoluble in water, it is transported in the blood plasma together with other lipophilic substances such as phospholipids , triglycerides or fatty acids with the help of transport vesicles, the lipoproteins .

The cholesterol and triglycerides supplied with food are absorbed from the intestine by the chylomicrons and transported from there to the liver . Lipoproteins of various densities (VLDL, IDL and LDL) transport self-produced and ingested cholesterol from the liver to the tissues. HDL take up cholesterol from the tissues and bring it back to the liver ( reverse cholesterol transport ). The cholesterol in lipoproteins is mainly esterified with fatty acids . The spectrum of these fatty acids can be influenced to a large extent by the triglycerides ingested with food. This is shown in particular by studies on population groups with special diets such as B. Vegetarians and Vegans .

There are two independent pathways in the human body for breaking down LDL cholesterol in the blood , the LDL receptor pathway and the so-called scavenger pathway . Most of the LDL cholesterol in plasma, around 65%, is metabolized via LDL receptors. LDL receptors are found in all cell types of the arteries and in hepatocytes (liver cells). In addition to the LDL receptor pathway, around 15% of the LDL cholesterol in the plasma is broken down via the scavenger pathway in the blood vessels. The macrophages are called scavenger cells . They have so-called scavenger receptors, via which chemically modified (oxidized) LDL can be absorbed and stored in an uninhibited manner and regardless of the concentration.

In summary, three different ways can be described that cholesterol (regardless of whether it is through food or self-synthesized) takes in the organism:

1. Excretion in the bile and thus in an enterohepatic circulation (liver → bile → intestine → blood via the portal vein → liver).
2. Conversion to bile acids, which are released into the intestines.
3. Release into the blood in the form of lipoproteins (VLDL → LDL → HDL) for the synthesis of steroids and the formation of membranes in other organs .

## Blood levels

The average total cholesterol level as well as the LDL and HDL levels of the healthy normal population differ from country to country and also depend on age and gender. There is a positive correlation between the blood cholesterol values ​​and the body mass index .

### Total cholesterol level

Average total cholesterol level of middle-aged German adults (data from 2816 participants in a health check-up offered free of charge by health insurance companies)

In general, the total cholesterol level increases significantly with age. As a rule, it is somewhat lower in young women than in young men. However, with age, this difference becomes even more pronounced, and older women end up having, on average, higher cholesterol levels than older men. Pregnancy is a special case in which the total cholesterol level is normally significantly increased.

The average total cholesterol level of the age group between 35 and 65 years in Germany is around 236 mg / dl (corresponds to 6.1 mmol / l), the standard deviation is ± 46 mg / dl. This roughly means that around two thirds of the German population in this age group have a total cholesterol value in the range between 190 mg / dl and 282 mg / dl and one sixth of the Germans in this age group have values ​​above or below this range. In some parts of China, the average cholesterol level is 94 mg / dl with normal values ​​between 70 mg / dl and 170 mg / dl, whereby the lower cholesterol levels correlate with a lower likelihood of heart disease and cancer.

### LDL cholesterol levels

The LDL cholesterol level is subject to a similar age and gender-dependent distribution. Here, too, the age-related increase is much more pronounced for women than for men. The mean value for the age group between 35 and 65 years is 164 mg / dl (standard deviation ± 44 mg / dl) for German women and 168 mg / dl (± 43 mg / dl) for men.

### HDL cholesterol levels

The average HDL level differs more between the sexes, with middle-aged women having higher HDL levels than men. The age dependency shows itself in both sexes in a decrease from the age of about 55 years. The average HDL level in German women in the age group between 35 and 65 years is 45 mg / dl (± 12 mg / dl), in men it is 37 mg / dl (± 11 mg / dl).

### Quotient

Occasionally, quotients are determined from these values ​​on the basis of the aforementioned parameters. The mean value of the quotient of LDL and HDL levels is 3.9 (± 1.6) for German women between 35 and 65 years, and 4.9 (± 1.9) for men. The corresponding average values ​​for the quotient of the total cholesterol and the HDL level are 5.7 (± 2.1) for women and 7.0 (± 2.3) for men.

### Measurement and laboratory reference values

The determination of the concentration of cholesterol in the blood in routine medical laboratories is one of the methods of determination that are subject to proficiency testing in Germany. A round robin test is the external quality control of laboratory parameters, which is controlled and certified by the German Medical Association . Every medical laboratory in Germany must adhere to the “Guidelines of the German Medical Association” (RiLiBÄK) . The reference range (often misleadingly referred to as "normal value") depends on the measuring device and the method. The reference ranges have been revised upwards several times in recent years. In order to rule out any falsification of the results, the determination is often not carried out until 12 to 16 hours after the last meal.

For a long time, only total cholesterol was determined in the laboratory, since the direct measurement of the various lipoproteins was not possible or very expensive. That has now changed. The LDL cholesterol is not determined directly, but from the directly measured values ​​for total cholesterol, triglycerides and HDL according to Friedewald et al. estimated as total cholesterol minus HDL cholesterol minus one fifth of the triglyceride value (all data in mg / dl). This method cannot be used for triglyceride levels above 400 mg / dL or in the presence of chylomicronemia . Various correction factors have been proposed to increase the precision of this estimation, but they have not yet entered clinical practice. The reference range for the LDL cholesterol level is given for women and men between 70 and 180 mg / dl.

For the reliable determination of cholesterol, after adequate sample preparation , the coupling of gas chromatography and HPLC with mass spectrometry can be used.

### Units and conversion

In West Germany, the unit “mg / dl” ( milligrams per deciliter ) is often used to indicate the concentration of cholesterol in the blood . In East Germany, on the other hand, as in the Anglo-Saxon-speaking area, the unit “mmol / l” (millimole per liter , compare milli and mole ) is predominantly used. For cholesterol (but not for triglycerides or other substances) the following relationship between these units of measurement applies:

1 mg / dl = 0.02586 mmol / l
1 mmol / l = 38.67 mg / dl

Example:

236 mg / dl = 236 x 0.02586 mmol / l = 6.10 mmol / l
6.10 mmol / l = 6.10 x 38.67 mg / dl = 236 mg / dl

The following conversion formulas apply to triglycerides:

1 mg / dl = 0.0113 mmol / l
1 mmol / l = 88.57 mg / dl

## Diseases

Familial hypercholesterolemia and gallstones ( biliary concrement) are known diseases associated with cholesterol .

### Familial hypercholesterolemia

There are hereditary disorders of the cholesterol metabolism (familial hypercholesterolemia), which lead to very high blood cholesterol levels regardless of food intake. In one of the known forms of hypercholesterolemia, the LDL receptors are only incompletely developed or completely absent.

Heterozygous carriers of these hereditary factors are more often affected than average by heart attacks and other vascular diseases at a young age . According to a study from 1991, this no longer applies to older people. Here the mortality even drops significantly and is only 44% compared to the standard.

The prevalence of the most common monogenetic hypercholesterolemia, the so-called autosomal dominant familial hypercholesterolemia , is about 1: 500. However, over the past 200 years there seems to have been a significant variability in the frequency of symptoms in those affected, suggesting an interaction between a changed environment (e.g. diet, lifestyle) and genotype . For more severe forms of hypercholesterolemia (such as familial hypercholesterolemia), drug therapies with statins , LDL apheresis and, in some cases, surgical forms of therapy are used.

