Prim Care Clin Office Pract 32 (2005) 1027–1055

Hyperlipidemia
Charles B. Eaton, MD, MSa,b,*
a

Memorial Hospital of Rhode Island, 111 Brewster Street, 2nd Floor, Pawtucket, RI 02860, USA b Brown Medical School, Box G, Providence, RI 02912, USA

Over the past 20 years, a large body of scientific evidence has accumulated that conclusively demonstrates a link between lipoprotein disorders and atherosclerosis, and its clinical manifestations of myocardial infarction, stroke, and sudden cardiac death. In addition, marked elevations of triglycerides are associated with acute pancreatitis. The third report of the Expert Panel on Detection, Evaluation and Treatment in Adults (Adult Treatment Panel [ATP] III) and its update in July 2004 have summarized current recommendations for the management of hyperlipidemia [1,2]. Although other organizations differ slightly in risk estimates and recommendations, they are generally similar for lipid management and draw from the same epidemiologic and clinical trial evidence [3]. This evidence supports that there is a graded relationship between atherogenic lipoproteins (total cholesterol, low-density lipoprotein [LDL] cholesterol, nonhigh–density lipoprotein [HDL] cholesterol, total cholesterol/HDL ratio) and coronary risk. A meta-analysis of 38 primary and secondary prevention trials [4] found that for every 10% reduction in total cholesterol, coronary heart disease mortality decreases by 15% and total mortality decreases by 11%. This article draws heavily on the ATP III [1] guidelines and their update in July 2004 [2] in making recommendations regarding therapy. Hyperlipidemia represents several different disorders of lipid metabolism, related to increased production or delayed degradation of atherogenic lipoprotein particles, or decreased synthesis or increased degradation of protective lipoprotein particles. Such metabolic derangements of

Dr. Eaton’s research in this area has been supported by Pfizer, Merck-Schering Plough, Astra Zenecca, and Merck-Johnson. * Memorial Hospital of Rhode Island, 111 Brewster Street, 2nd Floor, Pawtucket, RI 02860. E-mail address: Charles_Eaton@mhri.org 0095-4543/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2005.09.002 primarycare.theclinics.com

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lipoproteins are associated with serious health consequences, including increased risk of premature atherosclerosis or pancreatitis, depending on the type of lipid disorder. Lipoproteins are essential in transportation of free fatty acids and cholesterol throughout the body to be used for four major biological functions: energy use, lipid deposition, steroid hormone production, and bile acid formation. The major lipoproteins include: chylomicrons, chylomicron remnants, very low-density lipoprotein (VLDL) cholesterol, VLDL remnants, intermediate-density lipoprotein (IDL) cholesterol, LDL cholesterol, Lp(a) (lipoprotein [a]), and HDL cholesterol. Lipoproteins vary in the amount of esterified and unesterified cholesterol, triglyceride, phospholipids and apoproteins contained in each type of particle. The different apolipoproteins serve as cofactors for enzymes and ligands for receptors important in the metabolism of lipoproteins. Diet, genetic, and other metabolic factors contribute to the metabolism of each lipoprotein.

Lipoprotein metabolism and pathophysiology A brief review of the major lipoprotein particles and endogenous and exogenous lipid metabolism is helpful in understanding the different lipid disorders, their relationship to atherosclerosis, and present day and future therapies. There are five major lipoproteins, each with a different function. Chylomicrons Chylomicrons are very large particles that carry small amounts of dietary cholesterol and large amounts of triglycerides. They have a density of greater than 0.95 g/ml. Most patients who have triglyceride levels greater than 500 mg/dL have elevated chylomicrons. Chylomicrons and chylomicron remnants are the primary lipoproteins associated with absorption of fats and cholesterol from the diet. In intestinal cells, free fatty acids combine with glycerol to make triglycerides, and are packaged with small amounts of cholesterol esters to form micelles of chylomicron and seven carrier apolipoproteins. The main apoproteins found in chylomicrons are apoprotein B-48 (Apo B-48), with smaller amounts of Apo C-II, and Apo E as the chylomicrons enter the circulation. Apo B-48 does not bind to the LDL (Apo B-100) receptor in the liver, and therefore allows chylomicrons to stay in the circulation and be acted upon by lipoprotein lipase (LPL). Apo C-II is a co-factor for LPL, which hydrolyzes the triglyceride core of chylomicrons, gradually reducing their size and converting chylomicrons to chylomicron remnants and releasing free fatty acids. The released free fatty acids are used for energy or stored in adipose tissue. The chylomicron remnants are cleared by the liver by an Apo E receptor.

and C-III. C-II. Triglyceride levels between 150 mg/dL and 500 mg/dL are generally associated with elevated levels of VLDL particles. little IDL is measurable in plasma. resulting in increased m-RNA transcription and increased synthesis of . leads to decreased intracellular cholesterol levels.95 to 1. Similar to chylomicrons. by blocking the rate-limiting step of cholesterol synthesisdhydroxymethyl glutaric acid (HMG)-CoA-reductase. C-III. They have a density of 0. They carry a core of cholesterol esters and small amounts of triglyceride. which is the ligand for binding to the LDL receptor on the liver. C-III.006 to 1. A-II. and similar values for triglycerides. hypothyroidism). LPL activity is augmented by Apo-C-II ligand on VLDL and inhibited by Apo-C-III ligand. such that under fasting conditions. VLDL is the major carrier of triglyceride in the endogenous pathway of lipoprotein metabolism. and is hydrolyzed. Apo E and Apo C-II already mentioned. C-I. This feedback loop is exploited by statin medications. They have a density of 1. Typically lipid profiles associated with this condition give values of total cholesterol of around 300 mg/dL. Low-density lipoproteins LDL are the main atherogenic lipoproteins. however. besides the Apo B-48. VLDL remnants are generally either cleared by the Apo B/E receptor of the liver or remodeled by hepatic lipase into LDL cholesterol. which is under negative feedback via intracellular cholesterol levels. such as a defective Apo-E receptor as found in Type III dyslipidemia or in other metabolic states (ie.019 g/mL. They have a density of 1. under certain conditions.063 g/ml. and E. and are associated with Apo B-100. AIV. the triglyceride core of VLDL particles is acted upon by LPL. C-I. Very low-density lipoproteins VLDL are moderately large particles that carry endogenous triglycerides (60% by mass) and to a lesser extent cholesterol (20% by mass). and are associated with Apo B-100. Intermediate-density lipoproteins IDL carry both triglyceride and cholesterol esters.019 to 1.HYPERLIPIDEMIA 1029 Chylomicron remnants surface constituents also include Apo A-I. excess IDL is found in plasma. Plasma LDL cholesterol levels are under the control of LDL receptor activity found predominantly in the liver. and its synthesis is under the control of microsomal triglyceride transfer protein in the endoplasmic reticulum. IDL are usually cleared rapidly from the blood. and are associated with Apo B-100. releasing free fatty acids (FFA) and generating VLDL remnants and IDL as successive triglyceride is released. which. and E. VLDL is synthesized by the liver.006 g/ml.

