Robert L. Talbert
Hypercholesterolemia, elevated low-density lipoprotein, and low high-density lipoprotein (HDL) are unequivocally linked to increased risk for coronary heart disease (CHD) and cerebrovascular morbidity and mortality; low-density lipoprotein (LDL) is the primary target.
Multiple genetic abnormalities and environmental factors are involved in clinical lipid abnormalities and routinely used clinical laboratory measurements do not define the underlying abnormalities.
Initial therapy for any lipoprotein disorder is therapeutic lifestyle changes with restricted intake of total and saturated fat and cholesterol and a modest increase in polyunsaturated fat intake along with a program of regular exercise and weight reduction if needed.
If therapy is insufficient after therapeutic lifestyle changes, lipid-lowering agents should be chosen based on the specific lipoprotein disorder presentation and the severity of the lipid abnormality.
Considering compliance, adverse effects, and effectiveness, statins are the drugs of choice for patients with hypercholesterolemia because they are the most potent form of monotherapy and are cost-effective in patients with known coronary artery disease (CAD) or multiple risk factors and in high-risk primary prevention patients.
Patients not responding to statin monotherapy may be treated with combination therapy for hypercholesterolemia, but should be monitored closely because of an increased risk for adverse effects and drug interactions.
Hypertriglyceridemia usually responds well to niacin, gemfibrozil, and fenofibrate; high-dose niacin should be used cautiously in diabetics because of worsening glycemic control. Statins lower triglycerides to a variable extent depending on baseline triglyceride concentration and statin potency.
Low HDL-C is addressed with lifestyle modifications such as smoking cessation and increased exercise; niacin and gemfibrozil and fenofibrate can significantly increase HDL-C as well.
Lipid-lowering therapy is generally considered to be cost-effective, particularly in secondary intervention and high-risk patients.
Reductions in elevated total cholesterol and LDL-C reduce CHD mortality and total mortality; increasing HDL may reduce CHD events as well. Aggressive treatment of hypercholesterolemia results in fewer patients progressing to myocardial infarction, angina, and stroke, and reduces the need for interventions such as coronary artery bypass graft and percutaneous transluminal coronary angioplasty.
Lomitapide and mipomersen have been recently approved for the treatment of homozygous familial hypercholesterolemia. Both have novel mechanisms of action to lower total and LDL cholesterol.
Cholesterol, triglycerides, and phospholipids are the major lipids in the body and they are transported as complexes of lipid and proteins known as lipoproteins. Plasma lipoproteins are spherical particles with surfaces that consist largely of phospholipid, free cholesterol, and protein, and cores that consist mostly of triglyceride and cholesterol ester (Fig. 11-1). The three major classes of lipoproteins found in serum are low-density lipoproteins (LDL), high-density lipoproteins (HDL), and very-low-density lipoproteins (VLDL). VLDL is carried in the circulation as triglyceride and can be estimated by dividing the triglyceride concentration by 5 if the triglyceride concentration is below 250 mg/dL (2.83 mmol/L). Intermediate-density lipoprotein (IDL) resides between VLDL and LDL and is included in the LDL measurement in routine clinical measurement. Abnormalities of plasma lipoproteins can result in a predisposition to coronary, cerebrovascular, and peripheral vascular arterial disease and constitute one of the major risk factors for coronary heart disease (CHD). Accumulating evidence over the past decades had linked elevated total and LDL cholesterol and reduced HDL to the development of CHD. Premature coronary atherosclerosis, leading to the manifestations of ischemic heart disease (IHD; see Chap. 6), is the most common and significant consequence of dyslipidemia. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) published its third report summarizing these data and giving recommendations for the management of hypercholesterolemia in adults.1,2 This report and the later update modify earlier recommendations and provide a new way of risk stratifying patients based on multiple risk factors, the presence of diabetes, and the metabolic syndrome. The American Heart Association (AHA) also provides guidelines for primary and secondary prevention of CHD.3–5
FIGURE 11-1 Diagrammatic representation of the structure of lowdensity lipoprotein (LDL), the LDL receptor, and the binding of LDL to the receptor via apolipoprotein B-100. (From Ganong WF. Review of Medical Physiology, 22nd ed. New York: McGraw-Hill, 2005:303.)
Total cholesterol and LDL-C increase throughout life in men and women, representing an atherogenic pattern characteristic of Westernized society diets.6 Based on estimates from the AHA, 43.4% or 98.9 million American adults over age 20 years have total cholesterol levels of 200 mg/dL (5.17 mmol/L) or higher.7 More than half of individuals at borderline high risk remain unaware that they have hypercholesterolemia and fewer than half of highest-risk persons (those with symptomatic CHD) are receiving lipid-lowering treatment. About one-third of treated patients are achieving their LDL goal; fewer than 20% of CHD patients are at their LDL goal.8,9 Changes in the NCEP guidelines have increased the number of persons eligible for therapeutic lifestyle changes (TLCs) or lipid-lowering therapy by millions. NCEP estimates that only 26% of patients have an optimal LDL-C (<100 mg/dL [<2.59 mmol/L]) and that large numbers of patients are either untreated or undertreated.1 Unfortunately, those patients at highest risk are less likely to be treated to desirable levels of LDL.10 Although these numbers seem staggering in their enormity, substantial progress has been made, and the number of Americans with a desirable blood cholesterol level (<200 mg/dL [<5.17 mmol/L]) has risen to 49% from 45% from the earlier survey (1976 to 1980), while the average total cholesterol in this country has fallen from 220 mg/dL (5.69 mmol/L) in 1960 to 195 mg/dL for men and 201 mg/dL for women.7 Patients who are at risk but who have not yet experienced their first cardiovascular or cerebrovascular event (e.g., myocardial infarction [MI]) are termed primary prevention, whereas those with manifest vascular disease are termed secondary intervention.
Data from the Framingham study and from other studies demonstrate that the risk for developing cardiovascular disease is related to the degree of total cholesterol and LDL elevation in a graded, continuous fashion.11Hypercholesterolemia is additive to the other nonlipid risk factors for CHD, including cigarette smoking, hypertension, diabetes, low HDL levels, and electrocardiographic abnormalities. The presence of established CHD or prior MI increases the risk of MI five to seven times that seen in men or women without CHD, and LDL is a significant predictor of subsequent morbidity and mortality. About 50% of all MIs and at least 70% of CHD deaths occur in patients with known CHD, and these patients should therefore be a target for screening, identification, and treatment. Unfortunately, the identification of patients at high risk because of hypercholesterolemia or other lipid disorders is too frequently overlooked, because blood lipid levels are not always evaluated in this population even after an event such as MI.
A comparison of the United States to other countries shows similar relationships between total cholesterol and LDL, and an inverse relationship with HDL to coronary artery disease (CAD) mortality.11 On a positive note, the U.S. mortality rate is midway among the countries studied, and this country has had the greatest decline in CAD mortality (35% to 40%) in men and women over the past 10 years as compared with other countries. A decline in the prevalence of hypercholesterolemia in certain segments of the U.S. population parallels these trends in mortality.1 LDL and the ratio of LDL to HDL have also been used to assess risk, but their use adds little information to total cholesterol alone unless HDL is abnormally high or low. McQueen et al. found that the ratio of apolipoprotein (Apo) B to ApoA-I was more predictive and consistent across gender and ethnic groups.12 HDL transports cholesterol from lipid-laden foam cells to the liver. HDL has been shown to be protective for the occurrence of CHD, and an inverse relationship exists between CHD and HDL levels.13 Recent clinical trials attempting to raise HDL have failed to demonstrate clinically meaningful reductions in cardiovascular end points challenging the importance of increasing HDL fractions and ApoA-I.14
VLDL, the major lipoprotein associated with triglycerides, is enriched with cholesterol esters, and is smaller, denser, and more atherogenic than less dense VLDL. Routine measurement of triglycerides cannot distinguish between the types of VLDL present in plasma. Elevation of triglyceride-rich lipoproteins is associated with low HDL, and this ratio predicts increased risk. The 8-year followup of the Copenhagen male study found a clear gradient of risk of IHD with increasing triglyceride levels within each level of HDL cholesterol. When compared with the lowest tertile of triglyceride concentrations, the highest tertile had 2.2 relative risk for IHD and the relationship extended across all concentrations of HDL.15 The Helsinki Heart Study shows that hypertriglyceridemia and low HDL are associated with obesity (body mass index [BMI] >26 kg/m2), smoking, sedentary lifestyle, blood pressure of ≥140/90 mm Hg, and blood glucose above 79 mg/dL (4.4 mmol/L), and that the benefit of gemfibrozil (risk reduction 68%, P<0.03) was largely confined to overweight subjects.16 Hypertriglyceridemia in certain instances—for example, diabetes mellitus, nephrotic syndrome, and chronic renal disease, and perhaps in women—is associated with increased cardiovascular risk. This is thought to be a consequence of the presence of atherogenic lipoproteins and of hypertriglyceridemia being a marker for them, as triglycerides are usually not independently predictive for CHD.17
LIPOPROTEIN METABOLISM AND TRANSPORT
Cholesterol and triglycerides, as the major plasma lipids, are essential substrates for cell membrane formation and hormone synthesis, and provide a source of free fatty acids.18 Dyslipidemia may be defined as an elevation in total cholesterol, elevation in LDL cholesterol, elevation in triglycerides or low HDL cholesterol concentration, or some combination of these abnormalities. Lipids, being water immiscible, are not present in free form in the plasma, but rather circulate as lipoproteins. Hyperlipoproteinemia describes an increased concentration of the lipoprotein macromolecules that transport lipids in the plasma. The density of plasma lipoproteins is determined by their relative content of protein and lipid. Density, composition, size, and electrophoretic mobility divide lipoproteins into four classes (Table 11-1).
TABLE 11-1 Composition of Lipoprotein Isolated from Normal Subjects
LDL has been further divided into LDL1, or IDL (density 1.006 to 1.019 g/mL), and LDL2 (1.019 to 1.063 g/mL). LDL2 is the major LDL component in plasma and it carries 60% to 70% of the total serum cholesterol. HDL has been subfractionated into HDL2 (density 1.063 to 1.125 g/mL) and HDL3 (1.125 to 1.21 g/mL). Fluctuations in HDL are usually caused by alterations in the levels of HDL2. HDL normally carries about 20% to 30% of the total cholesterol. VLDL has also been subdivided into three classes, and it carries about 10% to 15% of serum cholesterol and most of the triglycerides in the fasting state. VLDL is the precursor for LDL, and VLDL remnants may also be atherogenic. Table 11-2 shows the characteristics of the protein constituent of lipoproteins known as Apos. The structure of LDL, the LDL receptor (LDL-R), and the binding of the LDL to the receptor via ApoB-100 are shown in Figure 11-1.
TABLE 11-2 Characteristics and Functions of Apolipoproteins
Chylomicrons, large triglyceride-rich particles containing Apos B-48, B-100, and E, are formed from dietary fat solubilized by bile salts in intestinal mucosal cells. Chylomicrons are normally not present in the plasma after a fast of 12 to 14 hours and are catabolized by lipoprotein lipase (LPL), which is activated by ApoC-II and in the vascular endothelium and hepatic lipase to form chylomicron remnants. The remnants that contain ApoE (Fig. 11-2) are taken up by the “remnant receptor,” which may be an LDL-R-related protein, in the liver. Free cholesterol is liberated intracellularly after attachment to the remnant receptor. Chylomicrons also function to deliver dietary triglyceride to skeletal muscle and adipose tissue. During the catabolism of nascent chylomicrons to remnants, triglyceride is converted to free fatty acids and Apos A-I, A-II, A-IV (free in plasma), C-I, C-II, and C-III, and phospholipids are transferred to HDL. Apos E and C-II are transferred to chylomicrons from HDL and eventually back through these metabolic events. Hepatic VLDL synthesis is regulated in part by diet and hormones, and is inhibited by uptake of chylomicron remnants in the liver. VLDL is secreted from the liver and serially converted via LPL to IDL, and, finally, to LDL. VLDL receptors are found in adipose tissue and muscle, and bear close homology to the structure of LDL-Rs.
FIGURE 11-2 Simplified diagram of lipoprotein systems for transporting lipids in humans. In the exogenous system, chylomicrons rich in triglycerides of dietary origin are converted to chylomicron remnants rich in cholesteryl esters by the action of lipoprotein lipase (LPL). In the endogenous system, very-low-density lipoproteins (VLDL) rich in triglycerides are secreted by the liver and converted to intermediate-density lipoproteins (LDL) and then to low-density lipoproteins (LDL) rich in cholesteryl esters. Some of the LDLs enter the subendothelial space of arteries, are oxidized, and then are taken up by macrophages, which become foam cells. The letters on the chylomicrons, chylomicron remnants, VLDL, IDL, and LDL identify the primary apoproteins (ApoB, ApoC, ApoE) found in them. (LDLR, low-density lipoprotein receptor.) (From Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine, 16th ed. New York, McGraw-Hill, 2005, p. 2289.)
LDL, the major cholesterol transport lipoprotein and having virtually only ApoB-100, is mostly derived from VLDL catabolism and cellular synthesis. When fasting and on low-fat intake in normal subjects, most cholesterol is synthesized and used in the extrahepatic organs, while most of the cholesterol carried by LDL is taken up by the liver for catabolism. In patients with homozygous familial hypercholesterolemia, enhanced synthesis of LDL may occur, because LDL clearance is reduced as a consequence of the lack of LDL-Rs. LDL is catabolized through interaction of cell surface receptors found on liver, adrenal, and peripheral cells (including fibroblasts and smooth muscle cells). These cells recognize ApoB-100 on LDL, and after binding to a receptor on the cell membrane, LDL is internalized and degraded. In the normal fasting state, approximately 70% of LDL is cleared through receptor-dependent mechanism, although this is highly dependent on the availability and type of saturated and monounsaturated or polyunsaturated fat from dietary sources. Ingestion of cholesterol and saturated fatty acids such as C12:0, C14:0, and C16:0 is associated with reduction in LDL-R activity, increased LDL production rate, and elevation in LDL plasma concentration. Receptor-independent mechanisms are also involved to a lesser extent in the catabolism of LDL, and these receptors are present in many tissues but are most active in animals in the adrenals and ovary. Increased intracellular cholesterol resulting from LDL catabolism inhibits the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme for intracellular cholesterol biosynthesis (Fig. 11-3). Additional consequences of increased intracellular cholesterol include reduced synthesis of LDL-R, which limits subsequent cholesterol uptake from the plasma, and accelerated activity of acyl-coenzyme A-to-cholesterol acyltransferase (ACAT) to facilitate cholesterol storage within cells. LDL cholesterol may also be excreted into bile and become part of the enterohepatic pool or may be lost in the stool. Lp(a) is a cholesterol-rich lipoprotein similar to LDL in composition and density and with close homology to fibrinogen; it is reported to be an important independent risk factor for the development of premature cardiovascular disease.
FIGURE 11-3 Biosynthetic pathway for cholesterol. The rate-limiting enzyme in this pathway is 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). (CETP, cholesterol ester transfer protein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very-low-density lipoprotein.) A. Exogenous pathway; B. Endogenous pathway; C. Reverse cholesterol transport. (Modified from Breslow JL. Genetic basis of lipoprotein disorders. J Clin Invest 1989;84:373.)