### Gallstones

Cholesterol is absorbed by the body with the bile acid in the intestine. Cholesterol is emulsified and absorbed in the small intestine . The solubility of cholesterol in total bile is 0.26%. When the composition of the bile changes, cholesterol stones are formed. 80% of gallstones are high in cholesterol and 50% are pure cholesterol stones. The formation of gallstones occurs not only in the gallbladder, but also in the liver.

### Other forms of illness

Lesser-known diseases are, for example, cholesterol storage disease ( xanthomatosis or Hand-Schüller-Christian syndrome ), in which cholesterol is pathologically stored in the skin, among other things.

Smith-Lemli-Opitz syndrome (SLO) occurs with a frequency of approx. 1: 60,000 in Europe . The reason for the disease with SLO syndrome is a defect in the last enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol reductase. The clinical picture is characterized by mental retardation, growth problems, developmental disorders and facial changes.

Furthermore, hypocholesterolemia is known, in which the cholesterol level is below 130 mg / dl in the blood. This occurs above all with liver damage such as cirrhosis of the liver , the genetic Tangier disease and with a manganese deficiency. Among other things, vitamin E can no longer be transported to its respective destination.

## Cholesterol and Coronary Heart Disease (CHD)

Cardiovascular diseases , in particular coronary artery disease ( CHD ), replaced infectious diseases as the most common cause of death in western industrialized nations as the standard of living rose in the 20th century. In the 1950s, the hypothesis of the American nutritionist Ancel Keys received a lot of attention that this development was additionally favored by the fact that increasing affluence was accompanied by a diet that was too fatty. In particular, a diet high in cholesterol (primarily meat , chicken eggs , milk , butter, and other dairy products ) leads to high cholesterol levels. The ingestion of food containing cholesterol is one of the many causes of a heart attack. Key himself relativized the importance of diet-related cholesterol intake for the cholesterol level in human blood as early as 1965: "In order to control the serum level, dietary cholesterol should not be completely ignored, but observing this factor alone is of little use."

### Meaning of the hypothesis

The hypothesis that a diet high in cholesterol and a high blood cholesterol level played a causal role in the development of heart attacks has become widespread in the scientific community and in the public eye over the past decades. Today it is an essential element in the prevention of heart attacks in medical practice. It led, particularly in the USA , but also in Europe, to the spread of artificially reduced or cholesterol-free foods (such as margarine ) and, moreover, to the routine prescription of drugs to lower cholesterol.

Today, cholesterol-lowering drugs represent the segment of the pharmaceutical market with the highest sales worldwide. In 2004, cholesterol-lowering drugs achieved sales of 27 billion US dollars worldwide, with a growth rate of 10.9%. The drug with the highest sales is atorvastatin (Lipitor ® , Sortis ® ) from the US manufacturer Pfizer , which achieved worldwide sales of 12.2 billion US dollars in 2005. However, this drug no longer plays an essential role on the German market since the health insurance companies introduced a fixed amount regulation for statins.

Around 25 million people around the world regularly take cholesterol-lowering preparations.

### Empirically obtained evidence

The cholesterol hypothesis is based exclusively on empirically obtained evidence. So far, however, no biological mechanism has been demonstrated which leads to plaque formation via cholesterol or an increased cholesterol level.

• In animal experiments, the administration of food (milk, egg yolk) with high cholesterol in rabbits and other predominantly vegetarian animals leads to the development of arteriosclerosis. This observation was first published in 1908 by the Russian scientist Alexander Ignatowski . However, the transferability of these results to humans is controversial, since their natural regulating mechanism for the level of cholesterol almost completely compensates for the intake of cholesterol through food. Therefore, similar studies were later carried out on pigs, which have a 70% homology to humans, and also on monkeys, with results similar to those of the hares. In some of the monkey species investigated (such as pigs mostly omnivores with a predominantly vegetarian diet), however, strong individual differences were found even within a species. In some individuals, the cholesterol level can be influenced by diet ("hyperresponders"), in others not (" hypo-responders ").
• Cholesterol is an integral part of arteriosclerotic plaques. This was proven in 1910 by the German chemist and later Nobel Prize winner Adolf Windaus .
• Ancel Keys published sensational comparative studies from six (1953) and seven (1966, 1970 and 1980) countries in which he found a cross-national correlation between the coronary heart disease rate and the proportion of animal fats in the diet for these countries showed. In Japan in particular , there was a low CHD rate with a low proportion of animal fats in the diet, while the opposite was found in the USA. Later, however, he was reproached for having deliberately only presented those of the country data sets published at the time that seem to support the correlation he postulated. Other studies examining the CHD rate of immigrant Japanese in the USA found an alignment of the lower Japanese rate with the USA CHD rate. This in turn could speak in favor of diet-related factors, but could also be explained by other factors that are related to lifestyle. Critics also question the comparability of the causes of death published by different countries, which was assumed in both cases, since cultural factors also played a role in determining the cause of death.
• In younger men up to about 45 years of age, a high total or LDL cholesterol level is associated with an increased incidence of coronary heart disease and represents a separate risk factor in addition to the other known risk factors. This means that this correlation is not alone can be explained by the correlation of the cholesterol level with other known CHD risk factors. Further known risk factors are age, gender, positive family history (i.e. occurrence of a heart attack in close relatives), smoking , diabetes mellitus , high blood pressure , obesity and lack of exercise. Contrary to popular belief, however, high cholesterol levels are not a risk factor for coronary heart disease for both younger and older women and older men.
• Due to a hereditary genetic defect, patients with familial hypercholesterolemia have a very high cholesterol level (often 400 mg / dl and more) and, at a young age, the risk of CHD is many times higher than that of the normal population. The life expectancy of these patients could be increased by awarding various lipid-lowering drugs. The CHD risk in these patients normalizes, however, at around 55 years of age.
• Numerous studies have demonstrated that taking drugs to lower cholesterol, especially in high-risk male CAD patients, can lead to a decrease in the risk of myocardial infarction, although this has generally been offset by an increase in other causes of death. In the past few years, the statins drug group was also able to demonstrate, for the first time, a slight life-prolonging benefit of taking a cholesterol-lowering preparation in individual studies. However, this was only shown in some of the studies carried out and only in middle-aged male high-risk CHD patients.
• People with a certain variant in the gene for the low-density lipoprotein receptor ( LDL receptor ) have lower blood cholesterol levels for life. The risk of heart attack is reduced by 23% in these people. However, the LDL receptor not only binds LDL, but also several other proteins, so that the connection has not yet been established through this fact.