peripheral vascular disease. The resultant pre b-HDL is converted into mature a-HDL by LCAT.063 and 1. dense LDL particles penetrate the endothelial cell barrier of the arterial wall more frequently than large.21 g/ml. with a prolonged residence time caused by this charged interaction. Under conditions of inflammation or oxidant stress. and intracellular pools that allow for the efflux of cholesterol and triglyceride. Lipid-poor Apo A-1 interacts with ABCA1. It has been proposed that subendothelial retention of LDL cholesterol is the initiating factor for atherosclerosis [6]. this process leads to atherosclerosis and its clinical sequelae of coronary artery disease. Internalization at the liver leads to bile acid formation. HDL-C is returned to liver through transfer of cholesterol ester by cholesterol ester transfer protein (CETP) to VLDL or selective uptake of cholesterol by hepatic SR-B1 pathway. LDL cholesterol can also enter macrophages and be taken up by the arterial wall through unregulated scavenger receptors. lipid poor particles containing Apo A-I and phospholipids. and sudden death. cholesterol acyl transferase (LCAT) (Fig. allows for lipid peroxidation of the phospholipids and unesterified cholesterol. They have the highest density of lipoproteins. Lipoproteins in atherosclerosis Abnormal lipoprotein metabolism is a major etiologic factor in atherosclerosis. HDL is synthesized in the liver and intestinal cells. High-density lipoproteins HDL are antiatherogenic lipoproteins.1030 EATON LDL receptors. HDL is involved in two important processes: reverse cholesterol transport under the control of cholesterol efflux regulatory protein (CERP) sometimes called ABCA-1. Small. and lecithin. A charged interaction between Apo B containing lipoproteins with proteoglycans in the extracellular matrix of arterial wall has been implicated in this process. Over 70% of patients who have premature coronary heart disease (CHD) have lipid disorders. The increased LDL receptor activity (Apo B-100 receptor) leads to increased removal of LDL from the plasma. stroke. removing excess cholesterol from intracellular cholesterol pools in macrophages and in the liver. chylomicron remnants. Nonhepatic LDL cholesterol is used for steroid production and cell membrane synthesis. which is important in the digestion of cholesterol and fat. The LDL cholesterol. between 1. Atherosclerosis can be induced by abnormal lipoproteins in animal models in absence of any other risk factors. which explains most of HDL’s antiatherogenic effects. 1) [5]. LDL can be internalized by the liver and other tissues for useful biologic functions. fluffy LDL particles. The nascent HDL particles interact with VLDL remnants. aneurysm formation. The net effect is to remove excess cholesterol from cells. and consists of small. This process leads to .

after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1). Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP.HYPERLIPIDEMIA 1031 Fig. Uptake by these receptors is associated with modification of LDL cholesterol through oxidization. newly synthesized lipid-poor apolipoprotein A-1 interacts with ABCA1. class B. Pre-bHDL is converted into mature-a-HDL by lecithin-cholesterol acyltransferase (LCAT. Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (white arrows). HDL cholesterol is returned to the liver through two pathways selective uptake of cholesterol by the hepatic scavenger receptor. Increasing HDL cholesterol levels. In reverse cholesterol transport. and LPL lipoprotein lipase. New Engl J Med 2004. or glycooxidation. The incorporation of modified LDL .) macrophage infiltration. FC denotes free cholesterol. PL phospholipids. (From Brewer HB.350:1491–4. removing excess cellular cholesterol and forming pre-b-HDL (green arrow). blue arrow). with permission. 1. resulting in an increase in the plasma HDL level. Model of reverse cholesterol transport mediated by high-density lipoprotein (HDL). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-1 Milano and phospholipids. with uptake by the liver through the LDL receptor (red arrows). type I (SR-B1. Apolipoprotein A-1 (ApoA-1) is synthesized by the liver and. black arrow). LRP LDL-related protein. or the transfer of cholesterol ester by cholesterol ester transfer protein (CETP) to VLDL-LDL. glycosylation. and the uptake of LDL cholesterol by macrophages through unregulated scavenger receptors. is secreted into plasma as lipid poor apolipoprotein A-1 (yellow arrow).

IDL cholesterol. and smooth muscle accumulation leads to further acceleration of the atherosclerotic plaque formation. leading to the efflux of cholesterol from subendothelial space in atherosclerotic plaques already described. This process of foam cell formation. HDL cholesterol. VLDL remnants. and are associated in epidemiologic studies with increased risk of coronary heart disease. however. It is thought that these large triglyceride rich particles cause an efflux of water from the pancreatic cells into the capillaries. a major mediator of endothelium-dependent vasodilation. and Lp(a) are taken up by macrophages and cause foam cell formation. Oxidized LDL cholesterol disrupts endothelial cell surfaces and impairs the release of nitrous oxide. Another potential pathway through which LDL cholesterol may promote atherosclerosis is by the upregulation of the angiotensin receptors on smooth muscle cells and lecithin-like oxidized LDL receptor-1 (LOX-1) on the endothelial cells. chylomicrons and chylomicron remnants are present in the systemic circulation. help with this effect. is antiatherogenic.1032 EATON cholesterol by tissue macrophages leads to the formation of foam cells. The most important mechanism for this effect is reverse cholesterol transport. in contrast to LDL. IDL. such as paraoxonase. Oxidized LDL cholesterol can also increase platelet aggregation and induce thromboxane release. These cholesterol-rich macrophages can rupture. Hypertriglyceridemia in pancreatitis Although the most important aspect of hyperlipidemia in clinical medicine is its association with premature coronary heart disease and stroke. carrying these large lipophilic particles and leading to dehydration of the pancreatic cells. and leading to further vessel wall and endothelial cell damage. This damage to the endothelium leads to increased platelet adherence and the release of cytokines that stimulate smooth muscle proliferation. They also impair endothelium-dependent function. severe hypertriglyceridemia is associated with pancreatitis. and VLDL cholesterol. Other contributing factors to this antiatherogenic effect include the role of HDL cholesterol in maintaining endothelial cell function. with markedly elevated triglyceride levels. protection against thrombosis via inhibition of calcium-induced procoagulant activity by Apo A-I. The exact pathophysiologic mechanism for this association is unclear. and the maintenance of normal blood viscosity through its effect on red cell deformability. releasing intracellular enzymes and oxygen free radicals. which contributes to vasoconstriction and intravascular thrombosis. In addition. Intracellular . Oxidatively modified LDL cholesterol also promotes proinflammatory and immune changes through cytokine release and antibody production that lead to further promotion of atherosclerosis. HDL has antioxidant properties. Although not as extensively studied as LDL cholesterol. greater than 750 mg/dL. platelet accumulation. and its associated enzymes.

or HDL cholesterol less than 40 mg/dL. because triglycerides values will vary significantly based upon fasting-fed status. Recent evidence. Step 3: Rule out secondary causes. which has been shown to be reasonably valid in a multitude of racial and ethnic cohorts. however. has demonstrated that nonfasting specimens using total cholesterol. the lipid values that define hyperlipidemia are generally lower than for adults. These are presented in Table 4 [9]. In addition. children . For children. A simple clinical rule for adult patients who have total cholesterol greater than 200 mg/dL. Tables 1 and 2 can be used to calculate the 10-year risk of hard CHD [1]. and therefore pancreatitis. Step 6: Follow-up with the patient. These patients usually have modest elevations of several risk factors that collectively lead to an increased risk of a cardiovascular event. or TC/HDL ratio greater than 5. Step 1: determine whether a patient has a lipid disorder that needs evaluation and treatment This is done by obtaining a fasting lipid profile and then determining the risk factors for cardiovascular disease. Selective screening for children is recommended for those who have a family history of premature coronary heart disease or a familial lipid disorder. non-HDL cholesterol. Step 5: Initiate therapy based upon goal of treatment. and places patients at high risk of acute and recurrent pancreatitis.8]. A fasting lipid profile is the preferred method to evaluate lipoprotein disorders. or have isolated low HDL cholesterol. Approach to the patient Management of patients who have lipid disorders can be broken down into six steps: Step 1: Determine whether a patient has a lipid disorder that needs evaluation and treatment. leading to autodigestion of the pancreatic cells. and total cholesterol/HDL ratio prospectively predict CHD risk as well as fasting lipid profiles [7. or triglycerides greater than 200 mg/dL. Step 4: Set treatment goals. Apo C-III deficiency is associated with very high levels of triglycerides.HYPERLIPIDEMIA 1033 levels of amylase and lipase enzymes then rise to toxic levels. The LDL goals for each risk category are given in Table 3. These patients can be identified by evaluating their risk of having a cardiovascular event through use of the Framingham risk equation. Some adult patients may have lipid disorders than need treatment with total cholesterol less than 200 mg/dL. Step 2: Define the lipid disorder.0 defines most patients who have a lipid disorder in need of evaluation and treatment.

