Hyperlipidemia Charles B. Eaton, MD, MS a,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 accumu- lated that conclusively demonstrates a link between lipoprotein disorders and atherosclerosis, and its clinical manifestations of myocardial infarc- tion, 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 sum- marized current recommendations for the management of hyperlipidemia [1,2]. Although other organizations differ slightly in risk estimates and rec- ommendations, 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 lipopro- teins (total cholesterol, low-density lipoprotein [LDL] cholesterol, non- high–density lipoprotein [HDL] cholesterol, total cholesterol/HDL ratio) and coronary risk. A meta-analysis of 38 primary and secondary preven- tion trials [4] found that for every 10% reduction in total cholesterol, cor- onary 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 metabo- lism, 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: [email protected]0095-4543/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2005.09.002 primarycare.theclinics.com Prim Care Clin Office Pract 32 (2005) 1027–1055
Transcript
Prim Care Clin Office Pract
32 (2005) 1027–1055
Hyperlipidemia
Charles B. Eaton, MD, MSa,b,*aMemorial Hospital of Rhode Island, 111 Brewster Street, 2nd Floor,
Pawtucket, RI 02860, USAbBrown Medical School, Box G, Providence, RI 02912, USA
Over the past 20 years, a large body of scientific evidence has accumu-lated that conclusively demonstrates a link between lipoprotein disordersand atherosclerosis, and its clinical manifestations of myocardial infarc-tion, stroke, and sudden cardiac death. In addition, marked elevationsof triglycerides are associated with acute pancreatitis. The third reportof the Expert Panel on Detection, Evaluation and Treatment in Adults(Adult Treatment Panel [ATP] III) and its update in July 2004 have sum-marized current recommendations for the management of hyperlipidemia[1,2]. Although other organizations differ slightly in risk estimates and rec-ommendations, they are generally similar for lipid management and drawfrom the same epidemiologic and clinical trial evidence [3]. This evidencesupports that there is a graded relationship between atherogenic lipopro-teins (total cholesterol, low-density lipoprotein [LDL] cholesterol, non-high–density lipoprotein [HDL] cholesterol, total cholesterol/HDL ratio)and coronary risk. A meta-analysis of 38 primary and secondary preven-tion trials [4] found that for every 10% reduction in total cholesterol, cor-onary heart disease mortality decreases by 15% and total mortalitydecreases by 11%. This article draws heavily on the ATP III [1] guidelinesand their update in July 2004 [2] in making recommendations regardingtherapy.
Hyperlipidemia represents several different disorders of lipid metabo-lism, related to increased production or delayed degradation of atherogeniclipoprotein particles, or decreased synthesis or increased degradationof 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
lipoproteins are associated with serious health consequences, including in-creased risk of premature atherosclerosis or pancreatitis, depending on thetype of lipid disorder. Lipoproteins are essential in transportation of freefatty acids and cholesterol throughout the body to be used for four majorbiological functions: energy use, lipid deposition, steroid hormone produc-tion, and bile acid formation. The major lipoproteins include: chylomi-crons, chylomicron remnants, very low-density lipoprotein (VLDL)cholesterol, VLDL remnants, intermediate-density lipoprotein (IDL) cho-lesterol, 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 par-ticle. The different apolipoproteins serve as cofactors for enzymes and li-gands for receptors important in the metabolism of lipoproteins. Diet,genetic, and other metabolic factors contribute to the metabolism ofeach lipoprotein.
Lipoprotein metabolism and pathophysiology
A brief review of the major lipoprotein particles and endogenous andexogenous lipid metabolism is helpful in understanding the differentlipid disorders, their relationship to atherosclerosis, and present day and fu-ture therapies. There are five major lipoproteins, each with a differentfunction.
Chylomicrons
Chylomicrons are very large particles that carry small amounts of dietarycholesterol and large amounts of triglycerides. They have a density of greaterthan 0.95 g/ml. Most patients who have triglyceride levels greater than 500mg/dL have elevated chylomicrons. Chylomicrons and chylomicron rem-nants are the primary lipoproteins associated with absorption of fatsand cholesterol from the diet. In intestinal cells, free fatty acids combinewith glycerol to make triglycerides, and are packaged with small amountsof cholesterol esters to form micelles of chylomicron and seven carrierapolipoproteins. The main apoproteins found in chylomicrons are apopro-tein B-48 (Apo B-48), with smaller amounts of Apo C-II, and Apo E asthe chylomicrons enter the circulation. Apo B-48 does not bind to theLDL (Apo B-100) receptor in the liver, and therefore allows chylomicronsto 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 coreof chylomicrons, gradually reducing their size and converting chylomi-crons to chylomicron remnants and releasing free fatty acids. The releasedfree fatty acids are used for energy or stored in adipose tissue. The chylo-micron remnants are cleared by the liver by an Apo E receptor.
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Chylomicron remnants surface constituents also include Apo A-I, A-II, A-IV, C-I, and C-III, besides the Apo B-48, Apo E and Apo C-II alreadymentioned.
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 areassociated with Apo B-100, C-I, C-II, C-III, and E. They have a density of0.95 to 1.006 g/ml. VLDL is synthesized by the liver, and its synthesis is un-der the control of microsomal triglyceride transfer protein in the endoplas-mic reticulum. VLDL is the major carrier of triglyceride in the endogenouspathway of lipoprotein metabolism. Triglyceride levels between 150 mg/dLand 500 mg/dL are generally associated with elevated levels of VLDL par-ticles. Similar to chylomicrons, the triglyceride core of VLDL particles isacted upon by LPL, and is hydrolyzed, releasing free fatty acids (FFA)and generating VLDL remnants and IDL as successive triglyceride is re-leased. LPL activity is augmented by Apo-C-II ligand on VLDL and in-hibited by Apo-C-III ligand. VLDL remnants are generally either clearedby the Apo B/E receptor of the liver or remodeled by hepatic lipase intoLDL cholesterol.
Intermediate-density lipoproteins
IDL carry both triglyceride and cholesterol esters, and are associated withApo B-100, C-III, and E. IDL are usually cleared rapidly from the blood, suchthat under fasting conditions, little IDL is measurable in plasma. They havea density of 1.006 to 1.019 g/mL; however, under certain conditions, such asa defective Apo-E receptor as found in Type III dyslipidemia or in other met-abolic states (ie, hypothyroidism), excess IDL is found in plasma. Typicallylipid profiles associated with this condition give values of total cholesterol ofaround 300 mg/dL, and similar values for triglycerides.
Low-density lipoproteins
LDL are the main atherogenic lipoproteins. They have a density of 1.019to 1.063 g/ml. They carry a core of cholesterol esters and small amounts oftriglyceride, and are associated with Apo B-100, which is the ligand for bind-ing to the LDL receptor on the liver. Plasma LDL cholesterol levels are un-der the control of LDL receptor activity found predominantly in the liver,which is under negative feedback via intracellular cholesterol levels. Thisfeedback loop is exploited by statin medications, which, by blocking therate-limiting step of cholesterol synthesisdhydroxymethyl glutaric acid(HMG)-CoA-reductase, leads to decreased intracellular cholesterol levels,resulting in increased m-RNA transcription and increased synthesis of
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LDL receptors. The increased LDL receptor activity (Apo B-100 receptor)leads to increased removal of LDL from the plasma.
