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 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: 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
1028 EATON

lipoproteins are associated with serious health consequences, including in-

creased 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 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 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 fu-
ture 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 rem-
nants 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 apopro-
tein 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 chylomi-
crons to chylomicron remnants and releasing free fatty acids. The released
free 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.
 HYPERLIPIDEMIA 1029

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 already
mentioned.

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, C-I, C-II, C-III, and E. They have a density of
0.95 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 endogenous
pathway of lipoprotein metabolism. Triglyceride levels between 150 mg/dL
and 500 mg/dL are generally associated with elevated levels of VLDL par-
ticles. Similar to chylomicrons, the triglyceride core of VLDL particles is
acted 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 cleared
by the Apo B/E receptor of the liver or remodeled by hepatic lipase into
LDL cholesterol.

Intermediate-density lipoproteins
IDL carry both triglyceride and cholesterol esters, and are associated with
Apo B-100, C-III, and E. IDL are usually cleared rapidly from the blood, such
that under fasting conditions, little IDL is measurable in plasma. They have
a density of 1.006 to 1.019 g/mL; however, under certain conditions, such as
a defective Apo-E receptor as found in Type III dyslipidemia or in other met-
abolic states (ie, hypothyroidism), excess IDL is found in plasma. Typically
lipid profiles associated with this condition give values of total cholesterol of
around 300 mg/dL, and similar values for triglycerides.

Low-density lipoproteins
LDL are the main atherogenic lipoproteins. They have a density of 1.019
to 1.063 g/ml. They carry a core of cholesterol esters and small amounts of
triglyceride, 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. This
feedback loop is exploited by statin medications, which, by blocking the
rate-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
1030 EATON

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 biologic
functions. Internalization at the liver leads to bile acid formation, which is
important 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 wall
through unregulated scavenger receptors. Under conditions of inflammation
or oxidant stress, this process leads to atherosclerosis and its clinical sequelae
of coronary artery disease, stroke, peripheral vascular disease, aneurysm
formation, and sudden death.

High-density lipoproteins
HDL are antiatherogenic lipoproteins. They have the highest density of
lipoproteins, between 1.063 and 1.21 g/ml. HDL is synthesized in the liver
and intestinal cells, and consists of small, lipid poor particles containing
Apo A-I and phospholipids. The nascent HDL particles interact with
VLDL remnants, chylomicron remnants, and intracellular pools that allow
for the efflux of cholesterol and triglyceride. HDL is involved in two impor-
tant processes: reverse cholesterol transport under the control of cholesterol
efflux 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 cholesterol
pools in macrophages and in the liver. The resultant pre b-HDL is converted
into mature a-HDL by LCAT. 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. The net effect is
to 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 abnormal
lipoproteins in animal models in absence of any other risk factors. It has
been proposed that subendothelial retention of LDL cholesterol is the ini-
tiating factor for atherosclerosis [6]. A charged interaction between Apo B
containing lipoproteins with proteoglycans in the extracellular matrix of ar-
terial wall has been implicated in this process. Small, dense LDL particles
penetrate the endothelial cell barrier of the arterial wall more frequently
than large, fluffy LDL particles. The LDL cholesterol, with a prolonged res-
idence time caused by this charged interaction, allows for lipid peroxidation
of the phospholipids and unesterified cholesterol. This process leads to
 HYPERLIPIDEMIA 1031

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
ABCA1, removing excess cellular cholesterol and forming pre-b-HDL (green arrow). Pre-b-
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.)