and the serum C-reactive protein concentration. alcohol intake. The point total is determined in each category and the 10-year risk determined in the bottom row.nhlbi. . Adapted from Adult Treatment Panel III.Table 1 Framingham 10-year CHD risk for men Age (years) 20–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 Age Total cholesterol (mg/dL) !160 160–199 200–239 240–279 R280 20–39 0 4 7 9 11 Age 20–39 Nonsmoker Smoker HDL cholesterol mg/dL R60 50–59 40–59 !40 Systolic blood pressure.gov/. Not included are diabetes mellitus (which is considered a CHD equivalent). Available at: http://www. mm Hg !120 120–129 130–139 140–159 R160 Point total 0 1 2 3 4 5 6 7 8 9 10-year risk (%) 1 1 1 1 1 2 2 3 4 5 Untreated 0 0 1 1 2 Point total 10 11 12 13 14 15 16 R17 0 8 40–49 0 5 50–59 0 3 60–69 0 1 70–79 0 1 Points ÿ1 0 1 2 Treated 0 1 2 2 3 10-year risk (%) 6 8 10 12 16 20 25 R30 40–49 0 3 5 6 8 50–59 0 2 3 4 5 60–69 0 1 1 2 3 70–79 0 0 0 1 1 Points ÿ9 ÿ4 0 3 6 8 10 11 12 13 These risk estimates for the development of coronary heart disease do not account for all important cardiovascular risk factors.nih. family history of CHD.

nhlbi.gov/. The point total is determined in each category and the 10-year risk determined in the bottom row. mm Hg !120 120–129 130–139 140–159 R160 Point total !9 9 10 11 12 13 14 15 16 17 10-year risk (%) !1 1 1 1 1 2 2 3 4 5 Untreated 0 1 2 3 4 Point total 18 19 20 21 22 23 24 R25 0 9 40–49 0 7 50–59 0 4 60–69 0 2 70–79 0 1 Points ÿ1 0 1 2 Treated 0 3 4 5 6 10-year risk (%) 6 8 11 14 17 22 27 R30 40–49 0 3 6 8 10 50–59 0 2 4 5 7 60–69 0 1 2 3 4 70–79 0 0 1 2 2 Points ÿ7 ÿ3 0 3 6 8 10 12 14 16 These risk estimates for the development of coronary heart disease do not account for all important cardiovascular risk factors. Not included are diabetes mellitus (which is considered a CHD equivalent). Available at: http://www. and the serum C-reactive protein concentration. family history of CHD. Adapted from Adult Treatment Panel III. alcohol intake.Table 2 Framingham 10-year risk of CHD in women Age (years) 20–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 Age Total cholesterol mg/dL !160 160–199 200–239 240–279 R280 20–39 0 4 8 11 13 Age 20–39 Nonsmoker Smoker HDL cholesterol mg/dL R60 50–59 40–59 !40 Systolic blood pressure.nih. .

and those who smoke cigarettes should be screened. family history of premature CHD (in first-degree relatives !55 in men. Abbreviations: ACS. Although the Frederickson classification of lipid disorder has historical relevance. diabetes mellitus. a ATP III risk factors for CHD: cigarette smoking. diabetes mellitus. triglyceride-dominant . age (men R45 years. they represent less than 20% of all dyslipidemias. or CHD & uncontrolled risk factor. obesity. and therefore has been abandoned by most clinicians. or CHD & DM. and represent metabolic derangement induced by unhealthy diets. DM. or pancreatitis. based upon clinical trials released since May 2001 release of ATP III. women R55 years).1036 EATON Table 3 ATP III-recommended goals of therapy and LDL level for initiation of drug therapy LDL goal (mg/dL) !160 !130 !130 !100 Non-HDL goal (mg/dL) !190 !160 !160 !130 LDL level to initiate drug treatment (mg/dL) O190b O160 O130 O100 Risk category Low risk Borderline risk Moderate risk Moderate-high risk 10-year risk 0–1 risk factorsa 2þ risk factors. b Up to the discretion of clinician whether to start drug therapy at LDL O160 mg/dL after a year of therapeutic lifestyle change attempted. or CHD and metabolic syndrome CHD equivalent Extremely high risk !100 !70 !130 !100 O100 O70 Goals include recommendations made in July 2004 white paper under therapeutic options. it carries little clinical utility because it has no prognostic value. or elevated hs-CRP. A simple schema of defining the lipid profile on the basis of the relevant lipid profile abnormality is the most useful: LDL-dominant lipid disorders. 10%–20% Moderateþ uncontrolled risk factor or metabolic syndrome. hypertension. and sedentary lifestyles. !65 in women). Most lipid disorders are polygenic. O20% ACS. Step 2: define the lipid disorder Although familial forms of hyperlipidemia are particularly important for family physicians treating entire families (and should lead to family screening. Lp(a) excess. or elevated coronary artery calcification score CHD & 2þ risk factors. acute coronary syndrome. low HDL cholesterol (!40 mg/dL). its presence removes one risk from the total. including children). 10%–20% 2þ risk factors. hypertension. HDL O60 is a negative risk factor. or strong family history. who have childhood obesity.

Most patients who have LDL-dominant lipid disorder have polygenic hypercholesterolemia with no familial association. mixed lipid disorders. Some patients who have LDL-dominant lipid disorders have genetic lipid disorders that are associated with significantly elevated LDL cholesterol. The LDL cholesterol goals are less than 70 mg/dL. and O50 mg/dL in women) and normal triglycerides (!150 mg/dL). These lipid disorders are described below: Low-density lipoprotein-dominant lipid disorders LDL-dominant lipid disorders are defined as those in patients whose LDL cholesterol is greater than their ATP III risk stratification goal and who have a normal HDL cholesterol (HDL cholesterol O40 mg/dL in men. or demonstrable genetic phenotypes. less than 100 mg/dL. and atherogenic dyslipidemia. Total cholesterol is usually above 300 mg/dL for heterozygotes and 500 mg/dL . depending upon the cardiovascular disease risk category (see Table 3). These LDL dominant genetic lipid disorders include familial hypercholesterolemia and familial defective Apo B-100. Many of these polygenic hypercholesterolemic patients are at least partially responsive to dietary therapy. but many require lipid-lowering drug therapy as well. usually less than 190 mg/dL.HYPERLIPIDEMIA 1037 Table 4 Lipid values for children and adolescents aged 2–19 Category Total cholesterol High Borderline high Desirable LDL cholesterol High Borderline high Desirable HDL cholesterol High Borderline high Desirable Triglyceride High Borderline high Desirable Concentration (mg/dL) 200 or higher 170–199 !170 130 or higher 110–129 !110 Under 10 years !40 40–45 O45 100 or higher 75–99 !75 Concentration (mg/dL) 10–19 years !35 35–45 O45 130 or higher 90–129 !90 lipid disorders. or less than 160 mg/dL. isolated low HDL cholesterol. Familial hypercholesterolemia Familial hypercholesterolemia (FH) is a relatively common autosomal dominant disorder that affects approximately 1 in 500 individuals. less than 130 mg/dL.