LDL can be internalized by the liver and other tissues for useful biologicfunctions. Internalization at the liver leads to bile acid formation, which isimportant in the digestion of cholesterol and fat. Nonhepatic LDL choles-terol is used for steroid production and cell membrane synthesis. LDL cho-lesterol can also enter macrophages and be taken up by the arterial wallthrough unregulated scavenger receptors. Under conditions of inflammationor oxidant stress, this process leads to atherosclerosis and its clinical sequelaeof coronary artery disease, stroke, peripheral vascular disease, aneurysmformation, and sudden death.
High-density lipoproteins
HDL are antiatherogenic lipoproteins. They have the highest density oflipoproteins, between 1.063 and 1.21 g/ml. HDL is synthesized in the liverand intestinal cells, and consists of small, lipid poor particles containingApo A-I and phospholipids. The nascent HDL particles interact withVLDL remnants, chylomicron remnants, and intracellular pools that allowfor the efflux of cholesterol and triglyceride. HDL is involved in two impor-tant processes: reverse cholesterol transport under the control of cholesterolefflux regulatory protein (CERP) sometimes called ABCA-1; and lecithin,cholesterol acyl transferase (LCAT) (Fig. 1) [5]. Lipid-poor Apo A-1 inter-acts with ABCA1, removing excess cholesterol from intracellular cholesterolpools in macrophages and in the liver. The resultant pre b-HDL is convertedinto mature a-HDL by LCAT. HDL-C is returned to liver through transferof cholesterol ester by cholesterol ester transfer protein (CETP) to VLDL orselective uptake of cholesterol by hepatic SR-B1 pathway. The net effect isto remove excess cholesterol from cells, which explains most of HDL’s anti-atherogenic effects.
Lipoproteins in atherosclerosis
Abnormal lipoprotein metabolism is a major etiologic factor in athero-sclerosis. Over 70% of patients who have premature coronary heart disease(CHD) have lipid disorders. Atherosclerosis can be induced by abnormallipoproteins in animal models in absence of any other risk factors. It hasbeen proposed that subendothelial retention of LDL cholesterol is the ini-tiating factor for atherosclerosis [6]. A charged interaction between Apo Bcontaining lipoproteins with proteoglycans in the extracellular matrix of ar-terial wall has been implicated in this process. Small, dense LDL particlespenetrate the endothelial cell barrier of the arterial wall more frequentlythan large, fluffy LDL particles. The LDL cholesterol, with a prolonged res-idence time caused by this charged interaction, allows for lipid peroxidationof the phospholipids and unesterified cholesterol. This process leads to
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macrophage infiltration, and the uptake of LDL cholesterol bymacrophages through unregulated scavenger receptors. Uptake by these re-ceptors is associated with modification of LDL cholesterol through oxidiza-tion, glycosylation, or glycooxidation. The incorporation of modified LDL
Fig. 1. Model of reverse cholesterol transport mediated by high-density lipoprotein (HDL), re-
sulting in an increase in the plasma HDL level. 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). Apolipoprotein A-1
(ApoA-1) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette
transporter 1 (ABCA1), is secreted into plasma as lipid poor apolipoprotein A-1 (yellow arrow).
In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-1 interacts with
HDL is converted into mature-a-HDL by lecithin-cholesterol acyltransferase (LCAT, black
arrow). HDL cholesterol is returned to the liver through two pathways selective uptake of cho-
lesterol by the hepatic scavenger receptor, class B, type I (SR-B1, blue arrow), or the transfer of
cholesterol ester by cholesterol ester transfer protein (CETP) to VLDL-LDL, with uptake by
the liver through the LDL receptor (red arrows). 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.
Long-term increases in the HDL level and reductions in the LDL level result from the partial
inhibition of CETP. FC denotes free cholesterol, PL phospholipids, LRP LDL-related protein,
and LPL lipoprotein lipase. (From Brewer HB. Increasing HDL cholesterol levels. New Engl J
Med 2004;350:1491–4; with permission.)
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cholesterol by tissue macrophages leads to the formation of foam cells.These cholesterol-rich macrophages can rupture, releasing intracellular en-zymes and oxygen free radicals, and leading to further vessel wall andendothelial cell damage. Oxidatively modified LDL cholesterol also pro-motes proinflammatory and immune changes through cytokine releaseand antibody production that lead to further promotion of atherosclerosis.Oxidized LDL cholesterol disrupts endothelial cell surfaces and impairs therelease of nitrous oxide, a major mediator of endothelium-dependentvasodilation. This damage to the endothelium leads to increased plateletadherence and the release of cytokines that stimulate smooth muscleproliferation. This process of foam cell formation, platelet accumulation,and smooth muscle accumulation leads to further acceleration of the ath-erosclerotic plaque formation. Oxidized LDL cholesterol can also increaseplatelet aggregation and induce thromboxane release, which contributesto vasoconstriction and intravascular thrombosis. Another potential path-way through which LDL cholesterol may promote atherosclerosis is bythe upregulation of the angiotensin receptors on smooth muscle cells andlecithin-like oxidized LDL receptor-1 (LOX-1) on the endothelial cells. Al-though not as extensively studied as LDL cholesterol, IDL cholesterol,VLDL remnants, and Lp(a) are taken up by macrophages and causefoam cell formation. They also impair endothelium-dependent function,and are associated in epidemiologic studies with increased risk of coronaryheart disease.
HDL cholesterol, in contrast to LDL, IDL, and VLDL cholesterol, isantiatherogenic. The most important mechanism for this effect is reversecholesterol transport, leading to the efflux of cholesterol from subendothe-lial space in atherosclerotic plaques already described. Other contributingfactors to this antiatherogenic effect include the role of HDL cholesterolin maintaining endothelial cell function, protection against thrombosis viainhibition of calcium-induced procoagulant activity by Apo A-I, and themaintenance of normal blood viscosity through its effect on red cell deform-ability. In addition, HDL has antioxidant properties, and its associated en-zymes, such as paraoxonase, help with this effect.
Hypertriglyceridemia in pancreatitis
Although the most important aspect of hyperlipidemia in clinical medi-cine is its association with premature coronary heart disease and stroke, se-vere hypertriglyceridemia is associated with pancreatitis. The exactpathophysiologic mechanism for this association is unclear; however, withmarkedly elevated triglyceride levels, greater than 750 mg/dL, chylomicronsand chylomicron remnants are present in the systemic circulation. It isthought that these large triglyceride rich particles cause an efflux of waterfrom the pancreatic cells into the capillaries, carrying these large lipophilicparticles and leading to dehydration of the pancreatic cells. Intracellular
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levels of amylase and lipase enzymes then rise to toxic levels, leading to au-todigestion of the pancreatic cells, and therefore pancreatitis. Apo C-III de-ficiency is associated with very high levels of triglycerides, and placespatients at high risk of acute and recurrent pancreatitis.
Approach to the patient
Management of patients who have lipid disorders can be broken downinto six steps:
Step 1: Determine whether a patient has a lipid disorder that needs eval-uation and treatment.
Step 2: Define the lipid disorder.Step 3: Rule out secondary causes.Step 4: Set treatment goals.Step 5: Initiate therapy based upon goal of treatment.Step 6: Follow-up with the patient.