macrophage infiltration, and the uptake of LDL cholesterol by

macrophages 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
1032 EATON

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 and
endothelial cell damage. Oxidatively modified LDL cholesterol also pro-
motes proinflammatory and immune changes through cytokine release
and antibody production that lead to further promotion of atherosclerosis.
Oxidized LDL cholesterol disrupts endothelial cell surfaces and impairs the
release of nitrous oxide, a major mediator of endothelium-dependent
vasodilation. This damage to the endothelium leads to increased platelet
adherence and the release of cytokines that stimulate smooth muscle
proliferation. 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 increase
platelet aggregation and induce thromboxane release, which contributes
to vasoconstriction and intravascular thrombosis. Another potential path-
way 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. Al-
though not as extensively studied as LDL cholesterol, IDL cholesterol,
VLDL remnants, and Lp(a) are taken up by macrophages and cause
foam cell formation. They also impair endothelium-dependent function,
and are associated in epidemiologic studies with increased risk of coronary
heart disease.
HDL cholesterol, in contrast to LDL, IDL, and VLDL cholesterol, is
antiatherogenic. The most important mechanism for this effect is reverse
cholesterol transport, leading to the efflux of cholesterol from subendothe-
lial space in atherosclerotic plaques already described. Other contributing
factors to this antiatherogenic effect include the role of HDL cholesterol
in maintaining endothelial cell function, protection against thrombosis via
inhibition of calcium-induced procoagulant activity by Apo A-I, and the
maintenance 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 exact
pathophysiologic mechanism for this association is unclear; however, with
markedly elevated triglyceride levels, greater than 750 mg/dL, chylomicrons
and chylomicron remnants are present in the systemic circulation. It is
thought that these large triglyceride rich particles cause an efflux of water
from the pancreatic cells into the capillaries, carrying these large lipophilic
particles and leading to dehydration of the pancreatic cells. Intracellular
 HYPERLIPIDEMIA 1033

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 places
patients at high risk of acute and recurrent pancreatitis.

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 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 needs

evaluation and treatment
This is done by obtaining a fasting lipid profile and then determining the
risk factors for cardiovascular disease. A simple clinical rule for adult pa-
tients who have total cholesterol greater than 200 mg/dL, or HDL cholesterol
less than 40 mg/dL, or triglycerides greater than 200 mg/dL, or TC/HDL
ratio greater than 5.0 defines most patients who have a lipid disorder in
need of evaluation and treatment. A fasting lipid profile is the preferred
method to evaluate lipoprotein disorders, because triglycerides values
will 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 with
total cholesterol less than 200 mg/dL. These patients usually have modest
elevations of several risk factors that collectively lead to an increased risk
of a cardiovascular event, or have isolated low HDL cholesterol. These pa-
tients can be identified by evaluating their risk of having a cardiovascular
event through use of the Framingham risk equation, which has been shown
to be reasonably valid in a multitude of racial and ethnic cohorts. Tables 1
and 2 can be used to calculate the 10-year risk of hard CHD [1]. The LDL
goals for each risk category are given in Table 3.
For children, the lipid values that define hyperlipidemia are generally
lower than for adults. These are presented in Table 4 [9]. Selective screening
for 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/.
Table 2
Framingham 10-year risk of CHD in women
Age (years) Points
20–34
7
35–39
3
40–44 0
45–49 3
50–54 6
55–59 8
60–64 10
65–69 12
70–74 14
75–79 16
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 8 6 4 2 1
240–279 11 8 5 3 2
R280 13 10 7 4 2
Age
20–39 40–49 50–59 60–69 70–79
Nonsmoker 0 0 0 0 0
Smoker 9 7 4 2 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 1 3
130–139 2 4
140–159 3 5
R160 4 6
Point total 10-year risk (%) Point total 10-year risk (%)
!9 !1 18 6
9 1 19 8
10 1 20 11
11 1 21 14
12 1 22 17
13 2 23 22
14 2 24 27
15 3 R25 R30
16 4
17 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/.
1036 EATON

Table 3
ATP III-recommended goals of therapy and LDL level for initiation of drug therapy
LDL level to
LDL Non-HDL initiate drug
Risk goal goal treatment
category 10-year risk (mg/dL) (mg/dL) (mg/dL)
Low risk 0–1 risk factorsa !160 !190 O190b
Borderline risk 2þ risk factors, 10%–20% !130 !160 O160
Moderate risk 2þ risk factors, 10%–20% !130 !160 O130
Moderate-high Moderateþ uncontrolled !100 !130 O100
risk risk factor or metabolic
syndrome, or strong
family history, or
elevated hs-CRP,
or elevated coronary
artery calcification
score
CHD equivalent CHD & 2þ risk factors, !100 !130 O100
O20%
Extremely high ACS, or CHD & DM, !70 !100 O70
risk or CHD & uncontrolled
risk factor, or CHD and
metabolic syndrome
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.

