Lipid Disorders

Essentials of Diagnosis

Total serum cholesterol greater than 200 mg/dL on two samples at least 2 weeks apart     LDL cholesterol greater than 100 mg/dL     HDL cholesterol less than 40 mg/dL     Triglycerides greater than 200 mg/dL

General Considerations

In recent years, a great deal of emphasis has been placed on the relationship between elevated serum cholesterol levels—especially low-density lipoprotein cholesterol low-density lipoprotein cholesterol complex (LDL-C)—and the incidence of coronary artery disease (CAD). Hyperlipidemia represents a public health epidemic that continues to parallel the increased prevalence of obesity and is intimately implicated in the development of CAD. It is estimated that approximately 100 million American adults have total serum cholesterol levels in excess of 200 mg/dL and more than 12 million adults would qualify for lipid-lowering therapy by current national standards. Lowering LDL levels through diet and medication has been shown to reduce the progression of CAD and CAD mortality. According to the Framingham study, a 10% decrease in cholesterol level is associated with a 2% decrease in incidence of CAD morbidity and mortality. Lipoproteins The major circulatory forms of cholesterol, cholesterol ester and triglyceride, are both insoluble in water; to circulate in an aqueous environment they combine with phospholipids and proteins in complexes known as lipoproteins. The protein components of these complexes, apoproteins, play an important role in the interaction between cell surface lipases and the lipoprotein receptors necessary for lipid catabolism. The six major classes of lipoproteins are listed in Table 2-1. Lipoprotein Metabolism Lipoprotein metabolism can be divided into exogenous and endogenous pathways, as shown in Figure 2-1.   Figure 2–1. Exogenous and endogenous pathways of lipoprotein metabolism. C = cholesterol; TG = triglyceride; MG = monoglyceride; DG = diglyceride; FFA = free fatty acid; LPL = lipoprotein lipase; APO = apolipoprotein; PL = phospholipids. Reproduced, with permission, from Mitchel Y: Evaluation and treatment of lipid disorders. Prac Diabetol 1987;6:6. Exogenous Pathway The exogenous pathway is mainly responsible for absorption of dietary fat in the postprandial state and its subsequent distribution to the tissues. It begins with the absorption of dietary cholesterol and free fatty acids in intestinal microvilli, where they are converted to cholesterol esters and triglycerides, respectively, and packaged into chylomicrons that are secreted into the lymphatic system and enter the systemic circulation. In the capillaries of adipose tissue and muscle, the chylomicrons interact with an enzyme, lipoprotein lipase, which cleaves core triglycerides into mono- and diglycerides and free fatty acids that are taken up by surrounding tissue. Triglyceride hydrolysis reduces the core size of the chylomicron, resulting in an excess of surface components that are transferred to high-density lipoprotein (HDL). The remaining particle, a chylomicron remnant, is greatly reduced in size; it contains approximately equal amounts of cholesterol and triglycerides, and it acquires atherogenic potential. The chylomicrons are rapidly removed from the circulation by the liver in a receptor-mediated process. The cholesterol can also be secreted, as bile acids, into the bile. Endogenous Pathway The endogenous pathway delivers cholesterol and triglyceride to the tissues in the fasting state. It begins with the synthesis and secretion of very-low-density lipoprotein (VLDL) by the liver. This triglyceride-rich lipoprotein, which is smaller than the chylomicron, also interacts with lipoprotein lipase in the capillaries, adipose tissue, and muscle. Triglycerides within the core of the particle are cleaved and taken up by the surrounding fat and muscle; the redundant surface components are transferred to the HDL fractions. The remaining particle (VLDL remnant, or intermediate-density lipoprotein [IDL]), is a smaller lipoprotein, similar to the chylomicron remnant in its lipid composition and atherogenic potential. Approximately 50% of VLDL remnants are removed by the liver through the LDL receptor, which recognizes apoprotein E or the VLDL remnant. The highly atherogenic LDL contains mostly cholesterol ester and only one apoprotein, B-100. Its function is the delivery of cholesterol to tissues that require it (gonads, adrenals, rapidly dividing cells). The liver also plays a role in removing LDL from the blood via the LDL receptor. Two thirds of LDL is removed in this fashion; the remainder is removed by a non-LDL-receptor-mediated pathway in Kupffer cells, smooth muscle cells, and macrophages. It is believed that this mode of LDL uptake contributes to the development of foam cells and atherosclerosis. HDL, which seems to exert a protective effect against the development of atherosclerosis, is synthesized in both the liver and intestine and receives components during the lipoprotein lipase reaction. HDL is composed of approximately 50% protein (apoprotein A-I, A-II) and 20% cholesterol and comprises two major subfractions in the blood: HDL2 and HDL3. The latter is a small, dense particle that is believed to be the precursor of the larger cholesterol-enriched HDL2. The transfer of surface components during the lipoprotein lipase reaction is felt to be important in the formation of HDL2 and HDL3. HDL2 is believed to exert its protective effect through its participation in reverse cholesterol transport (picking up cholesterol from the cells involved in the atherosclerotic process and delivering them to the liver for excretion). HDL levels are higher in premenopausal women than in men, contributing to the lower incidence of CAD in women. There has been recent interest in cholesterol ester transfer protein, which is involved with the enzyme lecithin cholesterol acyl transferase in driving the reverse cholesterol transport process in moving cholesterol from peripheral tissues into plasma and then back into the liver. Lipoprotein(a) Lipoprotein(a), a variation of LDL, is formed by two components: an LDL-like particle with apoprotein B-100 and a hydrophilic protein moiety known as apoprotein(a), which has a close structural homology with plasminogen. It may cause a perturbation in the thrombolytic system by binding to and displacing plasminogen from binding sites on fibrin, fibrinogen, and cell surfaces. It inhibits plasminogen activation by tPA through stearic hindrance of tPA-binding sites. Accumulation of lipoprotein(a) has been found in atherosclerotic lesions, and it is now believed to be an atherogenic lipoprotein. Elevated plasma levels greater than 30 mg/dL in humans appear to be associated with an increased risk for the development of CAD, with a rate of occurrence estimated to be two to five times greater than in normal controls. Lipoprotein(a) is thought to be inherited by autosomal codominance. Some studies restrict identification of lipoprotein(a) as a risk factor for CAD only in the setting of elevated plasma LDL levels. Others have found the condition to be an independent risk factor. Diet, age, sex, smoking, body mass index, and apoprotein E polymorphism have not been found to correlate with plasma levels of lipoprotein(a). Increased