Different mutations of the LDL receptor gene confer different effects on LDL cholesterol levels and CHD risk. c General population column refers to levels that need to be seen in a patient with no evaluable family members. Units are mg/dL. class 2. divided by 38. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. in which intracellular transport of LDL receptor protein from the endoplasmic reticulum to the golgi apparatus is blocked. siblings. but these physical findings are not pathognomic of FH. nieces. and are outlined in Table 5 [10]. FH generally requires a multiple drug regimen. class 3. Hunt SC. This defect is found in about 8 of 10.000 patients. or siblings of grandparents.72:171–6. Sitosterolemia Sitosterolemia is a relatively rare autosomal disorder in which plant sterols are absorbed in large quantities because of a defect in intestinal absorption of sterols. Am J Cardiol 1993.5 to convert to mmol/L. so that the LDL receptors do not cluster in the coated pits. because sitosterolemia and cerebrotendinous xanthomatosis can also present with tendon xanthomas. Schumacher MC. b Third-degree relatives refers to first cousins. These plant sterols accumulate in Table 5 Cholesterol criteria for heterozygous FH Age in years !18 20 30 R40 First-degree relative 220 240 270 290 (155) (170) (190) (205) Second-degree relativea 230 250 280 300 (165) (180) (200) (215) Third-degree relativeb 240 260 290 310 (170) (185) (210) (225) General populationc 270 290 340 360 (200) (220) (240) (260) Total cholesterol and LDL cholesterol (in parentheses) levels expected to diagnose heterozygous familial hypercholesterolemia with 98% specificity by demonstrating high cholesterol levels in family members. This disorder may be associated with elevated levels of cholesterol or normal cholesterol levels. Familial defective apoprotein B100 Familial defective Apo B100 is an autosomal dominant disorder that is clinically identical to FH. or nephews. however. Mutations to the LDL receptor locus have been discovered affecting four phenotypes: class 1. here the defect is in the Apo B-100 ligand on the LDL particle and not on the receptor itself. in which the LDL receptor binding protein is defective. in which the internalization of the receptor-LDL complex is defective. et al. Data from Williams R. LDL apheresis is recommended [11]. in which synthesis of the receptor is defective. and for more severe cases. uncles. .1038 EATON to 1000 mg/dL for homozygotes. Many FH patients have tendon xanthomas on themselves or in family members. The diagnostic criteria for heterozygous FH can be categorized as definite and probable. a Second-degree relatives refers to aunts. and class 4. grandparents.

coupled with the LDL component of this lipoprotein-inducing foam cell formation through a high-affinity macrophage receptor. and therefore Lp(a) competes with plasminogen for plasminogen receptors. glucose intolerance. and in other clinical situations they are not. fibrin. 150 to 199 mg/dL. Less frequently. or taking tamoxifen or immunosuppressive . 200 to 499 mg/dL. or hypothyroidism. previously known as pre-sinking beta-lipoprotein. Elevated Lp(a) is usually associated with markedly elevated total cholesterol levels greater than 300 mg/dL. leading to tendon xanthomas. The net effect of this homology is that Lp(a) leads to impaired fibrinolysis and thrombolysis. and very high. and it is treated with ezetimide and diets low in dietary sterols. or are undergoing hormone therapy. elevated triglycerides are associated with an elevated risk of coronary heart disease.080 g/ml. and is modulated by LCAT. as discussed in the lipoproteins metabolism section above. diabetes mellitus. Lp(a) is a specialized form of LDL linked by disulfide bridge to Apo(a). B-VLDL. leads to Lp(a)’s dual atherogenic and thrombogenic pathologic sequelae. Values greater than 30 mg/dL are associated with increased risk of premature atherosclerosis. This plasminogen-like effect. Many patients who have hypertriglyceridemia have acquired disorders such as obesity. and cholesterol ester transfer protein. IDL) and low levels of HDL cholesterol. Lipoprotein(a) excess Lp(a). hepatic triglyceride lipase. high. Overproduction or derangement in any of these catabolic pathways can lead to elevated triglycerides. This is because triglyceride elevations can be associated with a range of other atherogenic lipoprotein abnormalities (remnant lipoproteins.HYPERLIPIDEMIA 1039 plasma and tendons. and low HDL cholesterol) or an atherogenic lipoprotein profile that may add to the atherogenic potential of elevated triglycerides. The disorder’s typical onset is in childhood. is the most common lipid disorder in families that have a family member who has premature coronary artery disease [12]. Lp(a) has a density of 1. borderline high. less than 150 mg/dl. Triglyceride-dominant lipid disorders The association of elevated triglycerides and risk of CHD is not fully understood. and fibrinogen. small. The fourth kringle is very similar in structure to plasminogen. elevated triglycerides. it is an isolated lipid disorder. but usually in the setting of strong family history of premature CHD. Many patients who have elevated triglycerides also have metabolic syndrome [13] (three of the five following characteristics: trance obesity. renal disease. prehypertension. The ATP III guidelines classified serum triglycerides by coronary risk in adults as follows: normal. dense LDL cholesterol. or familial combined hyperlipidemia. The metabolic control of triglycerides is under the control of lipoprotein lipase. Apo(a) is protein chain composed of five doughnut-shaped domains called kringles. 500 mg/dL or more.045 to 1. so that in some clinical situations.

Clinically. or ‘‘chylomicronemia syndrome. and so on. Thus. It is often associated with obesity. Patients who have elevated LDL cholesterol and low HDL cholesterol are also classified as having a mixed lipid disorder. depending upon concomitant exposures such as weight gain. Familial hypertriglyceridemia Familial hypertriglyceridemia is an autosomal dominant disorder that is associated with moderate elevations of serum triglycerides in the 200 to 500 mg/dL range. and manifests as either elevated total cholesterol. Mixed lipid disorder Most patients who have elevated triglycerides also have elevations in either LDL cholesterol or low HDL cholesterol and elevation of other Apo B100-carrying lipoproteins. In many studies. hypertension. Thus a mixed lipid disorder is the most frequently found in most primary care practices.1040 EATON drugs that contribute to this lipid disorder. Patients who have familial hypertriglyceridemia and who are heterozygous for lipoprotein lipase genetic mutations typically have low HDL cholesterol levels as well. such patients are at no increased risk of CHD. . Four common subgroups of mixed lipid disorders that deserve special comment are familial combined hyperlipidemia. The explanation for this fact is that such large elevations in triglyceride levels are associated with large triglyceride-rich particles that are unable to enter the subendothelial space and thus initiate the atherosclerotic process. insulin resistance. Familial combined hyperlipidemia Familial combined hyperlipidemia (FCH) is found in about 1% to 2% of the population. insulin resistance. The phenotypic expression of these genetic defects may vary. and elevated uric acid. Familial or genetic lipid disorder associated with hypertriglyceridemia is discussed briefly below. and may develop severe symptoms with elevations greater than 1000 mg/dl. Clinical manifestations of this significant elevation. abdominal pain/pancreatitis. ruling out secondary causesdstep 3dis especially important in evaluating patients who have hypertriglyceridemia or mixed lipid disorders. Type III or broad band dyslipidemia. Severe hypertriglyceridemia Patients who have triglycerides greater than 500 mg/dL have severe hypertriglyceridemia and are at increased risk of pancreatitis. Patients who have severe hypertriglyceridemia may have partial LPL deficiency or Apo C-II deficiency. and lipemia retinalis. exogenous estrogens. hyperglycemia. patients who have severe hypertriglyceridemia present with eruptive xanthomas and hepatosplenomegaly. and atherogenic dyslipidemia. hyperapolipoproteinemia (Apo B excess syndrome).’’ include memory loss.