Step 1: determine whether a patient has a lipid disorder that needsevaluation and treatment
This is done by obtaining a fasting lipid profile and then determining therisk factors for cardiovascular disease. A simple clinical rule for adult pa-tients who have total cholesterol greater than 200 mg/dL, or HDL cholesterolless than 40 mg/dL, or triglycerides greater than 200 mg/dL, or TC/HDLratio greater than 5.0 defines most patients who have a lipid disorder inneed of evaluation and treatment. A fasting lipid profile is the preferredmethod to evaluate lipoprotein disorders, because triglycerides valueswill vary significantly based upon fasting-fed status. Recent evidence, how-ever, has demonstrated that nonfasting specimens using total cholesterol,non-HDL cholesterol, and total cholesterol/HDL ratio prospectively pre-dict CHD risk as well as fasting lipid profiles [7,8].
Some adult patients may have lipid disorders than need treatment withtotal cholesterol less than 200 mg/dL. These patients usually have modestelevations of several risk factors that collectively lead to an increased riskof a cardiovascular event, or have isolated low HDL cholesterol. These pa-tients can be identified by evaluating their risk of having a cardiovascularevent through use of the Framingham risk equation, which has been shownto be reasonably valid in a multitude of racial and ethnic cohorts. Tables 1and 2 can be used to calculate the 10-year risk of hard CHD [1]. The LDLgoals for each risk category are given in Table 3.
For children, the lipid values that define hyperlipidemia are generallylower than for adults. These are presented in Table 4 [9]. Selective screeningfor children is recommended for those who have a family history of prema-ture coronary heart disease or a familial lipid disorder. In addition, children
Table 1
Framingham 10-year CHD risk for men
Age (years) Points
20–34 �9
35–39 �4
40–44 0
45–49 3
50–54 6
55–59 8
60–64 10
65–69 11
70–74 12
75–79 13
Age
Total cholesterol (mg/dL) 20–39 40–49 50–59 60–69 70–79
!160 0 0 0 0 0
160–199 4 3 2 1 0
200–239 7 5 3 1 0
240–279 9 6 4 2 1
R280 11 8 5 3 1
Age
20–39 40–49 50–59 60–69 70–79
Nonsmoker 0 0 0 0 0
Smoker 8 5 3 1 1
HDL cholesterol mg/dL Points
R60 �1
50–59 0
40–59 1
!40 2
Systolic blood pressure, mm Hg Untreated Treated
!120 0 0
120–129 0 1
130–139 1 2
140–159 1 2
R160 2 3
Point total 10-year risk (%) Point total 10-year risk (%)
0 1 10 6
1 1 11 8
2 1 12 10
3 1 13 12
4 1 14 16
5 2 15 20
6 2 16 25
7 3 R17 R30
8 4
9 5
These risk estimates for the development of coronary heart disease do not account for all impor-
tant cardiovascular risk factors. Not included are diabetes mellitus (which is considered a CHD equiv-
alent), family history of CHD, alcohol intake, and the serum C-reactive protein concentration.
The point total is determined in each category and the 10-year risk determined in the bottom row.
Adapted from Adult Treatment Panel III. Available at: http://www.nhlbi.nih.gov/.
who have childhood obesity, hypertension, diabetes mellitus, or pancreatitis,and those who smoke cigarettes should be screened.
Step 2: define the lipid disorder
Although familial forms of hyperlipidemia are particularly important forfamily physicians treating entire families (and should lead to family screen-ing, including children), they represent less than 20% of all dyslipidemias.Most lipid disorders are polygenic, and represent metabolic derangement in-duced by unhealthy diets, obesity, and sedentary lifestyles. Although theFrederickson classification of lipid disorder has historical relevance, it car-ries little clinical utility because it has no prognostic value, and thereforehas been abandoned by most clinicians. A simple schema of defining the lipidprofile on the basis of the relevant lipid profile abnormality is the mostuseful: LDL-dominant lipid disorders, Lp(a) excess, triglyceride-dominant
Table 3
ATP III-recommended goals of therapy and LDL level for initiation of drug therapy
Goals include recommendations made in July 2004 white paper under therapeutic options,
based upon clinical trials released since May 2001 release of ATP III.
Abbreviations: ACS, acute coronary syndrome; DM, diabetes mellitus.a ATP III risk factors for CHD: cigarette smoking, hypertension, low HDL cholesterol
(!40 mg/dL), family history of premature CHD (in first-degree relatives !55 in men, !65
in women), age (men R45 years, women R55 years). HDL O60 is a negative risk factor; its
presence removes one risk from the total.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.
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lipid disorders, mixed lipid disorders, isolated low HDL cholesterol, andatherogenic dyslipidemia. These lipid disorders are described below:
Low-density lipoprotein-dominant lipid disordersLDL-dominant lipid disorders are defined as those in patients whose
LDL cholesterol is greater than their ATP III risk stratification goal andwho have a normal HDL cholesterol (HDL cholesterol O40 mg/dL inmen, and O50 mg/dL in women) and normal triglycerides (!150 mg/dL).The LDL cholesterol goals are less than 70 mg/dL, less than 100 mg/dL,less than 130 mg/dL, or less than 160 mg/dL, depending upon the cardiovas-cular disease risk category (see Table 3).
Most patients who have LDL-dominant lipid disorder have polygenic hy-percholesterolemia with no familial association, or demonstrable geneticphenotypes. Many of these polygenic hypercholesterolemic patients are atleast partially responsive to dietary therapy, but many require lipid-loweringdrug therapy as well. Some patients who have LDL-dominant lipid disor-ders have genetic lipid disorders that are associated with significantly elevatedLDL cholesterol, usually less than 190 mg/dL. These LDL dominant geneticlipid disorders include familial hypercholesterolemia and familial defectiveApo B-100.
Familial hypercholesterolemiaFamilial hypercholesterolemia (FH) is a relatively common autosomal
dominant disorder that affects approximately 1 in 500 individuals. Totalcholesterol is usually above 300 mg/dL for heterozygotes and 500 mg/dL
Table 4
Lipid values for children and adolescents aged 2–19
to 1000 mg/dL for homozygotes. Mutations to the LDL receptor locus havebeen discovered affecting four phenotypes: class 1, in which synthesis of thereceptor is defective; class 2, in which intracellular transport of LDL recep-tor protein from the endoplasmic reticulum to the golgi apparatus isblocked; class 3, in which the LDL receptor binding protein is defective;and class 4, in which the internalization of the receptor-LDL complexis defective, so that the LDL receptors do not cluster in the coated pits.Different mutations of the LDL receptor gene confer different effectson LDL cholesterol levels and CHD risk. The diagnostic criteria for hetero-zygous FH can be categorized as definite and probable, and are outlined inTable 5 [10]. Many FH patients have tendon xanthomas on themselves or infamily members, but these physical findings are not pathognomic of FH, be-cause sitosterolemia and cerebrotendinous xanthomatosis can also presentwith tendon xanthomas.
Familial defective apoprotein B100
Familial defective Apo B100 is an autosomal dominant disorder that isclinically identical to FH; however, here the defect is in the Apo B-100 ligandon the LDL particle and not on the receptor itself. This defect is found inabout 8 of 10,000 patients. FH generally requires a multiple drug regimen,and for more severe cases, LDL apheresis is recommended [11].