lipoprotein(a) levels have been noted in patients with diabetes mellitus or nephrotic syndrome and immediately following myocardial infarction. In other studies, no changes have been observed in lipoprotein(a) levels in patients with acute myocardial infarction or unstable angina. Of the hypolipidemic interventions, niacin, neomycin, and extracorporeal removal of cholesterol have been shown to affect elevated lipoprotein(a) levels. Estrogen and fenofibrate may also reduce lipoprotein(a) levels. Lipoproteins and Atherosclerosis Current concepts in atherosclerosis suggest that oxidation of LDL is involved in its pathogenesis. It is hypothesized that the critical role of oxidized LDL in atherogenesis is due to its rapid uptake by the foam cells lining the arterial intima, which are thought to have macrophage-like properties. The LDL is then oxidized, exerting a chemotactic effect on monocytes, leading to more uptake of LDL and thus to the formation of the atherosclerotic plaque. The endothelial cells and smooth muscles can also oxidize LDL. Support for this lipid oxidation hypothesis comes from evidence that antioxidants such as vitamin E inhibit formation of lesions in hypercholesterolemic rabbits. Observations in some population studies also show an association between low plasma vitamin E levels and CAD incidence. However, clinical trials have not substantiated a reduction in the rates of fatal or nonfatal myocardial infarction with daily vitamin E use.

Clinical Findings

History A history of lipid disorders should be sought in all routine evaluations and in patients with suspected or overt cardiovascular disease. Many individuals already know they have high cholesterol levels from screening tests performed at shopping malls, in other physicians' offices, or during prior hospitalization. A family history of premature cardiovascular disease is also useful. A history compatible with overt cardiovascular disease, especially in a young man or a premenopausal woman is highly suggestive of a lipoprotein disorder. In addition, a history or symptoms of other diseases associated with lipoprotein abnormalities (eg, diabetes mellitus, hypothyroidism, end-stage renal disease) should be sought (Table 2-2). Other risk factors for CAD should also be identified because they multiply the risk caused by lipid disorders (Table 2-3). Physical Examination Most individuals with lipid disorders have no specific physical findings. Depending on the duration and severity of the lipid disorder, they may have overt evidence of lipid deposition in the integument that follows certain phenotypes (I–V), as originally proposed by Frederickson and Lees. Eruptive xanthomas occur when triglyceride levels are high; they are seen in types I (increased chylomicrons caused by lipoprotein lipase deficiency), IV (familial combined hyperlipidemia), and V (familial hypertriglyceridemia). Tendon xanthomas are characteristic of type II (familial hypercholesterolemia) patients, who can also have tuberous xanthomas and xanthelasma; the latter, however, is nonspecific and can be found in individuals with normal lipid levels. Palmar and tuberoeruptive xanthomas are characteristic of type III (familial dysbetalipoproteinemia). Laboratory Assessment The Expert Panel Report of the National Cholesterol Education Program on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP) suggests that a fasting lipid profile should be obtained in all adults 20 years of age or older at least once every 5 years. Without a family history of premature CAD or a history of familial hyperlipidemia, cholesterol screening should not be done routinely in children. Cholesterol values in the general pediatric population may not always predict the future development of hypercholesterolemia in adults. For many years clinicians depended on total cholesterol and triglyceride measurements to determine specific patient treatment regimens. More sophisticated lipoprotein measurements were available only in research facilities. Recent advances have made lipoprotein subclass and apoprotein determinations available from many clinical laboratories. LDL-C has been shown to be a more accurate predictor of CAD risk than is total-C. Low levels of HDL-C and the subfractions HDL2 and HDL3 have also been shown to be more powerful than total-C in predicting CAD. Levels of plasma apoproteins are also accurate predictors of CAD risk. It is controversial whether increases in plasma apoprotein B levels (the major apoprotein of LDL) and decreases in levels of apoproteins A-I and A-II (the major apoproteins of HDL) are better predictors of increased coronary risk than are total-C, HDL-C, LDL-C, or the ratio of total-C to HDL-C. Nonetheless, a patient's risk of CAD can be adequately estimated by an accurate total-C measurement and a calculated LDL-C determination. (Mean serum cholesterol and calculated LDL-C values for various population groups have been reported on by the National Center for Health Statistics.) Serum total-C levels can be measured at any time of day in the nonfasting state because total-C concentrations do not vary appreciably after eating. Patients who are acutely ill, losing weight, or pregnant or who recently had a myocardial infarction or stroke should be studied at a later time because cholesterol levels may be suppressed. Venipuncture should be carried out in patients who have been in the sitting position for at least 5 min, with the tourniquet applied for the briefest time possible. The blood may be collected as either serum or plasma. The National Cholesterol Education Program has established guidelines for standardization of lipid and lipoprotein measurements because of the great variations in accuracy at different laboratories that have been reported. The recommendation is that intralaboratory precision and accuracy for cholesterol determinations be no more than 3%. In a recent study assessing compact chemical analyzers for routine office determinations, some of the machines tested were shown to have accuracy and precision above the older (l988) target of 5% variance. A rapid capillary blood (fingerstick) methodology for cholesterol measurement is currently under development and evaluation. LDL-C measurements are usually indirectly derived from the following formula: When using this formula with mm/L units, divide the triglyceride value by 2.3. A reliable direct method for measuring LDL-C is needed because the accuracy of indirect estimates of LDL-C reflects measurements of total-C, HDL-C, and triglycerides, each of which contributes some degree of imprecision. Because triglyceride values are influenced by food, the patient should fast for at least 12 h before blood is taken for the LDL-C determination. If the triglyceride values are higher than 4.52 mm/L (> 400 mg/dL), the LDL-C value will be even less accurate. Direct measurement of LDL in a specialized laboratory, using ultracentrifugation, may be necessary when significant hypertriglyceridemia persists despite fasting. Tests are now available for specific apolipoproteins. These tests have proven to be accurate predictors of cardiovascular risk in various research studies. Unfortunately, until more is known about their utility in clinical practice, they should not be used in routine clinical management.