### The role of high-density lipoprotein and low-density lipoprotein

The original hypothesis that an elevated cholesterol level is causally responsible for coronary heart disease has recently been represented in a somewhat modified form. A distinction is now made between HDL and LDL cholesterol, with a high HDL cholesterol level being viewed as favorable, whereas a high LDL level is viewed as less favorable. According to this concept, HDL is popularly referred to as “good” cholesterol, and LDL as “bad” or “bad” cholesterol. This idea is essentially based on the following observations:

• HDL is used to transport cholesterol from tissue to the liver, LDL is used to transport it in the opposite direction. On the basis of this finding, it is assumed that a high HDL level and a low LDL level lead to a proportionately greater amount of cholesterol being transported from the vessels to the liver and therefore less atherosclerotic plaques can form.
• The ratio of HDL and LDL correlates even more strongly than the total cholesterol level with the known risk factors for arteriosclerosis, such as age, gender, smoking, obesity and lack of exercise. If one only looks at the HDL and LDL levels without standardizing the known risk factors, the assumed relationship becomes very clear. However, after calculating these correlations, there is no higher prognostic power for the CHD risk than for the total cholesterol level.
• In scientific studies of the last 20-30 years it has been found that the arteriosclerotic plaques arise mainly from chemically modified (oxidized) LDL cholesterol (see also the section The lipoprotein-induced atherosclerosis hypothesis under arteriosclerosis ).

The European Atherosclerosis Society (EAS) is of the opinion that elevated LDL cholesterol levels in humans cause atherosclerosis .

### Target values ​​and guidelines

The hypothesis that cholesterol is causally responsible for heart attacks led to a large-scale public information campaign in the USA as early as the 1960s to warn the population of the possible dangers of high cholesterol levels. In 1984 the American news magazine Time warned in a cover story against the consumption of eggs and sausage. In 1985 the American Heart Association (AHA) established the National Cholesterol Education Program (NCEP ) to expand this campaign . Since its inception, the NCEP has been issuing recommendations for the treatment of patients with high cholesterol levels. In Germany, the German Society for Cardiology (DGK) is the relevant specialist society that publishes its own target values, but these are usually very similar to the American values. The industry- oriented Lipid League takes on a role comparable to that of the NCEP in Germany .

The basic guidelines of NCEP III, to which the European and German companies have joined, distinguish between three graded risk groups. Group 1 includes all patients who have already developed CHD or who are at a comparable risk (including diabetes, for example ). These patients have a 10-year risk of a cardiac event of> 20%. Group 2 includes patients who have at least two risk factors, and group 3 includes patients who have fewer than two risk factors.

Group 1 patients should make lifestyle changes (diet, etc.) if the LDL value is over 100 mg / dl, and drug therapy should be started if the LDL value is over 130 mg / dl. The goal for them should be to achieve LDL values ​​below 100 mg / dl.

Group 2 patients should change their lifestyle if their LDL values ​​are over 130 mg / dl, and start drug therapy if they are over 130 mg / dl or 160 mg / dl (depending on the specific risk calculation). The aim should be to achieve LDL values ​​below 130 mg / dl.

Group 3 patients should change their lifestyle and consider drug therapy if their LDL values ​​are above 160 mg / dl; drug therapy is strongly recommended from 190 mg / dl.

The following are considered risk factors:

• Smoke
• increased blood pressure (over 140/90 mmHg or current hypertensive treatment)
• low HDL cholesterol (<40 mg / dL)
• family history of coronary heart disease (first-degree male relatives under 55 or first-degree female relatives under 65)
• Age (men over 45, women over 55 years)

Lifestyle changes are recommended:

• Reduction of the consumed saturated fatty acids (<7% of total energy) and cholesterol
• Non-drug therapy options to lower LDL (e.g. plant sterols (2 g / day) etc.)
• Weight reduction
• increased physical activity

The use of these target values ​​is supported and advocated by the German specialist societies for cardiologists and internists.

### criticism

The requirement that an (LDL) cholesterol level above the published target values ​​may have to be reduced by changing diet and / or drug therapy was and is controversial. The most important points of criticism are listed below:

#### Doubts about the causal chain diet - cholesterol - coronary heart disease

The recommendations based on the cholesterol hypothesis should often lead to healthy people undergoing prophylactic drug therapy or changing their diet. On the basis of the extensive studies on this question, it was doubted that there is a triggering, causal connection between the cholesterol level and coronary heart disease (CHD).

• In humans, there is only a weak connection between diet and cholesterol level (see also the section Influence of diet on cholesterol level ). The recommendations for a change in diet are therefore mostly doomed to failure.
• Cholesterol is part of the cell membrane and one of the most common substances in the body. As the examples below show, it plays an important role in brain metabolism, among other things - which is why the body does not rely on an external supply, but regulates the level itself. It is difficult to foresee what side effects one could trigger in this mechanism with drug interventions.
• A high (LDL) cholesterol level only correlates with the number of coronary heart diseases in men up to 45 years of age. From a mere correlation , however, a causality cannot be inferred even for this population group . There could also be a spurious correlation . Rather, a common cause of the rise in cholesterol and the risk of CHD is more likely. Among other things, it is believed that cholesterol deposits in the arteries could be a repair measure that the body uses to respond to damaged blood vessels. If this repair measure is suppressed by reducing the free cholesterol, then this may reduce the risk of heart attack in extreme cases, but only at the price of other, possibly greater damage - such as an increased risk of cancer (see below). The next point of criticism fits this:
• A high (LDL) cholesterol level is statistically not associated with a reduction in life expectancy, at least in the elderly. The lowering of the heart attack risk, if it occurs at all, will in any case be compensated for by the increase in other fatal diseases.
• If a high serum (LDL) cholesterol level were a trigger for arteriosclerosis, pathological examinations of deceased patients should show a clear correlation between the (LDL) cholesterol level and the degree of arteriosclerotic changes in the vessels. This connection should be shown much more clearly than a possible correlation with the CHD rate, since only some of the heart attacks are triggered by arteriosclerosis. An analysis of all available autopsy studies on this question, published in 1998, comes to the only possible conclusion that there is no significant relationship between serum cholesterol and atherogenesis, taking into account the methodological weaknesses of the investigations.
• The largest nutritional intervention study ever conducted, published in early 2006, showed no benefits of a slightly reduced-fat diet. Neither the risk of cardiovascular disease nor the risk of stroke nor the risk of various types of cancer could be reduced by changing the diet (less fat, more fruit and vegetables). The study involved nearly 50,000 women between the ages of 50 and 79 who were followed over a period of approximately 8 years. The LDL cholesterol level of the study participants was only marginally reduced by an average of 2.7 mg / dl (0.07 mmol / l) due to the change in diet. In this study, however, the intake of fat was reduced by an average of 8.2% and the intake of saturated fatty acids was reduced by only 2.9%. The intake of fruit and vegetables was increased by 1.1 servings (1 small apple corresponds to one serving).
• An overview publication from 2013 also confirms the above-mentioned points of criticism and calls for a rational reassessment of the earlier dietary recommendations.

