Drugs for Hyperlipidemia



Drugs for Hyperlipidemia



Classification of Drugs for Hyperlipidemia







aAlso lovastatin (MEVACOR), fluvastatin (LESCOL), and pitavastatin (LIVALO).




Overview


Lipids are necessary molecules for human life. Cholesterol, which is an essential component of cell membranes, is the precursor to the sterol and steroid compounds that are synthesized in the body. Triglycerides, composed of three fatty acids and glycerol, are the main storage form of fuel used to generate high-energy compounds, such as adenosine triphosphate, that provide the energy for muscle contraction and metabolic reactions. Despite the vital functions of these and other lipids, elevated blood (serum) concentrations of cholesterol and triglycerides have been shown to be detrimental.


Whereas hyperlipidemia and hyperlipoproteinemia are general terms for elevated concentrations of lipids and lipoproteins in the blood, hypercholesterolemia and hypertriglyceridemia refer specifically to high concentrations of cholesterol and triglycerides, respectively. Hypercholesterolemia contributes to the pathogenesis of atherosclerosis and has been causally associated with coronary artery disease and other atherosclerotic vascular diseases (Fig. 15-1). Hypertriglyceridemia is a risk factor for pancreatitis, but its role in the development of atherosclerosis and heart disease remains uncertain. Clinical trials of drugs that reduce serum triglycerides have not consistently reduced cardiovascular events and have not reduced mortality.


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FIGURE 15-1 Comparison of normal (A) and atherosclerotic (B) arterial walls. Steps in the pathogenesis of atherosclerosis are as follows: (1) Damage to the endothelium is followed by invasion of macrophages. (2) Endothelial and macrophage growth factors stimulate smooth muscle cells to migrate into the tunica intima and to proliferate. (3) Oxidized cholesterol accumulates in and around macrophages (foam cells) and muscle cells. (4) Collagen and elastic fibers form a connective tissue matrix that results in a fibrous plaque.

Because coronary heart disease (CHD) is the main cause of premature death in industrialized countries, it is important to detect and eliminate modifiable risk factors associated with it. In addition to hyperlipidemia, these risk factors include hypertension, cigarette smoking, and a low high-density–lipoprotein (HDL) cholesterol level (<40 mg/dL). Other risk factors include male gender, family history of premature CHD (CHD in first-degree male relative under 55 years of age or first-degree female relative under 65 years of age), and advanced age (men over 45 years, women over 55 years). Diabetes mellitus and clinical manifestations of noncoronary forms of atherosclerotic disease (e.g., aortic aneurysm and carotid artery disease) are considered CHD risk equivalents when health care professionals are determining goals for treatment of hyperlipidemia. This means that persons with these conditions are considered to have the same risk for future occurrences of CHD as persons who already have some form of CHD (e.g., angina pectoris, myocardial infarction, or other types of clinically significant myocardial ischemia).


Women have a lower risk of heart disease until after menopause, and this lower risk may be partly a result of the favorable effect of estrogens on serum lipoprotein levels. Estrogens may also have beneficial effects on the microcirculation and energy metabolism.


After discussing lipoproteins, lipid transport, and the causes and types of hyperlipoproteinemia, this chapter describes how dietary restrictions, alone or in combination with drug treatment, can reduce serum lipoprotein levels and thereby reduce the risk of CHD.



Lipoproteins and Lipid Transport


Because lipids are insoluble in plasma water, they are transported in the blood in the form of lipoproteins. These substances have a core of hydrophobic (water-evading) lipids surrounded by a shell of hydrophilic (water-attracting) proteins and portions of phospholipids. There are numerous types of lipoproteins, including chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), intermediate-density lipoproteins, HDLs, and lipoprotein (a). The various types are distinguished in terms of their buoyant density, lipid and protein composition, and role in lipid transport. Moreover, each type is associated with a unique group of apoproteins. Some of the apoproteins are exchanged between different types of lipoproteins as they transport lipids to various tissues. The composition and metabolism of lipoproteins is depicted in Box 15-1.