Treatment

Rationale for Treatment The rationale of treatment of hyperlipidemia is based on the hypothesis that abnormalities in lipid and lipoprotein levels are risk factors for CAD and that changes in blood lipids can decrease the risk of disease and complications. Levels of plasma cholesterol and LDL have consistently been shown to directly correlate with the risk of CAD. Since the promulgation of the previous NCEP (Adult Treatment Panel II) guidelines, the results of numerous studies involving the primary and secondary prevention of CAD with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported. These trials have overwhelmingly demonstrated a significant reduction in CAD events, CAD mortality, and mortality from all other causes, in addition to ameliorating LDL-C, HDL-C, and triglyceride levels. Data from the West of Scotland Coronary Prevention Study and from the Air Force/Texas Coronary Atherosclerosis Prevention Study have provided cogent evidence that primary prevention of CAD in hypercholesterolemic individuals reduces the incidence of coronary events and, in the former study, death from cardiovascular events. Secondary prevention trials such as the Scandinavian Simvastatin Survival Study (4S) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study have revealed that lowering LDL cholesterol levels can retard the progression of coronary atherosclerosis and reduce CAD events, CAD mortality, and cerebrovascular events. These compelling data have prompted a more aggressive approach to the treatment of hyperlipidemia, culminating in the new NCEP (Adult Treatment Panel III [ATP III]) guidelines (Table 2-4). Although ATP III maintains attention to intensive treatment of patients with CAD, its major new focus is on primary prevention in patients with multiple risk factors (Table 2-5). Epidemiologic studies and clinical trials are consistent in supporting the observation that for individuals with serum cholesterol levels in the 6.47–7.76 mm/L (250–300 mg/dL) range, each l% reduction in serum cholesterol would yield about a 2% reduction in the rate of combined morbidity and mortality from coronary heart disease. The absolute magnitude of these benefits would even be greater in those individuals having other risk factors for CAD, such as cigarette smoking and hypertension. These risk relationships are the basis for recommending lower cholesterol cutpoints and goals for those who are at high risk for developing coronary heart disease. Recent meta-analyses have indicated that triglycerides are an independent risk factor for the development of CAD. In addition, serum triglyceride levels are inversely related to HDL levels, and a reduction in triglyceride levels is associated with a rise in HDL. Raising HDL may protect against CAD, therefore providing an additional rationale for treating hypertriglyceridemia. Treatment Guidelines Hypercholesterolemia The NCEP has classified all adult patients into those with desirable cholesterol values (5.17 mm/L [<200 mg/dL]), borderline high blood cholesterol values (5.17–6.l8 mm/L [200–239 mg/dL]), and high blood cholesterol values (6.21 mm/L [240 mg/dL]) (see Table 2-4). LDL-C values of <2.58 mm/L (l00 mg/dL) are considered optimal; those between 2.58 and 3.36 mm/L (100–129 mg/dL) are near optimal; those between 3.36 and 4.11 mm/L (130–159 mg/dL) are borderline high; those between 4.13 and 4.88 mm/L (160–189 mg/dL) are high; and those greater than or equal to 4.91 mm/L (190 mg/dL) are very high. HDL-C values of less than 1.03 mm/L (40 mg/dL) are considered to be low, and those greater than or equal to 1.54 mm/L (60 mg/dL) are considered to be high. The NCEP recommends an approach in adults based on LDL-cholesterol levels (Figure 2-2, Table 2-6). Management should always begin with dietary intervention, as outlined in Table 2-7. When response to diet is inadequate, the NCEP recommends the addition of pharmacologic therapy (Figure 2-3).   Figure 2–2. Model of steps in therapeutic lifestyle changes (TLC). Reprinted, with permission, from: Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285; 2491 (Fig. 1).   Figure 2–3. Progression of drug therapy in primary prevention. Reprinted, with permission, from: Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285; 2492 (Fig. 2). Hypertriglyceridemia Non-HDL cholesterol, comprising LDL and VLDL, is a secondary treatment goal in patients with hypertriglyceridemia (levels > 200 mg/dL). The non-HDL cholesterol goal is set at 30 mg/dL higher than the LDL target level. Triglyceride values of less than 1.69 mm/L (150 mg/dL) are regarded as optimal; those from 1.69 to 2.25 mm/L (150–199 mg/dL) are borderline high; those from 2.26 to 5.64 mm/L (200–499 mg/dL) are high; and values greater than or equal to 5.65 mm/L (500 mg/dL) are considered to be very high. A link between plasma triglycerides and disease is most apparent in patients with severe hypertriglyceridemia with chylomicronemia. These patients are prone to abdominal pain and pancreatitis. Both changes in lifestyle (control of weight, increased physical activity, restriction of alcohol, restriction of dietary fat to 10–20% of total caloric intake, reduction of high carbohydrate intake) and drug therapy are often required. Much of hypertriglyceridemia (2.82–5.65 mm/L [250–500 mg/dL]) is due to various exogenous or secondary factors (see Table 2-2), which include alcohol, diabetes mellitus, hypothyroidism, obesity, chronic renal disease, and drugs. Changes in lifestyle or treatment of the primary disease process may be sufficient to reduce triglyceride levels. Patients with high triglycerides that is familial in origin (type IV) are not at risk for premature CAD. Caloric restriction and increased exercise should be instituted as first-line therapies. Patients with familial combined hyperlipoproteinemia often have mild hypertriglyceridemia and are