#### Critical evaluation of the benefit and risk of drug-based cholesterol lowering

• In the opinion of critics, the results of studies on the lowering of cholesterol levels with drugs in no way justify the widespread use of these drugs. In a large number of studies, evidence has been provided that these drugs can effectively lower the cholesterol level. The successes in terms of real patient benefit, in particular a life-prolonging effect, are, however, small.
• The focus on the level of the cholesterol level and on the CHD risk leads to the fact that such cholesterol-lowering studies are presented by the authors as a success even if, as happened in individual studies, there is a considerable and significant amount in the treatment group statistically significant increases in cancers and deaths had come.
• The benefit of statins in reducing the risk of myocardial infarction, especially in male high-risk CHD patients, can also be explained by other mechanisms of action than by lowering the cholesterol level. This is also supported by the fact that the initial cholesterol level does not play a role in the success of a statin treatment.
• Compared to other groups of lipid-lowering drugs, statins are relatively rare, but U. severe side effects, some with fatal consequences.
• Medicinal lowering of the cholesterol level in the first trimester of pregnancy, e.g. B. with statins, leads with a high probability to the most severe malformations in the development of the central nervous system and the limbs of the child, comparable to damage caused by thalidomide . Prescribing cholesterol-lowering drugs during pregnancy is therefore contraindicated. Critics complain that a prescription to young women is still permissible while ensuring “reliable” contraception, which has led to numerous cases of this kind being documented in the medical literature.

#### Possible influence of economic factors on research, professional societies and published opinion

• If the guidelines and target values ​​are followed, the majority of the adult population are "CHD risk patients" in need of treatment. For example, a healthy 40-year-old German man with normal blood pressure who has never smoked and is not related to any coronary heart disease should have LDL and HDL values ​​that are average for his age group (168 mg / dl and 37 mg / dl, respectively) , are already considering drug therapy according to the guidelines. If he reaches the age of 45 with these average HDL and LDL values, he already belongs to "risk class 2", in which, according to the guidelines, he should lower his LDL level to 130 mg / dl by means of drug therapy . If he reaches an average age, it can be expected that he will regularly take medication to lower cholesterol for around 35 years. In contrast, there is not a single study to date that would show even a slight benefit from cholesterol lowering therapy for this “patient”. Critics therefore see these guidelines primarily as an instrument for increasing sales in the pharmaceutical industry.
• The vast majority of researchers in the field of cholesterol and coronary heart disease, including the authors of the NCEP guidelines and the board of directors of the German DGFF (Lipid League), are to a large extent financially dependent on funding from the pharmaceutical industry or even benefit personally from advice and lecture fees or stock options from these companies, for which cholesterol-lowering drugs are the biggest source of revenue. The consequences of this dependency are:
• The fact that, contrary to what is often suggested, a high cholesterol level is not statistically linked to a reduction in life expectancy, would be largely ignored by the cardiology experts.
• The same applies to indications of the importance of cholesterol levels for memory performance and alertness as well as indications that low cholesterol levels represent a risk factor for various cancers.
• Scientific studies that seem to show a link between coronary heart disease and cholesterol are cited six times more often than studies whose results tend to contradict this hypothesis, although the total number of published studies is in balance.
• Some of the results of studies that were unfavorable for the manufacturers of the cholesterol-lowering preparations are not published in full, for example in the case of the EXCEL study .
• The scientific quality of the drug studies on the subject of cholesterol lowering, which are almost exclusively financed by manufacturers, is being questioned. In 2005, for example, the German Institute for Quality and Efficiency in Health Care described the scientific quality of the statin studies as “poor”. In particular, the 4S study , cited as one of the most important pieces of evidence for the benefit of statin treatment, has come under considerable criticism from a methodological perspective.

The high level of funding from the pharmaceutical industry affects a large part of all medical research and development. University institutes also often finance their research with third-party funding. The pharmaceutical industry also tries to gain influence on public opinion and the practice of prescribing drugs through so-called “opinion leaders” who receive consulting and lecture fees. According to a study from 2001, about 3% of the marketing budget of the pharmaceutical industry - in the case of cholesterol-lowering preparations, this share would correspond to a three-digit million euro amount annually - in the form of substantial donations to a relatively small group of mostly internationally, nationally or regionally known professors poured out. There is no obligation in Germany to make these financial interdependencies transparent. Since January 2006, however, the "Deutsches Ärzteblatt" has been asking its authors to announce and publish such dependencies, in accordance with the practice in international specialist publications. In a study published in 2005, the anti-corruption organization Transparency International Germany criticized both the dependence of medical research on the pharmaceutical industry and what it considers to be the "everyday practice of the pharmaceutical industry" of "buying" medical opinion leaders, and speaks in this connection from a "structural corruption ".

• The chairwoman of the Association of German Medical Journalists (VDMJ) considers it common practice that medical journalists are also paid for their articles by the pharmaceutical industry. According to critics, the enormous economic weight of cholesterol-lowering preparations for the pharmaceutical industry leads, in the opinion of critics, to a frequent and uncritical thematization of cholesterol and cholesterol-lowering drugs in the public media.
• The dependence of most of the medical publications (e.g., Ärzte-Zeitung , Medical Tribune , Der Internist ) directed at medical practitioners (resident doctors or hospital doctors ) on the advertising budget of the large pharmaceutical companies prevents a critical discussion of the topic in such magazines. The editors of the specialist publication BDI aktuell of the Professional Association of German Internists (BDI) are introducing a critical article on the subject of lowering cholesterol with the words: "... and come to conclusions that no advertising-financed medical journal would be willing to print anywhere in Germany."
• Pharmacies in Germany participate in drug sales with a profit margin of 3% and a fixed surcharge of EUR 5.80 (EUR 8.10 less a cash register discount of EUR 2.30) per pack. As for the pharmaceutical industry, cholesterol-lowering drugs are therefore also a mainstay of sales for pharmacies. At the same time, pharmacist officials and pharmacists play an essential role in maintaining public awareness of the subject of measuring and lowering cholesterol levels. For example, officials from pharmacists 'associations or pharmacists' associations appear in health programs as “cholesterol experts” or publish guides on the subject of cholesterol lowering. Numerous pharmacies take part in the “Day of Cholesterol” organized by the Lipid League . In addition, the topic is regularly taken up in the free publications available in pharmacies in terms of the cholesterol-CHD hypothesis. In view of the clear conflict of interests, critics question whether this commitment only focuses on the patient's welfare.
• At the political level, industry- related think tanks like the Stockholm Network play a big role in spreading the message that lowering cholesterol is necessary and useful. In 2006 the Stockholm Network and its sub-organization Center for the New Europe (CNE) published a study entitled “Cholesterol: The importance of not doing enough for government action” (Cholesterol: The Public Policy Implications of Not Doing Enough) and predicts a “health crisis” by 2020 if the current practice of “cholesterol management” is not changed to include increased use of cholesterol-lowering drugs. One of the founders of the Stockholm Network is Pfizer board member Michael W. Hodin; Catherine Windels, who is also the Director of International Affairs for Pfizer, sits on the CNE's Board of Directors. The CNE reportedly receives over 50% of its funding from Pfizer, whose main revenue stream is the cholesterol-lowering drug Lipitor / Sortis; In addition, the pharmaceutical company Merck Sharp & Dohme (MSD), manufacturer of the cholesterol-lowering drugs Zocor and Ezetrol ( ezetimibe ), is to contribute to the financing of the organization. Zocor is MSD's mainstay of sales with \$ 4.4 billion in annual sales (2005). According to the Stockholm Network, the said report itself was funded by the pharmaceutical companies MSD and Schering Plow Corporation; The latter markets Ezetrol together with MSD.