Box 15-1   Lipoprotein Metabolism and Atherosclerosis


The liver is the central processing site for lipoprotein metabolism. Cholesterol is derived from three sources: (1) biosynthesis from acetyl-CoA, (2) delivery of dietary cholesterol by chylomicron remnants, and (3) endocytosis of low-density–lipoprotein (LDL) cholesterol by LDL receptors.


Triglycerides are formed in the liver from fatty acids, which are derived from lipolysis of triglycerides in adipose tissue. Triglycerides, cholesterol, and protein are packaged by Golgi bodies in the liver to form very-low-density lipoproteins (VLDLs), which are secreted into the circulation. The VLDLs accept apoproteins C and E from high-density lipoproteins (HDLs) and then return these apoproteins to HDL as they deliver triglycerides (as fatty acids) to adipose and other tissues via the action of lipoprotein lipase located in the capillary endothelium.





Very-Low-Density and Low-Density Lipoproteins


Golgi bodies in the liver form VLDLs from triglycerides, cholesterol, and protein and then secrete the VLDLs into the circulation. The VLDLs deliver triglycerides to adipose tissue in the same manner as do the chylomicrons. During the process, the VLDLs are transformed into intermediate-density lipoproteins and LDLs that contain a high percentage of cholesterol (Fig. 15-2).


image
FIGURE 15-2 Sites and mechanisms of drugs for hyperlipidemia. Ezetimibe inhibits the absorption of dietary and biliary cholesterol from the intestines. The HMG-CoA reductase inhibitors block the rate-limiting step in cholesterol biosynthesis. The bile acid–binding resins inhibit the reabsorption of bile acids from the gut. Niacin inhibits the secretion of very-low-density lipoproteins (VLDLs) from the liver, and fibrates such as gemfibrozil stimulate lipoprotein lipase to increase the hydrolysis of VLDL triglycerides and the delivery of fatty acids to adipose and other tissues. IDL, Intermediate-density lipoprotein.

The LDLs transport cholesterol to peripheral tissues for incorporation into cell membranes and steroids. In this process, the LDLs bind to specific LDL receptors that are located in the plasma membrane of cells and recognize apoprotein B-100 on the surface of LDL molecules. After binding to their receptors, the LDLs undergo endocytosis and are incorporated into lysosomes for further processing of cholesterol and protein.


The LDLs can also deliver cholesterol to nascent atheromas and thereby contribute to the development of atherosclerosis (see Fig. 15-1). In atheromas, cholesterol is phagocytosed by macrophages, which are transformed into foam cells as they become filled with oxidized cholesterol.



High-Density Lipoproteins


The HDLs are small lipoproteins whose high density is caused by their high ratio of protein to lipid. Nascent pre-β-HDL particles are formed in the liver and intestines from apoprotein A-I and a small quantity of cholesterol and phospholipid. The cholesterol is then esterified by lecithin–cholesterol acyltransferase so as to convert pre–β-HDL into mature α-HDL particles. As HDL circulates in the blood, it exchanges apoproteins C and E with VLDL, so as to enable delivery of VLDL triglycerides to adipose tissue via lipoprotein lipase.


HDL transports cholesterol from atheromas and peripheral tissues to the liver. During this process of reverse cholesterol transport, the α-HDLs acquire additional cholesterol from macrophages in blood vessel walls (via adenosine triphosphate–binding cassette transporters) and esterify the cholesterol via lecithin–cholesterol acyltransferase. The cholesteryl esters are either transported by HDL directly to the liver or are transferred to LDL for transport to the liver (indirect pathway). The contribution of reverse cholesterol transport to CHD has been supported by epidemiologic studies that show an inverse correlation between HDL levels and the risk of this disease.




Causes and Types of Hyperlipoproteinemia


Hyperlipoproteinemia occurs as a result of genetic or environmental factors that increase the formation of lipoproteins or reduce the clearance of lipoproteins from the circulation. These factors include biochemical defects in lipoprotein metabolism, excessive dietary intake of lipids, endocrine abnormalities, and use of drugs that perturb lipoprotein formation or catabolism. Table 15-1 provides information about the characteristics and types of hyperlipoproteinemia.