at risk of premature coronary heart disease. These patients should have dietary treatment first, followed, if necessary, by drugs. Patients with high triglycerides and clinical manifestations of CAD can be treated as though they have familial combined hyperlipoproteinemia. Low Serum HDL Cholesterol A low serum HDL cholesterol level has emerged as the strongest single lipoprotein predictor of coronary heart disease. Although clinical trials suggest that raising HDL will reduce the risk of CAD, the evidence is insufficient at this time to specify the goal of therapy. The major causes of reduced serum HDL-C are shown in Table 2-8. Clearly, attempts should be made to raise low HDL-C by nonpharmacologic means. When a low HDL is associated with an increased VLDL, therapeutic modification of the latter should be considered, but attempts to raise HDL levels by drugs when there are no other associated risk factors cannot be justified. Coronary Artery Disease Myocardial Infarction Numerous trials have demonstrated the efficacy of employing HMG-CoA reductase inhibitors in the primary and secondary prevention of CAD. Lipid-lowering agents especially benefit hypercholesterolemic patients at the greatest risk for coronary events—those with CAD and CAD equivalents, such as diabetes mellitus, symptomatic cerebrovascular disease, abdominal aortic aneurysm, and peripheral vascular disease. The NCEP now classifies these conditions as tantamount to having established CAD because of their high prevalence of overt and subclinical atherosclerosis. The goal LDL for CAD and its equivalents is less than 2.6 mm/L (100 mg/dL), and dietary modification should be implemented in patients exceeding this target level, with concurrent initiation of drug therapy also being a consideration. Patients should obtain a fasting lipid profile within 24 h of the onset of an acute coronary syndrome or several weeks after the event because LDL levels may remain depressed and yield spurious results. It is recommended that drug therapy be initiated whenever a patient is hospitalized and found to have an LDL-C above 100 mg/dL. Coronary Artery Bypass Grafts Progressive atherosclerosis has been identified as the single most important cause of occlusion of saphenous vein coronary artery grafts; it is found in approximately two thirds of grafts within 10 years. Low HDL-C, high LDL-C, and high apolipoprotein B are the most significant predictors of atherosclerotic disease in grafts. Many investigators believe that internal mammary artery bypass grafting is the coronary bypass procedure of choice because atherosclerosis progresses less rapidly with these grafts than with saphenous veins. Moreover, lipid-lowering therapy may improve the patency of bypass grafts. The Coronary Artery Bypass Graft Trial demonstrated that aggressive LDL reduction as compared to moderate LDL reduction attenuated the progression of atherosclerosis in saphenous vein coronary artery bypass grafts. It also concluded that low-dose warfarin was ineffective in achieving this end-point. Coronary Angioplasty Restenosis after successful coronary angioplasty has been observed in 25–40% of patients undergoing this procedure. Restenosis after angioplasty appears to result from intimal smooth muscle cell proliferation. Placement of coronary stents has reduced angioplasty restenosis rates, CAD events, and the need for repeat revascularization procedures. Stent patency may be improved with the subsequent administration of glycoprotein IIb/IIIa inhibitors and other antiplatelet agents, such as aspirin and clopidogrel, along with HMG-CoA reductase inhibitors. Diabetes Mellitus Although elevated triglycerides, low HDL-C, or both are common in patients with diabetes, clinical trial data support the identification of LDL-C as the primary focus of therapy. Diabetes is designated a CAD risk equivalent in ATP III, and the LDL goal should be below 100 mg/dL. Metabolic Syndrome Factors that characterize the metabolic syndrome are abdominal obesity, dyslipidemia (elevated triglycerides, small dense LDL particles, low HDL-C), raised blood pressure, insulin resistance, and prothrombotic and proinflammatory states. ATP III recognizes this syndrome as a secondary target of risk reduction therapy after the primary target, LDL-C. Nonpharmacologic Approaches Dietary Modification The NCEP recommends dietary modification as the first-line treatment for hyperlipidemia (see Table 2-7). It advises a diet that limits cholesterol intake to no more than 200 mg daily and fat intake of less than 30% of total calories, saturated fat constituting less than 7% of daily caloric intake. High intakes of saturated fat, cholesterol, and calories (in excess of body requirements) are implicated as causes for elevated plasma cholesterol. Current recommendations for dietary modification are founded largely on both population-based observational studies and smaller, controlled dietary trials. Saturated, polyunsaturated, and monounsaturated fats are thought to raise, lower, and have no effect on serum cholesterol, respectively. It has been postulated that monounsaturated fats (eg, olive oil, rapeseed oil), which consist mainly of oleic acid, lower serum cholesterol as much as do polyunsaturated fats, which consist mainly of linoleic acid. The monounsaturated fats offer the added benefit of maintaining heart-protective HDL-C levels. One randomized trial involving postmyocardial infarction patients suggested that intake of n-3 polyunsaturated fatty acids reduced nonfatal myocardial infarction, cerebrovascular accidents, and mortality rates as compared with vitamin E and placebo. However, the study was limited by relatively high drug discontinuation rates. The favorable effects of polyunsaturated fat on serum cholesterol have been counterbalanced by evidence that high intake not only tends to lower HDL levels