Nascent HDL is derived from liver and gut synthesis primarily in the form of ApoA-I phospholipid disks.13 Esterification of free cholesterol in nascent HDL and from peripheral tissues to cholesteryl esters by lecithin-cholesterol acyltransferase (LCAT) results in the production of HDL3. Further addition of tissue cholesterol to HDL3 results in the formation of HDL2. HDL2 can also be formed from remodeling of chylomicrons and VLDL catabolism. It may be converted back to HDL3 by the action of hepatic lipase and by the transfer of cholesteryl esters to the liver, LDL, and VLDL. ApoA-I production is increased by estrogens, leading to higher HDL levels in women and in individuals receiving estrogen. Transfer of excess cholesterol from peripheral tissues by HDL is called reverse cholesterol transport. Putative HDL receptors in peripheral cells facilitate the uptake of cholesterol by HDL, which transfers cholesterol to either VLDL and LDL or the liver for secretion into bile or conversion into bile acids. These processes serve to rid peripheral tissue (e.g., coronary arteries) of excessive amounts of cholesterol, and account for some of the protective effects noted with increasing HDL in women and other factors that elevate HDL levels. Variants of the cholesterol ester transfer protein (CETP) have been demonstrated in humans, and the B1B1 genotype is associated with lower HDL and progression of coronary atherosclerosis. Inhibition of CETP leads to elevations in HDL; unfortunately when CETP inhibitors were tested in clinical trials, they did not induce regression of atherosclerotic plaque and were associated with higher blood pressure and CHD events.19–22 The effect of CETP inhibition on blood pressure and HDL is disconcordant with some of these agents.23
The “response-to-injury” hypothesis states that risk factors such as oxidized LDL, mechanical injury to the endothelium (e.g., percutaneous transluminal angioplasty), excessive homocysteine, immunologic attack, or infection-induced (e.g., Chlamydia, herpes simplex virus-1) changes in endothelial and intimal function lead to endothelial dysfunction and a series of cellular interactions that culminate in atherosclerosis. C-reactive protein (CRP) is an acute phase reactant and a marker for inflammation; it may be useful in identifying patients at risk for developing CAD.24 The transcription factor Kruppel-like factor 2 (KLF2) may be induced by statins in liver sinusoidal endothelial cells (SEC), orchestrating an efficient vasoprotective response. Upregulation of hepatic endothelial KLF2-derived transcriptional programs by statins confers vasoprotection and stellate cell deactivation, reinforcing the therapeutic potential of these drugs for liver diseases that course with endothelial dysfunction.
The eventual outcomes of this atherogenic cascade are clinical events such as angina, MI, arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. Atherosclerotic lesions are thought to arise from transport and retention of plasma LDL cholesterol through the endothelial cell layer into the extracellular matrix of the subendothelial space. Once in the artery wall, LDL is chemically modified through oxidation and nonenzymatic glycation. Mildly oxidized LDL then recruits monocytes into the artery wall, which become transformed into macrophages. Macrophages have tremendous potential for accelerating LDL oxidation and ApoB accumulation, and altering the receptor-mediated uptake of LDL into the artery wall from the usual LDL-R to a “scavenger receptor” not regulated by cell content of cholesterol. Oxidized LDL increases plasminogen inhibitor levels (promotion of coagulation), induces the expression of endothelin (vasoconstrictive substance), inhibits the expression of nitric oxide (a vasodilator and platelet inhibitor), and is toxic to macrophages if highly oxidized. As oxidation of biologically active lipids proceeds, other lipids such as lysophosphatidylcholine, hydroperoxides, aldehydic breakdown products of fatty acids, and oxysterol are formed, which continue the reaction within the tissue. These events lead to a massive accumulation of cholesterol. The cholesterol-laden macrophages become foam cells; foam cells are the earliest recognized cells of the arterial fatty streak.
Oxidized LDL provokes an inflammatory response, which is mediated by a number of chemoattractants and cytokines. Examples of each that appear to be involved at different stages of lesion development include monocyte chemoattractant protein 1 (MCP-1), monocyte colony-stimulating factor (M-CSF), gro, vascular cell adhesion molecule (VCAM-1), E-selectin (ELAM-1), intercellular adhesion molecule (ICAM-1), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factors (TGF-α and TGF-β), interleukin-1 (IL-1) and interleukin-6 (IL-6), and the ratio of interleukin-10 (IL-10) and interleukin-12 (IL-12). It appears that some of these factors (e.g., MCP-1 and M-CSF) participate early in the process of monocyte–macrophage attachment and transmigration across the endothelium, whereas others (PDGF and VCAM-1) promote later lesion growth.25The extent of oxidation and the inflammatory response is under genetic control of a major gene termed Ath-1 based on murine model studies. The process of aging may lead to lipoproteins that are more susceptible to oxidation and have longer resident time in the vascular compartment. Two proteins associated with HDL—ApoJ and paraoxonase (PON)—appear to play an important role to minimize the oxidation of LDL-C.26 Increased recognition of the role of these growth-regulatory molecules provides the possibility of future directions for antagonists to regulatory molecules such as PDGF, TGF-β, and the interleukins. Repeated injury and repair within an atherosclerotic plaque eventually lead to a fibrous cap protecting the underlying core of lipids, collagen, calcium, and inflammatory cells such as T lymphocytes. Maintenance of the fibrous plaque is critical to prevent plaque rupture and subsequent coronary thrombosis.27 An imbalance between plaque synthesis and degradation may lead to a weakened or vulnerable plaque prone to rupture. The fibrous cap may become weakened through decreased synthesis of the extracellular matrix or increased degradation of the matrix. The cytokine interferon-γ, produced by T lymphocytes, inhibits the ability of smooth muscle cells to synthesize collagen, a structurally important component of the fibrous cap. A family of enzymes known as matrix metalloproteinases can degrade all major constituents of the vascular extracellular matrix: collagen, elastin, and proteoglycans.28
Lipoprotein disorders are classified into six categories, which are commonly used for phenotypical description of dyslipidemia (Table 11-3). Specific genetic defects with disrupted protein, cell, and organ function give rise to several disorders within each family of lipoproteins (Table 11-4). In other words, an elevated cholesterol level does not necessarily equate with familial hypercholesterolemia or type IIa, as cholesterol may also be elevated in other lipoprotein disorders and the lipoprotein pattern does not describe the underlying genetic defect. The preceding discussion has focused on primary or genetic dyslipoproteinemia; it should be remembered that secondary forms exist and that several drugs may also elevate lipid levels (Table 11-5). These secondary forms of hyperlipidemia should be initially managed by correcting the underlying abnormality, including modification of drug therapy when appropriate.
TABLE 11-3 Fredrickson-Levy-Lees Classification of Hyperlipoproteinemia
TABLE 11-4 Lipoprotein Disorders
TABLE 11-5 Secondary Causes of Lipoprotein Abnormalities
Familial hypercholesterolemia is characterized by (a) a selective elevation in the plasma level of LDL; (b) deposition of LDL-derived cholesterol in tendons (xanthomas) and arteries (atheromas); and (c) inheritance as an autosomal dominant trait with homozygotes more severely affected than heterozygotes. Homozygotes (prevalence 1 in 1,000,000) have severe hypercholesterolemia (650 to 1,000 mg/dL [16.8 to 25.9 mmol/L]), with the early appearance of cutaneous xanthomas and fatal CHD generally before the age of 20. The primary defect in familial hypercholesterolemia is the inability to bind LDL to the LDL-R or, rarely, a defect of internalizing the LDL-R complex into the cell after normal binding. Homozygotes have essentially no functional LDL-Rs. This leads to lack of LDL degradation by cells and unregulated biosynthesis of cholesterol, with total cholesterol and LDL-C being inversely proportional to the deficit in LDL-Rs. Heterozygotes have only about one half of the normal number of LDL-Rs, total cholesterol levels in the range of 300 to 600 mg/dL (7.76 to 15.52 mmol/L), and cardiovascular events beginning in the third and fourth decades of life.
Familial LPL deficiency is a rare, autosomal recessive trait characterized by a massive accumulation of chylomicrons and corresponding increase in plasma triglycerides or a type I lipoprotein pattern. VLDL concentration is normal. The presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is proportional to dietary fat intake, and consequently to the elevation of chylomicrons. LPL is normally released from vascular endothelium or by heparin and hydrolyzes chylomicrons and VLDL (see Fig. 11-2). Diagnosis is based on low or absent enzyme activity with normal human plasma or ApoC-II, a cofactor of the enzyme. Accelerated atherosclerosis is not associated with this disease. Abdominal pain, pancreatitis, eruptive xanthomas, and peripheral polyneuropathy characterize type V (VLDL and chylomicrons). Symptoms may occur in childhood, but usually the disorder is expressed at a later age. The risk of atherosclerosis is increased with this disorder. These patients are commonly obese, hyperuricemic, and diabetic, and alcohol intake, exogenous estrogens, and renal insufficiency tend to be exacerbating factors.
• Most patients are asymptomatic for many years prior to clinically evident disease.
• Patients with the metabolic syndrome may have three or more of the following: abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance ± glucose intolerance, prothrombotic state, or proinflammatory state.
• None to chest pain, palpitations, sweating, anxiety, shortness of breath, loss of consciousness or difficulty with speech or movement, abdominal pain, and sudden death.
• None to abdominal pain, pancreatitis, eruptive xanthomas, peripheral polyneuropathy, high blood pressure, BMI >30 kg/m2, or waist size >40 in (102 cm) in men (35 in [89 cm] in women).
• Elevations in total cholesterol, LDL, triglycerides, ApoB, and CRP.
• Low HDL.
Other Diagnostic Tests
• Lipoprotein(a), and small, dense LDL (pattern B), HDL subclassification, ApoE isoforms, ApoA-I, fibrinogen, folate, and lipoprotein-associated phospholipase A2.
• Various screening tests for manifestations of vascular disease (ankle-brachial index, exercise testing, magnetic resonance imaging) and diabetes (fasting glucose, oral glucose tolerance test, hemoglobin A1c).
Patients with familial type III hyperlipoproteinemia (also called dysbetalipoproteinemia, broadband, or β-VLDL) develop the following clinical features after 20 years of age: xanthoma striata palmaris (yellow discolorations of the palmar and digital creases), tuberous or tuberoeruptive xanthomas (bulbous cutaneous xanthomas), and severe atherosclerosis involving the coronary arteries, internal carotids, and abdominal aorta. A defective structure of ApoE does not allow normal hepatic surface receptor binding of remnant particles derived from chylomicrons and VLDL (known as IDL); aggravating factors such as obesity, diabetes, or pregnancy may promote overproduction of ApoB–containing lipoproteins. Although homozygosity for the defective allele (E2/E2) is common (1 in 100), only 1 in 10,000 expresses the full-blown picture, and interaction with other genetic or environmental factors, or both, is needed to produce clinical disease.
Familial combined hyperlipidemia is characterized by elevations in total cholesterol, triglycerides, decreased HDL, increased ApoB, and small, dense LDL.29 It is associated with premature CHD and may be difficult to diagnose since the lipid levels do not consistently display the same pattern.
Type IV hyperlipoproteinemia is common and occurs in adulthood primarily in patients who are obese, diabetic, and hyperuricemic and do not have xanthomas. It may be secondary to alcohol ingestion and can be aggravated by stress, progestins, oral contraceptives, thiazides, or β-blockers. Two genetic patterns occur in type IV hyperlipoproteinemia: familial hypertriglyceridemia, which does not carry a great risk for premature CAD, and familial combined hyperlipidemia, which is associated with increased risk of cardiovascular disease.
Rare forms of lipoprotein disorders may include hypobetalipoproteinemia, abetalipoproteinemia, Tangier disease, LCAT deficiency (fish-eye disease), cerebrotendinous xanthomatosis (CTX), and sitosterolemia. Most of these rare lipoprotein disorders do not result in premature atherosclerosis, with the exceptions of familial LCAT deficiency, CTX, and sitosterolemia with xanthomatosis. Their treatment consists of dietary restriction of plant sterols (sitosterolemia with xanthomatosis), chenodeoxycholic acid (CTX), or, potentially, blood transfusion (LCAT deficiency).
A fasting lipoprotein profile including total cholesterol, LDL-C, HDL-C, and triglycerides should be measured in all adults 20 years of age or older at least once every 5 years.1 If the profile is obtained in the nonfasted state, only total cholesterol and HDL-C will be usable because LDL-C is usually a calculated value; if total cholesterol is ≥200 mg/dL (≥5.17 mmol/L), or if HDL-C is <40 mg/dL (<1.03 mmol/L), a followup fasting lipoprotein profile should be obtained. After a lipid abnormality is confirmed (Table 11-6), major components of the evaluation are the history (including age, gender, and, if female, menstrual and hormone replacement status), physical examination, and laboratory investigations. A complete history and physical examination should assess (a) presence or absence of cardiovascular risk factors (Table 11-7) or definite cardiovascular disease in the individual; (b) family history of premature cardiovascular disease or lipid disorders; (c) presence or absence of secondary causes of lipid abnormalities, including concurrent medications (see Table 11-5); and (d) presence or absence of xanthomas or abdominal pain, or history of pancreatitis, renal or liver disease, peripheral vascular disease, abdominal aortic aneurysm, or cerebral vascular disease (carotid bruits, stroke, or transient ischemic attack [TIA]). An important change in the ATP III guidelines is that diabetes mellitus is regarded as a CHD risk equivalent.1 The presence of diabetes in patients without known CHD is associated with the same level of risk as in patients without diabetes but having confirmed CHD.30,31 ATP III identifies four categories of risk that modify the goals and modalities of LDL-lowering therapy (Table 11-8).2 The highest category is known CHD or CHD risk equivalents, which is defined as the risk for major coronary events equal to or greater than established CHD, that is, >20% per 10 years (2% per year). The next category is moderately high risk consisting of patients with multiple (2+) risk factors in which 10-year risk for CHD is 10% to 20%. Moderate risk is defined as ≥2 risk factors and a 10-year risk of ≤10%. The lowest risk category is persons with zero to one risk factor. Risk is estimated from Framingham risk scores.32 Risk is estimated based on the patient’s age, LDL-C or total cholesterol level, blood pressure, the presence of diabetes, and smoking status (Table 11-7). This approach for a single patient is referred to as case finding or patient-based approach, whereas large-scale screening and recommendations for the general populace, healthcare providers, and the food industry are called a population-based approach.
TABLE 11-6 Classification of Total, LDL, and HDL Cholesterol, and Triglycerides
TABLE 11-7 Major Risk Factors (Exclusive of LDL Cholesterol) that Modify LDL Goalsa
TABLE 11-8 LDL Cholesterol Goals and Cut Points for Therapeutic Lifestyle Changes (TLCs) and Drug Therapy in Different Risk Categoriesa
Measurement of plasma cholesterol (which is about 3% lower than serum determinations), triglyceride, and HDL-C levels after a 12-hour or longer fast is important, as triglycerides may be elevated in nonfasted individuals; total cholesterol is only modestly affected by fasting. Analytic and biologic variability can have a major impact on the measurement and interpretation of cholesterol (or any other laboratory test). Analytic variability can be minimized through the use of adequate quality control procedures, including internal training, routine calibration and monitoring, and external proficiency testing. Even with these measures, the coefficient of variability in the best procedures can acceptably be up to 5%, and when combined with average biologic variability, total variability may be as high as about 22%. Analytic variability with desktop equipment generally is greater in the finger-stick capillary blood methods, usually yielding measurements less than those from a clinical laboratory, and this technology should be considered for use only as a screening method. Reliance on desktop methods can result in misclassification of 7% to 14% of patients if capillary blood is used. Two determinations, 1 to 8 weeks apart, with the patient on a stable diet and weight, and in the absence of acute illness, are recommended to minimize variability and to obtain a reliable baseline.1 If the total cholesterol is greater than 200 mg/dL (5.17 mmol/L), a second determination is recommended, and if the values are more than 30 mg/dL (0.78 mmol/L) apart, the average of three values should be used. Familiarity with the method and quality control procedures employed by local laboratories is essential for interpretation of reported values. If the physical examination and history are insufficient to diagnose a familial disorder, then agarose-gel lipoprotein electrophoresis is useful to determine which class of lipoproteins is affected. If the triglyceride levels are below 400 mg/dL (4.52 mmol/L) and neither type III hyperlipidemia nor chylomicrons are detected by electrophoresis, then one can calculate VLDL and LDL concentrations: VLDL = triglyceride/5; LDL = total cholesterol – (VLDL – HDL).