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 for
family 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 the
Frederickson classification of lipid disorder has historical relevance, it car-
ries little clinical utility because it has no prognostic value, and therefore
has been abandoned by most clinicians. 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, Lp(a) excess, triglyceride-dominant
 HYPERLIPIDEMIA 1037

Table 4
Lipid values for children and adolescents aged 2–19
Category Concentration (mg/dL) Concentration (mg/dL)
Total cholesterol
High 200 or higher
Borderline high 170–199
Desirable !170
LDL cholesterol
High 130 or higher
Borderline high 110–129
Desirable !110
HDL cholesterol Under 10 years 10–19 years
High !40 !35
Borderline high 40–45 35–45
Desirable O45 O45
Triglyceride
High 100 or higher 130 or higher
Borderline high 75–99 90–129
Desirable !75 !90

lipid disorders, mixed lipid disorders, isolated low HDL cholesterol, and
atherogenic dyslipidemia. 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, 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 genetic
phenotypes. Many of these polygenic hypercholesterolemic patients are at
least partially responsive to dietary therapy, but many require lipid-lowering
drug therapy as well. Some patients who have LDL-dominant lipid disor-
ders have genetic lipid disorders that are associated with significantly elevated
LDL cholesterol, usually less than 190 mg/dL. These LDL dominant genetic
lipid disorders include familial hypercholesterolemia and familial defective
Apo B-100.

Familial hypercholesterolemia
Familial hypercholesterolemia (FH) is a relatively common autosomal
dominant disorder that affects approximately 1 in 500 individuals. Total
cholesterol is usually above 300 mg/dL for heterozygotes and 500 mg/dL
1038 EATON

to 1000 mg/dL for homozygotes. Mutations to the LDL receptor locus have
been discovered affecting four phenotypes: class 1, in which synthesis of the
receptor is defective; class 2, in which intracellular transport of LDL recep-
tor protein from the endoplasmic reticulum to the golgi apparatus is
blocked; class 3, in which the LDL receptor binding protein is defective;
and class 4, in which the internalization of the receptor-LDL complex
is defective, so that the LDL receptors do not cluster in the coated pits.
Different mutations of the LDL receptor gene confer different effects
on LDL cholesterol levels and CHD risk. The diagnostic criteria for hetero-
zygous FH can be categorized as definite and probable, and are outlined in
Table 5 [10]. Many FH patients have tendon xanthomas on themselves or in
family members, but these physical findings are not pathognomic of FH, be-
cause sitosterolemia and cerebrotendinous xanthomatosis can also present
with tendon xanthomas.

Familial defective apoprotein B100

Familial defective Apo B100 is an autosomal dominant disorder that is
clinically identical to FH; however, here the defect is in the Apo B-100 ligand
on the LDL particle and not on the receptor itself. This defect is found in
about 8 of 10,000 patients. FH generally requires a multiple drug regimen,
and for more severe cases, LDL apheresis is recommended [11].

Sitosterolemia
Sitosterolemia 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 of
cholesterol or normal cholesterol levels. These plant sterols accumulate in

Table 5
Cholesterol criteria for heterozygous FH
Age in First-degree Second-degree Third-degree General
years relative relativea relativeb 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.
 HYPERLIPIDEMIA 1039

plasma and tendons, leading to tendon xanthomas. The disorder’s typical

onset is in childhood, and it is treated with ezetimide and diets low in dietary
sterols.