but may promote gallstone formation. Trans-fatty acids are formed by commercial hydrogenation processes, which harden polyunsaturate-rich marine and vegetable oils. In the United States, consumption of dietary trans-fatty acids averages about 8–10 g/d, or approximately 6–8% of total daily fat intake, much of it in the form of margarine. Lipid profiles are known to be adversely affected by a high trans-fatty-acid diet, which depresses mean HDL-C levels and elevates mean LDL-C levels. Patients at increased risk of atherosclerosis should therefore limit their intake of this type of fat. Stearic acid, which contributes substantially to the fatty acid composition in beef and other animal products, has been found to be as effective as oleic acid (monounsaturated fat) in lowering plasma cholesterol, when either one replaced palmitic acid (saturated fat). These findings have implications for the use of lean beef as a meat choice in a lipid-lowering diet. The ATP III also emphasizes the use of plant stanols and sterols and viscous (soluble) fiber as therapeutic dietary options to enhance the lowering of LDL-C. Clearly, research remains equivocal on certain key issues: the most effective macronutrient composition of a lipid-lowering diet and the relationship of exogenous cholesterol to serum lipid levels. Exercise Daily physical activity is recommended as an adjunct to dietary modification for the initial treatment of hyperlipidemia. Cross-sectional and prospective studies have provided evidence suggesting that increased physical activity reduces the risk of morbidity and mortality from CAD. An independent relationship between exercise and fitness, and the level of total-C, HDL, LDL, and triglycerides has yet to be established definitively, however. The effects of exercise on plasma lipids and lipoproteins may be a consequence of changes in body weight, diet, or medication use. It thus appears that individuals with high total cholesterol, LDL, and triglyceride levels and those with low HDL levels can show favorable changes in these parameters with physical training (both endurance and resistance). A randomized, controlled trial examined dietary modification and aerobic exercise with controls and concluded that the combination of diet and exercise reduced LDL levels but not HDL levels. Moreover, diet or exercise alone did not significantly alter LDL levels. What still needs to be defined, however, is the intensity, duration, and frequency of exercise necessary to benefit patients. Pharmacologic Treatment Lipid-Lowering Drugs Bile Acid Sequestrants The bile acid-binding resins cholestyramine, colestipol, and colesevelam are primarily used as second-line therapy and in combination with other agents to treat hypercholesterolemia without concurrent hypertriglyceridemia (Tables 2-9 and 2-10). The Lipid Research Clinics Coronary Primary Prevention Trial demonstrated a reduction in myocardial infarctions and CAD deaths in hypercholesterolemic men without CAD using cholestyramine. (1) Mode of action—These agents bind bile acids in the intestinal lumen, interrupting the enterohepatic circulation of bile acids, which are subsequently excreted in the feces. Increased synthesis of bile acids from endogenous cholesterol is then stimulated, resulting in the depletion of the hepatic cholesterol pool. This, in turn, leads to a compensatory increase in the biosynthesis of cholesterol and in the number of specific high-affinity LDL receptors on the liver cell membrane. The increased number of high-affinity LDL receptors expressed on hepatocytes stimulates an enhanced rate of LDL catabolism from plasma and thereby lowers the concentration of this lipoprotein. (2) Clinical use—With their interruption of the enterohepatic circulation of bile acids and consequent stimulation of endogenous LDL biosynthesis, bile acid resins may have a synergistic effect with concomitant administration of HMG-CoA reductase inhibitors. They are indicated as adjunct therapy to reduce serum cholesterol in patients with primary hypercholesterolemia. Their use should be preceded by dietary therapy, which should address both the specific type of hyperlipoproteinemia in the patient and the patient's body weight, because obesity has been shown to be a contributing factor in hyperlipoproteinemia. Resin use can cause a 5–20% increase in VLDL levels, hence, it should be restricted to hypercholesterolemic patients with only slightly increased triglyceride levels. The increase in VLDL seen with resin use usually starts during the first few weeks of therapy and disappears 4 weeks after the initial rise. It is thought that excessive increases in the VLDL particles may blunt the LDL-lowering effect of the drug by competitively binding the upregulated LDL receptors on the hepatocyte. The resins should, therefore, not be used in patients whose triglyceride levels exceed 3.5 mmol/L unless they are accompanied by a second drug with triglyceride-lowering effects; some suggest not using resins if the triglyceride level exceeds 2.5 mmol/L. A general rule of thumb is that the LDL concentration is seldom raised if the triglyceride level exceeds 7 mmol/L, and bile acid resin treatment would not be effective in this setting. Cholestyramine and colestipol are powders that must be mixed with water or fruit juice before ingestion and are taken in two or three divided doses with or just after meals. Colestipol is also available in tablet form for greater ease of administration. Colesevelam is a newer bile acid resin, which may have fewer adverse effects and drug interactions than older resins due to its novel structure and higher affinity for bile acids. It should be noted that bile acid sequestrants can decrease absorption of some antihypertensive agents, including thiazide diuretics and propranolol. As a general recommendation, all other drugs should be