Because total cholesterol is composed of cholesterol derived from LDL, VLDL, and HDL, determination of HDL is useful when total plasma cholesterol is elevated. HDL may be elevated by moderate alcohol ingestion (less than two drinks per day), physical exercise, smoking cessation, weight loss, oral contraceptives, phenytoin, and terbutaline. Smoking, obesity, a sedentary lifestyle, and drugs such as β-blockers lower HDL. Only exercise and smoking cessation could be recommended as interventions for low HDL concentrations. Niacin and gemfibrozil also increase HDL concentrations.
The range of lipid concentrations represents a population mean plus or minus two standard deviations and does not define the risk of disease. Reference values for plasma total, LDL, and HDL cholesterol concentrations for men and women, as well as various ethnic groups, are available from the NHANES III.6 Cholesterol and triglycerides increase throughout life until about the fifth decade for men and the sixth decade for women. Past these ages, total cholesterol and LDL plateau and fall slightly. HDL tends to fall slightly with time and more rapidly after menopause in women. Institution of a population-based approach for cholesterol reduction should shift the entire curve to the left, and the potential reduction in cardiovascular mortality would be proportional to mean reductions at any cholesterol concentration.
Based on a careful review of the experimental pathologic, genetic, and epidemiologic evidence relating to the relationship between blood cholesterol levels and CHD, the ATP III of the NCEP recommends that a fasting lipoprotein profile and risk factor assessment be used in the initial classification of adults.1,33 If total cholesterol is less than 200 mg/dL (5.17 mmol/L), then the patient has a desirable blood cholesterol level (Table 11-6). Cholesterol levels between 200 and 239 mg/dL (5.17 and 6.18 mmol/L) are classified as borderline high blood cholesterol levels, and assessment of risk factors (Table 11-7) is needed to more clearly define disease risk. Blood cholesterol levels of 240 mg/dL (6.21 mmol/L) and above are classified as high blood cholesterol levels. Clinicians are awaiting the publication of ATP IV and it is anticipated that these categories of lipoproteins may be revised downward. If the total cholesterol is below 200 mg/dL (5.17 mmol/L) and the HDL is above 40 mg/dL (1.03 mmol/L), no further followup is recommended for patients without known CHD and who have fewer than two risk factors. In patients with evidence of CHD or other clinical atherosclerotic disease, the LDL goal is less than 100 mg/dL (2.59 mmol/L) and most patients will require diet and/or drug intervention. In patients with very high risk (known CHD and multiple risk factors) the LDL goal may be set at <70 mg/dL (<1.81 mmol/L) based on evidence from newer studies.33 Decisions regarding classification and management are based on the LDL-C levels as outlined in Table 11-8. An increasing number of persons have the metabolic syndrome that is characterized by abdominal obesity, atherogenic dyslipidemia (elevated triglycerides, small LDL particles, low HDL-C), raised blood pressure, insulin resistance (with or without glucose intolerance), and prothrombotic and proinflammatory states. ATP III recognizes the metabolic syndrome as a secondary target of risk reduction therapy after LDL-C has been addressed and if the metabolic syndrome is present, the patient is considered to have a CHD risk equivalent. Other lipid targets include non-HDL goals for patients with triglycerides >200 mg/dL (>2.26 mmol/L). Non-HDL is calculated by subtracting HDL from total cholesterol and the targets are 30 mg/dL (0.78 mmol/L) greater than LDL for each risk stratum. Non-HDL takes into consideration atherogenic particles such as remnant lipoproteins and IDL that are not measured in routine clinical laboratory testing.34 HDL raising has potential benefit, but no specific goals are set in the current guidelines and the evidence is modest to support aggressively increasing HDL levels.35
The Expert Panel on Children and Adolescents of the NCEP recommends screening in higher-risk children (positive family history or parental high blood cholesterol, ≥240 mg/dL [≥6.21 mmol/L]).36 The American Academy of Pediatrics categorizes total and LDL cholesterol into acceptable (<75th percentile; total cholesterol <170 mg/dL [<4.40 mmol/L]), borderline (75th to 95th percentile; total cholesterol 170 to 199 mg/dL [4.40 to 5.15 mmol/L], LDL cholesterol 110 to 129 mg/dL [2.84 to 3.34 mmol/L]), and elevated (>95th percentile; total cholesterol >200 mg/dL [>5.17 mmol/L], LDL cholesterol >130 mg/dL [>3.36 mmol/L]).36 The rationale, in part, for this approach is based on the recognition that atherosclerosis begins in the childhood and adolescent years as documented in the pathobiologic determinants of atherosclerosis in youth (PDAY) and the Bogalusa studies.37 Similarly, if children with high blood lipids or lipoprotein levels are identified, and the levels in the parents are unknown, the parents should be screened as well, as they are likely to be at high risk. Racial and gender differences do exist in the determination of lipoprotein fractions, and these factors should be considered in screening. Use of the serum cholesterol level alone may be of insufficient specificity or sensitivity, depending on the cut points used in screening, and other discretionary factors, such as hypertension, smoking, obesity, high-fat diet, and use of cholesterol-raising medication, may be needed to correctly identify children at risk. Presently, children over the age of 10 years are candidates for drug therapy if a trial of diet (6 months to 1 year) proves to be inadequate and LDL-C remains above 190 mg/dL (4.91 mmol/L), or above 160 mg/dL (4.14 mmol/L) if two or more risk factors or CHD are present in the child or adolescent, or if there is a history of premature CHD. In children with diabetes mellitus, pharmacologic treatment should be considered when LDL cholesterol is ≥130 mg/dL (≥3.36 mmol/L).36 The Dietary Intervention Study in Children (DISC) in pubertal children found that a fat-restricted diet modestly lowered LDL-C and maintained psychological well-being and dietary changes are acceptable to children.38,39 Although bile acid sequestrants have been the recommended drugs for this population, clinical trials demonstrate that statin therapy is effective and well tolerated in pediatric populations.40,41 The long-term consequences of drug therapy in this population are unknown. In special instances, familial hypercholesterolemia (particularly the homozygous form), or the existence of CHD or two or more risk factors in the child, would prompt the earlier institution of drug therapy after a trial of dietary intervention.
The goals of therapy expressed as LDL-C levels and the level of initiation of TLC and drug therapy are provided in Tables 11-8 and 11-9 for adults and children, respectively. While these goals are surrogate end points, the primary reason to institute TLC and drug therapy is to reduce the risk first or recurrent events such as MI, angina, heart failure, ischemic stroke, or other forms of peripheral arterial disease such as carotid stenosis or abdominal aortic aneurysm.
TABLE 11-9 Cut Points for Total Cholesterol and LDL Concentrations in Children and Adolescents
Establishing targeted changes and outcomes with consistent reinforcement of goals and measures at followup visits to attain goals is important to reduce barriers for optimizing TLC and pharmacologic therapy.1 TLC should be implemented in all patients prior to considering drug therapy. The components of TLC include reduced intakes of saturated fats and cholesterol, dietary options to reduce LDL such as plant stanols and sterols and increased soluble fiber intake, weight reduction, and increased physical activity. In general, physical activity of moderate intensity 30 minutes/day for most days of the week should be encouraged.42,43 Patients with known CAD or at high risk should be evaluated before undertaking vigorous exercise. Weight and BMI should be determined at each visit and lifestyle patterns to induce a weight loss of 10% should be discussed in persons who are overweight. All patients should also be counseled to stop smoking and to meet the Joint National Committee VII guidelines for control of hypertension.
Individualized diet counseling that provides acceptable substitutions for unhealthy foods and ongoing reinforcement by a registered dietitian are necessary for maximal effect. The objectives of dietary therapy are to progressively decrease the intake of total fat, saturated fatty acids (i.e., saturated fat), and cholesterol, and to achieve a desirable body weight. Typical American diets now include 13% to 20% of total calories from saturated fat and a cholesterol intake of 350 to 450 mg/day, both in excess of a “heart-healthy” diet for normal Americans, let alone patients with a lipid disorder. Excessive dietary intake of cholesterol and saturated fatty acids lead to decreased hepatic clearance of LDL and deposition of LDL and oxidized LDL in peripheral tissues. The targeted saturated fatty acids have carbon chain lengths of 12 (lauric acid), 14 (myristic acid), and 16 (palmitic acid). The rationale for using a nutritionally balanced low-fat, low-cholesterol diet for the treatment of hypercholesterolemia is based on the following principles: (a) it represents a reasonable extension of the diet recommended for the general public; (b) it progressively decreases the major cholesterol-raising constituent of the diet; (c) it precludes large intakes of polyunsaturated fats; and (d) it facilitates weight reduction by removing foods of high caloric density.44–47
Dietary expertise in providing a wide range of options and suggestions in preparation of food can make the difference between a good and an inadequate response to diet. Information concerning eating out in a healthy fashion and advice for shopping are also important factors for success in diet therapy. An example is being aware of products with misleading labels such as coffee creamers that state they contain “no cholesterol,” when they may contain hydrogenated (saturated) fats or oils (e.g., palmitic acid, palm kernel oil, or coconut oil), which makes them undesirable because of their saturated fat content. Variations in polyunsaturated and saturated fat and cholesterol intake influence the LDL concentration, but the amount of cholesterol has been found to have a greater effect than the proportion of polyunsaturated or saturated fat. There were also racial differences in elevation of LDL with high saturated fat diets being greater in whites than in other racial groups. The isomeric form of fatty acids is also important.44 Fatty acids with the cis configuration are the preferred substrate for the ACAT reaction and significantly increase hepatic LDL-R clearance while reducing LDL cholesterol production rate. The trans isomeric form cannot be used by ACAT and is biologically inactive with no effect on LDL concentration.
Ideally, therapeutic TLC including reduced intake of saturated fats and cholesterol, increased stanol/sterol and fiber intake, weight reduction, and increased physical activity should be used to attain lower LDL-C and to achieve reductions in CHD risk (Table 11-10). TLC may obviate the need for drug therapy, augment LDL-lowering drug therapy, and allow for lower doses. Weight control plus increased physical activity reduces risk beyond LDL cholesterol lowering, is the primary management approach for the metabolic syndrome, and raises HDL and reduces non-HDL cholesterol.48,49 Many persons should be given a 3-month trial (two visits spaced 6 weeks apart) of dietary therapy and TLC before advancing to drug therapy unless patients are at very high risk (severe hypercholesterolemia, known CHD, CHD risk equivalents, multiple risk factors, strong family history). Although changes in blood lipid levels may change before 3 months, adoption of a different eating pattern may require a longer period of time. It is important to involve all family members, especially if the patient is not the primary person preparing food. Both the NCEP and AHA have excellent Internet-based resources to aid patients in altering their diet in a culturally sensitive manner (http://www.americanheart.org/presenter.jhtml?identifier=1200009; http://www.nhlbi.nih.gov/health/index.htm). If all of the recommended dietary changes from NCEP, the estimated reduction, on average, in LDL would range from 20% to 30%.1 Adherence to diet and interindividual variability in macronutrient intake would obviously influence the eventual LDL level achieved. Based on the NHANES data, less than one half of the patients who should be instructed on heart-healthy diet receive any dietary instructions.
TABLE 11-10 Macronutrient Recommendations for the TLC Diet
Other dietary interventions or diet supplements may be useful in certain patients with lipid disorders. Increased intake of soluble fiber in the form of oat bran, pectins, certain gums, and psyllium products can result in useful adjunctive reductions in total and LDL cholesterol, but these dietary alterations or supplements should not be substituted for more active forms of treatment. Total daily fiber intake should be about 20 to 30 g/day, with about 25% or 6 g/day being soluble fiber.1 Studies with psyllium seed in doses of 10 to 15 g/day show reductions in total and LDL cholesterol ranging from about 5% to 20%.50,51They have little or no effect on HDL-C or triglyceride concentrations. These products may also be useful in managing constipation associated with the bile acid sequestrants. Psyllium binds cholesterol in the gut and also reduces hepatic production and clearance. Fish oil supplementation provides an increased amount of the omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. In epidemiologic studies, ingestion of large amounts of cold water, oily fish is associated with a reduction in CHD risk, but it is unclear whether the same advantage is conferred with commercially prepared fish oil products. Each 20 g/day ingestion of fish lowers CHD risk by 7% and eating fish once weekly or more should reduce CHD mortality.52 Fish oil supplementation has a fairly large effect in reducing triglycerides and VLDL-C, but it either has no effect on total and LDL cholesterol or may cause elevations in these fractions. Other actions of fish oil may account for their protective effects. These effects include quantitative and qualitative alterations in the synthesis of prostanoid substances, changes in immune function and cellular proliferation, and potential antioxidative actions.53 Responses noted with fish oil are further discussed in Pharmacologic Therapy below.54
Fat substitutes such as olestra (Olean, sucrose polyester, Procter and Gamble), a mixture of hexa-, hepta-, and octa-esters formed from the reaction of sucrose with long-chain fatty acids, are approved by the FDA as a nondigestible, nonabsorable, noncaloric fat substitute for snack foods. Olestra is heat stable, an advantage over several other fat substitutes, enabling it to be used in the preparation of fried and baked foods. It is similar in composition to triglycerides, but olestra is not hydrolyzed in the GI tract by pancreatic lipase, and, consequently, is not taken up by the intestinal mucosa. The principal adverse effects associated with olestra use are bloating, flatulence, diarrhea, and “anal leakage.” Because of the ability of olestra to solubilize lipophilic substances, there has been concern over potential drug interactions in which lipophilic drugs (e.g., cyclosporin, or colchicine) or vitamins (vitamins A, D, E, and K) are solubilized in olestra and excreted in the feces.
Recent studies have demonstrated the LDL-lowering effect of plant sterols, which are isolated from soybean and tall pine-tree oils. Ingestion of 2 to 3 g/day will reduce LDL by 6% to 15%.1 Plant sterols can be esterified to unsaturated fatty acids (creating sterol esters) to increase lipid solubility. Hydrogenating sterols produces plant stanols and, with esterification, stanol esters. The efficacy of plant sterols and plant stanols is considered to be comparable. Because lipids are needed to solubilize stanol/sterol esters, they are usually available in commercial margarines. The presence of plant stanols/sterols is listed on the food label. When margarine products are used, persons must be advised to adjust caloric intake to account for the calories contained in the products. Benecol® (McNeil), as an example, is a butter-like spread that contains a plant stanol ester, an ingredient that can lower cholesterol and that is derived from plant stanols found naturally in small amounts in foods such as wheat, rye, and corn.55 In August 2007, the FDA issued a warning about the consumption of red yeast rice and red yeast rice/policosanol-containing products. These products contained lovastatin that could interact with other drugs and would have the same toxicity of statins but would not be recognized by the consumer and the reduction in LDL is minimal.56
Drug therapy is indicated following an adequate trial of TLC changes as outlined in Tables 11-8 and 11-9.