SitosterolemiaSitosterolemia is a relatively rare autosomal disorder in which plant ste-
rols are absorbed in large quantities because of a defect in intestinal absorp-tion of sterols. This disorder may be associated with elevated levels ofcholesterol or normal cholesterol levels. These plant sterols accumulate in
Table 5
Cholesterol criteria for heterozygous FH
Age in
years
First-degree
relative
Second-degree
relativeaThird-degree
relativebGeneral
populationc
!18 220 (155) 230 (165) 240 (170) 270 (200)
20 240 (170) 250 (180) 260 (185) 290 (220)
30 270 (190) 280 (200) 290 (210) 340 (240)
R40 290 (205) 300 (215) 310 (225) 360 (260)
Total cholesterol and LDL cholesterol (in parentheses) levels expected to diagnose hetero-
zygous familial hypercholesterolemia with 98% specificity by demonstrating high cholesterol
levels in family members. Units are mg/dL; divided by 38.5 to convert to mmol/L.a Second-degree relatives refers to aunts, uncles, grandparents, nieces, or nephews.b Third-degree relatives refers to first cousins, siblings, or siblings of grandparents.c General population column refers to levels that need to be seen in a patient with no evalu-
able family members.
Data from Williams R, Hunt SC, Schumacher MC, et al. Diagnosing heterozygous familial
hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol
1993;72:171–6.
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plasma and tendons, leading to tendon xanthomas. The disorder’s typicalonset is in childhood, and it is treated with ezetimide and diets low in dietarysterols.
Lipoprotein(a) excessLp(a), previously known as pre-sinking beta-lipoprotein, is the most com-
mon lipid disorder in families that have a family member who has prematurecoronary artery disease [12]. Lp(a) has a density of 1.045 to 1.080 g/ml. Val-ues greater than 30 mg/dL are associated with increased risk of prematureatherosclerosis. Lp(a) is a specialized form of LDL linked by disulfide bridgeto Apo(a), and is modulated by LCAT. Apo(a) is protein chain composed offive doughnut-shaped domains called kringles. The fourth kringle is verysimilar in structure to plasminogen, and therefore Lp(a) competes with plas-minogen for plasminogen receptors, fibrin, and fibrinogen. The net effect ofthis homology is that Lp(a) leads to impaired fibrinolysis and thrombolysis.This plasminogen-like effect, coupled with the LDL component of this lipo-protein-inducing foam cell formation through a high-affinity macrophagereceptor, leads to Lp(a)’s dual atherogenic and thrombogenic pathologic se-quelae. Elevated Lp(a) is usually associated with markedly elevated totalcholesterol levels greater than 300 mg/dL, or familial combined hyperlipid-emia. Less frequently, it is an isolated lipid disorder, but usually in the set-ting of strong family history of premature CHD.
Triglyceride-dominant lipid disordersThe association of elevated triglycerides and risk of CHD is not fully un-
derstood. This is because triglyceride elevations can be associated witha range of other atherogenic lipoprotein abnormalities (remnant lipopro-teins; small, dense LDL cholesterol; B-VLDL; IDL) and low levels ofHDL cholesterol, so that in some clinical situations, elevated triglyceridesare associated with an elevated risk of coronary heart disease, and in otherclinical situations they are not. The ATP III guidelines classified serum tri-glycerides by coronary risk in adults as follows: normal, less than 150 mg/dl;borderline high, 150 to 199 mg/dL; high, 200 to 499 mg/dL; and very high,500 mg/dL or more. Many patients who have elevated triglycerides alsohave metabolic syndrome [13] (three of the five following characteristics:trance obesity, glucose intolerance, prehypertension, elevated triglycerides,and low HDL cholesterol) or an atherogenic lipoprotein profile that mayadd to the atherogenic potential of elevated triglycerides. The metaboliccontrol of triglycerides is under the control of lipoprotein lipase, hepatic tri-glyceride lipase, and cholesterol ester transfer protein, as discussed in the lipo-proteinsmetabolism section above. Overproduction or derangement in any ofthese catabolic pathways can lead to elevated triglycerides.
Many patients who have hypertriglyceridemia have acquired disorderssuch as obesity, diabetes mellitus, renal disease, or hypothyroidism, or areundergoing hormone therapy, or taking tamoxifen or immunosuppressive
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drugs that contribute to this lipid disorder. Thus, ruling out secondarycausesdstep 3dis especially important in evaluating patients who have hy-pertriglyceridemia or mixed lipid disorders. Familial or genetic lipid disor-der associated with hypertriglyceridemia is discussed briefly below.
Familial hypertriglyceridemiaFamilial hypertriglyceridemia is an autosomal dominant disorder that is
associated with moderate elevations of serum triglycerides in the 200 to 500mg/dL range. It is often associated with obesity, insulin resistance, hypergly-cemia, hypertension, and elevated uric acid. Patients who have familial hy-pertriglyceridemia and who are heterozygous for lipoprotein lipase geneticmutations typically have low HDL cholesterol levels as well. The phenotypicexpression of these genetic defects may vary, depending upon concomitantexposures such as weight gain, insulin resistance, exogenous estrogens,and so on.
Severe hypertriglyceridemiaPatients who have triglycerides greater than 500 mg/dL have severe hy-
pertriglyceridemia and are at increased risk of pancreatitis. In many studies,such patients are at no increased risk of CHD. The explanation for this factis that such large elevations in triglyceride levels are associated with largetriglyceride-rich particles that are unable to enter the subendothelial spaceand thus initiate the atherosclerotic process. Clinically, patients who havesevere hypertriglyceridemia present with eruptive xanthomas and hepato-splenomegaly, and may develop severe symptoms with elevations greaterthan 1000 mg/dl. Clinical manifestations of this significant elevation, or‘‘chylomicronemia syndrome,’’ include memory loss, abdominal pain/pan-creatitis, and lipemia retinalis. Patients who have severe hypertriglyceride-mia may have partial LPL deficiency or Apo C-II deficiency.
Mixed lipid disorderMost patients who have elevated triglycerides also have elevations in ei-
ther LDL cholesterol or low HDL cholesterol and elevation of other ApoB100-carrying lipoproteins. Thus a mixed lipid disorder is the most frequentlyfound in most primary care practices. Patients who have elevated LDLcholesterol and low HDL cholesterol are also classified as having a mixedlipid disorder. Four common subgroups of mixed lipid disorders that de-serve special comment are familial combined hyperlipidemia, hyperapoli-poproteinemia (Apo B excess syndrome), Type III or broad banddyslipidemia, and atherogenic dyslipidemia.
Familial combined hyperlipidemiaFamilial combined hyperlipidemia (FCH) is found in about 1% to 2% of
the population, and manifests as either elevated total cholesterol,
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triglycerides, or both in various family members. It usually does not mani-fest itself until adulthood, and is exacerbated by diets high in fats and simplesugars and by weight gain. It is associated with an increased risk of CHD.
Apoprotein B excess or hyperapolipoproteinemiaThis is a relatively common disorder that may be a variant of familial
combined hyperlipidemia. Subjects who have this disorder have normalLDL cholesterol levels (!160 mg/dL) but have elevated Apo B levels(O135 mg/dL) and decreased LDL/Apo B ratio less than 1.2, suggestiveof LDL phenotype, type B or increased small, dense LDL cholesterol.
Type III dyslipidemia or broad band dyslipoproteinemiaType III dyslipidemia or broad band dyslipidemia is a familial lipid dis-
order associated with elevations of beta-migrating VLDL (b-VLDL) choles-terol. b-VLDL represents a combination of chylomicron remnants andpartially degraded VLDL that is triglyceride-poor and cholesterol-rich.This lipid disorder is the result of a defective Apo E receptor. Clinically,it is usually associated with both elevated triglycerides (O300 mg/dL) andelevated total cholesterol (O300 mg/dL), and many, but not all, patientshave physical examination findings of a corneal arcus, tuboeruptive xantho-mas over pressure points, or palmar xanthomata. It is associated with ab-normal (E2/E2) phenotype of the Apo E receptor. It usually manifestsitself in the fourth decade, or after significant weight gain or onset of the di-abetes mellitus or hypothyroidism. Diagnosis can be confirmed by evaluat-ing VLDL/TG ratio of greater than 0.35 using ultracentrification methods.Although this lipid disorder is relatively rare, making this diagnosis impor-tant clinically because it responds very well to fibrates and niacin, but is rel-atively resistant to statins, cholesterol absorption inhibitors, and bile acidsequestrates.