Lipoprotein(a) excess
Lp(a), previously known as pre-sinking beta-lipoprotein, is the most com-
mon lipid disorder in families that have a family member who has premature
coronary 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 premature
atherosclerosis. Lp(a) is a specialized form of LDL linked by disulfide bridge
to Apo(a), and is modulated by LCAT. Apo(a) is protein chain composed of
five doughnut-shaped domains called kringles. The fourth kringle is very
similar in structure to plasminogen, and therefore Lp(a) competes with plas-
minogen for plasminogen receptors, fibrin, and fibrinogen. The net effect of
this 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 macrophage
receptor, leads to Lp(a)’s dual atherogenic and thrombogenic pathologic se-
quelae. Elevated Lp(a) is usually associated with markedly elevated total
cholesterol 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 disorders

The association of elevated triglycerides and risk of CHD is not fully un-
derstood. This is because triglyceride elevations can be associated with
a range of other atherogenic lipoprotein abnormalities (remnant lipopro-
teins; small, dense LDL cholesterol; B-VLDL; IDL) and low levels of
HDL cholesterol, so that in some clinical situations, elevated triglycerides
are associated with an elevated risk of coronary heart disease, and in other
clinical 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 also
have 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 may
add to the atherogenic potential of elevated triglycerides. The metabolic
control of triglycerides is under the control of lipoprotein lipase, hepatic tri-
glyceride lipase, and cholesterol ester transfer protein, as discussed in the lipo-
proteins metabolism section above. Overproduction or derangement in any of
these catabolic pathways can lead to elevated triglycerides.
Many patients who have hypertriglyceridemia have acquired disorders
such as obesity, diabetes mellitus, renal disease, or hypothyroidism, or are
undergoing hormone therapy, or taking tamoxifen or immunosuppressive
1040 EATON

drugs that contribute to this lipid disorder. Thus, ruling out secondary
causesdstep 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 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. 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 genetic
mutations typically have low HDL cholesterol levels as well. The phenotypic
expression of these genetic defects may vary, depending upon concomitant
exposures such as weight gain, insulin resistance, exogenous estrogens,
and so on.

Severe hypertriglyceridemia
Patients 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 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. Clinically, patients who have
severe hypertriglyceridemia present with eruptive xanthomas and hepato-
splenomegaly, and may develop severe symptoms with elevations greater
than 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 disorder

Most patients who have elevated triglycerides also have elevations in ei-
ther LDL cholesterol or low HDL cholesterol and elevation of other Apo
B100-carrying lipoproteins. Thus a mixed lipid disorder is the most frequently
found in most primary care practices. Patients who have elevated LDL
cholesterol and low HDL cholesterol are also classified as having a mixed
lipid 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 band
dyslipidemia, and atherogenic dyslipidemia.

Familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is found in about 1% to 2% of
the population, and manifests as either elevated total cholesterol,
 HYPERLIPIDEMIA 1041

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 simple
sugars and by weight gain. It is associated with an increased risk of CHD.

Apoprotein B excess or hyperapolipoproteinemia

This is a relatively common disorder that may be a variant of familial
combined hyperlipidemia. 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 1.2, suggestive
of LDL phenotype, type B or increased small, dense LDL cholesterol.

Type III dyslipidemia or broad band dyslipoproteinemia

Type 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 and
partially 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) and
elevated total cholesterol (O300 mg/dL), and many, but not all, patients
have 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 manifests
itself 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 acid
sequestrates.

Atherogenic dyslipidemia
This is a nonfamilial lipid disorder characterized by elevated triglycerides
(O200 mg/dL) and reduced HDL cholesterol (!40 mg/dl), and is associated
with small, dense LDL. Usually lipid abnormalities in this triad are only
marginally abnormal. Nuclear magnetic resonance (NMR) spectroscopy
and other sophisticated techniques are required to determine LDL particle
size 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).