There are now numerous randomized, double-blinded clinical trials demonstrating that reduction of LDL reduces CHD event rates in primary prevention, secondary intervention, and angiographic trials.57Generally speaking, for every 1% reduction in LDL, there is a 1% reduction in CHD event rates.1 However, if treatment extends beyond the typical duration of a clinical trial (2 to 5 years), the accumulated benefit could be greater. Elevations of HDL of 1% result in approximately 2% reduction in CHD events.13,58 Of interest, angiographic trials, which typically cause small changes in luminal diameter (e.g., about a 0.04-mm difference in change between placebo and active treatment), result in fewer clinical events such as MI or the need for revascularization. This unexpected finding suggests that plaque size and luminal encroachment by plaque may be less important than the effects that cholesterol lowering may have on the activity in the plaque and endothelial dysfunction. These studies provide a strong rationale for attempting to lower plasma cholesterol and LDL in patients with hypercholesterolemia.
Although many efficacious lipid-lowering drugs exist, none is effective in all lipoprotein disorders, and all such agents are associated with some adverse effects.59 Lipid-lowering drugs can be broadly divided into agents that decrease the synthesis of VLDL and LDL, agents that enhance VLDL clearance, agents that enhance LDL catabolism, agents that decrease cholesterol absorption, agents that elevate HDL, or some combination of these characteristics (Table 11-11). Table 11-12 lists recommended drugs of choice for each lipoprotein phenotype and alternate agents. Table 11-13 lists available products and their doses.
TABLE 11-11 Effects of Drug Therapy on Lipids and Lipoproteins
TABLE 11-12 Lipoprotein Phenotype and Recommended Drug Treatment
TABLE 11-13 Comparison of Drugs Used in the Treatment of Hyperlipidemia
Treatment of type I hyperlipoproteinemia is directed toward reduction of chylomicrons derived from dietary fat with the subsequent reduction in plasma triglycerides. Total daily fat intake should be no more than 10 to 25 g/day, or approximately 15% of total calories. Secondary causes of hypertriglyceridemia (see Table 11-5) should be excluded or, if present, the underlying disorder should be treated appropriately. Type V hyperlipoproteinemia also requires a stringent restriction of the fat component of dietary intake; in addition, drug therapy is indicated, as outlined in Table 11-12, if the response to diet alone is inadequate. Medium-chain triglycerides, which are absorbed without chylomicron formation, may be used as a dietary supplement for caloric intake if needed for types I and V. Hepatic fibrosis has been reported with medium-chain triglycerides. Omega-3 fatty acids may be useful in LPL deficiency in some patients. In patients with ApoC-II deficiency, infusion of plasma may normalize plasma triglyceride levels.
Primary hypercholesterolemia (familial hypercholesterolemia, familial combined hyperlipidemia, type IIa hyperlipoproteinemia) is treated with the bile acid resins or sequestrants (BARs, colestipol, cholestyramine, and colesevelam), HMG Co-A reductase inhibitors (statins), niacin, or ezetimibe. Of these choices, statins are first choice because they are the most potent LDL-lowering agents. Statins interrupt the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis, by inhibiting HMG-CoA reductase (see Fig. 11-3). Currently available products include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and pitvastatin.60 Rosuvastatin is the most potent statin currently on the market. Table 11-14 lists the pharmacokinetic properties of the statins.61The plasma half-lives for all the statins are reported to be short except for atorvastatin and rosuvastatin, and this may account for their potency. In CURVES, the largest head-to-head comparison of statins, atorvastatin was found to be the most potent drug for lowering total cholesterol and LDL-C, with reductions in LDL-C of 38%, 46%, 51%, and 54% for the 10-, 20-, 40-, and 80-mg doses, respectively.62Metabolic studies with statins in normal volunteers and patients with hypercholesterolemia suggest reduced synthesis of LDL-C, as well as enhanced catabolism of LDL mediated through LDL-Rs, as the principal mechanisms for lipid-lowering effects. Total and LDL cholesterol are reduced in a dose-related fashion by 30% or more on average when added to dietary therapy, with the effects being more pronounced in nonfamilial than in familial hypercholesterolemia. Combination therapy with bile acid sequestrants and lovastatin is rational as LDL-R numbers are increased, leading to greater degradation of LDL-C; intracellular synthesis of cholesterol is inhibited, and enterohepatic recycling of bile acids is interrupted. Combination therapy with a statin plus ezetimibe is also so rational since ezetimibe inhibits cholesterol absorption across the gut border and adds 12% to 20% further reduction when combined to a statin or other drugs.63 However, the combination of a statin and ezetimibe has not been shown to affect surrogate end points such as carotid intimal medial thickness (CIMT) even with further reduction in LDL cholesterol.64 Elevation of serum transaminase levels (primarily alanine aminotransferase) to greater than three times the upper limit of normal occurs in approximately 1.3% of patients on moderate to high doses of statins and serious muscle toxicity occurs in <0.6% of patients.65Meta-analysis of placebo-controlled studies with statins demonstrates a low risk of abnormal ALT or CK and a low risk of myopathy without or with rhabdomyolysis.66 Lens opacities have been reported with lovastatin; however, in the age groups studied, these abnormalities are common and tend to wax and wane with time irrespective of drug therapy, and no statistical association is known to exist. As a category of monotherapy, the HMG-CoA reductase inhibitors are the most potent total and LDL cholesterol–lowering agents and among the best tolerated.65,66 In an analysis of more than 75,000 patients allocated to statins in clinical trials, Alsheikh-Ali et al. found that risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. A highly significant inverse relationship between achieved LDL-C levels and rates of newly diagnosed cancer was observed (R2 = 0.43, P = 0.009).67 The WHO Foundation Collaborating Centre for International Drug Monitoring has issued a report suggesting that a rare relationship may exist between statin use and the onset of upper motor neuron diseases such as amyotrophic lateral sclerosis, but this association remains uncertain.68Statin use is associated with a small risk of diabetes (9%).69 There are numerous pharmacokinetic and pharmacodynamic differences among statins and patients that give rise to variable response to therapy.70
TABLE 11-14 Pharmacokinetics of the Statins
The primary action of BAR is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids and a markedly increased excretion of acidic steroids in the feces. This decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the number of LDL-Rs on the hepatocyte membrane. The increased number of receptors stimulates an enhanced rate of catabolism from plasma and lowers LDL levels. CETP, which is correlated with total and LDL cholesterol concentrations, is also reduced by BAR, perhaps by interfering with hepatic microsomal cholesterol content, but this effect is not as great as with statins.71 Patients with homozygous familial hypercholesterolemia genetically lack the ability to increase synthesis of LDL-Rs and BARs are generally ineffective. The increase in hepatic cholesterol biosynthesis may be paralleled by increased hepatic VLDL production and, consequently, BARs may aggravate hypertriglyceridemia in patients with combined hyperlipidemia. GI complaints of constipation, bloating, epigastric fullness, nausea, and flatulence are most commonly reported.1 With intensive education, patients can learn to tolerate resins on a long-term basis as evidenced by adherence in clinical trials to active drug regimens, but in routine clinical practice 40% or more of patients will discontinue therapy within 1 year; however, with pharmacists’ interventions, adherence rates can be improved.72,73 These adverse effects can be managed by increasing the fluid intake, modifying the diet to increase bulk, and using stool softeners. The other major limiting complaint is the gritty texture and bulk; these problems may be minimized by mixing the powder with orange drink or juice. Tablet forms of bile acid sequestrants should help in improving compliance with this form of therapy, whereas the bar does not improve compliance.74 Other potential adverse effects include impaired absorption of fat-soluble vitamins A, D, E, and K; hypernatremia and hyperchloremia; GI obstruction; and reduced bioavailability of acidic drugs such as coumarin anticoagulants, nicotinic acid, thyroxine, acetaminophen, hydrocortisone, hydrochlorothiazide, loperamide, and possibly iron. Hyperchloremic metabolic acidosis, hypernatremia, and GI obstruction have been reported almost exclusively in children, and malabsorption of fat-soluble vitamins is probably most common with high doses (e.g., 30 g/day of cholestyramine) of the BARs. Drug interactions may be avoided by alternating administration times with an interval of 6 hours or greater between the BAR and other drugs. Colestipol and cholestyramine have comparable side effects; however, colestipol may have better palatability because it is odorless and tasteless. Colesevelam is the newest BAR and total and LDL-C reduction is dose related. The adverse effects are qualitatively similar to the older BAR but may occur less often. Because of adverse effects occurring commonly with BAR at higher doses, BARs are increasingly used in combination with other drugs, as low doses are tolerated well and they work in a complementary fashion with other agents.
Niacin (nicotinic acid) may also be used in primary hypercholesterolemia in combination with bile acid sequestrants or as monotherapy for this disorder and others (Table 11-12). Niacin reduces the hepatic synthesis of VLDL, which, in turn, leads to a reduction in the synthesis of LDL. Factors responsible for decreased production of VLDL include inhibition of lipolysis with a decrease in free fatty acids in plasma, decreased hepatic esterification of triglycerides, and a possible direct effect on the hepatic production of ApoB.75 The complementary action of niacin and bile acid sequestrants to increase catabolism and decrease synthesis of LDL may account for the additive effects of this combination in hyperlipidemia. Niacin also increases HDL by reducing its catabolism. It selectively decreases hepatic removal of HDL ApoA-I but not removal of cholesterol esters, thereby increasing the capacity of retained ApoA-I to augment reverse cholesterol transport in isolated hepatic cells. The principal use of niacin is for mixed hyperlipemia or as a second-line agent in combination therapy for hypercholesterolemia. It is also considered to be the first-line agent or an alternative for the treatment of hypertriglyceridemia and diabetic dyslipidemia.76,77 There are numerous smaller trials suggesting that lower doses of niacin may be combined with statins or gemfibrozil to minimize adverse effects and maximize response. One meta-analysis showed that combination therapy was no more effective than high-dose statin therapy.78 These combinations require careful monitoring because interactions do occur.
Niacin has many adverse drug reactions that occur commonly; fortunately, most of the symptoms and biochemical abnormalities seen do not require discontinuation of therapy. Cutaneous flushing and itching appear to be prostaglandin mediated and can be reduced by aspirin 325 mg given shortly before niacin ingestion.1,79 Flushing seems to be related to rising plasma concentrations of niacin; taking the dose with meals and slowly titrating the dose upward may minimize these effects. Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which may mediate niacin-induced vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging.80,81 GI intolerance and flushing are common problems. Acanthosis nigricans, a darkening of the skin in skinfold areas and an external marker of insulin resistance, may be seen with high doses of niacin. Sustained-release products may minimize these complaints in some patients, but controlled trials with regular-release products do not demonstrate much of a difference between sustained- and regular-release products. The only legend form of niacin, Niaspan®(Abbott), is an ER form of niacin with pharmacokinetics intermediate between instant and sustained-release products that are sold as food supplements rather than legend products. In controlled trials, Niaspan® is reported to have fewer dermatologic reactions and has a low risk for hepatotoxicity. When combined with statins, this combination produces large reductions in LDL and increases in HDL.82 Potentially important laboratory abnormalities occurring with niacin therapy include elevated liver function tests, hyperuricemia, and hyperglycemia. Recent experience with niacin in diabetes suggests that some diabetic patients do not have worsened glycemic control with dose titration and sustained-release products.83 BMI and fasting plasma glucose predict loss of blood glucose control.84 With less than 3 g/day, the degree of liver function test elevation is generally not marked and often transient, and a temporary reduction in dosage frequently corrects the problem. Niacin-associated hepatitis is more common with sustained-release preparations, and their use should be restricted to patients intolerant of regular-release products.83,85 Sustained-release products are often more expensive and given the lack of data for reduced adverse effects and increased incidence of hepatitis, regular-release products should always be used first. Preexisting gout and diabetes may be exacerbated by niacin; these patients should be monitored more closely and their medication titrated appropriately. Patients with well-controlled type 2 diabetes mellitus do not have significant changes in glycemic control with niacin at doses of 2 g/day or less.85 Niacin is contraindicated in patients with active liver disease. Dry eyes and other ophthalmologic complaints are also occasionally noted. Concomitant alcohol and hot drinks may magnify flushing and pruritus with niacin and they should be avoided at the time of ingestion. Nicotinamide should not be used in the treatment of hyperlipidemia, as it does not effectively lower cholesterol or triglyceride levels.
Combined hyperlipoproteinemia (type IIb) may be treated with statins, niacin, or gemfibrozil combinations to lower LDL cholesterol without elevating VLDL and triglycerides. Niacin is the most effective agent and may be combined with a bile acid sequestrant. BARs alone in this disorder may elevate VLDL and triglycerides, and their use as single agents for treating combined hyperlipoproteinemia should be avoided. Fibric acid (gemfibrozil, fenofibrate) monotherapy is effective in reducing VLDL, but a reciprocal rise in LDL may occur, and total cholesterol values may remain relatively unchanged. Gemfibrozil reduces the synthesis of VLDL and, to a lesser extent, ApoB, with a concurrent increase in the rate of removal of triglyceride-rich lipoproteins from plasma. Plasma HDL concentrations may rise 10% to 15% or more with fibrates. Fenofibrate may have fewer drug interactions than gemfibrozil, but fenofibrate has been reported to worsen renal function.86 Ezetimibe could also be used in combination therapy in type IIb. GI complaints with fibric acid derivatives occur in 3% to 5% of patients, rash in 2% of patients, dizziness in 2.4% of patients, and transient elevations in transaminase levels and alkaline phosphatase in 4.5% and 1.3% of patients, respectively.87 Gemfibrozil and probably fenofibrate may enhance the formation of gallstones associated with an increase in the lithogenic index; however, the rate is low (0.5% to 7%) and similar to that seen with placebo in the Helsinki Heart Study.87 Fibric acid derivatives may potentiate the effects of oral anticoagulants and international normalized ratio (INR) should be monitored very closely with this combination.
Type III hyperlipoproteinemia may be treated with fibric acid derivatives or niacin. Although fibric acid derivatives have been suggested as the drugs of choice for this disorder, given the lack of data supporting its efficacy in altering cardiovascular mortality in the major studies on hypercholesterolemia, and numerous, well-documented, and serious adverse effects, it is reasonable to consider niacin. Gemfibrozil increases the activity of LPL and reduces to a lesser extent the synthesis or secretion of VLDL from the liver into the plasma. A myositis syndrome of myalgia, weakness, stiffness, malaise, and elevations in creatinine phosphokinase and aspartate aminotransaminase is seen with the fibric acid derivatives, and it seems to be more common in patients with renal insufficiency.87 Enhanced hypoglycemic effects are reported to occur when fibric acid derivatives are given to patients on sulfonylurea compounds, but the mechanisms for these interactions are not well understood.