Atherogenic dyslipidemiaThis is a nonfamilial lipid disorder characterized by elevated triglycerides
(O200 mg/dL) and reduced HDL cholesterol (!40 mg/dl), and is associatedwith small, dense LDL. Usually lipid abnormalities in this triad are onlymarginally abnormal. Nuclear magnetic resonance (NMR) spectroscopyand other sophisticated techniques are required to determine LDL particlesize and density with precision. Small, dense LDL cholesterol is almost uni-formly found in patients who have high triglycerides, low HDL cholesterol,and elements of metabolic syndrome (truncal obesity, insulin resistance,type 2 diabetes).
Most patients who have low HDL cholesterol (!40 mg/dL) have anotherconcomitant lipid abnormality, usually elevated triglycerides. Occasionally,
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isolated low levels of HDL cholesterol are found, and in most situationsthey are associated with increased CHD risk. Low levels of HDL cholesterolare related to impaired synthesis of Apo A-I, increased catabolism of HDL,or enzymatic abnormalities associated with HDL metabolism (see the sec-tion on HDL metabolism, above). Some patients who have healthy lifestyleshave very low total cholesterol values, concomitantly low HDL cholesterol,and normal triglyceride levels. These patients do not appear to be at in-creased risk of CHD, and can be difficult to differentiate from those with ge-netic causes of isolated low HDL cholesterol who have an increased risk. Bymeasuring Apo A-I levels (O90 mg/dL), such low-risk patients can be dif-ferentiated from those who have familial hypoalphalipoproteinemia.
Familial hypoalphalipoproteinemiaFamilial hypoalphalipoproteinemia is an autosomal dominant disorder
with HDL cholesterol levels below the tenth percentile (30–40 mg/dL). Itis associated with mutations in the Apo A-I gene, and with increased riskof premature CHD.
Familial high-density lipoprotein deficiency and Tangiers diseaseFamilial HDL deficiency is a rare autosomal dominant disorder with very
low HDL levels (!20 mg/dL), and is associated with premature CHD.Tangier disease is an autosomal codominant disorder in which heterozy-gotes have half the normal concentrations of HDL cholesterol. The HDL-mediated efflux of intracellular cholesterol is impaired, and thus foam cellsaccumulate in the body, leading to large orange tonsils, hepatosplenome-galy, and peripheral neuropathy. Both familial HDL deficiency and Tangi-ers disease involve mutations of ATP-binding cassette recorder gene (ABC1)that encodes CERP.
Lecithin, cholesterol acyl transferase deficiencyLCAT is involved in the esterification of free cholesterol acquired by
HDL cholesterol to cholesterol esters (see the section on HDL metabolism,above). Mutations of LCAT in the homozygous state lead to extremely lowlevels of HDL cholesterol and severe corneal opacities, so-called ‘‘fish eyesyndrome.’’ This rare condition is usually not associated with prematureCHD, but can be associated with premature CHD with some mutations.
Step 3: rule out secondary causes
A variety of clinical diseases and medications can cause secondary hyper-lipidemia. These should be searched for before lipid-lowering drug therapyis initiated. Common medical diseases associated with lipoprotein disordersinclude diabetes mellitus, hypothyroidism, uremia, nephrotic syndrome, and
1043HYPERLIPIDEMIA
liver disease. Less common medical diseases associated with hyperlipidemiainclude glycogen storage disease, lipodystrophies, Cushing’s syndrome,growth hormone deficiency, acromegaly, anorexia nervosa, Werner’s syn-drome, acute intermittent porphyria, primary biliary cirrhosis, hepatoma,systemic lupus,monoclonalgammopathies, lymphoma,andmultiplemyeloma.It is therefore suggested that before initiating drug therapy, all patientshave a complete physical examination and blood tests, including glucose,thyroid-stimulating hormone (TSH), liver function tests, blood urea nitro-gen (BUN), and creatinine. Additional tests such as complete blood count(CBC), serum protein electrophoresis, cortisol, growth hormone, protopor-phrins, and fetal protein are only recommended when clinical suspicionwarrants a concern.
Medications associated with dyslipidemia include alcohol, oral contra-ceptives, glucocorticoids, protease inhibitors, atypical antipsychotics (cloza-pine, olanzapine), oral isotretoin, and cyclosporine. Cigarette smoking andphysical inactivity are associated with modest depression of HDL choles-terol values.
Step 4: set treatment goals
Although the association between atherogenic lipoproteins and cardio-vascular risk is continuous and graded, the absolute benefits of treatmentas measured by number needed to treat (NNT) and cost-effectiveness arenot. Patients who have the greatest risk of heart attack or stroke get themost benefit from treatment using NNT and cost-effectiveness as the mea-sures of benefit. Therefore the National Cholesterol Education Panel AdultTreatment Guidelines III proposes to set differential goals of lipid-loweringtherapy based upon the degree of risk for having a CHD event. The goals oftherapy and the threshold for initiating drug therapy are given in Table 3.The primary goal is based upon the LDL cholesterol. For patients whohave triglycerides greater than 200 mg/dl before drug therapy, a non-HDL goal (total cholesterol-HDL) is used as a secondary goal once theLDL goal has been reached [1]. The moderate high risk and extremelyhigh risk categories have been added as therapeutic options in a subsequentwhite paper [2], and have been included in Table 3.
Step 5: initiate therapy based upon goal of treatment
Most lipid disorders respond to lifestyle changes such as diet, physical ac-tivity, and cigarette smoking cessation. The article ‘‘Lifestyle and CoronaryHeart Disease Prevention’’ by Pinto and colleagues elsewhere in this issuediscusses these therapeutic lifestyle behavioral interventions in the primarycare physician office setting in more detail. Studies have shown that primarycare physicians can be trained to perform effective dietary counseling for lipidlowering; however, time and reimbursement issues may limit this option.
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Referral of patients to a qualified nutrition health professional for medicalnutrition therapy may be helpful for many patients. The National Heart,Lung, and Blood Institute (NHLBI) interactive Web site (http://www.nhlbi.nih.gov/) for patients carries patient education handouts regardinghyperlipidemia, as well as many recipes and tips for dietary change.
A detailed discussion of recommended dietary changes is beyond thescope of this article. A brief description of dietary recommendations as out-lined in the ATP III guidelines is given below in Box 1.
Should a patient fail to respond to these dietary and physical activity rec-ommendations, additional therapeutic options recommended by the ATPIII guidelines include use of dietary sources of viscous fiber (5–10 g/day),use of plant stanols/sterols (2 g/day), use of soy protein as a replacementof animal fats, and diets high in n-3 fatty acids in the form of fatty fish orvegetable oils as therapeutic options.
