Cholesterol Debate: Past, Present and Future (2)

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Cholesterol destroyer: "bad" is still bad, but is "good" good?

Now that the lipidogram has become a standard component of a medical examination, we can easily get an extremely valuable individual "snapshot" of the state of cholesterol metabolism. However, this information can easily be disorienting. In the lipidogram, we see cholesterol divided into the main components: HDL – high–density lipoproteins and LDL - low-density lipoproteins. Together, they make up most of the total cholesterol index.

Since high LDL levels have been shown to contribute to the development of atherosclerosis, this form of cholesterol has been called "bad cholesterol". However, the ability of HDL, known as "good cholesterol," to save the day remains a matter of debate. When studying the characteristics of cholesterol levels in the population, certain evidence has been obtained in favor of the fact that there is an inverse relationship between the concentration of HDL and the risk of developing cardiovascular diseases. In other words, it seems that high HDL levels in the population are associated with a low incidence of myocardial infarction.

From a mechanistic point of view, this makes sense. In the body, HDL performs the function of removing cholesterol from specialized cells of the immune system – macrophages, which helps to prevent its accumulation in the walls of our blood vessels. Moreover, it has been suggested that HDL has antioxidant and anti-inflammatory properties, which is not bad with regard to the risk of developing diseases of the cardiovascular system. However, it's not that simple. Under certain conditions, HDL molecules are damaged, transforming into something that contributes to damage to blood vessels. Thus, at the individual level, the concentration of HDL cannot be an informative parameter.

The idea that an increase in HDL levels can be beneficial to the body arose from the results of clinical studies, including a trial of a drug for the treatment of coronary disease (1965-1974), in which the effects of niacin (aka vitamin B3, nicotinic acid, nicotinamide) were evaluated. To date, niacin is the most effective drug approved by the U.S. Food and Drug Administration to increase the level of HDL cholesterol. An interesting fact is that niacin simultaneously reduces the level of cholesterol, which makes up the LDL fraction, as well as another type of blood lipids – triglycerides. Because of this, it is difficult to determine whether the protective effects of niacin are really due to an increase in the concentration of HDL. Fibrates (salts or esters of fibroic acid), such as TriCor and Lopid, represent another class of compounds that can significantly increase HDL levels, however, like niacin, these drugs also affect LDL and triglyceride concentrations.

Despite the existence of a number of uncertainties, several pharmaceutical companies have engaged in studying the potential cardioprotective effects of selective increase in HDL levels in the bloodstream. Based mainly on the results of Alan Tall from Columbia University Medical Center, many pharmaceutical laboratories are working on methods of selective action on a molecule known as the transport protein of cholesterol esters, for simplicity called CETP (from the English cholesterol ester transfer protein). Studies have shown that blocking the activity of CETP leads to an increase in the content of HDL in the blood and, based on the belief that this increase is beneficial to health, it is believed that the drugs having the described effect can be an excellent alternative to what is already on the market. However, the first trial of the CETP inhibitor drug led to disastrous consequences.

It has been demonstrated that when administered individually, torcetrapib, a CETP inhibitor drug manufactured by Pfizer, increases the level of HDL without significantly changing the concentration of HDL. The developers hoped that these biochemical data would transform into a protective effect on the human heart. However, a clinical study showed that when used in combination with another cholesterol-lowering drug of the statin group (to which we will return later), torcetrapib therapy was associated with an increase in the frequency of deaths from cardiovascular diseases by 50% compared with placebo. Such results were obtained due to the revealed ability of torcetrapib to increase blood pressure.

Critical statements regarding torcetrapib gave rise to the idea that it was not a "pure" drug, especially given the fact that the increase in blood pressure is in no way related to the mechanism of action of torcetrapib. Due to the appearance of such reasoning, the idea of using CETP inhibitors was not completely rejected.

Many experts have high hopes for the CETP inhibitor anacetrapib being developed by Merck. During the phase III clinical trial, data were obtained according to which anacetrapib had a pronounced effect, manifested in an increase in HDL levels when taken by patients already taking statin drugs. At the same time, none of the unintended effects observed during therapy with torcetrapib were recorded.

However, is the level of HDL really important in cases where the concentration of LDL is controllable? In other words, is there any benefit from increasing the level of HDL against the background of adequate control over the concentration of LDL? The conclusions drawn on the basis of the results obtained in the AIM-HIGH study indicate that in this case the correct answer is "no". In May 2011, the National Institute of Heart, Lung and Blood Diseases of the United States announced its intention to prematurely terminate this clinical trial, the purpose of which was to study the effects of using niacin while taking statins, indicating its uselessness as the reason. The decision was made after experts took into account the negative results of the ACCORD study, which demonstrated that taking fibrate group drugs in combination with statins does not provide an additional positive effect on the health of patients with diabetes.

All this undoubtedly creates some confusion regarding the modern dogma "HDL is good", and doctors have already begun to make adjustments to the approaches to treating patients with low HDL levels in the case of normal or low LDL values. Given the currently available data, when it comes to predisposition to diseases of the cardiovascular system, LDL is the main risk factor. Does it make sense to reinterpret the results of early studies demonstrating the existence of a relationship between high HDL levels and a low incidence of myocardial infarction?