Isolated low high-density lipoprotein cholesterol

(hypoalphalipoproteinemia)
Most patients who have low HDL cholesterol (!40 mg/dL) have another
concomitant lipid abnormality, usually elevated triglycerides. Occasionally,
1042 EATON

isolated low levels of HDL cholesterol are found, and in most situations
they are associated with increased CHD risk. Low levels of HDL cholesterol
are 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 lifestyles
have 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. By
measuring Apo A-I levels (O90 mg/dL), such low-risk patients can be dif-
ferentiated from those who have familial hypoalphalipoproteinemia.

Familial hypoalphalipoproteinemia
Familial hypoalphalipoproteinemia is an autosomal dominant disorder
with HDL cholesterol levels below the tenth percentile (30–40 mg/dL). It
is associated with mutations in the Apo A-I gene, and with increased risk
of premature CHD.

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), 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 cells
accumulate 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 deficiency

LCAT 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 low
levels of HDL cholesterol and severe corneal opacities, so-called ‘‘fish eye
syndrome.’’ This rare condition is usually not associated with premature
CHD, 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 therapy
is initiated. Common medical diseases associated with lipoprotein disorders
include diabetes mellitus, hypothyroidism, uremia, nephrotic syndrome, and
 HYPERLIPIDEMIA 1043

liver disease. Less common medical diseases associated with hyperlipidemia

include 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, monoclonal gammopathies, lymphoma, and multiple myeloma.
It is therefore suggested that before initiating drug therapy, all patients
have 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 suspicion
warrants 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 and
physical 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 treatment
as measured by number needed to treat (NNT) and cost-effectiveness are
not. Patients who have the greatest risk of heart attack or stroke get the
most benefit from treatment using NNT and cost-effectiveness as the mea-
sures of benefit. 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. The goals of
therapy and the threshold for initiating drug therapy are given in Table 3.
The primary goal is based upon the LDL cholesterol. For patients who
have triglycerides greater than 200 mg/dl before drug therapy, a non-
HDL goal (total cholesterol-HDL) is used as a secondary goal once the
LDL goal has been reached [1]. The moderate high risk and extremely
high risk categories have been added as therapeutic options in a subsequent
white 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 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. Studies have shown that primary
care physicians can be trained to perform effective dietary counseling for lipid
lowering; however, time and reimbursement issues may limit this option.
1044 EATON

Referral of patients to a qualified nutrition health professional for medical

nutrition 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 regarding
hyperlipidemia, as well as many recipes and tips for dietary change.
A detailed discussion of recommended dietary changes is beyond the
scope 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 ATP
III 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 replacement
of animal fats, and diets high in n-3 fatty acids in the form of fatty fish or
vegetable oils as therapeutic options.

Herbal and botanical dietary supplements

Despite widespread promotion, there are few data on the product stan-
dardization, efficacy, and safety of herbal and botanical supplements for
the lowering of cholesterol and the prevention of heart disease. Red yeast
rice has been shown to lower cholesterol; however, standardization is an is-
sue. Data are inconsistent (but generally negative) in US trials for garlic and
guggilipid. 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 increased
physical activity should be encouraged in all overweight
people.
 Prevention of weight gain should be emphasized for all
persons.
 A diet to maximize LDL lowering should limit intake of
saturated 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 elevated
triglycerides or low HDL cholesterol. Carbohydrates should be
eaten mainly in the form of whole grains.
 HYPERLIPIDEMIA 1045

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 therapy
When deciding on the choice of drug therapy and the dose of the medi-
cation for lipid disorder treatment, several factors need to be weighed. These
include the efficacy of the therapy for a given lipid disorder, the degree of
LDL or non-HDL lowering desired to reach therapeutic goals, the cost of
the medication, possible side effects, and drug-drug and drug-nutrient inter-
actions. 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 demon-
strated in randomized clinical trials to improve total mortality as well as pre-
vent recurrent cardiovascular events, and therefore, 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 the risk of major coronary
events 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 of
cholesterol synthesis. This leads to a decrease in the intracellular pool of
free cholesterol in the hepatic cells, which through a negative feedback
loop, triggers the synthesis of LDL receptors (Apo B100 receptors) by the he-
patocyte. These LDL receptors migrate to the coated pits on liver cells, and
absorb 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 given
dose. 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- CAI, BAS, niacin
co-reductase inhibitor
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.
1046 EATON