It usually manifests itself in the fourth decade. or both in various family members. but is relatively resistant to statins. It is associated with an increased risk of CHD. making this diagnosis important clinically because it responds very well to fibrates and niacin. b-VLDL represents a combination of chylomicron remnants and partially degraded VLDL that is triglyceride-poor and cholesterol-rich. and bile acid sequestrates. patients have physical examination findings of a corneal arcus. low HDL cholesterol. or after significant weight gain or onset of the diabetes mellitus or hypothyroidism. insulin resistance. Isolated low high-density lipoprotein cholesterol (hypoalphalipoproteinemia) Most patients who have low HDL cholesterol (!40 mg/dL) have another concomitant lipid abnormality.35 using ultracentrification methods. and is associated with small. type 2 diabetes).HYPERLIPIDEMIA 1041 triglycerides. This lipid disorder is the result of a defective Apo E receptor. Diagnosis can be confirmed by evaluating VLDL/TG ratio of greater than 0. usually elevated triglycerides.2. type B or increased small. It usually does not manifest itself until adulthood. Nuclear magnetic resonance (NMR) spectroscopy and other sophisticated techniques are required to determine LDL particle size and density with precision. tuboeruptive xanthomas over pressure points. but not all. and many. it is usually associated with both elevated triglycerides (O300 mg/dL) and elevated total cholesterol (O300 mg/dL). and is exacerbated by diets high in fats and simple sugars and by weight gain. Small. Occasionally. Type III dyslipidemia or broad band dyslipoproteinemia Type III dyslipidemia or broad band dyslipidemia is a familial lipid disorder associated with elevations of beta-migrating VLDL (b-VLDL) cholesterol. Subjects who have this disorder have normal LDL cholesterol levels (!160 mg/dL) but have elevated Apo B levels (O135 mg/dL) and decreased LDL/Apo B ratio less than 1. suggestive of LDL phenotype. cholesterol absorption inhibitors. Although this lipid disorder is relatively rare. It is associated with abnormal (E2/E2) phenotype of the Apo E receptor. Apoprotein B excess or hyperapolipoproteinemia This is a relatively common disorder that may be a variant of familial combined hyperlipidemia. Atherogenic dyslipidemia This is a nonfamilial lipid disorder characterized by elevated triglycerides (O200 mg/dL) and reduced HDL cholesterol (!40 mg/dl). or palmar xanthomata. . dense LDL cholesterol is almost uniformly found in patients who have high triglycerides. and elements of metabolic syndrome (truncal obesity. Usually lipid abnormalities in this triad are only marginally abnormal. dense LDL. dense LDL cholesterol. Clinically.

and with increased risk of premature CHD.1042 EATON isolated low levels of HDL cholesterol are found. Familial hypoalphalipoproteinemia Familial hypoalphalipoproteinemia is an autosomal dominant disorder with HDL cholesterol levels below the tenth percentile (30–40 mg/dL). Some patients who have healthy lifestyles have very low total cholesterol values. above). but can be associated with premature CHD with some mutations. above). leading to large orange tonsils. By measuring Apo A-I levels (O90 mg/dL). These should be searched for before lipid-lowering drug therapy is initiated. Both familial HDL deficiency and Tangiers disease involve mutations of ATP-binding cassette recorder gene (ABC1) that encodes CERP. and normal triglyceride levels. such low-risk patients can be differentiated from those who have familial hypoalphalipoproteinemia. and peripheral neuropathy. and . These patients do not appear to be at increased risk of CHD. or enzymatic abnormalities associated with HDL metabolism (see the section on HDL metabolism. Step 3: rule out secondary causes A variety of clinical diseases and medications can cause secondary hyperlipidemia. so-called ‘‘fish eye syndrome. The HDLmediated efflux of intracellular cholesterol is impaired. and can be difficult to differentiate from those with genetic causes of isolated low HDL cholesterol who have an increased risk. concomitantly low HDL cholesterol. Low levels of HDL cholesterol are related to impaired synthesis of Apo A-I. Common medical diseases associated with lipoprotein disorders include diabetes mellitus. Familial high-density lipoprotein deficiency and Tangiers disease Familial HDL deficiency is a rare autosomal dominant disorder with very low HDL levels (!20 mg/dL). hepatosplenomegaly. Lecithin. nephrotic syndrome. and is associated with premature CHD. hypothyroidism. It is associated with mutations in the Apo A-I gene. cholesterol acyl transferase deficiency LCAT is involved in the esterification of free cholesterol acquired by HDL cholesterol to cholesterol esters (see the section on HDL metabolism.’’ This rare condition is usually not associated with premature CHD. and in most situations they are associated with increased CHD risk. Tangier disease is an autosomal codominant disorder in which heterozygotes have half the normal concentrations of HDL cholesterol. Mutations of LCAT in the homozygous state lead to extremely low levels of HDL cholesterol and severe corneal opacities. and thus foam cells accumulate in the body. uremia. increased catabolism of HDL.

atypical antipsychotics (clozapine. oral isotretoin. and creatinine. lymphoma. systemic lupus. Less common medical diseases associated with hyperlipidemia include glycogen storage disease. Therefore the National Cholesterol Education Panel Adult Treatment Guidelines III proposes to set differential goals of lipid-lowering therapy based upon the degree of risk for having a CHD event. hepatoma. and have been included in Table 3. . time and reimbursement issues may limit this option. Studies have shown that primary care physicians can be trained to perform effective dietary counseling for lipid lowering. anorexia nervosa. protoporphrins. thyroid-stimulating hormone (TSH). The moderate high risk and extremely high risk categories have been added as therapeutic options in a subsequent white paper [2]. glucocorticoids. The goals of therapy and the threshold for initiating drug therapy are given in Table 3. lipodystrophies. oral contraceptives. however. cortisol.HYPERLIPIDEMIA 1043 liver disease. liver function tests. For patients who have triglycerides greater than 200 mg/dl before drug therapy. Step 4: set treatment goals Although the association between atherogenic lipoproteins and cardiovascular risk is continuous and graded. growth hormone. primary biliary cirrhosis. blood urea nitrogen (BUN). monoclonal gammopathies. including glucose. a nonHDL goal (total cholesterol-HDL) is used as a secondary goal once the LDL goal has been reached [1]. and cigarette smoking cessation. Patients who have the greatest risk of heart attack or stroke get the most benefit from treatment using NNT and cost-effectiveness as the measures of benefit. growth hormone deficiency. olanzapine). Cigarette smoking and physical inactivity are associated with modest depression of HDL cholesterol values. physical activity. and multiple myeloma. Additional tests such as complete blood count (CBC). Cushing’s syndrome. Werner’s syndrome. It is therefore suggested that before initiating drug therapy. acromegaly. serum protein electrophoresis. and fetal protein are only recommended when clinical suspicion warrants a concern. acute intermittent porphyria. The article ‘‘Lifestyle and Coronary Heart Disease Prevention’’ by Pinto and colleagues elsewhere in this issue discusses these therapeutic lifestyle behavioral interventions in the primary care physician office setting in more detail. Step 5: initiate therapy based upon goal of treatment Most lipid disorders respond to lifestyle changes such as diet. protease inhibitors. all patients have a complete physical examination and blood tests. and cyclosporine. Medications associated with dyslipidemia include alcohol. The primary goal is based upon the LDL cholesterol. the absolute benefits of treatment as measured by number needed to treat (NNT) and cost-effectiveness are not.

 Polyunsaturated fats can range up to 10% of total calories.  Intakes of trans fatty acids should be kept low. Additional concerns about drug interaction make these treatments potentially dangerous if added to standard lipid-lowering drug Box 1. use of soy protein as a replacement of animal fats. nhlbi.gov/) for patients carries patient education handouts regarding hyperlipidemia. A detailed discussion of recommended dietary changes is beyond the scope of this article.  Carbohydrates should be limited to 60% of total calories. Carbohydrates should be eaten mainly in the form of whole grains. Should a patient fail to respond to these dietary and physical activity recommendations. Lung. Red yeast rice has been shown to lower cholesterol. and safety of herbal and botanical supplements for the lowering of cholesterol and the prevention of heart disease. and limited to 50% of total calories in persons who have elevated triglycerides or low HDL cholesterol. standardization is an issue. and Blood Institute (NHLBI) interactive Web site (http://www. Herbal and botanical dietary supplements Despite widespread promotion. The National Heart.nih.  A diet to maximize LDL lowering should limit intake of saturated fats to less than 7% of calories. A brief description of dietary recommendations as outlined in the ATP III guidelines is given below in Box 1. ATP III dietary recommendations  Weight loss through reduced caloric intake and increased physical activity should be encouraged in all overweight people. and diets high in n-3 fatty acids in the form of fatty fish or vegetable oils as therapeutic options.  Less than 200 mg per day of cholesterol should be consumed. . Data are inconsistent (but generally negative) in US trials for garlic and guggilipid. efficacy. use of plant stanols/sterols (2 g/day). additional therapeutic options recommended by the ATP III guidelines include use of dietary sources of viscous fiber (5–10 g/day).  Prevention of weight gain should be emphasized for all persons. there are few data on the product standardization. however.  Intake of monosaturated fats can range up to 20% of total calories.1044 EATON Referral of patients to a qualified nutrition health professional for medical nutrition therapy may be helpful for many patients. as well as many recipes and tips for dietary change.