## Cholesterol and risk of stroke

The relationship between cholesterol and strokes is complex, especially since cholesterol is not the only risk factor for strokes, but blood pressure also has a strong influence. In general, however, it has been shown in recent years that high cholesterol levels mean a higher risk of ischemic arteriothrombotic strokes, i.e. strokes that are caused by a vascular occlusion caused by atherosclerosis. At the same time, however, higher cholesterol levels protect against strokes caused by cerebral haemorrhage (hemorrhagic stroke). Conversely, low cholesterol levels mean a higher risk of hemorrhagic stroke. The connection was found in many different studies, so that as of 2019 it can be assumed that cholesterol "probably" plays a causal role. In terms of therapy, this means that cholesterol-lowering therapy, for example with statins, lowers the risk of ischemic strokes. However, you must also ensure that your blood pressure is set correctly, as high blood pressure increases the risk of all types of stroke. Low cholesterol levels with high blood pressure mean an even higher risk of hemorrhagic stroke.

## Cholesterol and cancers

### Serum Cholesterol Levels and Cancer Risk

In cancer, for example, the cholesterol level is higher in women with breast cancer than in healthy people. The reason for this could be that a breakdown product of cholesterol, oxysterol, is very similar to estrogen and also has a growth-promoting effect.

As liver cancer progresses, cholesterol formation is reduced and, as a result, the serum cholesterol level also falls.

### Cholesterol lowering drugs and their influence on cancer risk

In addition, the question of whether lowering cholesterol has a preventive effect on certain types of cancer or whether it even favors the development of cancer is of particular importance.

#### Increasing the risk of cancer

A meta-analysis of prospective cholesterol lowering studies published in July 2007 found a significant correlation between cancer risk and statin use. The lower the LDL cholesterol levels achieved, the higher the proportion of patients who developed cancer. Within an observation period of between one and five years, in the group of patients with the lowest achieved LDL cholesterol levels, about one additional cancer disease per 1000 patients was observed.

The CARE study published in 1996 showed a significant increase in breast cancer cases in the pravastatin-treated group. In the CARE study, this phenomenon is explained by a random anomaly and a low 'event rate'; a causal relationship is considered unlikely, as there is no biological explanation for this phenomenon, and the number of breast cancer cases in the comparison group (placebo group) is unusually low and in the LIPID long-term study of pravastatin in 1508 women no increase in breast cancer cases was observed. In the PROSPER study published in 2002 with a comparatively high mean age (and therefore cancer risk) of the subjects compared to other statin studies, a statistically significant increase in cancer incidence was found in the group treated with pravastatin. The 4S and HPS studies also showed a (non-significant) increase in cancer incidence in the group treated with simvastatin.

#### Lowering the risk of cancer

In recent years, on the basis of various case-control studies, the opposite hypothesis has received great attention, namely that statins may even have a preventive effect against various cancers (including prostate cancer , colorectal cancer , breast cancer , kidney cancer ). The basis for the sometimes euphoric media coverage was the following observation: Among those patients who had developed the respective cancer, the proportion of patients who had taken cholesterol-lowering drugs was lower than in a comparison group without cancer.

However, such non-randomized case-control studies are only of limited statistical significance and, in particular, do not allow any statements about cause-effect relationships (see also case-control study ). The effect observed here can also be based, for example, on the fact that patients with high cholesterol levels, who are known to have a lower cancer rate, are more frequently prescribed cholesterol-lowering drugs. This prescribing practice, even with a completely ineffective drug, would result in a lower rate of cancer in those patients who take the drug.

#### No influence on cancer risk

The question of whether statins have a preventive effect against colorectal carcinoma was examined in an analysis of a large cohort study published in 2006 . However, there was no significant increase in cancer risk in the group of patients treated with cholesterol-lowering agents.

A meta-analysis of the numerous statin studies published in the same year also comes to the conclusion that lowering cholesterol with statins clearly has no preventive effect on cancer, neither on all cancers nor on individual types of cancer, but neither does the development of cancer statistically significantly favored.

The clearly negative results of the last two studies mentioned make further studies on the hoped-for cancer-preventive effect of cholesterol-lowering preparations seem meaningless according to experts.

## Cholesterol and diet

The chicken egg is often denounced as the "cholesterol bomb" because of the high cholesterol content in the egg yolk.

Following a diagnosis of high cholesterol, the recommended first step is usually a low-fat, low-cholesterol diet. However, this recommendation is controversial. A comprehensive account of this question was published in 1981 by the Institute for Social Medicine and Epidemiology of the Federal Health Office .

### Recommendation for high cholesterol

According to the recommendations of the DGFF (Lipid League), the following points should be considered when eating:

1. Little fat meat, offal, sausage products, cheese and egg yolks
2. Low-fat preparation
3. Little animal food
4. Fresh fruit and vegetables several times a day
5. Use of vegetable oil
6. Refrain from alcohol
7. Sufficient exercise

### Influence of diet on cholesterol levels

Critics, on the other hand, maintain that the influence of a short-term change in diet on the cholesterol level is only minor, since the composition of the food only has a small share in the formation of cholesterol.

The 2015 US Department of Agriculture Draft Dietary Advice no longer advises against high cholesterol products to reduce the risk of heart attacks and strokes, but instead advises against excessive consumption of saturated fat.

A prospective study, the joint study Nutrition Survey and Risk Factor Analysis (VERA, from 1985 to 1988 with 25,000 participants), showed that even with different amounts of saturated and unsaturated fatty acids, both the HDL and the LDL values, if at all , only changed minimally. Against this, the objection is again made that the composition of the LDL is ignored: there are indications that it would make a difference which fatty acids (unsaturated or saturated) the lipoprotein LDL is “equipped” with.

Even if these relationships are confirmed, it remains unproven that the proportion of unsaturated fats in the diet itself has an influence on the composition of the LDL and which unsaturated fatty acids have which effect.

It is undisputed that a high level of low-density lipoproteins (LDL cholesterol) in the blood promotes the development of coronary artery disease. LDL transport cholesterol from the liver to the body's cells. When LDL cholesterol is oxidized, it is preferentially deposited on the walls of the blood vessels. In this case, soluble fiber such as beta-glucan from dietary barley can counteract this. These bind excess cholesterol and bile acids in the digestive tract so that they are no longer reabsorbed into the blood in the small intestine. A diet rich in beta-glucan increases their excretion in the stool. Beta-glucan from barley is preferred for the nutritional treatment of hypercholesterolemia . Beta-glucan suppliers can be, for example, barley bread, barley baked goods and beta-glucan barley as a side dish as well as barley flakes with a high beta-glucan content. Already 3 g beta-glucan from barley per day as part of a varied and balanced diet, demonstrably lowering the cholesterol level with sufficient exercise and thus reducing a significant risk factor for coronary heart disease. The daily intake must take place over a period of at least two to three weeks in order to achieve a significant lowering of the LDL cholesterol level in the blood.