Herbal and botanical dietary supplementsDespite widespread promotion, there are few data on the product stan-
dardization, efficacy, and safety of herbal and botanical supplements forthe lowering of cholesterol and the prevention of heart disease. Red yeastrice has been shown to lower cholesterol; however, standardization is an is-sue. Data are inconsistent (but generally negative) in US trials for garlic andguggilipid. Additional concerns about drug interaction make these treat-ments potentially dangerous if added to standard lipid-lowering drug
Box 1. ATP III dietary recommendations
� Weight loss through reduced caloric intake and increasedphysical activity should be encouraged in all overweightpeople.
� Prevention of weight gain should be emphasized for allpersons.
� A diet to maximize LDL lowering should limit intake ofsaturated fats to less than 7% of calories.
� Intakes of trans fatty acids should be kept low.� Less than 200 mg per day of cholesterol should be consumed.� Intake of monosaturated fats can range up to 20% of total
calories.� Polyunsaturated fats can range up to 10% of total calories.� Carbohydrates should be limited to 60% of total calories, and
limited to 50% of total calories in persons who have elevatedtriglycerides or low HDL cholesterol. Carbohydrates should beeaten mainly in the form of whole grains.
therapy, and thus a careful medication history, including over-the-counter,herbal, and supplemental medications, should be taken on each patient be-fore initiation of drug therapy.
Drug therapyWhen deciding on the choice of drug therapy and the dose of the medi-
cation for lipid disorder treatment, several factors need to be weighed. Theseinclude the efficacy of the therapy for a given lipid disorder, the degree ofLDL or non-HDL lowering desired to reach therapeutic goals, the cost ofthe medication, possible side effects, and drug-drug and drug-nutrient inter-actions. Table 6 matches the recommended drug therapy with type of lipiddisorder:
Statinsdhydroxymethyl glutaric acid-Co-reductase inhibitorsStatins are the only class of lipid-lowering drugs that have been demon-
strated in randomized clinical trials to improve total mortality as well as pre-vent recurrent cardiovascular events, and therefore, are the drugs of choicefor LDL dominant lipid disorders or mixed lipid disorder in which LDLlowering is the goal of therapy. Statins lower the risk of major coronaryevents by 30% in secondary prevention trials and 34% in primary preven-tion trials [4]. This is true for men and women, and those over age 65 or un-der. Statins lower LDL cholesterol by inhibiting the rate-limiting step ofcholesterol synthesis. This leads to a decrease in the intracellular pool offree cholesterol in the hepatic cells, which through a negative feedbackloop, triggers the synthesis of LDL receptors (Apo B100 receptors) by the he-patocyte. These LDL receptors migrate to the coated pits on liver cells, andabsorb excess plasma LDL cholesterol via these upregulated LDL receptors,leading to lowering of the plasma LDL cholesterol.
Statins vary in the degree of lowering of LDL cholesterol for a givendose. 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 Drug of choice Secondary drugs Comments
LDL dominant StatindHMG-
co-reductase inhibitor
CAI, BAS, niacin
Mixed Statin, fibrate, niacin Type IIIdfibrate
drug of choice
Triglyceride dominant Fibrate Niacin, fish oil
Isolate low HDL Niacin CTEP inhibitord
not yet available
Lp(a) excess Niacin
Abbreviations: BAS, bile acid sequestrant; CAI, cholesterol absorption inhibitor.
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dose of statins, as well as the other pertinent pharmacologic characteristicsof each drug.
Absolute contraindications to statin therapy are active or chronic liverdisease. Relative contraindications include concomitant use of certain drugs,including cyclosporine, macrolide antibiotics, various antifungals, and cyto-chrome P-450 inhibitors. Concomitant use with fibrates and niacin shouldbe done with caution because of increased risk of liver toxicity and myopa-thy. The most common side-effects of statin therapy are headache, nausea,sleep disturbance, and muscle aches. The risk of severe myopathy is low. Se-vere myopathy, defined as creatine kinase (CK) elevations over 10 times theupper limit of normal is found in about 1 in 1000 cases. In over 12 millionpatients taking statins, there have only been 772 cases of rhabdomyolysisand 72 deaths. Risk factors for statin-associated myopathy are: age greaterthan 80; small body frame and frailty; chronic renal insufficiency; diabetesmellitus; multiple medications; perioperative period; concomitant use of: fi-brates, niacin, cyclosporine, azole antifungals, macrolide antibiotics, HIVprotease inhibitors, nefazodone, verapamil, amiodorone, or large doses ofgrapefruit juice (O1 quart); and alcohol abuse [14].
The following recommendations should reduce the incidence and severityof statin-related myopathy. Measure baseline CK, alanine aminotransferase
(ALT), and aspartate aminotransferase (AST). If the CK level is less than 3times upper limit of normal (ULN), proceed with initiating medications. Ifthe CK level is 3 to 10 times ULN, decrease exercise, evaluate for thyroidmyopathy with a TSH and check for drug or herbal interactions. If theCK is still 3 to 10 times ULN, begin statin therapy if the benefits outweighthe risks. If symptoms of muscle soreness, tenderness or pain, or brownurine develop, stop statin therapy and recheck the CK. If the CK is greaterthan 10 times ULN, then discontinue the statin and niacin or fibric acid if oncombination therapy. If the CK is 3 to 10 times ULN, monitor symptomsand CK weekly. If the CK progresses to 10 times ULN, discontinue the sta-tin. If the CK levels decrease to less than 3 times ULN, you can restart sta-tins at half the previous dose or the equivalent dose of a different statin (halfthe original dose), and monitor CK and symptoms. If the CK is normal, butthe patient still has muscle aches and soreness, then lower the dose or changeto a less potent statin. Some investigators have tried administering coen-zyme Q with a significant reduction in muscle symptoms, but clinical trialsof this treatment have not been reported.
Statin drugs are rated as category X for pregnancy, and their use shouldbe discontinued before conception. Animal data suggest that statins are as-sociated with adverse fetal outcomes, but limited human data suggest thatstatins are not major teratogens. Analysis of the Food and Drug Adminis-tration (FDA) surveillance database suggests a possible link between centralnervous system (CNS) and limb abnormalities with exposure to lipophilicstatins in the first trimester. There is no evidence that statins worsen cogni-tive function or increase the risk of cancer; however, statins have been im-plicated in development of peripheral neuropathy, and this risk appears toincrease after 2 years of use. Many statins are renally excreted, so thedose should be adjusted for patients who have chronic renal insufficiency.Atorvastatin and fluvastatin are not metabolized by the kidneys and donot need to be dose-adjusted, but other statins do. Patients who have chronicliver disease and who need statin therapy should abstain from alcohol anduse hydrophilic statins such as pravastatin or rosuvastatin. Use of ezeti-mibe or bile acid sequestrant as a first-line drug or in combination withstatins is preferred, whereas use with niacin or fibrates is contraindicatedin patients who have chronic liver disease.
Cholesterol absorption inhibitorsCholesterol absorption inhibitors (CAI) are a new class of lipid-lowering
drugs. Ezetimbe is the first drug available in this class. CAI impair the ab-sorption of dietary and biliary cholesterol at the brush border of the intes-tine by blocking the Niemann-Pick C1 receptor. This lowering of thecholesterol content of bile in the enterohepatic circulation leads to decreasedintrahepatic cholesterol, which in turn promotes the synthesis of the LDLreceptors. This upregulation of the number of LDL receptors leads to theenhanced clearance of LDL cholesterol from the systemic circulation, and
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thus to lower plasma cholesterol levels. Ezetimide is available in a 10 mgdose, and averages 18% LDL lowering in clinical trials. No clinical trialshave been performed that have evaluated the benefits of this modest LDLlowering on the primary or secondary prevention of cardiovascular disease.Ezetimide is synergistic with other lipid-lowering agents, including statins,whereby an additional 9% to 14% LDL lowering has been found. Ezetimideis relatively safe, with limited evidence of myopathy or liver dysfunction todate. Gemfibrozil increases the level of ezetimide with unclear clinical impli-cations. Fenofibrate has been used safely in combination with ezetimide.