Statins lower the risk of major coronary events by 30% in secondary prevention trials and 34% in primary prevention trials [4]. and therefore. the cost of the medication. fibrate. cholesterol absorption inhibitor. and drug-drug and drug-nutrient interactions. the degree of LDL or non-HDL lowering desired to reach therapeutic goals. and those over age 65 or under. triggers the synthesis of LDL receptors (Apo B100 receptors) by the hepatocyte. fish oil CTEP inhibitord not yet available Comments Abbreviations: BAS. herbal. niacin Fibrate Niacin Niacin Secondary drugs CAI. BAS. These LDL receptors migrate to the coated pits on liver cells. Table 6 matches the recommended drug therapy with type of lipid disorder: Statinsdhydroxymethyl glutaric acid-Co-reductase inhibitors Statins are the only class of lipid-lowering drugs that have been demonstrated in randomized clinical trials to improve total mortality as well as prevent recurrent cardiovascular events. and thus a careful medication history. which through a negative feedback loop. leading to lowering of the plasma LDL cholesterol. Table 7 lists the degree of LDL lowering one would expect for each Table 6 Matching of class of drug therapy and type of lipid disorder Type of lipid disorder LDL dominant Mixed Triglyceride dominant Isolate low HDL Lp(a) excess Drug of choice StatindHMGco-reductase inhibitor Statin. CAI. This is true for men and women. Drug therapy When deciding on the choice of drug therapy and the dose of the medication for lipid disorder treatment. Statins vary in the degree of lowering of LDL cholesterol for a given dose. are the drugs of choice for LDL dominant lipid disorders or mixed lipid disorder in which LDL lowering is the goal of therapy. Statins lower LDL cholesterol by inhibiting the rate-limiting step of cholesterol synthesis. These include the efficacy of the therapy for a given lipid disorder. and supplemental medications. several factors need to be weighed. This leads to a decrease in the intracellular pool of free cholesterol in the hepatic cells. should be taken on each patient before initiation of drug therapy. . including over-the-counter. niacin Type IIIdfibrate drug of choice Niacin.HYPERLIPIDEMIA 1045 therapy. possible side effects. bile acid sequestrant. and absorb excess plasma LDL cholesterol via these upregulated LDL receptors.

various antifungals. diabetes mellitus. The risk of severe myopathy is low. macrolide antibiotics. perioperative period. small body frame and frailty. macrolide antibiotics. In over 12 million patients taking statins. The most common side-effects of statin therapy are headache. amiodorone. nausea. Risk factors for statin-associated myopathy are: age greater than 80. as well as the other pertinent pharmacologic characteristics of each drug. or large doses of grapefruit juice (O1 quart). nefazodone. verapamil. The following recommendations should reduce the incidence and severity of statin-related myopathy. cyclosporine. and cytochrome P-450 inhibitors. 3A5 None Rosuvastatin Hydrophilic Limited 2C9 None dose of statins. multiple medications. including cyclosporine. niacin. HIV protease inhibitors. Absolute contraindications to statin therapy are active or chronic liver disease. chronic renal insufficiency.1046 EATON Table 7 Average dose response of statin medications Statin Atorvastatin Dose 10 20 40 80 20 40 10 20 40 80 10 20 40 80 5 10 20 40 80 5 10 20 40 mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg LDL lowering 37% 43% 49% 55% 21% 27% 21% 29% 37% 55% 20% 24% 29% 33% 23% 27% 32% 37% 42% 38% 43% 48% 53% Solubility Lipophilic Cytochrome 450 metabolism 3A4 Effect of food on absorption None Fluvastatin Lovastatin Lipophilic Lipophilic 2C9 3A4 Neglibile Increased Pravastatin Hydrophilic Decreased Simvastatin Lipophilic 3A4. concomitant use of: fibrates. Severe myopathy. azole antifungals. Relative contraindications include concomitant use of certain drugs. sleep disturbance. alanine aminotransferase . there have only been 772 cases of rhabdomyolysis and 72 deaths. defined as creatine kinase (CK) elevations over 10 times the upper limit of normal is found in about 1 in 1000 cases. Concomitant use with fibrates and niacin should be done with caution because of increased risk of liver toxicity and myopathy. Measure baseline CK. and alcohol abuse [14]. and muscle aches.

and aspartate aminotransferase (AST). Patients who have chronic liver disease and who need statin therapy should abstain from alcohol and use hydrophilic statins such as pravastatin or rosuvastatin. statins have been implicated in development of peripheral neuropathy. This upregulation of the number of LDL receptors leads to the enhanced clearance of LDL cholesterol from the systemic circulation. CAI impair the absorption of dietary and biliary cholesterol at the brush border of the intestine by blocking the Niemann-Pick C1 receptor. you can restart statins at half the previous dose or the equivalent dose of a different statin (half the original dose). discontinue the statin. and monitor CK and symptoms. begin statin therapy if the benefits outweigh the risks. If symptoms of muscle soreness. If the CK is normal. If the CK is greater than 10 times ULN. monitor symptoms and CK weekly. so the dose should be adjusted for patients who have chronic renal insufficiency. There is no evidence that statins worsen cognitive function or increase the risk of cancer.HYPERLIPIDEMIA 1047 (ALT). and . Animal data suggest that statins are associated with adverse fetal outcomes. If the CK is still 3 to 10 times ULN. or brown urine develop. If the CK is 3 to 10 times ULN. Some investigators have tried administering coenzyme Q with a significant reduction in muscle symptoms. Atorvastatin and fluvastatin are not metabolized by the kidneys and do not need to be dose-adjusted. Statin drugs are rated as category X for pregnancy. If the CK level is less than 3 times upper limit of normal (ULN). Ezetimbe is the first drug available in this class. whereas use with niacin or fibrates is contraindicated in patients who have chronic liver disease. tenderness or pain. stop statin therapy and recheck the CK. evaluate for thyroid myopathy with a TSH and check for drug or herbal interactions. then lower the dose or change to a less potent statin. If the CK level is 3 to 10 times ULN. Many statins are renally excreted. and this risk appears to increase after 2 years of use. proceed with initiating medications. Use of ezetimibe or bile acid sequestrant as a first-line drug or in combination with statins is preferred. decrease exercise. and their use should be discontinued before conception. but limited human data suggest that statins are not major teratogens. but other statins do. then discontinue the statin and niacin or fibric acid if on combination therapy. which in turn promotes the synthesis of the LDL receptors. If the CK levels decrease to less than 3 times ULN. but the patient still has muscle aches and soreness. Analysis of the Food and Drug Administration (FDA) surveillance database suggests a possible link between central nervous system (CNS) and limb abnormalities with exposure to lipophilic statins in the first trimester. If the CK progresses to 10 times ULN. This lowering of the cholesterol content of bile in the enterohepatic circulation leads to decreased intrahepatic cholesterol. however. but clinical trials of this treatment have not been reported. Cholesterol absorption inhibitors Cholesterol absorption inhibitors (CAI) are a new class of lipid-lowering drugs.