administered either 1 h before or 4 h after the bile acid sequestrant. The cholesterol-lowering effect of 4 g of cholestyramine appears to be equivalent to 5 g of colestipol. The response to therapy is variable in each individual, but a 15–30% reduction in LDL cholesterol may be seen with colestipol (20 g/day), cholestyramine (16 g/day), or colesevelam (3.8 g/day) treatments. The fall in LDL concentration becomes detectable 4–7 days after the start of treatment, and approaches 90% of maximal effect in 2 weeks. The initial dose should be 4 g of cholestyramine, 5 g of colestipol, or 1.88 g of colesevelam twice a day, and if there is an inadequate response, the dosage can be titrated upward accordingly. Using more than the maximum dosage does not increase the antihypercholesterolemic effect of the drug appreciably, but because it does increase side effects, it decreases compliance. Because resins are virtually identical in action, the choice is based on potential drug interactions and patient preference, specifically taste and the ability to tolerate the ingestion of bulky material. If resin treatment is discontinued, cholesterol levels return to pretreatment levels within a month. In patients with heterozygous hypercholesterolemia who have not achieved desirable cholesterol levels on resin-plus-diet therapy, the combination therapy of bile acid resins and HMG-CoA reductase inhibitors or nicotinic acid can further lower serum cholesterol, triglyceride, and LDL levels and increase serum HDL concentration. (3) Side effects—The side effects of bile acid resins include constipation, gastrointestinal irritation or bleeding, cholelithiasis, liver function test abnormalities, myalgias, dizziness, vertigo, and anxiety. Fibric Acid Derivatives Fibric acid derivatives are a class of drugs that inhibit the production of VLDL while enhancing VLDL clearance, as a result of the stimulation of lipoprotein lipase activity. These drugs reduce plasma triglycerides and concurrently raise HDL-C levels. Their effects on LDL-C are less marked and more variable. The Helsinki Heart Study demonstrated not only decreased triglycerides, decreased LDL-C and increased HDL-C in men treated with gemfibrozil, but also a decrease in the number of myocardial infarctions compared with placebo. (1) Mode of action—These drugs increase the activity of the enzyme lipoprotein lipase, enhancing the catabolism of VLDL and triglycerides and promoting the transfer of cholesterol to HDL. VLDL production also appears to be decreased. Gemfibrozil has a more pronounced inhibiting effect on VLDL synthesis than clofibrate. Because gemfibrozil and clofibrate reduce LDL-C concentrations by less than 10%, they cannot be considered first-line agents for the treatment of hypercholesterolemia. (2) Clinical use—It is well established that fibric-acid derivatives are first-line therapy to reduce the risk of pancreatitis in patients with very high levels of plasma triglycerides. Results from the Helsinki Heart Study have also suggested that hypertriglyceridemic patients with low HDL values can derive a cardioprotective effect from gemfibrozil. A Veterans Administration study found that gemfibrozil confers a significant risk reduction in major cardiovascular events in patients with established CAD and low HDL levels as their primary lipid disorder. However, it is not currently recommended to treat isolated low HDL levels with pharmacologic intervention. The newer generation of fibric acid derivatives, such as fenofibrate, may decrease total cholesterol and LDL levels to a greater extent than gemfibrozil or clofibrate. Fenofibrate also reduces lipoprotein(a) levels and increases LDL size and buoyancy, as does nicotinic acid. These drugs should not be used as first-line therapy for hypercholesterolemic patients unless hypertriglyceridemia is present; type IIb hyperlipidemic patients would benefit from this therapy. HMG-CoA reductase inhibitors combined with fibric acid derivatives are excellent therapy for severe type IIb hyperlipidemia, however, creatine phosphokinase (CPK) values must be closely monitored. Nicotinic acid or bile acid resins plus gemfibrozil are also a reasonable combination for type IIb disease, but HDL levels may drop slightly with the latter combination. (3) Side effects—The side effects of fibric acid derivatives include cholelithiasis, gastrointestinal disturbance, myalgias from myositis, and liver function test abnormalities. Nicotinic Acid Nicotinic acid, a water-soluble vitamin that, at doses much higher than those at which its vitaminic actions occur, lowers VLDL and LDL levels and increases HDL levels. It has been shown to reduce overall morbidity and mortality caused by coronary heart disease and to produce regression of some of the signs of atheroma. (1) Mode of action—The mode of action of nicotinic acid is unknown and appears to be independent of the drug's role as a vitamin. One of its important actions is believed to be partial inhibition of free fatty acid release from adipose tissue. Experiments show that nicotinic acid inhibits the accumulation of cyclic-adenosinemonophosphate (AMP) stimulated by lipolytic hormones; the cAMP concentration controls the activity of triglyceride lipase and thus lipolysis. Nicotinic acid decreases the synthesis of VLDL and LDL by the liver and has been reported to increase the rate of triglyceride removal from the plasma as a result of increased lipoprotein lipase activity. (2) Clinical use—Through its beneficial effects on VLDL-TG, LDL-C and HDL-C levels, nicotinic acid is indicated for most forms of hyperlipoproteinemia (types II, III, IV, and V) and for patients with depressed HDL. It is the most potent medication among lipid-lowering agents for the augmentation of HDL levels. It is also particularly useful for patients who have elevated plasma VLDL-TG levels as a part of their