With obesity come lipid disorders such as elevated LDL-cholesterol and high plasma - triglycerides (→ hypertriglyceridemia on). After weight loss , a decrease in total cholesterol and LDL cholesterol can be observed within a short time. Compared to other lipids, the triglycerides decrease most clearly with weight reduction. It was found that a weight reduction of 7 to 10 kg brings a clear improvement in the lipid parameters. There is a negative correlation between HDL cholesterol and body weight . With a body mass index > 30, lower values ​​for HDL cholesterol in plasma are measured regardless of the age and gender of the person concerned. When fasting or following a diet with less than 1000 kcal per day, the HDL cholesterol level initially falls. HDL cholesterol only rises when weight remains constant or there is a lower energy deficit. With physical training, however, it remains constant even with rapid weight loss. A long-term change in the composition of fat - in particular the partial replacement of saturated fats with unsaturated fats - can reduce the risk of cardiovascular diseases in men. However, it is not clear which unsaturated fat is the ideal substitute.

Reduced cholesterol levels have been observed in vegetarians and vegans , the cause of which has not been clarified, as this could also be a side effect of a different, generally more health-conscious lifestyle. A more original way of life or genetic dispositions could also be responsible for lower cholesterol levels. This is supported by the fact that groups like the Maasai or Samburu men, who eat almost exclusively milk and meat, have significantly lower cholesterol levels compared to Americans. Japanese, who are less affected by arteriosclerosis in their homeland, suffered heart attacks as often as Americans after migrating to the USA. This is often cited as evidence of the correctness of the cholesterol hypothesis. However, a more precise evaluation showed that this was independent of the food composition and the determined cholesterol level. Rather, maintaining the Japanese lifestyle, regardless of diet, had a positive effect: Japanese, who ate as fat as Americans, but otherwise largely retained their traditional way of life, suffered less from atherosclerosis - even less than Japanese, who continued to be low in fat / a Japanese diet but got used to the American lifestyle.

Neil Barnard et al. According to the study, the number of industry-funded studies looking at the effects of diet on cholesterol levels increased from 0% in the 1950s to 60% in 2010-2019. Among the industry-funded intervention studies that determined the effect of egg consumption on cholesterol levels , 34% showed a significant effect, 51% of the non-industry-funded studies. The authors recommend that readers, editors and the public pay attention to the sources of funding when interpreting the study results and conclusions.

### Influence of a diet containing beta-glucan from barley and oats on cholesterol levels

Beta-glucans are water-soluble dietary fibers that are found in concentrated form in oat bran and in the interior of certain types of barley, so-called beta-glucan barley. If foods rich in beta-glucan are regularly consumed, an elevated cholesterol level drops significantly after just a few weeks. If the cholesterol content in the blood is high, the dietary fat is increasingly deposited on the vessel walls, so that important blood vessels can clog. Therefore, high cholesterol levels are an important risk factor for coronary heart disease. Beta-glucan from barley binds excess cholesterol and bile acids in the digestive tract and transports both out of the body. This stimulates the liver to produce new bile acids from cholesterol and the LDL cholesterol level drops. Already 3 g beta-glucan per day from beta-glucan-rich foods such as barley baked goods, barley flakes, barley salads or oat bran as part of a varied and balanced diet has been shown to lower the cholesterol level and thus reduce a major risk factor for heart and vascular diseases.

### Influence of diet on cholesterol levels from prostaglandins

In addition to the controversial thesis of the influence of direct cholesterol intake through food, there is also an influence of nutrition on cholesterol synthesis by influencing the synthesis of prostaglandins. Prostaglandins are tissue hormones that, among other things, control the synthesis of cholesterol, with one prostaglandin acting in one direction (e.g. the cholesterol-lowering series-1 PGE1) and another in the opposite direction (here series-2 PGE2). The formation of series 1 or series 2 prostaglandins is in turn influenced by the ratio of polyunsaturated fatty acids (omega-3 to omega-6) in the diet. In addition to cholesterol synthesis, prostaglandins also control other factors in the development of arteriosclerosis , e.g. B. Lipoprotein (A) and inflammatory parameters. The dietary recommendations to influence the prostaglandins favorably to lower cholesterol would be for example:

### Cholesterol and pregnancy

Low cholesterol levels in the expectant mother (total cholesterol below 160 mg / dl) are a risk factor for premature birth and low birth weight.

### Cholesterol and breast milk

Breast milk contains a very high proportion of cholesterol (approx. 25 mg / 100 g, cow's milk only contains approx. 12 mg / 100 g).

## Cholesterol, Psyche and Memory

### Cholesterol and violence

A study published in 2005 showed a statistically significant association between low total cholesterol levels in children and dropouts from school. Children and young people with a total cholesterol level below the - percentile (<145 mg / dl) had to have been made in their school career from school almost three times more likely. The authors take this as a further indication that low cholesterol levels are associated with increased aggressiveness. ${\ displaystyle 0 {,} 25}$

### Cholesterol and depression

Various studies have shown that low cholesterol levels are a risk factor for the occurrence of depression . For example, young, healthy women with a total cholesterol level below 4.14 mmol / l (160 mg / dl) were about twice as likely to develop depression as women with medium to high cholesterol levels.

The use of cholesterol-lowering medication apparently also promotes the development of depression. A study of 234 elderly, depressed patients showed that those patients who took cholesterol-lowering drugs had a statistically significant, almost 80% higher relative risk of relapse than patients without this medication. A placebo-controlled study on patients over 70 years of age showed that the mood of the patients in the patient group treated with a cholesterol-lowering drug was statistically significantly negatively affected.

A cohort study in which patients who had taken statins continuously for a period of four years were compared with those who had not taken statins at all or only intermittently reported on the possible positive effects of statin intake on the psyche. The first group showed a reduced prevalence of depression, which, however, was not related to the level of cholesterol lowering. The validity of this study is, however, impaired by the fact that patients who dropped out of the study, for example because of possible side effects of taking medication, could not be included in the analysis.

### Cholesterol and memory

The influence of lowering cholesterol on memory performance was examined in various studies. In a study published in 2000 on 192 healthy adults, it was found that both the memory performance and the attentiveness of the test subjects in the group treated with the cholesterol-lowering drug lovastatin were significantly worse than in the control group. The difference in performance was significantly related to the absolute LDL cholesterol levels after treatment; that is, lower cholesterol levels were associated with poor memory performance. A study carried out on 326 middle-aged women and published in 2003 also showed a linear correlation between memory performance and LDL cholesterol levels.

A review article published in 2003 describes 60 cases of total memory loss associated with statin treatment. After discontinuation of statin treatment, the memory disorders completely or partially disappeared in slightly less than half of the documented cases.

### Cholesterol Lowering and Nightmares

Low serum cholesterol levels appear to be linked to the occurrence of nightmares. In addition, there are individual case reports in which a direct connection between the use of cholesterol-lowering drugs and the occurrence of nightmares has been described.

### Elevated cholesterol due to stress

A study from 2005 demonstrated a connection between increased psychological stress and an increase in cholesterol levels. This relationship was evident both in the short term and within a period of three years. However, the extent of this phenomenon was very different for different test subjects. The test persons, who also showed a relatively high rise in cholesterol under the influence of stress for a short time, also had particularly high increases over the longer period.

## drug

The first means of lowering cholesterol were bile acid exchange resins (Cholestipol) . Later fibrates as well as nicotinic acid preparations and their derivatives came onto the market. Today, statins and cholesterol reuptake inhibitors are used almost exclusively in this area of ​​indication, and in individual cases fibrates.