but rather 1 hour prior or 3 hours later. Bile acid sequestrants Bile acid sequestrants (BAS) have been used safely for over 40 years in the treatment of hyperlipidemia. and thus (similar to ezetimide) lower the intrahepatic cholesterol levels. when nonHDL cholesterol lowering is an important goal of therapy. Bile acids are synergistic in their LDL lowering with statins. depending on the dose used. Expected LDL lowering is 15% to 30%. women of child-bearing age. BAS are effective in patients who have mild-to-moderate elevations of LDL cholesterol. They can be used in children and in adults. leading via the negative feedback loop to enhanced LDL receptor synthesis. whereby an additional 9% to 14% LDL lowering has been found. and a reasonable choice for mixed lipid disorders and diabetic dyslipidemia. Ezetimide is relatively safe. but they may make triglyceride dominant lipid disorders and Type III dyslipidemia worse. patients who have liver disease. The mechanism for the lowering of triglycerides appears to be related to activation of the peroxisome proliferation-activated receptors (PPARS). and may interfere with other drugs. Ezetimide is synergistic with other lipid-lowering agents. Side effects of gastrointestinal (GI) distress and constipation limit compliance. with limited evidence of myopathy or liver dysfunction to date. decreased synthesis of VLDL by the liver. and during pregnancy. and averages 18% LDL lowering in clinical trials. Gemfibrozil increases the level of ezetimide with unclear clinical implications. These agents bind bile acids in the terminal ileum. preventing the reabsorption of biliary cholesterol. and downregulation of Apo C-III gene.1048 EATON thus to lower plasma cholesterol levels. cholesytramine as a resin. Fenofibrate has been used safely in combination with ezetimide. and other medications should not be taken concomitantly. Available drugs include cholestelam in a pill form. and in combination therapy when higher doses of statins lead to increased side effects or risk of toxicity when moderate LDL lowering is the goal. so that a multivitamin is recommended. and raise HDL cholesterol on average 15% to 25%. No clinical trials have been performed that have evaluated the benefits of this modest LDL lowering on the primary or secondary prevention of cardiovascular disease. including statins. and colestipol as a resin or pill. BAS are particularly helpful for children. enhanced clearance of VLDL by the stimulation of LPL. Fibrates lower triglycerides by 35% to 50%. They are therefore the drug of choice for triglyceride dominant lipid disorder. Ezetimide is available in a 10 mg dose. The HDL raising associated with fibrates is associated with the direct . Fibrates Fibrates or fibric acid derivatives have been demonstrated in clinical trials to reduce cardiovascular events. and are associated with significant triglyceride lowering and non-HDL cholesterol lowering. BAS decrease the absorption of fat-soluble vitamins.

and isolated low HDL cholesterol. are used. liver toxicity. Niacin can induce insulin resistance and thus worsen glucose control. and reduce triglycerides 25% to 30% in a dose-response manner. There is a theoretical reduction in the risk of myopathy if fluvastatin or pravastatin. Frequent side effects limit the tolerability of niacin despite its therapeutic efficacy. Most GI side effects can be diminished if the patient takes the medicine with meals. Short-acting preparation or crystalline niacin is given three times daily. Liver toxicity is relatively common. increased transfer of Apo A-I from HDL to VLDL. and increased in 2-week intervals by 100 mg per dose until 500 mg three times a day is reached. and raises HDL by delaying clearance and reducing the transfer of cholesterol from HDL to VLDL.5 g per day to 3 g per day. and reduced inhibition by lower levels of VLDL on the hepatic synthesis of Apo A-I. gallstones. and therefore monitoring prothrombin time and using a lower dose may be indicated. Most side effects dissipate Fibrates in combination with statins and with cyclosporine are associated with greater risk of myopathy. Niacin is reported to lower Lp(a) by 35% by an unknown mechanism [16]. Gemfibrozil and fenofibrate are fibrates that are available in the United States. which are not extensively metabolized by the cytochrome P-450 3A4 system (CYP3A4 system). whereas sustained-release preparations can be given once daily. so it should not be used cyclosporine-treated patients. as well as induce hyperuricemia and gout. Niacin has been shown to lower LDL cholesterol 10% to 25%. Effective doses for niacin range from 1. The risk of myopathy appears less when fenofibrate is used in combination with statins. nausea. and therefore lower doses should be used with patients who have renal insufficiency. Fenofibrate is potentially nephrotoxic when used in combination with cyclosporine. and periodic liver function testing is recommended. Fenofibrate is metabolized by the kidneys. Gemfibrozil potentiates the action of warfarin. and gradually increases the dose. Use of a sustainedrelease preparation reduced flushing significantly.HYPERLIPIDEMIA 1049 stimulation of the synthesis of Apo A-I and A-II. Niacin Niacin or nicotinic acid is available in several formulations and is effective in treating patients who have LDL dominant lipid disorders. Potential side effects include such GI side-effects as dyspepsia. 80 mg baby aspirin given 30 minutes before each dose will decrease the flushing side-effects. but this is uncertain [15]. mixed lipid disorder. bloating and cramping. Niacin . and myopathy. The side effects and tolerability can be improved with careful slow titration of crystalline niacin and pretreatment with aspirin. raise HDL cholesterol 15% to 35%. Absolute contraindications include severe renal disease and severe liver disease. Nicotinic acid inhibits the hepatic production of VLDL and therefore LDL cholesterol. and thus liver function testing is required for the duration of therapy. Onset of hepatic injury is not predictable. It is recommended that crystalline niacin be started at 100 mg three times a day with meals.

5 g per day. and exercise. and torcetrapib increased the size of the HDL particles and Apo A-I levels. In general. and with pharmacologic therapy. This results in significant LDL lowering of 53% to 74% [11]. the benefits of CETP inhibition on reducing coronary heart disease need to be shown before this class of drugs can uniformly recommended. it is not yet available for clinical use. torcetrapib. If the secondary goal of non-HDL is not reached because of elevated triglycerides. raised HDL cholesterol 61%. Although this class of drugs looks promising. usually beginning with a statin. Torcetrapib also lowered LDL cholesterol and Apo B levels. Drug-resistant patients The ATP III guidelines recommend concomitant treatment in high-risk individuals with lifestyle interventions such as weight loss in overweight patients. and increased LDL size. Cholesterol ester transfer protein inhibitors High levels of CETP are correlated with low levels of HDL cholesterol. (See ‘‘Traditional and Emerging Risk Factors for Cardiovascular Disease’’ by this author elsewhere in this issue). Fish oils (omega-3-fatty acids. Simvastatin plus ezetimide is associated with 45% to 60% LDL lowering. then ezetimide or niacin can be used. HDL2 was raised more than HDL3. then combination therapy with fibrate or the addition of fish oils can be tried. and some experts have suggested routine screening of homocysteine levels once a stable dose of niacin is attained [17]. All Apo B containing lipoproteins including Lp(a) are removed. 1 to 4 g daily are associated with 20% to 30% triglyceride lowering and. statins plus fibrates are associated with a risk of myopathy defined as CK greater than 3 times ULN of 1/100. Use of pravastatin or fluvastatin with fenofibrate appears to be the safest combination that will improve the lipid profile and reduce the risk of serious myopathy. Combination therapy is recommended. raised HDL cholesterol 46% and. or heterozygous hypercholesterolemia that fails to respond to combination .1050 EATON can also raise homocysteine levels. Recently. diet. Ultimately. Low-density lipoprotein apheresis LDL apheresis refers to the removal of circulating LDL cholesterol by plasma exchange and affinity chromatography. in combination with atorvastatin. Indications for this therapy are limited to severe hypercholesterolemia such as homozygous familial hypercholesterolemia. If the patient has not reached the LDL goal. have been shown to reduce recurrent CHD in European trials [20]. HDL raising appears to be beneficial in concert with LDL lowering in statin plus niacin trials [19]. at 1. Niacin plus lovastatin is associated with 30% to 42% lowering of LDL cholesterol. Many patients do not reach their LDL goals with this approach. a randomized controlled trial [18] has demonstrated that the CETP inhibitor.