Two fibric acid derivatives (gemfibrozil and fenofibrate) are approved in the United States. Both reduce LDL-C by 20% to 25% in heterozygous familial hypercholesterolemia. The response of LDL-C, HDL-C, and triglycerides to this category of drug is very dependent on the specific lipoprotein type (e.g., type IIa vs. IIb) and the baseline triglyceride concentration.88
As a potential alternative therapy, for this phenotype, numerous epidemiologic and normal volunteer studies have found that diets high in omega-3 polyunsaturated fatty acids (from fish oil), mostly commonly eicosapentaenoic acid, reduce cholesterol, triglycerides, LDL-C, and VLDL-C, and may elevate HDL-C.54 The effects of fish oil on lipoprotein metabolism are mediated through a reduction in VLDL production and suppression of VLDL ApoB. In patients with hypertriglyceridemia, either phenotypes type IIb or type V, a diet high in omega-3 fatty acids given for 4 weeks reduced cholesterol 27% and 45%, and triglyceride 64% and 79%, in the type IIb and type V patients, respectively.52 A diet high in eicosapentaenoic acid given to hyperlipidemic hemodialysis patients resulted in significant decreases in cholesterol and triglycerides for as long as 13 weeks. Fish oil supplementation may be most useful in patients with hypertriglyceridemia; however, its role in treatment is not well defined. Potential complications of fish oil supplementation, such as thrombocytopenia and bleeding disorders, have been noted, especially with high doses (eicosapentaenoic acid 15 to 30 g/day), and well-controlled trials are needed to determine if fish oils are safe and effective before their use may be broadly recommended. Based a recent meta-analysis, fish consumption lowers the risk of CHD, but nutraceuticals have not been adequately tested.52 Recently, a prescription form of concentrated fish oil, Lovaza®, has become available.54 This product lowers triglycerides by 14% to 30% and raises HDL by about 10% depending on baseline values. Another fish oil derivative product being considered by the FDA, Epanova contains EPA and DHA in their free fatty acid form at a total concentration of 50% to 60% EPA and 15% to 25% DHA along with other potentially active omega-3 fatty acids stored in a patent-protected capsule with a patent-protected coating designed to maximize bioavailability and tolerability.
Combination drug therapy may be considered after adequate trials of monotherapy and for patients documented compliant to the prescribed regimen. Two or three lipoprotein profiles at 6-week intervals should confirm lack of response prior to initiation of combination therapy. Cholestyramine may be added in patients with fasting hypertriglyceridemia, but it should not be used as the initial drug, because triglycerides are likely to increase. Contraindications to and drug interactions with combined therapy should be carefully screened, as well as consideration of the extra cost of drug product and monitoring that may be required. In general, a statin and a BAR or niacin with a BAR provide the greatest reduction in total and LDL cholesterol. Regimens intended to increase HDL levels should include either gemfibrozil or niacin, and it should be remembered that statins combined with either of these drugs may result in a greater incidence of hepatotoxicity or myositis. This is particularly important for statins that are eliminated via cytochrome 3A4 or through glucuronidation.61 Familial combined hyperlipidemia may respond better to a fibric acid and a statin than to a fibric acid and a BAR.89
Severe forms of hypercholesterolemia—such as familial hypercholesterolemia, familial defective ApoB-100, severe polygenic hypercholesterolemia, familial combined hyperlipidemia, and familial dysbetalipoproteinemia (type III)—may require more intensive therapy. In particular, familial hypercholesterolemia patients often require combination therapy (two or three drugs) and are managed with surgical therapy (partial ileal bypass), plasmapheresis (LDL-apheresis), and liver transplantation (to replace LDL-Rs).
It is important to remember that lipoprotein pattern types I, III, IV, and V are associated with hypertriglyceridemia, and that these primary lipoprotein disorders and underlying diseases should be excluded prior to implementing therapy (see Table 11-5). In a national survey, approximately one-third of participants tested had a triglyceride concentration exceeding 150 mg/dL (1.70 mmol/L).90 A positive family history of CHD is important in identifying patients at risk for premature atherosclerosis.17,91 If a patient with CHD has elevated triglycerides, the associated abnormality is probably a contributing factor to CHD and should be treated.33
High serum triglycerides (see Tables 11-6 and 11-12) should be treated by achieving desirable body weight, consumption of a low saturated fat and cholesterol diet, regular exercise, smoking cessation, and restriction of alcohol (in selected patients). ATP III identifies the sum of LDL and VLDL (termed non-HDC [total cholesterol – HDL]) as a secondary target of therapy in persons with high triglycerides (≥200 mg/dL [≥2.26 mmol/L]).1,33 This approach is used when triglycerides exceed 200 mg/dL (2.26 mmol/L) and accounts for atherogenic particles carried in VLDL and remnant particles. The goal for non-HDL in persons with high serum triglycerides can be set at 30 mg/dL (0.78 mmol/L) higher than that for LDL on the premise that a VLDL level ≤30 mg/dL (≤0.78 mmol/L) is normal. In patients with borderline high triglycerides but with accompanying risk factors of established CHD disease, family history of premature CHD, concomitant LDL elevation or low HDL, and genetic forms of hypertriglyceridemia associated with CHD (familial dysbetalipoproteinemia, familial combined hyperlipidemia), drug therapy with niacin should be considered. Niacin may be used cautiously in diabetics based on the results of the ADMIT trial, which found triglycerides were reduced by 23%, HDL-C increased by 29%, only a slight increase in glucose (mean 8.7 mg/dL [0.5 mmol/L]), and no change in hemoglobin A1c.92 Elevated BMI and plasma glucose predict loss of glycemic control.84 Alternative therapies include gemfibrozil or fenofibrate, statins, and fish oil.17,93,94 Fibrates may increase LDL, and their use in borderline high triglyceridemia requires careful monitoring to detect this deleterious change in lipid profile. Statins may also be used, because they provide modest reductions in triglycerides and modest elevations in HDL. Higher doses of statins may reduce HDL as well as LDL and triglycerides with amount of reduction related to the baseline concentration and dose.17,94 The goal of therapy in this situation is to lower triglycerides and VLDL particles that may be atherogenic, increase HDL, and reduce LDL.
Very high triglycerides are associated with pancreatitis and other consequences of the chylomicron syndrome. At this level of elevation of triglycerides, a genetic form of hypertriglyceridemia often coexists with other causes of elevated triglycerides such as diabetes. Dietary fat restriction (10% to 20% of calories as fat), weight loss, alcohol restriction, and treatment of the coexisting disorder are the basic elements of management. Drugs useful in hypertriglyceridemia include gemfibrozil or fenofibrate, niacin, and higher-potency statins (atorvastatin, rosuvastatin, pitvastatin, and simvastatin). Gemfibrozil and fenofibrate are the preferred drugs in diabetics because of the effect of niacin on glycemic control unless the newer ER forms are used. Fenofibrate may be preferred in combination with statin therapy since it does not impair glucuronidation and minimizes potential drug interactions. Success in treatment is defined as a reduction in triglycerides below 500 mg/dL (5.65 mmol/L).1
Low HDL Cholesterol
Low HDL is a strong independent risk predictor of CHD. ATP III redefined low HDL-C as <40 mg/dL (<1.03 mmol/L), but specified no goal for HDL-C raising.1 Low HDL may be a consequence of insulin resistance, physical inactivity, type 2 diabetes, cigarette smoking, very high carbohydrate intake, and certain drugs (see Table 11-5). In low HDL the primary target remains LDL according to ATP III, but emphasis shifts to weight reduction, increased physical activity, and smoking cessation, and, if drug therapy is required, to fibric acid derivatives and niacin. Niacin has the potential for the greatest increase in HDL and the effect is more pronounced with regular or immediate-release forms than with sustained-release forms.95
Diabetic dyslipidemia is characterized by hypertriglyceridemia, low HDL, and LDL that is minimally elevated. Small, dense LDL (pattern B) in diabetes is more atherogenic than larger, more buoyant forms of LDL (pattern A); routine lipoprotein profiles do not differentiate between pattern A and pattern B.96–98 Diabetes in ATP III is a CHD risk equivalent and the primary target is LDL with a goal of treatment being to lower LDL-C <100 mg/dL (<2.59 mmol/L).1 When LDL is >130 mg/dL (>3.36 mmol/L), most patients will require simultaneous TLCs and drug therapy. When LDL-C is between 100 and 129 mg/dL (2.59 and 3.34 mmol/L), intensifying glycemic control, adding drugs for the atherogenic dyslipidemia (fibric acid derivatives, niacin), and intensifying LDL-C–lowering therapy are options. Because the primary target is LDL-C in diabetic dyslipidemia, statins are considered by many to be initial drugs of choice.1,33 The relative risk reduction for CHD in diabetics versus nondiabetics is greater in the West of Scotland (37% vs. 20%),99 AFCAPS/TexCAPS (43% vs. 36%),100 CARE (25% vs. 23%),101 and 4S (55% vs. 32%) trials.102 All statins are fairly comparable in triglyceride lowering and because statins differ in potency for LDL reduction, a ratio of LDL reduction to triglyceride reduction can be applied. Statin therapy may protect against the development of diabetes.30 The most recent trial to evaluate the benefit of LDL lowering in type 2 diabetes mellitus is the Collaborative Atorvastatin Diabetes Study (CARDS).103 This was a randomized, double-blind, placebo-controlled comparison of atorvastatin 10 mg/day versus placebo in 2,838 diabetics to reduce first CHD events. Baseline LDL was 118 mg/dL (3.05 mmol/L) and with atorvastatin LDL fell by 46 mg/dL (1.19 mmol/L). The primary end point, a composite of acute CHD death, nonfatal MI, hospitalized unstable angina, resuscitated cardiac arrest, coronary revascularization, or stroke, was reduced by 37%. This study suggests that all diabetics should have an LDL much lower than 100 mg/dL (2.59 mmol/L) and these results are consistent with the Heart Protection Study analysis of diabetic patients.104
Fenofibrate, according to the DIAS trial, reduced the angiographic progression of CAD in type 2 diabetes.105 Fewer CHD events were seen with fenofibrate compared with placebo, but the difference was not significant. Fibric acids principally lower VLDL and triglycerides while increasing HDL with only modest lowering of total and LDL cholesterol; on occasion, fibric acid derivatives may increase LDL levels. Fibric acid derivatives tend to improve glucose tolerance, in contrast to niacin; the greatest effect has been seen with bezafibrate. The Helsinki Heart Study found gemfibrozil to be most effective in diabetic dyslipidemia.106 Although the effect of statins on triglycerides and HDL abnormalities commonly seen in diabetes is less than with fibric acids, the subgroup analyses cited earlier suggest that they reduce CHD risk significantly. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) the combination of a statin and fenofibrate in patients with type 2 diabetes did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone.107 Cholestyramine in diabetic patients may result in lower LDL levels, but VLDL and triglyceride levels, which are commonly elevated in diabetes, may be further increased in this population. Resins may aggravate constipation, which is common in diabetics. As demonstrated in the ADMIT and ADVENT trials, immediate-release and ER niacin are very effective in raising HDL and lowering triglycerides and LDL.92,108
Hypercholesterolemia is an independent risk factor for CHD in the elderly (>65 years old), as it is in the younger patient. The attributable risk, which is the difference in absolute rates of CHD between segments of the population with higher or lower serum cholesterol levels, increases with age. Older patients potentially benefit to a greater extent from cholesterol lowering than younger populations. Data from studies of elderly men in a variety of settings are consistent with a relative risk of at least 1.5 in the highest compared with the lowest quartile of cholesterol levels and a relative risk reduction of 22% for heart-related mortality.109–111 Treatment of hypercholesterolemia in the elderly may bring about a comparable reduction in absolute risk to that obtained in younger persons.1 Subgroup analyses of the West of Scotland (primary) and 4S (secondary) intervention studies show that elderly patients have lower CHD risk reduction (relative risk reduction of 27% and 29%, respectively) as compared with younger patients (relative risk reduction of 40% and 39%, respectively).99,112 The Framingham study suggests that elderly women are at higher risk because of high blood cholesterol levels, but no other large studies included women, and their risks or benefits from cholesterol reduction are not well defined. Primary prevention in younger patients requires about 2 years before reduction in CHD risk is apparent, and this lag time should be taken into consideration in patient selection for therapy. Nonlipid CHD risk factors do not decline in relative risk with aging, and aggressive management of the modifiable nonlipid risk factors is important in the older patient. High-risk elderly patients are less likely to be prescribed statins and their potent benefits are not realized.113 Because most women with CHD are elderly and also at risk for osteoporosis, they are logical candidates for diet therapy with consideration of calcium intake consistent with osteoporosis prevention, exercise, and perhaps estrogen replacement therapy. Recent evidence suggests that statins may reduce the risk of osteoporosis; however, there are conflicting data from various studies.114
Drug therapy in principle differs little from younger patients, and older patients respond to lipid-lowering drugs as well as younger patients.115,116 Based on the Heart Protection Study with more elderly patients than any other trial, simvastatin 40 mg/day produced the CHD event rate reduction in patients over 70 years of age as in younger patients.117 The gain in life expectancy may be small depending on the age at the start of treatment and the magnitude of cholesterol reduction. Changes in body composition, renal function, and other physiologic changes of aging may make older patients more susceptible to adverse effects of lipid-lowering drug therapy. In particular, older patients are more likely to have constipation (BARs), skin and eye changes (niacin), gout (niacin), gallstones (fibric acid derivatives), and bone/joint disorders (fibric acid derivatives, statins). Therapy should be started with lower doses and titrated up slowly to minimize adverse effects.
Cholesterol is an important determinant of CHD in women, but the relationship is not as strong as that seen in men. HDL may be a more important predictor of disease in women.4 LDL and HDL genetic regulation in women and men does not appear to be different. Based on the Nurses’ Health Study, obesity is an important determinant of CHD in women, with the relative risk being 3.3 in the highest Quetelet’s index (weight in kilograms divided by the square of the height in meters) as compared with the lowest category (i.e., <21 vs. ≥29); low HDL levels usually accompany obesity.118 No major differences exist in the influence of exercise, alcohol ingestion, and smoking on lipid levels between men and women. Women in the highest tertile of cholesterol appear to be more responsive to dietary therapy than those in the lower tertiles, and more responsive than formulas based on men predict.
Based on the HERS119 and WHI trials,120–122 recently published national guidelines recommended similar types of lifestyle and risk factor goals and interventions as recommended by NCEP for the entire population.4 Hormone therapy may continue to have a role for postmenopausal symptoms; however, a notable exception is hormone replacement therapy and heart protection. Combined estrogen plus progestin hormone therapy should not be initiated to prevent CVD in postmenopausal women. Combined estrogen plus progestin hormone therapy should not be continued to prevent CVD in postmenopausal women. Other forms of menopausal hormone therapy (e.g., unopposed estrogen) should not be initiated or continued to prevent CVD in postmenopausal women pending the results of ongoing trials. Results of the WISDOM trial confirm lack of benefit as seen in HERS and WHI.123 In a recent post hoc analysis of the WHI, women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend did not meet statistical significance.120 Based on the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), women experience the same benefit of LDL cholesterol lowering as men with rosuvastatin.124
Cholesterol and triglyceride levels rise progressively throughout pregnancy, with an average increment in cholesterol of 30 to 40 mg/dL (0.78 to 1.03 mmol/L) occurring around the 36th to 39th weeks. Triglyceride levels may go up by as much as 150 mg/dL (1.70 mmol/L). Drug therapy is neither instituted nor usually continued during pregnancy. If the patient is very high risk, a BAR may be considered since there is no systemic drug exposure.1 Statins are category X and are contraindicated. Ezetimibe might be an alternative since it is a category C drug (animal studies have shown that the drug exerts teratogenic or embryocidal effects, and there are no adequate, well-controlled studies in pregnant women, or no studies are available in either animals or pregnant women), but no data are available in humans. Dietary therapy is the mainstay of treatment, with emphasis on maintaining a nutritionally balanced diet as per the needs of pregnancy.