### Fibrates

The active ingredients bezafibrate, fenofibrate and gemfibrozil are currently in use. Fibrates are characterized by a good lowering of triglycerides and are therefore mainly used today in diabetics.

### Statins

Statins are currently considered to be the most effective drugs for lowering cholesterol. They belong to the group of HMG-CoA reductase inhibitors (CSE inhibitors) because they inhibit the key enzyme in cholesterol synthesis in the cell, β-hydroxy-β-methylglutaryl-coenzyme A reductase. As a result, the cell no longer produces the cholesterol it needs itself, but instead absorbs cholesterol from the blood via LDL receptors.

### Ezetimibe

The active ingredient ezetimibe is a selective cholesterol reuptake inhibitor (or cholesterol absorption inhibitor) that works in the intestine and specifically blocks the Niemann-Pick C1-Like 1 ( NPC1L1 ) protein. NPC1-L1 sits in the membrane of enterocytes in the wall of the small intestine and is responsible for the absorption of cholesterol and phytosterols from the intestine.

### PCSK9 inhibitors

The enzyme proprotein convertase subtilisin / kexin type 9 ( PCSK9 ) is an important intrinsic determinator of the LDL level. It binds the LDL receptor irreversibly and therefore reduces the rate of absorption of LDL from the blood with a correspondingly higher LDL level. A rare gene variant with reduced PCSK9 activity showed a significantly lower LDL level with a lower rate of coronary heart disease. This led to the development of specific monoclonal antibodies directed against PCSK9 ( PCSK9 inhibitors ).

In 2015, the following PCSK9 inhibitors were approved as medicinal substances in the European Union : Alirocumab as a praluent from Sanofi and Evolocumab as a repatha from Amgen .

For alirocumab and evolocumab, phase III studies on almost 7,000 patients with increased LDL levels despite statin therapy showed that the two monoclonal antibodies were very effective. On average, the LDL level fell by 61–62%. In post hoc analyzes, despite the relatively short study period of 12-18 months, an approximately 50% reduction in severe cardiovascular events was found. The antibodies must be injected subcutaneously every two weeks or monthly .

Serious side effects have not yet been described. The most common side effects are general allergic reactions and irritation in the area of ​​the injection site (less than 10% of patients each).

With Bococizumab , another PCSK9 antibodies in development.

### ATP citrate lyase inhibitor

With bempedoic acid , a new mechanism of action is being tested. A key enzyme in cholesterol biosynthesis, ATP citrate lyase, is inhibited. Bempedoic acid is a prodrug and requires activation by the enzyme ACSVL1 (very long chain acetyl-CoA synthetase 1), which is only present in the liver but not in most of the peripheral cells. This is a major difference from statins . The CLEAR Harmony study was able to show that bempedoic acid can further reduce the LDL serum level in patients under the maximum tolerated statin dose. With bempedoic acid, the serum level of LDL cholesterol was 84.4 mg / dl 12 weeks after the start of therapy, without 102.4 mg / dl. A reduction in cardiovascular mortality could not be demonstrated. There is no approval in the USA or in Europe.

In January 2020, the European Medicines Agency (EMA) issued a positive recommendation for approval in the EU. The European Commission usually follows this recommendation.

## Studies

Numerous studies have examined the effect of cholesterol levels on the incidence of cardiovascular disease, as well as other issues related to cholesterol levels. The large number of studies makes it fundamentally problematic to use individual studies to justify an effect, since carrying out several studies to answer the same question can invalidate the supposed statistical significance of a single study. On average, twenty studies that are methodically correct in themselves are sufficient to “prove” a non-existent effect in a statistically significant manner. Metastudies are therefore of particular importance in connection with the topic of cholesterol. However, these too are influenced by the so-called “ publication bias ”.

### Framingham Study

One of the seminal studies in the study of CHD risk factors was the Framingham Study , which is now considered the most important epidemiological study in the United States. She examined 6000 people from two generations in Framingham, Massachusetts . To date, over 1000 scientific publications have been produced through the Framingham Study. In the course of this study it was shown, among other things, that smoking and obesity are important CHD risk factors. It was also found that the incidence of CHD in men between the ages of 30 and 59 is increased according to the level of cholesterol in the blood. In men in their thirties, those with the highest total blood cholesterol were four times more likely than those with the lowest cholesterol. There was no such connection for women or for people over 50 years of age. A review of the Framingham Study in 1987 showed that in people over 50, falling cholesterol levels correlated with increased mortality. A decrease in cholesterol by 1 mg / dl per year was associated with an increase in the overall death rate of 11% and an increase in the death rate from heart disease by 14%.

### Meta-studies

The American National Heart, Lung and Blood Institute conducted meta-studies of the health benefits of lowering cholesterol. 19 studies were analyzed. 650,000 people and 70,000 deaths were examined: Low cholesterol levels are not associated with a general increase in life expectancy, but only relate to cardiovascular diseases, they increase the risk of stroke and the risk of cancer. However, it is still controversial where the cause and effect lie; At the time of measurement, both low and high cholesterol levels could also be caused by (not yet diagnosed) diseases in the early stages. What is certain is that very high, very low and falling cholesterol levels are associated with increased mortality , although it remains unclear whether the cholesterol is the cause or just an indication of a deteriorated state of health.

### CARE

The CARE study ( C holesterol A nd R ecurrent E vent Study ) with patients having 3 to 20 months, previous myocardial infarction showed as a result of reduction in LDL cholesterol 115-174 mg / dl, a non-statistically significant reduction of Reinfarktraten and the frequency of Koronartods (from 5.7% in the control group to 4.6% in the treatment group after five years). The decrease in CHD deaths was offset by an increase in other causes of death in the treatment group. The treatment group showed advantages for non-fatal heart attacks and the number of strokes.

### EXCEL

The first statin study began in 1990 under the name Expanded Clinical Evaluation of Lovastatin (EXCEL) . 8,245 people with "moderately elevated" cholesterol levels took part in the study. The three treatment groups received lovastatin in different doses, the control group of 1,650 patients received a placebo . A first evaluation of the study published in 1991 showed an increase in mortality from 0.2% in the control group to 0.5% in the mean of the three treatment groups, which was marginally statistically significant. The lovastatin manufacturer MSD Sharp & Dohme did not publish any figures on the further course of mortality in this study .

### 4S

The Scandinavian Simvastatin Survival Study is briefly referred to as the 4S study. Within the first five years of treatment, among the 4444 patients involved with a history of heart attack or stable angina pectoris at least six months ago, the LDL cholesterol level was reduced by an average of 35% and the HDL cholesterol level was increased by an average of 8%. In the same period, CHD mortality was reduced from 8.5% to 5.0%, and the rate of definitive myocardial infarction decreased from 12.1% to 7.4%.

There is considerable methodological criticism of this study, e.g. B. from the ad-free drug telegram for the evaluation of drugs. The age distribution of the simvastatin and placebo group could not be taken from the published data, at the same time typical age-related diseases occurred much more frequently in the placebo group. There was no standardization for other drugs taken at the same time, such as aspirin. In addition, the CHD risk profile of the control group was significantly less favorable. And finally, it seemed suspicious that in an alleged double-blind study in patients in the simvastatin group, the dose was doubled after six months, in whom the cholesterol level had not fallen. The authors later had to admit that the patient population was not completely randomized.