Bile acid sequestrantsBile acid sequestrants (BAS) have been used safely for over 40 years in
the treatment of hyperlipidemia. They can be used in children and in adults,and during pregnancy. BAS are effective in patients who have mild-to-mod-erate elevations of LDL cholesterol, but they may make triglyceride domi-nant lipid disorders and Type III dyslipidemia worse. These agents bindbile acids in the terminal ileum, preventing the reabsorption of biliary cho-lesterol, and thus (similar to ezetimide) lower the intrahepatic cholesterollevels, leading via the negative feedback loop to enhanced LDL receptorsynthesis. Bile acids are synergistic in their LDL lowering with statins.Available drugs include cholestelam in a pill form, cholesytramine as a resin,and colestipol as a resin or pill. Expected LDL lowering is 15% to 30%, de-pending on the dose used. Side effects of gastrointestinal (GI) distress andconstipation limit compliance. BAS decrease the absorption of fat-solublevitamins, and may interfere with other drugs, so that a multivitamin is rec-ommended, and other medications should not be taken concomitantly, butrather 1 hour prior or 3 hours later. BAS are particularly helpful for chil-dren, women of child-bearing age, patients who have liver disease, and incombination therapy when higher doses of statins lead to increased side ef-fects or risk of toxicity when moderate LDL lowering is the goal.
FibratesFibrates or fibric acid derivatives have been demonstrated in clinical trials
to reduce cardiovascular events, and are associated with significant triglyc-eride lowering and non-HDL cholesterol lowering. They are therefore thedrug of choice for triglyceride dominant lipid disorder, and a reasonablechoice for mixed lipid disorders and diabetic dyslipidemia, when non-HDL cholesterol lowering is an important goal of therapy. Fibrates lowertriglycerides by 35% to 50%, and raise HDL cholesterol on average 15%to 25%. The mechanism for the lowering of triglycerides appears to be re-lated to activation of the peroxisome proliferation-activated receptors(PPARS), decreased synthesis of VLDL by the liver, enhanced clearanceof VLDL by the stimulation of LPL, and downregulation of Apo C-IIIgene. The HDL raising associated with fibrates is associated with the direct
1049HYPERLIPIDEMIA
stimulation of the synthesis of Apo A-I and A-II, increased transfer of ApoA-I from HDL to VLDL, and reduced inhibition by lower levels of VLDLon the hepatic synthesis of Apo A-I. Gemfibrozil and fenofibrate are fibratesthat are available in the United States. Absolute contraindications includesevere renal disease and severe liver disease. Potential side effects includesuch GI side-effects as dyspepsia, nausea, bloating and cramping, gallstones,liver toxicity, and myopathy. Most GI side effects can be diminished if thepatient takes the medicine with meals, and gradually increases the dose.Most side effects dissipate
Fibrates in combination with statins and with cyclosporine are associatedwith greater risk of myopathy. The risk of myopathy appears less when fe-nofibrate is used in combination with statins. There is a theoretical reduc-tion in the risk of myopathy if fluvastatin or pravastatin, which are notextensively metabolized by the cytochrome P-450 3A4 system (CYP3A4 sys-tem), are used, but this is uncertain [15]. Gemfibrozil potentiates the actionof warfarin, and therefore monitoring prothrombin time and using a lowerdose may be indicated. Fenofibrate is metabolized by the kidneys, and there-fore lower doses should be used with patients who have renal insufficiency.Fenofibrate is potentially nephrotoxic when used in combination with cyclo-sporine, so it should not be used cyclosporine-treated patients.
NiacinNiacin or nicotinic acid is available in several formulations and is effec-
tive in treating patients who have LDL dominant lipid disorders, mixed lipiddisorder, and isolated low HDL cholesterol. Niacin has been shown to lowerLDL cholesterol 10% to 25%, raise HDL cholesterol 15% to 35%, and re-duce triglycerides 25% to 30% in a dose-response manner. Nicotinic acidinhibits the hepatic production of VLDL and therefore LDL cholesterol,and raises HDL by delaying clearance and reducing the transfer of choles-terol from HDL to VLDL. Niacin is reported to lower Lp(a) by 35% byan unknown mechanism [16]. Effective doses for niacin range from 1.5 gper day to 3 g per day. Short-acting preparation or crystalline niacin is giventhree times daily, whereas sustained-release preparations can be given oncedaily. Frequent side effects limit the tolerability of niacin despite its thera-peutic efficacy. The side effects and tolerability can be improved with carefulslow titration of crystalline niacin and pretreatment with aspirin. It is rec-ommended that crystalline niacin be started at 100 mg three times a daywith meals, and increased in 2-week intervals by 100 mg per dose until500 mg three times a day is reached. 80 mg baby aspirin given 30 minutesbefore each dose will decrease the flushing side-effects. Use of a sustained-release preparation reduced flushing significantly. Liver toxicity is relativelycommon, and periodic liver function testing is recommended. Onset of he-patic injury is not predictable, and thus liver function testing is requiredfor the duration of therapy. Niacin can induce insulin resistance and thusworsen glucose control, as well as induce hyperuricemia and gout. Niacin
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can also raise homocysteine levels, and some experts have suggested routinescreening of homocysteine levels once a stable dose of niacin is attained [17].(See ‘‘Traditional and Emerging Risk Factors for Cardiovascular Disease’’by this author elsewhere in this issue).
Cholesterol ester transfer protein inhibitorsHigh levels of CETP are correlated with low levels of HDL cholesterol.
Recently, a randomized controlled trial [18] has demonstrated that theCETP inhibitor, torcetrapib, raised HDL cholesterol 46% and, in combina-tion with atorvastatin, raised HDL cholesterol 61%. HDL2 was raised morethan HDL3, and torcetrapib increased the size of the HDL particles andApo A-I levels. Torcetrapib also lowered LDL cholesterol and Apo B levels,and increased LDL size. Although this class of drugs looks promising, it isnot yet available for clinical use. HDL raising appears to be beneficial inconcert with LDL lowering in statin plus niacin trials [19]. Ultimately, thebenefits of CETP inhibition on reducing coronary heart disease need to beshown before this class of drugs can uniformly recommended.
Drug-resistant patientsThe ATP III guidelines recommend concomitant treatment in high-risk
individuals with lifestyle interventions such as weight loss in overweight pa-tients, diet, and exercise; and with pharmacologic therapy, usually beginningwith a statin. Many patients do not reach their LDL goals with this ap-proach. Combination therapy is recommended. If the patient has notreached the LDL goal, then ezetimide or niacin can be used. Niacin plus lov-astatin is associated with 30% to 42% lowering of LDL cholesterol. Simvas-tatin plus ezetimide is associated with 45% to 60% LDL lowering. If thesecondary goal of non-HDL is not reached because of elevated triglycerides,then combination therapy with fibrate or the addition of fish oils can betried. Use of pravastatin or fluvastatin with fenofibrate appears to be thesafest combination that will improve the lipid profile and reduce the riskof serious myopathy. In general, statins plus fibrates are associated witha risk of myopathy defined as CK greater than 3 times ULN of 1/100.Fish oils (omega-3-fatty acids, 1 to 4 g daily are associated with 20% to30% triglyceride lowering and, at 1.5 g per day, have been shown to reducerecurrent CHD in European trials [20].