lipid profile. It is important to remember, however, that a diet low in cholesterol and saturated fats is the foundation of therapy for hyperlipoproteinemia. Nicotinic acid is available in 100-, 125-, 250-, and 500-mg tablets as well as in a time-release form. The typical dosage is 3–7 g/day given in three divided doses. Therapeutic effects of the drug are usually not seen until the patient reaches a total daily dose of at least 3 g. A greater response may be attained with periodic increases to a maximum of 7–8 g/day, although the incidence of adverse effects also increases with higher doses. In general, it is best to use the lowest dose that will achieve the desired alterations in plasma lipoprotein levels. (3) Side effects and contraindications—Unfortunately, many patients cannot tolerate therapeutic doses of nicotinic acid, whose primary side effects are cutaneous flushing and gastrointestinal disturbance, and appropriate steps should be taken to minimize these untoward effects. Taking two aspirins 30 min before the nicotinic acid will reduce flushing; taking the nicotinic acid with meals can ameliorate dyspepsia. Regardless of the dose, it is important to draw laboratory test samples at regular intervals to monitor potential adverse effects. These include assessment of liver function (bilirubin, alkaline phosphatase, and transaminase levels), uric acid levels, and serum glucose levels. Nicotinic acid is contraindicated in patients with active peptic ulcer disease. Because the drug may also impair glucose tolerance, it is contraindicated in patients with poorly controlled diabetes. Nicotinic acid is also associated with reversible elevations of liver enzymes and uric acid and should not be used in patients with hepatic disease or a history of symptomatic gout. Patients taking a time-release form of nicotinic acid have a lower incidence of flushing than do patients with unmodified nicotinic acid (this side effect is thought to be related to the rate of gastrointestinal absorption). This is outweighed, however, by the far greater incidence of gastrointestinal and constitutional symptoms experienced by patients on the time-release form. These include nausea, vomiting, diarrhea, fatigue, and impaired male sexual function. In addition, even with low doses, the time-release preparation may be associated with more hepatotoxicity, entailing greater alkaline phosphatase and transaminase elevations. Other adverse effects of nicotinic acid include pruritus (which responds to aspirin), acanthosis nigricans, cardiac arrhythmias, gout, and myopathy. Hepatic 3-Methylglutaryl Coenzyme A Reductase Inhibitors These inhibitors (HMG-CoA) inhibit the conversion of HMG-CoA to mevalonic acid, a rate-limiting step in the synthesis of cholesterol in the liver and intestines, the two main sites for production of cholesterol in the body. HMG-CoA reductase inhibitors produce the greatest reduction in levels of LDL cholesterol, the primary atherogenic lipoprotein, along with ameliorating HDL and triglyceride levels to a lesser extent. In modest daily doses, HMG-CoA reductase inhibitors reduce total and LDL-C at a rate of 15–50% and may reduce triglycerides by 10–30%. Although effective as monotherapy, HMG-CoA reductase inhibitors can be combined to good effect with bile acid sequestrants when a greater effect on cholesterol is required, or with fibric acid derivatives when an additive effect on triglyceride levels is desired. These combinations may, however, increase the risk of rhabdomyolysis. (1) Mode of action—Most cholesterol that is endogenously produced is synthesized in the liver. HMG-CoA reductase inhibitors interrupt an early rate-limiting step in cholesterol synthesis: the conversion of HMG-CoA to mevalonic acid. Because the synthesis rates of LDL receptors are inversely related to the amount of cholesterol in cells, the action of HMG-CoA reductase inhibitors reduces cholesterol synthesis and cellular concentrations of cholesterol and increases the expression of LDL receptors in the liver. Furthermore, because LDL receptors are responsible for clearing about two thirds to three quarters of plasma LDL (and associated cholesterol), HMG-CoA reductase inhibitors may promote the clearance of LDL as well as VLDL remnants. By reducing cholesterol synthesis, they may also interfere with the hepatic formation of lipoproteins. As cholesterol synthesis is maximal at night, it is recommended that HMG-CoA reductase inhibitors be given at bedtime. (2) Clinical use—HMG-CoA reductase inhibitors have revolutionized the treatment of hyperlipidemia by their potency, efficacy, and tolerability and have evolved into first-line therapy for most forms of hyperlipidemia. Numerous studies with reductase inhibitors involving primary and secondary prevention of CAD have demonstrated a reduction in CAD events, CAD mortality, cerebrovascular events, and mortality from all other causes. Increased LDL receptor activity and decreased LDL synthesis are responsible for the hypocholesterolemic effect of the drug. This increase in LDL receptor activity occurs in response to a decrement in cholesterol synthesis by HMG-CoA reductase inhibition. LDL may be reduced by either its increased clearance from the plasma or its decreased production. Reductase inhibitors exhibit pleiotropic effects beyond the lowering of LDL cholesterol levels. The reduction in coronary events and mortality rates is not solely attributable to the attenuation of atherosclerosis and improvement in vessel patency. They are postulated to possess antiinflammatory properties, contribute to coronary plaque stabilization, and improve endothelial cell function, conditions that are increasingly recognized as emerging areas of therapy for the treatment of coronary artery disease. They also reduce C-reactive protein levels, which are markers of inflammation and strong