Nevertheless, the Arzneitelegramm confirmed in 2004 that the 4S study provided evidence for the first time that male patients with a history of myocardial infarction or stable angina pectoris could benefit from medicinal cholesterol lowering in the sense of extending life. This result has now been confirmed by two further studies (HPS and LIPID). However, the journal advises against the use of statins in women and over 70 year olds without arteriosclerotic disease.

### PROCAM

The PROCAM study ( Pro Spective Ca rdiovascular M ünster Study ) began in 1979 in Munster and examined nearly 50,000 members of the company and employees of the civil service. It revealed indications that not only the level of total cholesterol, but also the ratio of the various cholesterol fractions (LDL, HDL, triglycerides) could be decisive for the CHD risk assessment. Risk calculators for heart attack and stroke were developed on the basis of the study.

### LIPID

The LIPID study ( L ong-Term I INTERVENTION with P ravastatin in I schaemic D isease-Study ) indicated nearly 10,000 subjects with at least 3 to 36 months had a heart attack or hospital discharge by unstable angina with total cholesterol from 155 mg / dl and average LDL cholesterol values ​​of 150 mg / dl show that the LDL was reduced by an average of 25% more than with placebo and the HDL was increased by 5%. The total mortality was reduced from 14% to 11%, the CHD mortality from 8.3% to 6.2%. The effect did not depend on the initial total or LDL cholesterol level. Other causes of death, such as cancer and suicide, also decreased in the treatment group. This means that critics question the comparability of the two groups. Unlike usual, corresponding average values ​​cannot be found in the study.

### HPS

In the Anglo-Scandinavian Heart Protection Study, 20,536 patients with coronary heart disease or other atherosclerotic diseases or hypertension etc. showed a slight but significant reduction in overall mortality from 14.7% in the placebo group to approx. 12.9% in the detect group treated with the cholesterol-lowering drug simvastatin ; d. that is, around 50 people have to be treated for five years to prevent death ( NNT = 56). The statistical methods used to calculate this conclusion of the study are not without controversy. The cost efficiency was also, u. a. because of the high prices for simvastatin. However, the basis of these calculations changed with the introduction of the simvastatin generics in 2003. Whether the positive effect seen in the study is due to the cholesterol-lowering effect or to other mechanisms of action of the statins is controversial and the subject of current research.

### 4D

The 4D study (“Die Deutsche Diabetes Dialyse” study) examined the effects of atorvastatin (Lipitor / Sortis) in the treatment of dialysis patients with type 2 diabetes who have a very high cardiovascular risk. The placebo-controlled study included 1,255 patients followed over four years. In the treatment group, the LDL cholesterol level was reduced by an average of 42%. However, there was no benefit in CHD deaths or overall mortality. Instead, there was a statistically significant doubling of the number of fatal strokes in the treatment group.

### Hu 1999

Hu u. a. investigated in their 1999 study: "A Prospective Study of Egg Consumption and Risk of Cardiovascular Disease in Men and Women" with over 117,000 test subjects the suspected connection between egg consumption and CHD or stroke. An increased risk with increased egg consumption could only be determined for diabetics. There was no significant association for the group as a whole.

### Carotid Intima-Media Thickness

Weingärtner u. a. examined 583 employees of the Saarland University Hospital without cardiovascular diseases or lipid-lowering drugs with regard to cholesterol homeostasis (cholesterol synthesis / cholesterol absorption) and earlier atherosclerosis. Data from this study show that not only total cholesterol and the Framingham risk score, but also differences in cholesterol homeostasis are directly associated with carotid intima-media thickness .

### HUNT 2

Petturson et al. a. evaluated prospective data on deaths among 52,087 Norwegian participants in the HUNT-2 study (Nord-Trøndelag Health Study) who had no previous cardiovascular diseases at the start of the study. The authors examined the relationship between total cholesterol and various mortality rates. They found a slightly significant but inverse relationship between total cholesterol levels and cardiovascular and total mortality in women. Women with a cholesterol level of more than 7 mmol / l (270 mg / dl) had the lowest risk of mortality, those with a cholesterol level of less than 5 mmol / l (193 mg / dl) the highest. In men, the lowest mortality risk was found with a cholesterol level between 5 and 5.9 mmol / l (193–228 mg / dl). The results would therefore speak against the use of cholesterol-lowering drugs in women. Another result of the study was that the mortality between smokers and non-smokers was increased by a factor of 3, regardless of the cholesterol level. Only in women who smoked was there a further significant increase in mortality when the cholesterol level was increased. Overall, cholesterol was thought to play a negligible role in mortality for both women and men due to the low severity of the results.

## literature

Biochemistry and physiology

• Hans-Jürgen Holtmeier: Cholesterol. On physiology, pathophysiology and clinic. Springer, Berlin 1996, ISBN 3-540-60671-8 (comprehensive book)
• E. Buddecke: Outline of biochemistry. 5th edition. de Gruyter, Berlin 1977, ISBN 3-11-004796-9 .
• Georg Löffler, Petro E. Petrides: Biochemistry and Pathobiochemistry. 8th edition. Springer, Heidelberg 2007, ISBN 978-3-540-32680-9 .

Distribution of lipid values ​​in Germany

Representative of the cholesterol-CHD hypothesis

• P. Schwandt, W. Richter, K. Parhofer: Handbook of fat metabolism disorders. 2nd Edition. Schattauer, Stuttgart 2001, ISBN 3-7945-1977-9 . (The three editors are former board members of the Lipid League )
• Christiane Eckert-Lill: Fighting Cholesterol. 2nd Edition. Govi, Eschborn 2003, ISBN 3-7741-0990-7 . (The author acts as managing director pharmacy of the Federal Association of Pharmacists' Associations, ABDA)

Critical work on the cholesterol-CHD hypothesis

• Dieter Borgers, Michael Berger (Ed.): Cholesterol - Risk for Prevention and Health Policy. Blackwell Wissenschaft, Berlin / Vienna 1995, ISBN 3-89412-212-9 .
• Uffe Ravnskov, Udo Pollmer : The Myth of Cholesterol. 4th, completely revised and supplemented edition. Hirzel, Stuttgart 2008, ISBN 978-3-7776-2123-4 .
• Jörg Blech: The inventors of the disease. How we are made into patients. S. Fischer, Frankfurt 2003, ISBN 3-10-004410-X , p. 78 ff. (Including on the economic exploitation of the cholesterol problem)
• Ray Moynihan, Alan Cassels: Selling sickness. How the world's biggest pharmaceutical companies are turning us all into patients . Nation Books, New York 2005, ISBN 1-56025-697-4 .
• Walter Hartenbach : The cholesterol lie. The fairy tale of bad cholesterol. Herbig, Munich 2002, ISBN 3-7766-2277-6 .

Others

Commons : Cholesterol  - Collection of pictures, videos and audio files
Wiktionary: Cholesterol  - explanations of meanings, word origins, synonyms, translations

## Individual evidence

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