Low-density lipoprotein apheresisLDL apheresis refers to the removal of circulating LDL cholesterol by
plasma exchange and affinity chromatography. All Apo B containing lipo-proteins including Lp(a) are removed. This results in significant LDL lower-ing of 53% to 74% [11]. Indications for this therapy are limited to severehypercholesterolemia such as homozygous familial hypercholesterolemia,or heterozygous hypercholesterolemia that fails to respond to combination
1051HYPERLIPIDEMIA
dietary plus pharmacologic interventions. Liver transplantation and partialideal bypass surgery, although used in the past, have been abandoned astherapy in refractory patients in favor of LDL apheresis.
Gene therapyA potential future therapy is gene therapy. In LDL receptor deficiency,
insertion of VLDL receptor via adenovirus vector leads to long-term reduc-tion in cholesterol and the prevention of atherosclerosis. In limited humantrials, five patients’ hepatocytes were transfected after partial wedge resec-tion, and the transfected hepatocyctes were reinfused via the portal vein.Three of the five patients responded with significant and prolonged reduc-tion of total and LDL-cholesterol [21]. Although promising, safety concernshave limited this approach.
Hospital settingLipid-lowering drug therapy should be started during acute hospitaliza-
tion or at discharge for acute myocardial infarction (MI) and acute coro-nary syndromes. Both the safety and effectiveness of this approach havebeen demonstrated [22]. This logic can be extended to coronary artery by-pass graft (CABG) carotid surgery, stroke, transient ischemic attack(TIA), and peripheral vascular surgery, but such an approach has notbeen tested in effectiveness trials. Concerns about inaccurate lipid levelscaused by acute phase response should not prevent initiating statin therapy,but rather follow-up lipid levels at 6 to 12 weeks will determine subsequentdosing or withdrawal of therapy [23].
Diabetic dyslipidemiaDiabetes mellitus is considered a ‘‘CHD equivalent’’ risk for cardiovascu-
lar disease according to ATP III guidelines, and dyslipidemia of greater than100 mg/dL should be treated to lower levels. Primary and secondary preven-tion trials with statins have demonstrated a reduction in cardiovascularevents in both groups. The Heart Protection Study (HPS) [24] demonstrateda significant risk reduction, even for diabetics whose initial LDL cholesterolwas less than 116 mg/ dL. As previously discussed, many type 2 diabeticshave mixed lipid disorders with elevated LDL cholesterol, low HDL choles-terol, and elevated triglycerides caused, in large part, by insulin resistance,obesity, 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 initialstep. Dietary changes focusing on limiting carbohydrates and preventingweight gain are most important. Many patients will need combination ther-apy. Addition of fenofibrate, niacin, ezetimibe, or fish oils may be needed totreat hypertriglyceridemia and the elevated non-HDL cholesterol. Fatty infil-tration of the liver, which is common in diabetics who have modest elevationsin liver function test (1.5–2.5 � ULN), is not a contraindication to statin use
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or lipid medications. In fact, many patients’ liver function tests will improve iflipid lowering therapy is initiated; however, careful monitoring of the liverfunction test and avoidance of niacin is recommended in such situations.
Renal and cardiac transplant patientsCardiovascular disease is a major cause of premature death, and allograft
loss in renal and cardiac transplantation and hyperlipidemia appears to playan important role in this process. Hyperlipidemia is common in transplantpatients, caused by both the underlying diseases leading to transplantation(ie, diabetes mellitus and hypertension), and by the use of immunosuppres-sive therapy with corticosteroids, cyclosporine, or sirolimus. Cyclosporineinhibits the CYP3A4 cytochrome pathway, which leads to increased statinlevels, and therefore an increased risk of myopathy in statins that are metab-olized through this pathway (lovastatin, simvastatin, atorvastatin). Pravas-tatin and fluvastatin therefore appear to be the drugs of choice for patientswho have LDL dominant disorders and are on cyclosporine therapy.
Human immunodeficiency virusDyslipidemia is associated with the treatment of HIV infection, particu-
larly with protease inhibitors (PI), which can raise total and LDL cholesteroland triglycerides. Patients on treatment for HIV with PI are also at increasedrisk of cardiovascular disease and myocardial infarction. Therefore treat-ment of the lipid disorder is indicated. Protease inhibitors (indinavir, ritona-vir, nelfinavir, saquinavir, aprenavir) are metabolized by the CYP3A4cytochrome pathway; thus statins metabolized through this pathway maylead to increased statin levels and, therefore, to increased risk of myopathy.Pravastatin and fluvastatin, which are not metabolized by this pathway, arethe statins of choice in HIV patients who need PI and LDL lowering. Feno-fibrate or gemfibrozil can be used for triglyceride elevations, but combinationtherapy of gemfibrozil and statins in HIV patients requiring PI therapy iscontraindicated because of this increased risk of myopathy. An alternativeapproach is to change the HIV therapy to a regimen not using PI therapy.
ElderlyThe benefits of lipid lowering in the elderly have been questioned. Epide-
miologic studies show a reduced relative risk for total cholesterol as the pop-ulation ages; however, the absolute risk of CHD increases, so that thepopulation attributable risk also increases, suggesting that lipid-loweringtherapy is beneficial. Until recently, few clinical trials demonstrating thebenefits of lipid lowering therapy in the primary and secondary preventionof cardiovascular disease have included the elderly. Data from the Scandi-navian Simvastatin Survival Study (4S) [25], Cholesterol and RecurrentEvents (CARE) trial [26], Long-term Intervention with Pravastatin in Ische-mic Disease (LIPID) [27], HPS [28], Prospective Study of Pravastatin in the
1053HYPERLIPIDEMIA
Elderly at Risk (PROSPER) [29], and Cardiovascular Health Study (CHS)[30] all show benefit in the elderly, including patients up to age 82 in thePROSPER study. Thus the preponderance of the evidence now suggeststhat lipid-lowering therapy is indicated in the elderly. Given these facts,the risks versus the benefits of lipid-lowering therapy in the elderly shouldbe weighed carefully. Clearly patients who have malnutrition and limitedlife expectancies should not be treated with low fat diets and aggressivelipid-lowering therapy. Treatment of the elderly needs to take into accountthe fact that many elderly patients have varying degrees of renal insufficiencyand are taking multiple medications that may lead to drug-drug interac-tions, and that both the cost of medication and the complexity of the drugregimens may lead to medication adherence issues. Atorvastatin and fluvas-tatin do not require adjustment for renal insufficiency, and pravastatin, flu-vastatin, and rosuvstatin are not metabolized by the CYP3A4 system. Thesefactors should be taken into account when prescribing statin therapy in theelderly.
Step 6: Follow-up with the patient
Medication and lifestyle adherence is a significant problem in clinicalpractice. Studies have shown that between 15% and 50% of subjects startedon lipid-lowering agents will continue to take this medication after 1 year[31–33]. Patient education, discussion of the pros and cons of taking themedication, concomitant focus on diet and lifestyle, and pharmacotherapyand periodic office visits will help with adherence. The ATP III cholesterolguidelines recommend re-evaluating patients every 6 weeks until the patientis at goal, which is usually attained with four visits, and then twice yearlythereafter.
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