Drug therapy in children is not recommended until the age of 8 years or older, and the guidelines for institution of therapy and the goals of therapy are different from those in adults (see Table 11-9).125Younger children are generally managed with TLCs until after the age of 2 years.1,47 Although bile acid sequestrants have been recommended in the past as first-line therapy, there is now evidence that statins are safe and effective in children and provide greater lipid lowering than BAR.126–129 Severe forms of hypercholesterolemia (e.g., familial hypercholesterolemia) may require more aggressive treatment.
Concurrent Disease States
Nephrotic syndrome, end-stage renal disease, and hypertension compound the risk of dyslipidemia and may present difficult-to-treat lipid abnormalities. Abnormalities of lipoprotein metabolism in the nephrotic syndrome include elevated total and LDL cholesterol, Lp(a), VLDL, and triglycerides. The Apo C-III-to-C-II ratio is elevated, consistent with greater LPL inhibitor activity, and the extent of hypoalbuminemia is correlated with dyslipidemia. The basic abnormality appears to be one of overproduction of LDL-ApoB from VLDL, rather than reduced clearance of LDL-C and related proteins. Protein restriction and a “vegan” diet correct lipid abnormalities to some extent. Statins have been shown to be effective in reducing elevated total and LDL cholesterol in the nephrotic syndrome, although the levels do not usually return to normal.130 Fibric acid derivatives and statins reduce small, dense LDL-C by different mechanisms, suggesting a potential role for combination therapy to optimize lowering of small, dense LDL-C and remnant lipoproteins. Statins appear to be safe and effective for lowering LDL cholesterol in renal insufficiency, but they may not affect CHD end points.131,132
Renal insufficiency without proteinuria leads to hypertriglyceridemia, slightly elevated total and LDL cholesterol (particularly with chronic ambulatory peritoneal dialysis), and low HDL levels (especially during hemodialysis). These abnormalities are thought to be caused by a deficiency in ApoC-II, perhaps as a result of sustained use of heparin during hemodialysis and depletion of LPL, carbohydrate-induced obesity and hypertriglyceridemia, loss of carnitine during hemodialysis, use of acetate buffer (acetate is a precursor to fatty acid synthesis) during hemodialysis, and decreased LCAT activity during hemodialysis. Dialysis does not correct the lipid abnormalities. Renal transplantation may correct lipid abnormalities in some patients; however, in others, the use of transplantation-related medications such as corticosteroids, cyclosporine, and certain antihypertensive agents (see Chaps. 3 and 70) may aggravate the lipid abnormalities. Cyclosporine interferes with the metabolism of statins metabolized by cytochrome P450 3A4 (Table 11-14), and patients need to be observed closely for myositis and worsening renal function. Of interest, correction of lipid abnormalities may improve renal hemodynamics. Pravastatin and fluvastatin may be safer than other statins, but this needs to be validated in larger, long-term trials. Diet will modify lipoprotein levels and polyunsaturated fatty acids may have a role in impeding the progression of renal disease as well as the cardiovascular complications. Bile acid sequestrants do not correct the lipid abnormalities seen in renal insufficiency. Lovastatin or its active metabolite may accumulate in renal insufficiency, and lower doses of reductase inhibitors should be used to avoid adverse effects. Gemfibrozil may be used with caution as its pharmacokinetics is unchanged and it lowers triglycerides and increases HDL.133 Statins (simvastatin, lovastatin, and atorvastatin) and fibric acid derivatives may increase the risk of severe myopathy, and attention to symptoms of myositis is needed. Niacin may also be useful in nondiabetic patients with renal insufficiency.
Hypertensive patients have a greater-than-expected prevalence of high blood cholesterol levels and, conversely, patients with hypercholesterolemia have a higher-than-expected prevalence of hypertension caused by the metabolic syndrome. Recommendations for the management of hypertension in patients with hypercholesterolemia include avoiding the use of drugs that elevate cholesterol such as diuretics and β-blockers and using agents that either are lipid neutral or may reduce cholesterol slightly (see Chap. 3).1 Bile acid sequestrants may bind to thiazide diuretics and some β-blockers, and may interfere with their absorption; reaction may be avoided by giving the antihypertensive 1 hour before or 4 hours after the resin. Niacin may magnify the hypotensive effects of vasodilators.
The clinical benefits of lipid-lowering therapy for primary and secondary interventions are now well established based on the results of studies showing a reduction in CHD morbidity and mortality.134–136The balance of benefits and costs has been examined in a few studies. The cost per year of life saved has been estimated to range from less than $10,000 to over $1 million depending on the presence or absence of CHD, age of the patient, baseline total or LDL-C level and reduction in cholesterol, and number of risk factors present. In general, intervention in patients with known CHD, those who have CHD risk equivalents, or those with a 10-year risk of 10% to 20% is cost-effective with statin therapy, while other types of therapy may be cost-effective if certain assumptions concerning compliance, efficacy, and so forth are met. The range for secondary intervention based on the 4S study is $3,800 for a 70-year-old man with a high cholesterol level to $27,400 per year of life gained for a middle-aged woman with an average cholesterol level.137 In contrast, primary prevention in men based on the West of Scotland trial averages about $35,000 per year of life gained.138 These studies demonstrate that primary and secondary interventions are well within the accepted boundary of less than $50,000 for a medical intervention to be considered cost-effective. Based on the specific lipoprotein phenotype, fibric acid derivatives, niacin, or combination therapy of statins plus BAR may be cost-effective. Cost-effectiveness is maximized by treating high-risk patients and those with established CHD.
Specialty lipid clinics have become increasingly popular and many use pharmacists to provide direct patient care in this setting. An interesting recent analysis shows that a specialty clinic may be more expensive ($659 ± $43 vs. $477 ± $42 per patient, P <0.001) than usual care. However, the overall cost-effectiveness is improved when expressed as program costs per unit (mmol/L) reduction in the LDL-C, a measure of cost-effectiveness that was significantly lower for specialized care ($758 ± $58 vs. $1,058 ± $70, P = 0.002) because more patients achieve their targeted goal.139 Project ImPACT demonstrated that pharmacists, working collaborative with patients and physicians, can improve persistence and compliance and that nearly two-thirds of patients achieved their NCEP lipid goal.140 Other programs show similar trends.73,141,142
Partial ileal bypass has been used in severe heterozygous and homozygous familial hypercholesterolemia; however, it is ineffective in the latter case. Ileal bypass removes the site of bile acid reabsorption, depleting the bile acid pool and increasing the catabolism of cholesterol. A randomized trial of diet versus surgery, Program on the Surgical Control of the Hyperlipidemias (POSCH), reported that total and LDL cholesterol were decreased (23.3% and 37.7%, respectively) and HDL increased (4.3%) in patients who had undergone ileal bypass for hypercholesterolemia.143 Overall death was delayed by nearly 3 years (P = 0.032) and CHD mortality was delayed by nearly 4 years (P = 0.046) by surgery, as compared with the control group. Revascularization procedures were delayed by an average of 7 years (P<0.001). Postsurgery diarrhea was more common in the surgical group, as was the rate of kidney stones (4% vs. 0.4%), gallstones (10% vs. 2%), and bowel obstruction (13.5% vs. 3.6%).
Portacaval shunts have been used to decrease the formation of LDL-C and reductions of 10% to 20% have been reported. Plasma exchange combined with niacin was found to reduce plasma cholesterol levels by about 50% in homozygous familial hypercholesterolemia over 5 years, and coronary atherosclerosis did not progress as documented by angiography. LDL-apheresis, selective removal of LDL-C via a filtering system, plus statin therapy is effective in LDL-C and appears to affect the progression of vascular disease. LDL-apheresis may be combined with statin therapy for greater effect. Combined liver and heart transplantation in homozygous familial hypercholesterolemia reduces total and LDL cholesterol concentrations from about 1,100 and 900 mg/dL (28.45 and 23.27 mmol/L) to about 300 and 185 mg/dL (7.76 and 4.78 mmol/L), prior to and after surgery, respectively. Liver transplantation replaced the missing LDL-Rs, enhanced catabolism, and reduced lipoprotein synthesis in this patient.
Summary of Major Studies
Primary and secondary prevention diet and drug trials have been performed to determine whether lowering of cholesterol will prevent CHD; Tables 11-15 and 11-16 summarize these trials. A number of earlier angiographic studies demonstrated that cholesterol reduction leads to regression of atherosclerosis and plaque stabilization. Most of the primary and secondary studies were double blinded, randomized, and placebo controlled, lasting for 5 years or longer, and most had sufficient patient numbers to be meaningful. Exceptions to these qualifications were seen in the early studies such as the Newcastle and Edinburgh trials, which were small and generally did not show much benefit, and the Coronary Drug Project (CDP) using dextrothyroxine, which was terminated early due to adverse effects on CHD mortality. The Helsinki Heart Study, using gemfibrozil, resulted in a reduction in nonfatal MI, which was the primary contributor to reduced CHD incidence (Table 11-15).16
TABLE 11-15 Primary Prevention Trials with Lipid-Lowering Drugs
TABLE 11-16 Secondary Prevention Trials with Lipid-Lowering Drugs
Total and LDL cholesterol were reduced an average of 13.4% and 20.3%, respectively, by cholestyramine in the LRC-CPPT, and the reduction of lipid levels was related to the amount of drug ingested (e.g., one to two packets, 5.4% reduction in total cholesterol, vs. five or more packets, 19% reduction).144 The prescribed dose of cholestyramine was 24 g, or six packets, per day. The cholestyramine group experienced a 19% reduction in risk (P <0.05) of the primary end point—definite CHD death and/or definite nonfatal MI—reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal MI. Other end points were reduced by 25%, 20%, and 21% for new positive exercise tests, angina, and coronary bypass surgery, respectively. Death from all causes was not significantly reduced by cholestyramine secondary to more accidents and violence in this group. The mean falls in total and LDL cholesterol in the cholestyramine group were 8% and 12% relative to levels in placebo-treated men, providing evidence that for every 1% reduction in cholesterol, a 2% decline in CHD mortality can be realized.
AFCAPS/TexCAPS, a primary prevention trial conducted in 6,605 men and women aged 57 to 63 years with average total cholesterol and LDL (<221 and <150 mg/dL [<5.72 and <3.88 mmol/L], respectively) who were treated with lovastatin 20 to 40 mg/day for 5.2 years, a 37% reduction (P <0.001) was shown in the risk for first acute major coronary event (fatal or nonfatal MI, unstable angina, or sudden cardiac death).100 The need for revascularization procedures was also reduced by 33% (P <0.001). The implications of this trial are enormous; potentially millions of “normal” people could benefit from lipid lowering with statins based on these results. The number of patients who need to be treated (NNT, Table 11-15) for primary prevention ranges from 43 in the West of Scotland trial to 71 in the Helsinki Heart Study. This range is within the typical boundary used for treatment decisions and described previously; cost-effectiveness is achieved routinely in patients with moderate to high risk. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) tested pravastatin 40 mg/day versus placebo in hypertensive patients with at least one CHD risk factor. Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention.145 The Women’s Health Initiative trial proved to be disappointing with no beneficial effects on CHD event reduction in the hormone replacement arm (conjugated equine estrogens [CEE] + medroxyprogesterone) or the CEE alone arm compared with placebo.119,121 Women did experience greater risk for thromboembolism, a slight increase in breast cancer, and a reduced risk of hip fracture. Consequently, hormone replacement therapy can no longer be recommended for cardiovascular protection.4 Publication of the recent WISDOM trial found that when combined hormone therapy (N = 2,196) was compared with placebo (N = 2,189), there was a significant increase in the number of major cardiovascular events (7 vs. 0, P = 0.016) and venous thromboembolism (22 vs. 3, hazard ratio 7.36 [95% CI 2.20 to 24.60]) confirming the findings of HERS and WHI. There were no statistically significant differences in numbers of breast or other cancers’ cerebrovascular events, fractures, and overall death.123
Niacin in the CDP significantly reduced definite, nonfatal MI as compared with placebo (10.1% vs. 13.9%), whereas clofibrate did not reduce death from any cause or nonfatal or fatal MI at the 5-year followup period.146
One of the most important studies published in the last few years is the 4S trial, a secondary intervention trial in a large number of patients.147 Simvastatin, 20 to 40 mg/day, reduced LDL cholesterol by 35% and reduced the risk of death from any cause by 30%. Coronary deaths were also reduced with simvastatin (relative risk, 0.58; confidence interval, 0.46 to 0.73). Therapy was also shown to be effective in women (18% to 19% of patients enrolled) and in the elderly (≥60 years). Indeed, the relative risk of death or major coronary event was reduced to a greater extent in the elderly than in younger patients. Death from noncardiovascular causes was similar for simvastatin and placebo (2.1% and 2.2%, respectively). The survival curves for simvastatin and placebo began to separate at 1 year and became more divergent with additional followup. The 4S study clearly demonstrates the benefit in cholesterol lowering and placates long-held fears of death from non-CHD causes. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study (N = 7,498 men and 1,516 women) has investigated the effect of pravastatin on CHD mortality in patients with prior MI or unstable angina and mean cholesterol level of 219 mg/dL (5.66 mmol/L) over 6 years.148 Pravastatin reduced the risk of CHD mortality by 24% (8.3% vs. 6.4%, P = 0.0004) and total mortality by 23% (14.1% vs. 11%, P = 0.00002); stroke was also reduced by 20% (4.3% vs. 3.5%, P = 0.22), and there was reduction in the need for coronary artery bypass graft (11.3% vs. 8.9%, P = 0.0001) or percutaneous transluminal coronary angioplasty (5.3% vs. 4.4%, P = 0.04).
The Veterans Administration High-Density Lipoprotein Intervention Trial (VA-HIT) was a double-blind trial that compared gemfibrozil (1,200 mg/day) with placebo in 2,531 men with CHD, an HDL cholesterol level of ≤40 mg/dL (≤1.03 mmol/L), and an LDL cholesterol level of ≤140 mg/dL (≤3.62 mmol/L).149 The primary study outcome was nonfatal MI or death from coronary causes. The median followup was 5.1 years. At 1 year, the mean HDL cholesterol level was 6% higher, the mean triglyceride level was 31% lower, and the mean total cholesterol level was 4% lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 21.7% of the patients assigned to placebo and in 17.3% of the patients assigned to gemfibrozil. The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22% (P = 0.006). This trial presents the strongest evidence to date that raising HDL-C and lowering triglycerides reduce risk for CHD.
The Atorvastatin Versus Revascularization Treatments (AVERT) study compared atorvastatin 80 mg/day with percutaneous transluminal coronary angioplasty.150 The followup period was 18 months. Of the patients who received aggressive lipid-lowering treatment with atorvastatin, 13% had ischemic events, as compared with 21% of the patients who underwent angioplasty. The incidence of ischemic events was thus 36% lower in the atorvastatin group over an 18-month period (P = 0.048, which was not statistically significant after adjustment for interim analyses). This reduction in events was because of a smaller number of angioplasty procedures, coronary artery bypass operations, and hospitalizations for worsening angina (the most common end point). As compared with the patients who were treated with angioplasty and usual care, the patients who received atorvastatin had a significantly longer time to the first ischemic event (P = 0.03). In low-risk patients with stable CAD, aggressive lipid-lowering therapy is at least as effective as angioplasty and usual care in reducing the incidence of ischemic events.