HYPERLIPIDEMIA 1051 dietary plus pharmacologic interventions. transient ischemic attack (TIA). low HDL cholesterol. and elevated triglycerides caused. obesity. Although promising. Primary and secondary prevention trials with statins have demonstrated a reduction in cardiovascular events in both groups. This logic can be extended to coronary artery bypass graft (CABG) carotid surgery. and dyslipidemia of greater than 100 mg/dL should be treated to lower levels. many type 2 diabetics have mixed lipid disorders with elevated LDL cholesterol. Many patients will need combination therapy. Three of the five patients responded with significant and prolonged reduction of total and LDL-cholesterol [21]. Hospital setting Lipid-lowering drug therapy should be started during acute hospitalization or at discharge for acute myocardial infarction (MI) and acute coronary syndromes. Dietary changes focusing on limiting carbohydrates and preventing weight gain are most important. in large part. which is common in diabetics who have modest elevations in liver function test (1. Addition of fenofibrate. or fish oils may be needed to treat hypertriglyceridemia and the elevated non-HDL cholesterol. stroke. Gene therapy A potential future therapy is gene therapy. is not a contraindication to statin use . five patients’ hepatocytes were transfected after partial wedge resection.5–2. by insulin resistance. even for diabetics whose initial LDL cholesterol was less than 116 mg/ dL. but rather follow-up lipid levels at 6 to 12 weeks will determine subsequent dosing or withdrawal of therapy [23]. and the transfected hepatocyctes were reinfused via the portal vein. have been abandoned as therapy in refractory patients in favor of LDL apheresis. In LDL receptor deficiency. Liver transplantation and partial ideal bypass surgery. safety concerns have limited this approach. and peripheral vascular surgery. insertion of VLDL receptor via adenovirus vector leads to long-term reduction in cholesterol and the prevention of atherosclerosis.5 Â ULN). As previously discussed. and dietary indiscretion. Focus on glycemic control with HgA1c less than 8 g/dL and initiation of a statin to reach LDL goal is the initial step. Fatty infiltration of the liver. The Heart Protection Study (HPS) [24] demonstrated a significant risk reduction. but such an approach has not been tested in effectiveness trials. niacin. although used in the past. Diabetic dyslipidemia Diabetes mellitus is considered a ‘‘CHD equivalent’’ risk for cardiovascular disease according to ATP III guidelines. Both the safety and effectiveness of this approach have been demonstrated [22]. In limited human trials. Concerns about inaccurate lipid levels caused by acute phase response should not prevent initiating statin therapy. ezetimibe.

however. simvastatin. particularly with protease inhibitors (PI). Fenofibrate or gemfibrozil can be used for triglyceride elevations. few clinical trials demonstrating the benefits of lipid lowering therapy in the primary and secondary prevention of cardiovascular disease have included the elderly. saquinavir. Prospective Study of Pravastatin in the . Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) [27]. Cyclosporine inhibits the CYP3A4 cytochrome pathway. Pravastatin and fluvastatin. cyclosporine. nelfinavir. aprenavir) are metabolized by the CYP3A4 cytochrome pathway. and by the use of immunosuppressive therapy with corticosteroids. Pravastatin and fluvastatin therefore appear to be the drugs of choice for patients who have LDL dominant disorders and are on cyclosporine therapy. which can raise total and LDL cholesterol and triglycerides. but combination therapy of gemfibrozil and statins in HIV patients requiring PI therapy is contraindicated because of this increased risk of myopathy. to increased risk of myopathy. Human immunodeficiency virus Dyslipidemia is associated with the treatment of HIV infection. HPS [28].1052 EATON or lipid medications. In fact. Protease inhibitors (indinavir. Data from the Scandinavian Simvastatin Survival Study (4S) [25]. thus statins metabolized through this pathway may lead to increased statin levels and. however. so that the population attributable risk also increases. which are not metabolized by this pathway. therefore. diabetes mellitus and hypertension). An alternative approach is to change the HIV therapy to a regimen not using PI therapy. Hyperlipidemia is common in transplant patients. suggesting that lipid-lowering therapy is beneficial. Cholesterol and Recurrent Events (CARE) trial [26]. Elderly The benefits of lipid lowering in the elderly have been questioned. or sirolimus. ritonavir. careful monitoring of the liver function test and avoidance of niacin is recommended in such situations. Until recently. and allograft loss in renal and cardiac transplantation and hyperlipidemia appears to play an important role in this process. caused by both the underlying diseases leading to transplantation (ie. Renal and cardiac transplant patients Cardiovascular disease is a major cause of premature death. are the statins of choice in HIV patients who need PI and LDL lowering. and therefore an increased risk of myopathy in statins that are metabolized through this pathway (lovastatin. Epidemiologic studies show a reduced relative risk for total cholesterol as the population ages. Patients on treatment for HIV with PI are also at increased risk of cardiovascular disease and myocardial infarction. the absolute risk of CHD increases. many patients’ liver function tests will improve if lipid lowering therapy is initiated. Therefore treatment of the lipid disorder is indicated. which leads to increased statin levels. atorvastatin).

Biology of atherosclerosis. and Cardiovascular Health Study (CHS) [30] all show benefit in the elderly. and then twice yearly thereafter. and pravastatin. [3] Broedl UC. Clearly patients who have malnutrition and limited life expectancies should not be treated with low fat diets and aggressive lipid-lowering therapy. [4] Gould AL. [5] Brewer HB. p. 110:227–39. 02–5125. These factors should be taken into account when prescribing statin therapy in the elderly. and rosuvstatin are not metabolized by the CYP3A4 system. Cholesterol reduction yields clinical benefit: impact of statin trials. Bethesda (MD): US Department of Health and Human Services. National Institutes of Health. [2] Grundy SM. Santanello NC.350:1491–4. The ATP III cholesterol guidelines recommend re-evaluating patients every 6 weeks until the patient is at goal. et al. Primer in preventive cardiology. Given these facts. the risks versus the benefits of lipid-lowering therapy in the elderly should be weighed carefully. et al. American Heart Associaton. et al. Luepker RV. In: Pearson TA. Rossouw JE. Merz NB. evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). NIH Publication No. Criqui MH. Patient education.HYPERLIPIDEMIA 1053 Elderly at Risk (PROSPER) [29]. editors. [6] St. and pharmacotherapy and periodic office visits will help with adherence. Final report. Geiss HC.97:946–52. Thus the preponderance of the evidence now suggests that lipid-lowering therapy is indicated in the elderly. 2002. Studies have shown that between 15% and 50% of subjects started on lipid-lowering agents will continue to take this medication after 1 year [31–33]. Atorvastatin and fluvastatin do not require adjustment for renal insufficiency. including patients up to age 82 in the PROSPER study. Cleeman JI. J Gen Intern Med 2003.18:190–5. Clair RW. Treatment of the elderly needs to take into account the fact that many elderly patients have varying degrees of renal insufficiency and are taking multiple medications that may lead to drug-drug interactions. Parhofer KG. and that both the cost of medication and the complexity of the drug regimens may lead to medication adherence issues. 17. . fluvastatin. Circulation 2004. Circulation 1998. References [1] Third report of the National Cholesterol Education Program (NCEP) expert panel on detection. concomitant focus on diet and lifestyle. Comparison of current guidelines for primary prevention of coronary heart disease: risk assessment and lipid-lowering therapy. which is usually attained with four visits. 1994. National Heart Lung and Blood Institute. discussion of the pros and cons of taking the medication. N Engl J Med 2004. Step 6: Follow-up with the patient Medication and lifestyle adherence is a significant problem in clinical practice. Implications of recent clinical trials for the National Cholesterol Program Adult Treatment Panel III guidelines. Increasing HDL cholesterol levels.

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