predictors of coronary events. One primary prevention trial suggested that pravastatin use may delay or prevent the development of diabetes mellitus, which is intimately linked to a constellation of multiple CAD risk factors known as the metabolic syndrome. Some studies have indicated that reductase inhibitors may prevent the onset of congestive heart failure, osteoporosis, and Alzheimer's disease as well. (3) Side effects, drug interactions, and contraindications—HMG-CoA reductase inhibitors are contraindicated in pregnancy, lactation, hypersensitivity to the drugs, and active liver disease. Immunosuppressive drugs, fibric acid derivatives, nicotinic acid, and erythromycin all may increase the risk of rhabdomyolysis. Concurrent use with warfarin (Coumadin) may potentiate the anticoagulant effect. Bile acid sequestrants decrease the bioavailability of the drug. ACE inhibitors may cause hyperkalemia when used with HMG-CoA reductase inhibitors. Digoxin tends to raise simvastatin levels. Although the HMG-CoA reductase inhibitors are well tolerated, 10% of patients experience unwanted side effects. Although liver enzymes are elevated in 0.5–2% of patients, the patients are asymptomatic, and values may revert to normal on discontinuation of treatment. It is recommended that treatment be stopped if enzymes increase to a level three times that of normal. Myositis, myalgia, and myopathy have been reported with increased creatine kinase levels in 5% of patients. Creatine kinase may increase further with the combined use of HMG-CoA reductase inhibitors with fibrates or nicotinic acid. Cerivastatin has been discontinued from production due to a high incidence of rhabdomyolysis and death, especially when combined with gemfibrozil. Although the question of cataract induction has been brought up with the use of these agents, clinical studies with lovastatin have not shown an increase in lens opacity. Recently cases of peripheral neuropathy have been described with these agents. Estrogens and Progestogens Women are at increased risk of atherosclerosis after menopause. This is thought to be due to the lack of the protective effect of estrogen on lipoproteins. In this connection, several investigators have observed reductions in total-C and LDL in women taking exogenous estrogens compared with women not receiving any estrogen supplements. Exogenous estrogens can also produce modest elevations in HDL cholesterol (Table 2-11). There is, however, an increased risk of endometrial hyperplasia, possibly leading to endometrial cancer, with unopposed estrogen therapy. Therefore, in treating a postmenopausal woman with an intact uterus, it is advisable to add progesterone to offset the possible carcinogenic effect of estrogen on the uterus. By doing so, however, the beneficial effects on the lipoprotein profile induced by estrogens tend to be lost (Table 2-12). The Heart Estrogen/Progestin Replacement Study concluded that hormone replacement therapy (HRT) for the secondary prevention of CAD did not confer a reduction in CAD events or CAD mortality rates overall in the 4.1-year average follow-up period. In addition, a higher rate of venous thromboembolism and gallbladder disease was noted in the patients taking HRT. A subsequent angiographic end-point study demonstrated no benefit with estrogen or the combination of estrogen and medroxyprogesterone on the progression of coronary atherosclerosis compared with placebo in postmenopausal women with established CAD. The Women's Health Initiative trial recently showed that the combination of a conjugated estrogen with methoxyprogesterone increased the rate of coronary events, strokes, breast cancers, and thromboembolic diseases despite significant reductions in LDL-C and HDL-C levels. Combination Drug Therapy When treating patients with most severe genetic dyslipidemias, such as heterozygous familial hypercholesterolemia or familial combined hyperlipidemia, it is common for single-drug therapy to fail to achieve satisfactory plasma lipoprotein levels, even with HMG-CoA reductase inhibitors. In this setting, combination drug therapy is often successful in controlling plasma lipid levels (see Table 2-10). With less severe disorders, it is beneficial sometimes to use a combination of low-dose therapeutic agents with complementary effects rather than high doses of either agent alone in order to minimize their individual dose-related toxicities. Common lipid-modifying agents to be used in combination regimens are the bile acid resins cholestyramine, colestipol, and colesevelam. They have the advantage of not being absorbed and thus cause fewer drug interactions. When the resins are used in full doses in combination with niacin, LDL-C levels are reduced 32–55% in patients with familial hyperlipidemia. Niacin is poorly tolerated by some patients, however, particularly because of its side effects. Recently a combination niacin–lovastatin formulation has become available for use in the treatment of hyperlipidemia. Bile acid sequestrants can also be used in combination with fibric acid derivatives; some studies have shown an LDL-C reduction of 36–42%. Bile acid sequestrants and HMG-CoA reductase inhibitors used together are highly effective in lowering plasma LDL-C concentrations. A study of cholestyramine and lovastatin use in 62 patients showed a mean reduction in total-C of 48% and LDL-C levels of 59%. The antifungal agent ketoconazole has an inhibitory effect on several enzymes linked to cytochrome P450. Large doses of this compound have been demonstrated to reduce total-C and LDL-C levels substantially, probably through inhibition of cholesterol synthesis at the demethylation-of-lanosterol step. The effects of low-dose ketoconazole (400 mg) alone and in combination with cholestyramine (12 g/day) have led to reductions in LDL-C levels of 22% and 31–41%, respectively.