Pravastatin in the elderly individuals at risk for vascular disease (PROSPER) studied men and women in the age range of 70 to 82 years and found that pravastatin 40 mg/day reduced CHD events by 24% with no effect on cognitive function.151 A more recent trial, TIMI-22 (also known as Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE-IT]) enrolled 4,162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy).152 An intensive lipid-lowering statin regimen with atorvastatin 80 mg/day provided greater protection against death or major cardiovascular events than does a standard regimen. This study clearly points to “lower is better” for LDL concentration and will likely lead to revision in guideline goals to lower LDL levels. The Treatment to New Targets (TNT) assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg/dL (2.6 mmol/L) in patients with stable CHD.153,154 Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day providing further evidence that intensive lipid lowering brings greater benefits.
Statins reduce the incidence of strokes among patients at increased risk for cardiovascular disease; whether they reduce the risk of stroke after a recent stroke or TIA was addressed by Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL).155 During a median followup of 4.9 years, 265 patients (11.2%) receiving atorvastatin 80 mg/day and 311 patients (13.1%) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2%; adjusted hazard ratio, 0.84; 95% confidence interval, 0.71 to 0.99; P = 0.03; unadjusted P = 0.05).155 JUPITER randomized healthy patients to rosuvastatin on placebo and, on the basis of elevated CRP, found a 55% reduction in vascular events (event rate 1.11 vs. 0.51 per 100 person-years; hazard ratio 0.45, P <0.0001).24
Recent clinical trials attempting to increase HDL-C have been disappointing and one was stopped early due to futility.156 Neither the AIM-HIGH nor HPS2-THRIVE trial demonstrated a reduction in cardiovascular end points.14Both trials included background therapy with statins ± ezetimibe and the changes in HDL-C were somewhat smaller than expected. Some have suggested that extensive prior treatment may have depleted the lipid core making plaque less susceptible to rupture leading to clinical events.
The CETP inhibitor torcetrapib was associated with a substantial increase in HDL cholesterol and decrease in LDL cholesterol. It was also associated with an increase in blood pressure, and there was no significant decrease in the progression of coronary atherosclerosis. The lack of efficacy may be related to the mechanism of action of this drug class or to molecule-specific adverse effects. Other means of raising HDL cholesterol (HDL mimetics, which include ApoA-I mutants and peptide mimetics of ApoA-I, and HDL Milano A, a synthetic form of HDL) still hold hope of HDL modification leading a reduction in clinical events.
The enzyme ACAT esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects. Unfortunately, when tested in clinical trials, ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis.157
With the failure of AIM-HIGH and HPS2-THRIVE, the HDL hypothesis, raising HDL-C lowers cardiovascular risk, may be called into question. Others argue that trial design limited the outcome in these studies and a true test of the HDL-C hypothesis remains to be completed.
Statins differ in their pharmacokinetic properties and in pleiotropic effects (i.e., non–lipid lowering). The contribution of lipid lowering alone (a class effect) versus other effects (antiinflammatory, antithrombotic, etc.) continues to create controversy.
Proteinuria has been associated with high-dose rosuvastatin therapy (40 mg/day), but a review of a clinical trial database revealed an increase in eGFR for rosuvastatin-treated patients was consistent across all major demographic and clinical subgroups of interest, including patients with baseline proteinuria, baseline eGFR <60 mL/min/1.73 m2 (<0.58 mL/s/m2), and in patients with hypertension and/or diabetes.158
Mipomersen is an oligonucleotide inhibitor of ApoB-100 synthesis indicated as an adjunct to lipid-lowering medications and diet to reduce LDL cholesterol, ApoB, total cholesterol, and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia. The average reduction in LDL cholesterol is ∼25% with the most common adverse events being injection site pain (∼10%).159Lomitapide oral capsule is a microsomal triglyceride transfer protein (MTP) inhibitor. Inhibiting MTP reduces the level of cholesterol that the liver and intestines assemble and secrete into the circulation.160The average decrease in LDL cholesterol beyond baseline is ∼40%. Hepatic steatosis associated with lomitapide may be a risk factor for progressive liver disease including steatohepatitis and cirrhosis. GI complaints and mild to moderate elevations in liver enzymes have been reported with both drugs.
The role of nontraditional risk factors (hsCRP, homocysteine, etc.) is continuing to be clarified and may lead to recommendations for the use of these tests in patient evaluation.
EVALUATION OF THERAPEUTIC OUTCOMES
Short-term evaluation of therapy for hyperlipidemia is based on response to diet and drug treatment as measured in the clinical laboratory by total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides for patients being treated for primary intervention, as well as on response to secondary intervention. The interval for followup is dependent on the severity of illness, and patients with known CAD or multiple risk factors should be monitored more closely. Less commonly used laboratory measurements include CRP, homocysteine, ApoB, and Lp(a) levels. Because many patients being treated for primary hyperlipidemia have no symptoms and may not have any clinical manifestations of a genetic lipid disorder such as xanthomas or eruptions, monitoring and outcome are solely laboratory based. In patients treated for secondary intervention, symptoms of atherosclerotic cardiovascular disease, such as angina or intermittent claudication, may improve over months to years. If patients have xanthomas or other external manifestations of hyperlipidemia, these lesions should regress with therapy. Lipid measurements should be obtained in the fasted state to minimize interference from chylomicrons, and once the patient is stable, monitoring is needed at intervals of 6 months to 1 year. The goals for LDL and HDL cholesterol are provided in Tables 11-8 and 11-9.
Patients with multiple risk factors and established CHD should also be monitored and evaluated for progress in managing their other risk factors such as hypertension, smoking cessation, exercise and weight control, and glycemic control if diabetic. The goals are to maintain a blood pressure of below 130/80 mm Hg or less (presence of diabetes or renal insufficiency), stop smoking, maintain an ideal body weight, exercise for at least 20 minutes three or more times per week, and keep plasma glucose below 100 mg/dL (5.6 mmol/L) (threshold for glucose intolerance). Invasive evaluation, such as cardiac catheterization, is useful in patients with established CHD and is typically used for planning revascularization rather than monitoring of lipid-lowering therapy.
Evaluation of dietary therapy is part of the outcome evaluation for treating hyperlipidemia and the assistance of a dietitian is recommended. Use of diet diaries and recall survey instruments enables information about diet to be collected in a systematic fashion and may improve patient adherence to dietary recommendations. Patients on resin therapy should have a FLP panel checked every 4 to 8 weeks until a stable dose; triglycerides should be checked at stable dose to insure they have not increased. Niacin requires baseline liver function tests, uric acid, and glucose; repeat tests are appropriate at doses of 1,000 to 1,500 mg/day. Symptoms of myopathy or diabetes-like symptoms should be investigated and may require CK or glucose determinations; more frequent monitoring in diabetics may be necessary. A FLP 4 to 8 weeks after the initial dose or dose changes with statins is appropriate. Liver function tests should be obtained at baseline and periodically thereafter based on package insert information; recognized experts believe that monitoring for hepatotoxicity and myopathy should be symptom triggered.59,66 Ezetimibe requires little specific monitoring; however, with the publication of the SEAS trial, there is concern over the increased risk of cancer.161 Other studies underway will clarify this issue.
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines [erratum appears in Circulation 2004;110(6):763]. Circulation 2004;110:227–239.
3. Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: Endorsed by the National Heart, Lung, and Blood Institute [erratum appears in Circulation 2006;113(22):e847]. Circulation 2006;113:2363–2372.
4. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115:1481–1501.
5. Fletcher B, Berra K, Ades P, et al. Managing abnormal blood lipids: A collaborative approach. Circulation 2005;112: 3184–3209.
6. Ford ES, Mokdad AH, Giles WH, Mensah GA. Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults: Findings from the National Health and Nutrition Examination Survey, 1999 to 2000 [see comment]. Circulation 2003;107: 2185–2189.
7. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation 2013;127:e6–e245.
8. Arnett DK, Jacobs DR Jr, Luepker RV, Blackburn H, Armstrong C, Claas SA. Twenty-year trends in serum cholesterol, hypercholesterolemia, and cholesterol medication use: The Minnesota Heart Survey, 1980-1982 to 2000-2002. Circulation 2005;112:3884–3891.
9. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: Heart disease and stroke statistics—2010 update: A report from the American Heart Association. Circulation 2010;121:948–954.
10. Foley KA, Denke MA, Kamal-Bahl S, et al. The impact of physician attitudes and beliefs on treatment decisions: Lipid therapy in high-risk patients. Med Care 2006;44:421–428.
11. Menotti A, Lanti M, Nedeljkovic S, Nissinen A, Kafatos A, Kromhout D. The relationship of age, blood pressure, serum cholesterol and smoking habits with the risk of typical and atypical coronary heart disease death in the European cohorts of the Seven Countries Study. Int J Cardiol 2006;106: 157–163.
12. McQueen MJ, Hawken S, Wang X, et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): A case–control study. Lancet 2008;372:224–233.
13. Rader DJ. Mechanisms of disease: HDL metabolism as a target for novel therapies. Nat Clin Pract Cardiovasc Med 2007;4:102–109.
14. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–2267.
15. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Triglyceride concentration and ischemic heart disease: An eight-year follow-up in the Copenhagen Male Study. Circulation 1998;97:1029–1036.
16. Huttunen JK, Manninen V, Manttari M, et al. The Helsinki Heart Study: Central findings and clinical implications. Ann Med 1991;23:155–159.
17. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: Its etiology, effects and treatment. CMAJ 2007;176:1113–1120.
18. Ganong WF. Pathophysiology of Disease: An Introduction to Clinical Medicine, 5th ed. New York: McGraw Hill, 2006.
19. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis [see comment]. N Engl J Med 2007;356:1304–1316.
20. Libby P, Aikawa M, Jain MK. Vascular endothelium and atherosclerosis. Handb Exp Pharmacol 2006;176:285–306.
21. Miller DT, Ridker PM, Libby P, Kwiatkowski DJ. Atherosclerosis: The path from genomics to therapeutics. J Am Coll Cardiol 2007;49:1589–1599.
22. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089–2099.
23. Sofat R, Hingorani AD, Smeeth L, et al. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation 2010;121:52–62.
24. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: A prospective study of the JUPITER trial. Lancet 2009;373:1175–1182.
25. Eagle KA, Ginsburg GS, Musunuru K, et al. Identifying patients at high risk of a cardiovascular event in the near future: Current status and future directions: Report of a National Heart, Lung, and Blood Institute working group. Circulation 2010;121:1447–1454.
26. Kujiraoka T, Hattori H, Miwa Y, et al. Serum apolipoprotein j in health, coronary heart disease and type 2 diabetes mellitus. J Atheroscler Thromb 2006;13:314–322.
27. Libby P. How our growing understanding of inflammation has reshaped the way we think of disease and drug development. Clin Pharmacol Ther 2010;87:389–391.
28. Huang CY, Wu TC, Lin WT, et al. Effects of simvastatin withdrawal on serum matrix metalloproteinases in hypercholesterolaemic patients. Eur J Clin Invest 2006;36:76–84.
29. Suviolahti E, Lilja HE, Pajukanta P. Unraveling the complex genetics of familial combined hyperlipidemia. Ann Med 2006;38:337–351.
30. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: A scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007;30:162–172.
31. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute scientific statement [erratum appears in Circulation 2005;112(17):e297]. Circulation 2005;112:2735–2752.
32. Grundy SM, Pasternak R, Greenland P, Smith S Jr, Fuster V. AHA/ACC scientific statement: Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: A statement for healthcare professionals from the American Heart Association and the American College of Cardiology. J Am Coll Cardiol 1999;34:1348–1359.
33. Grundy SM, Cleeman JI, Merz CN, et al. A summary of implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol 2004;24: 1329–1330.
34. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. J Am Coll Cardiol 2004;44:720–732.
35. Singh IM, Shishehbor MH, Ansell BJ. High density lipoprotein as a therapeutic target. A systematic review. JAMA 2007;298:786–798.
36. Daniels SR, Greer FR, Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics 2008;122:198–208.
37. Strong JP, Malcom GT, Oalmann MC, Wissler RW. The PDAY Study: Natural history, risk factors, and pathobiology. Pathobiological Determinants of Atherosclerosis in Youth. Ann N Y Acad Sci 1997;811:226–235 [discussion 35–37].
38. Lauer RM, Obarzanek E, Hunsberger SA, et al. Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: The Dietary Intervention Study in Children. Am J Clin Nutr 2000;72:1332S–1342S.
39. Van Horn L, Obarzanek E, Friedman LA, Gernhofer N, Barton B. Children’s adaptations to a fat-reduced diet: The Dietary Intervention Study in Children (DISC). Pediatrics 2005;115:1723–1733.
40. Iughetti L, Predieri B, Balli F, Calandra S. Rational approach to the treatment for heterozygous familial hypercholesterolemia in childhood and adolescence: A review. J Endocrinol Invest 2007;30:700–719.
41. Wierzbicki AS, Viljoen A. Hyperlipidaemia in paediatric patients: The role of lipid-lowering therapy in clinical practice. Drug Saf 2010;33:115–125.
42. Trejo-Gutierrez JF, Fletcher G. Impact of exercise on blood lipids and lipoproteins. J Clin Lipidol 2007;1: 175–181.
43. Williams MA, Haskell WL, Ades PA, et al. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: A scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116:572–584.
44. Eckel RH, Borra S, Lichtenstein AH, Yin-Piazza SY, Trans Fat Conference Planning Group. Understanding the complexity of trans fatty acid reduction in the American diet: American Heart Association Trans Fat Conference 2006: Report of the Trans Fat Conference Planning Group. Circulation 2007;115:2231–2246.
45. American Heart Association Nutrition Committee, Lichtenstein AH, Appel LJ, et al. Diet and lifestyle recommendations revision 2006: A scientific statement from the American Heart Association Nutrition Committee [erratum appears in Circulation 2006;114(1):e27]. Circulation 2006;114:82–96.
46. Sacks FM, Lichtenstein A, Van Horn L, et al. Soy protein, isoflavones, and cardiovascular health: An American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 2006;113:1034–1044.
47. Gidding SS, Dennison BA, Birch LL, et al. Dietary recommendations for children and adolescents: A guide for practitioners: Consensus statement from the American Heart Association [erratum appears in Circulation 2005;112(15):2375]. Circulation 2005;112:2061–2075.
48. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Curr Opin Cardiol 2006;21:1–6.
49. Assmann G, Guerra R, Fox G, et al. Harmonizing the definition of the metabolic syndrome: Comparison of the criteria of the Adult Treatment Panel III and the International Diabetes Federation in United States American and European populations. Am J Cardiol 2007;99:541–548.
50. Shrestha S, Volek JS, Udani J, et al. A combination therapy including psyllium and plant sterols lowers LDL cholesterol by modifying lipoprotein metabolism in hypercholesterolemic individuals. J Nutr 2006;136: 2492–2497.
51. Petchetti L, Frishman WH, Petrillo R, Raju K. Nutriceuticals in cardiovascular disease: Psyllium. Cardiol Rev 2007;15:116–122.
52. He K, Song Y, Davigius ML, et al. Accumulated evidence on fish consumption and coronary heart disease mortality: A meta-analysis of cohort studies. Circulation 2004;109:2705–2711.