Primary hyperlipoproteinemias are relatively rare disorders, each of which is caused by a monogenic defect (a specific defect at a single gene). In some disorders, LDL cholesterol (LDL-C) levels are severely elevated because of a deficiency of LDL receptors or a defect in the structure of apoprotein B. In the latter case, LDL receptors do not recognize LDL, so LDL removal from the circulation is markedly impaired. In another disorder, VLDL and triglyceride levels are severely elevated because of a lipoprotein lipase deficiency that prevents delivery of triglycerides to adipose tissue.


Most cases of hyperlipoproteinemia do not result from a single gene defect but instead result from the influence of several genes that predispose the patient to milder forms of hyperlipoproteinemia, particularly in the presence of excessive dietary intake of lipids. These milder forms, called polygenic-environmental hyperlipoproteinemias, which are much more common than primary hyperlipoproteinemias, are responsible for most cases of accelerated atherosclerosis.


Secondary hyperlipoproteinemias are commonly caused by the presence of alcoholism, diabetes mellitus, or uremia or by the use of drugs such as β-adrenoceptor antagonists, isotretinoin, oral contraceptives, or thiazide diuretics. They are less commonly caused by hypothyroidism, nephrotic syndrome, or obstructive liver disease.



Guidelines for Management of Hypercholesterolemia


The National Cholesterol Education Program (NCEP) has issued periodic evidence-based guidelines for the management of high blood cholesterol and related disorders. The latest recommendations encourage more aggressive reductions in LDL-C in high-risk patients.


The NCEP guidelines (Table 15-2) establish LDL-C goals and levels for initiating therapeutic lifestyle changes (TLCs) and drug therapy for persons in different risk categories. For high-risk patients (who already have CHD or have CHD risk equivalents), the basic goal is to achieve an LDL-C level of less than 100 mg/dL, and TLC and drug therapy should be initiated if the patient’s LDL-C level is higher than 100 mg/dL. The updated guidelines suggest an optional LDL-C goal for high-risk patients of less than 70 mg/dL, particularly for those whose LDL-C level is less than 100 mg/dL at baseline. This optional goal is based on clinical trials that show that high-risk patients benefit from LDL-C reduction regardless of their baseline level.



TABLE 15-2


National Cholesterol Education Program Guidelines for Management of High Blood Cholesterol Levels for Adults in Different Risk Categories*






























RISK CATEGORY LDL-C GOAL INITIATE TLC* CONSIDER DRUG THERAPY*
High risk: CHD or CHD equivalents† (10-year risk‡ of CHD >20%) <100 mg/dL (optional: <70 mg/dL) ≥100 mg/dL (optional: >70 mg/dL) ≥100 mg/dL (optional: >70 mg/dL)
Moderately high risk: 2+ risk factors§ (10-year risk of CHD 10%-20%) <130 mg/dL (optional: <100 mg/dL) ≥130 mg/dL (optional >100 mg/dL) ≥130 mg/dL (optional: >100 mg/dL)
Intermediate risk: 2+ risk factors (10-year risk of CHD <10%) <130 mg/dL ≥130 mg/dL ≥160 mg/dL
Low risk: 0 or 1 risk factor (10-year risk <1%) <160 mg/dL ≥160 mg/dL ≥190 mg/dL (optional: 160-190 mg/dL)


image


CHD, Coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TLC, therapeutic lifestyle change.


*LDL-C levels at which TLC or drug therapy initiated.


†Includes myocardial infarction, angina, myocardial ischemia, noncoronary forms of atherosclerosis, and diabetes mellitus.


‡Electronic 10-year risk calculators available at www.nhlbi.nih.gov/guidelines/cholesterol.


§Risk factors include cigarette smoking, hypertension, low HDL-C, family history of premature CHD, and age (see chapter text for details).


From Adult Treatment Panel III Guidelines, issued in 2001 and updated in 2004.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Drugs for Hyperlipidemia

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