Perhaps we will get more information in the process of continuing to study the effectiveness of anacetrapib. However, what is the point that its effects are tested against the background of taking a statin? In order to assess the real consequences of an increase in HDL levels, it is necessary to find a way to selectively study the effects of changes in HDL concentrations. However, there are always ethical issues to consider. It is impossible to deprive a patient of the opportunity to take a drug that reliably has a positive effect on his health, just to dot the "e" in the name of science.

However, medical science has always declared (and implemented as much as possible) the need to take into account the individual characteristics of each patient. There are a large number of people who would benefit from the confidence that increasing the level of HDL is a new real alternative. This is definitely important enough for patients who cannot take statins due to undesirable side effects. There must be a way to ensure equal opportunities in the fight against heart disease for all patients, and perhaps it's time to restructure the existing approach.

Cholesterol contradictions and why it is necessary to reconsider the approach to therapy

For many high-risk patients who do not respond to agitation about the benefits of diet and exercise, the easiest way to control LDL concentration is taking statins. Drugs of the statin group suppress the natural ability of the human body to synthesize cholesterol, which leads to a decrease in LDL in the blood. These drugs have undoubtedly helped a large number of people, especially those who inherited a genetic predisposition to elevated cholesterol levels. However, some patients simply cannot tolerate statin therapy and, accordingly, specialists should provide them with alternative options.

Taking all drugs of the statin group is associated with negative side effects, especially when using high dosages [Bays H. Statin safety: An overview and assessment of the data—2005. AmJ Cardiol 2006;97(8A):6C-26C]. These undesirable reactions include problems with memory and sleep, as well as, most often, muscle problems.

The condition of the muscles of some patients suffers slightly, while the more serious problems experienced by other patients attract some attention from specialists. It, as well as data published in November 2010 in the Lancet journal in the article Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomized trial, showed a significant increase in the number of patients who, as a result of taking high doses of statins (80 mg per day) develops a muscle disease known as myopathy, formed the basis of the following safety statement issued by the U.S. Food and Drug Administration (FDA):

[06-08-2011] The FDA recommends limiting the use of the highest of the approved dosages of the cholesterol-lowering drug simvastatin (80 mg) due to the increased risk of muscle damage. Simvastatin at a dose of 80 mg should be used only for the treatment of patients who have already been taking the drug at this dosage for 12 or more months without signs of muscle damage (myopathy). Simvastatin at a dose of 80 mg should not be prescribed to new patients, including patients already taking lower doses of the drug. In addition to the listed new restrictions, the US Food and Drug Administration requires changes to the labeling of simvastatin, consisting in the addition of new contraindications (can not be used simultaneously with certain drugs) and dose restrictions of simvastatin when used in combination with certain drugs.

The registered incidence of adverse reactions associated with statin administration during randomized clinical trials was 5%, but in real conditions this indicator can reach 20% [Armitage J. The safety of statins in clinical practice. Lancet 2007; 370(9601):1781-90; Radcliffe KA, Campbell WW. Statin myopathy. Curr Neurol Neurosci Rep 2008; 8(1):66-72]. It is believed that this discrepancy is due to the selection of patients to participate in these randomized clinical trials, which, as a rule, meant the exclusion of groups characterized by a higher frequency of statin intolerance (women and the elderly). Moreover, patients who abuse alcohol and already have a disease (for example, diabetes) are usually excluded from clinical trials or taking a cocktail of drugs. However, in practice, such patients are usually prescribed statins.

To date, there is no standardized method of treating patients who have developed an undesirable reaction in response to statin therapy. In a promising article [Needed: Pragmatic Clinical Trials for Statin-Intolerant Patients], published in December 2011 in the New England Journal of Medicine, Patricia Maningat and Jan Breslow from Rockefeller University discuss this issue and lay the foundation for the need for pragmatic (practical) clinical trials with involving patients with statin intolerance.

In contrast to randomized clinical trials conducted, as a rule, on a homogeneous sample of patients, pragmatic clinical trials would be more appropriate in real conditions and would provide detailed information that would allow doctors and healthcare professionals to determine more personalized approaches to treatment. The authors also note the fact that most of the new therapeutic approaches are being tested against the background of the use of statins, which makes it impossible to determine the effectiveness of individual administration of such drugs for patients with statin intolerance.

Quite often you can hear a joke that statins should be added to drinking water, and the growing number of patients who are prescribed statins increases the share of truth in this joke. Undoubtedly, an increase in the number of patients taking statins will contribute to an increase in the frequency of negative side effects. It is possible that conducting pragmatic clinical trials is not the most economically effective strategy, planning such a study is also associated with certain difficulties, but for specialists, the possibility of meeting the needs of each patient with high cholesterol is an extremely important issue. Modern standards of treatment are definitely outdated. It's time to start a dialogue, the purpose of which will be to correct them.

Portal "Eternal youth" http://vechnayamolodost.ru31.01.2012