53. von Schacky C, Harris WS. Cardiovascular benefits of omega-3 fatty acids. Cardiovasc Res 2007;73:310–315.
54. McKenney JM, Sica D. Role of prescription omega-3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy 2007;27:715–728.
55. Bhattacharya S. Therapy and clinical trials: Plant sterols and stanols in management of hypercholesterolemia: Where are we now? Curr Opin Lipidol 2006;17:98–100.
56. Berthold HK, Unverdorben S, Degenhardt R, Bulitta M, Gouni-Berthold I. Effect of policosanol on lipid levels among patients with hypercholesterolemia or combined hyperlipidemia: A randomized controlled trial. JAMA 2006;295:2262–2269.
57. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–1278.
58. Link JJ, Rohatgi A, de Lemos JA. HDL cholesterol: Physiology, pathophysiology, and management. Curr Probl Cardiol 2007;32:268–314.
59. McKenney JM. Introduction. Report of the National Lipid Association’s Safety Task Force: The nonstatins. Am J Cardiol 2007;99:1C–58C.
60. Wensel TM, Waldrop BA, Wensel B. Pitavastatin: A new HMG-CoA reductase inhibitor. Ann Pharmacother 2010;44:507–514.
61. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: Drug–drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 2006;112: 71–105.
62. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES Study). Am J Cardiol 1998;81:582–587.
63. Robinson JG, Davidson MH. Combination therapy with ezetimibe and simvastatin to achieve aggressive LDL reduction. Expert Rev Cardiovasc Ther 2006;4:461–476.
64. Nissen SE. ENHANCE and ACCORD: Controversy over surrogate end points. Curr Cardiol Rep 2008;10:159–161.
65. Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol 2007;49:1753–1762.
66. McKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:17.
67. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: Insights from large randomized statin trials. J Am Coll Cardiol 2007;50: 409–418.
68. Edwards IR, Star K, Kiuru A. Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: An analysis of individual case safety reports from vigibase. Drug Saf 2007;30:515–525.
69. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–742.
70. Mangravite LM, Thorn CF, Krauss RM. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J 2006;6:360–374.
71. McPherson R. Comparative effects of simvastatin and cholestyramine on plasma lipoproteins and CETP in humans. Can J Clin Pharmacol 1999;6:85–90.
72. Tsuyuki RT, Bungard RJ. Poor adherence with hypolipidemic drugs: A lost opportunity. Pharmacotherapy 2001;21:576–582.
73. Tsuyuki RT, Olson KL, Dubyk AM, Schindel TJ, Johnson JA. Effect of community pharmacist intervention on cholesterol levels in patients at high risk of cardiovascular events: The Second Study of Cardiovascular Risk Intervention by Pharmacists (SCRIP-plus). Am J Med 2004;116:130–133.
74. McCrindle BW, O’Neill MB, Cullen-Dean G, Helden E. Acceptability and compliance with two forms of cholestyramine in the treatment of hypercholesterolemia in children: A randomized, crossover trial. J Pediatr 1997;130:266–273.
75. Zhang Y, Schmidt RJ, Foxworthy P, et al. Niacin mediates lipolysis in adipose tissue through its G-protein coupled receptor HM74A. Biochem Biophys Res Commun 2005;334:729–732.
76. Carlson LA. Nicotinic acid: The broad-spectrum lipid drug. A 50th anniversary review. J Intern Med 2005;258: 94–114.
77. Shepherd J, Betteridge J, Van Gaal L, European Consensus Panel. Nicotinic acid in the management of dyslipidaemia associated with diabetes and metabolic syndrome: A position paper developed by a European Consensus Panel. Curr Med Res Opin 2005;21:665–682.
78. Sharma M, Ansari MT, Abou-Setta AM, et al. Systematic review: Comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia. Ann Intern Med 2009;151:622–630.
79. Stern RH. The role of nicotinic acid metabolites in flushing and hepatoxicity. J Clin Lipidol 2007;1:191–193.
80. Lai E, De Lepeleire I, Crumley TM, et al. Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1. Clin Pharmacol Ther 2007;81:849–857.
81. Maccubbin D, Koren MJ, Davidson M, et al. Flushing profile of extended-release niacin/laropiprant versus gradually titrated niacin extended-release in patients with dyslipidemia with and without ischemic cardiovascular disease. Am J Cardiol 2009;104:74–81.
82. McKenney JM, Jones PH, Bays HE, et al. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis 2007;192:432–437.
83. McKenney J. Niacin for dyslipidemia: Considerations in product selection. Am J Health Syst Pharm 2003;60: 995–1005.
84. Libby A, Meier J, Lopez J, Swislocki AL, Siegel D. The effect of body mass index on fasting blood glucose and development of diabetes mellitus after initiation of extended-release niacin. Metab Syndr Relat Disord 2010;8:79–84.
85. Guyton JR, Bays HE. Safety considerations with niacin therapy [see comment]. Am J Cardiol 2007;99:19.
86. Forsblom C, Hiukka A, Leinonen ES, Sundvall J, Groop PH, Taskinen MR. Effects of long-term fenofibrate treatment on markers of renal function in type 2 diabetes: The FIELD Helsinki substudy. Diabetes Care 2010;33:215–220.
87. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol 2007;99:19.
88. Sveger T, Flodmark CE, Nordborg K, Nilsson-Ehle P, Borgfors N. Hereditary dyslipidaemias and combined risk factors in children with a family history of premature coronary artery disease. Arch Dis Child 2000;82: 292–296.
89. Grundy SM, Vega GL, Yuan Z, Battisti WP, Brady WE, Palmisano J. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial) [erratum appears in Am J Cardiol 2006;98(3): 427–428]. Am J Cardiol 2005;95:462–468.
90. Ford ES, Li C, Zhao G, Pearson WS, Mokdad AH. Hypertriglyceridemia and its pharmacologic treatment among US adults. Arch Intern Med 2009;169:572–578.
91. Capell WH, Eckel RH. Treatment of hypertriglyceridemia. Curr Diab Rep 2006;6:230–240.
92. Elam MB, Hunninghake DB, Davis KB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: The ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial. JAMA 2000;284:1263–1270.
93. McKenney JM, Sica D. Prescription omega-3 fatty acids for the treatment of hypertriglyceridemia. Am J Health Syst Pharm 2007;64:595–605.
94. Oh RC, Lanier JB. Management of hypertriglyceridemia. Am Fam Physician 2007;75:1365–1371.
95. McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med 2004;164: 697–705.
96. Gadi R, Samaha FF. Dyslipidemia in type 2 diabetes mellitus. Curr Diab Rep 2007;7:228–234.
97. Tan KC. Management of dyslipidemia in the metabolic syndrome. Cardiovasc Hematol Disord Drug Targets 2007;7:99–108.
98. Garg A, Simha V. Update on dyslipidemia. J Clin Endocrinol Metab 2007;92:1581–1589.
99. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301–1307.
100. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622.
101. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009.
102. Anonymous. Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol 1993;71:393–400.
103. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial [see comment]. Lancet 2004;364:685–696.
104. Collins R, Armitage J, Parish S, Sleight P, Peto R, Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions [see comment]. Lancet 2004;363:757–767.
105. Anonymous. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: The Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001;357:905–910.
106. Backes JM, Gibson CA, Ruisinger JF, Moriarty PM. Fibrates: What have we learned in the past 40 years? Pharmacotherapy 2007;27:412–424.
107. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563–1574.
108. Grundy SM, Vega GL, McGovern ME, et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: Results of the assessment of diabetes control and evaluation of the efficacy of Niaspan trial [see comment]. Arch Intern Med 2002;162:1568–1576.
109. Davidson MH, Kurlandsky SB, Kleinpell RM, Maki KC. Lipid management and the elderly. Prev Cardiol 2003;6: 128–133.
110. Mazza A, Tikhonoff V, Schiavon L, Casiglia E. Triglycerides + high-density-lipoprotein-cholesterol dyslipidaemia, a coronary risk factor in elderly women: The CArdiovascular STudy in the ELderly. Intern Med J 2005;35:604–610.
111. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ. Statins for secondary prevention in elderly patients: A hierarchical Bayesian meta-analysis. J Am Coll Cardiol 2008;51:37–45.
112. Anonymous. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344: 1383–1389.
113. Berger AK, Duval SJ, Armstrong C, Jacobs DR Jr, Luepker RV. Contemporary diagnosis and management of hypercholesterolemia in elderly acute myocardial infarction patients: A population-based study [see comment]. Am J Geriatr Cardiol 2007;16:15–23.
114. Hatzigeorgiou C, Jackson JL. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and osteoporosis: A meta-analysis. Osteoporos Int 2005;16:990–998.
115. Blue Cross Blue Shield Association, Technology Evaluation Center. Special report: The efficacy and safety of statins in the elderly. Technol Eval Cent Assess Program Exec Summ 2007;21:1–3.
116. Anonymous. Pravastatin benefits elderly patients: Results of PROSPER study. Cardiovasc J S Afr 2003;14:48.
117. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial [see comment] [summary for patients in Curr Cardiol Rep 2002;4(6):486–487]. Lancet 2002;360:7–22.
118. Abate N. Obesity and cardiovascular disease. Pathogenetic role of the metabolic syndrome and therapeutic implications. J Diabetes Complications 2000;14:154–174.
119. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–613.
120. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297: 1465–1477.
121. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial [see comment]. JAMA 2004;291: 1701–1712.
122. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: The Women’s Health Initiative: A randomized trial [see comment]. JAMA 2003;289: 2673–2684.
123. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in the women’s international study of long duration oestrogen after menopause (WISDOM): A randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ 2007;335:239. doi:10.1136/bmj.39266.425069.AD.
124. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: Results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069–1077.
125. Davis V, Schatz D, Winter W. Pediatric lipid disorders in clinical practice. eMedicine 2006, http://www.emedicine.com/ped/topic2787.htm.
126. Clauss SB, Holmes KW, Hopkins P, et al. Efficacy and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia. Pediatrics 2005;116:682–688.
127. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: A randomized controlled trial [see comment]. JAMA 2004;292:331–337.
128. de Jongh S, Ose L, Szamosi T, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: A randomized, double-blind, placebo-controlled trial with simvastatin. Circulation 2002;106:2231–2237.
129. O’Gorman CS, Higgins MF, O’Neill MB. Systematic review and metaanalysis of statins for heterozygous familial hypercholesterolemia in children: Evaluation of cholesterol changes and side effects. Pediatr Cardiol 2009;30:482–489.
130. Toto RD, Grundy SM, Vega GL. Pravastatin treatment of very low density, intermediate density and low density lipoproteins in hypercholesterolemia and combined hyperlipidemia secondary to the nephrotic syndrome. Am J Nephrol 2000;20:12–17.
131. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395–1407.
132. Baber U, Toto RD, de Lemos JA. Statins and cardiovascular risk reduction in patients with chronic kidney disease and end-stage renal failure. Am Heart J 2007;153:471–477.
133. Samuelsson O, Attman PO, Knight-Gibson C, et al. Effect of gemfibrozil on lipoprotein abnormalities in chronic renal insufficiency: A controlled study in human chronic renal disease. Nephron 1997;75:286–294.
134. Peterson AM, McGhan WF. Pharmacoeconomic impact of non-compliance with statins. Pharmacoeconomics 2005;23:13–25.
135. Tarraga-Lopez PJ, Celada-Rodriguez A, Cerdan-Oliver M, et al. A pharmacoeconomic evaluation of statins in the treatment of hypercholesterolaemia in the primary care setting in Spain [erratum appears in Pharmacoeconomics 2006;24(1):106]. Pharmacoeconomics 2005;23:275–287.
136. Cziraky MJ, Watson KE, Talbert RL. Targeting low HDL-cholesterol to decrease residual cardiovascular risk in the managed care setting. J Manag Care Pharm 2009;14: S3–S28.
137. Johannesson M, Jonsson B, Kjekshus J, Olsson AG, Pedersen TR, Wedel H. Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. Scandinavian Simvastatin Survival Study Group. N Engl J Med 1997;336:332–336.
138. Caro J, Klittich W, McGuire A, et al. The West of Scotland coronary prevention study: Economic benefit analysis of primary prevention with pravastatin. BMJ 1997;315: 1577–1582.
139. Schectman G, Wolff N, Byrd JC, Hiatt JG, Hartz A. Physician extenders for cost-effective management of hypercholesterolemia. J Gen Intern Med 1996;11: 277–286.
140. Bluml BM, McKenney JM, Cziraky MJ. Pharmaceutical care services and results in project ImPACT: Hyperlipidemia [see comment]. J Am Pharm Assoc 2000;40:157–165.
141. Charrois TL, Johnson JA, Blitz S, Tsuyuki RT. Relationship between number, timing, and type of pharmacist interventions and patient outcomes. Am J Health Syst Pharm 2005;62:1798–1801.
142. Yamada C, Johnson JA, Robertson P, Pearson G, Tsuyuki RT. Long-term impact of a community pharmacist intervention on cholesterol levels in patients at high risk for cardiovascular events: Extended follow-up of the second study of cardiovascular risk intervention by pharmacists (SCRIP-plus). Pharmacotherapy 2005;25: 110–115.
143. Buchwald H, Campos CT, Boen JR, Nguyen PA, Williams SE. Disease-free intervals after partial ileal bypass in patients with coronary heart disease and hypercholesterolemia: Report from the Program on the Surgical Control of the Hyperlipidemias (POSCH). J Am Coll Cardiol 1995;26: 351–357.
144. Anonymous. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251: 351–364.
145. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) [see comment]. JAMA 2002;288:2998–3007.
146. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: Long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245–1255.
147. Strandberg TE, Pyorala K, Cook TJ, et al. Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S). Lancet 2004;364:771–777.
148. Tonkin AM, Colquhoun D, Emberson J, et al. Effects of pravastatin in 3260 patients with unstable angina: Results from the LIPID study. Lancet 2000;356:1871–1875.
149. Rubins HB, Robins SJ, Collins D. The Veterans Affairs High-Density Lipoprotein Intervention Trial: Baseline characteristics of normocholesterolemic men with coronary artery disease and low levels of high-density lipoprotein cholesterol. Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Intervention Trial Study Group. Am J Cardiol 1996;78:572–575.
150. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999;341:70–76.
151. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet 2002;360: 1623–1630.
152. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes [see comment] [erratum appears in N Engl J Med 2006;354(7):778]. N Engl J Med 2004;350:1495–1504.
153. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435.
154. Waters DD, LaRosa JC, Barter P, et al. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study. J Am Coll Cardiol 2006;48:1793–1799.
155. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549–559.
156. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: Trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279–1291.
157. Nissen SE, Tuzcu EM, Brewer HB, et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis [see comment] [erratum appears in N Engl J Med 2006;355(6):638]. N Engl J Med 2006;354:1253–1263.
158. Vidt DG, Harris S, McTaggart F, Ditmarsch M, Sager PT, Sorof JM. Effect of short-term rosuvastatin treatment on estimated glomerular filtration rate. Am J Cardiol 2006;97:1602–1606.
159. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: A randomised, double-blind, placebo-controlled trial. Lancet 2010;375: 998–1006.
160. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: A single-arm, open-label, phase 3 study. Lancet 2013;381:40–46.
161. Pedersen TR. Lipid-lowering drugs and risk for cancer. Curr Atheroscler Rep 2009;11:350–357.