Table 7
Average dose response of statin medications
LDL Cytochrome Effect of food
Statin Dose lowering Solubility 450 metabolism on absorption
Atorvastatin 10 mg 37% Lipophilic 3A4 None
20 mg 43%
40 mg 49%
80 mg 55%
Fluvastatin 20 mg 21% Lipophilic 2C9 Neglibile
40 mg 27%
Lovastatin 10 mg 21% Lipophilic 3A4 Increased
20 mg 29%
40 mg 37%
80 mg 55%
Pravastatin 10 mg 20% Hydrophilic Decreased
20 mg 24%
40 mg 29%
80 mg 33%
Simvastatin 5 mg 23% Lipophilic 3A4, 3A5 None
10 mg 27%
20 mg 32%
40 mg 37%
80 mg 42%
Rosuvastatin 5 mg 38% Hydrophilic Limited 2C9 None
10 mg 43%
20 mg 48%
40 mg 53%

dose of statins, as well as the other pertinent pharmacologic characteristics

of each drug.
Absolute contraindications to statin therapy are active or chronic liver
disease. 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 should
be 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 the
upper limit of normal is found in about 1 in 1000 cases. In over 12 million
patients taking statins, there have only been 772 cases of rhabdomyolysis
and 72 deaths. Risk factors for statin-associated myopathy are: age greater
than 80; small body frame and frailty; chronic renal insufficiency; diabetes
mellitus; multiple medications; perioperative period; concomitant use of: fi-
brates, niacin, cyclosporine, azole antifungals, macrolide antibiotics, HIV
protease inhibitors, nefazodone, verapamil, amiodorone, or large doses of
grapefruit juice (O1 quart); and alcohol abuse [14].
The following recommendations should reduce the incidence and severity
of statin-related myopathy. Measure baseline CK, alanine aminotransferase
 HYPERLIPIDEMIA 1047

(ALT), and aspartate aminotransferase (AST). If the CK level is less than 3

times upper limit of normal (ULN), proceed with initiating medications. If
the CK level is 3 to 10 times ULN, decrease exercise, evaluate for thyroid
myopathy with a TSH and check for drug or herbal interactions. If the
CK is still 3 to 10 times ULN, begin statin therapy if the benefits outweigh
the risks. If symptoms of muscle soreness, tenderness or pain, or brown
urine develop, stop statin therapy and recheck the CK. If the CK is greater
than 10 times ULN, then discontinue the statin and niacin or fibric acid if on
combination therapy. If the CK is 3 to 10 times ULN, monitor symptoms
and 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 (half
the original dose), and monitor CK and symptoms. If the CK is normal, but
the patient still has muscle aches and soreness, then lower the dose or change
to a less potent statin. Some investigators have tried administering coen-
zyme Q with a significant reduction in muscle symptoms, but clinical trials
of this treatment have not been reported.
Statin drugs are rated as category X for pregnancy, and their use should
be discontinued before conception. Animal data suggest that statins are as-
sociated with adverse fetal outcomes, but limited human data suggest that
statins are not major teratogens. Analysis of the Food and Drug Adminis-
tration (FDA) surveillance database suggests a possible link between central
nervous system (CNS) and limb abnormalities with exposure to lipophilic
statins 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 to
increase after 2 years of use. Many statins are renally excreted, so the
dose should be adjusted for patients who have chronic renal insufficiency.
Atorvastatin and fluvastatin are not metabolized by the kidneys and do
not need to be dose-adjusted, but other statins do. Patients who have chronic
liver disease and who need statin therapy should abstain from alcohol and
use hydrophilic statins such as pravastatin or rosuvastatin. Use of ezeti-
mibe or bile acid sequestrant as a first-line drug or in combination with
statins is preferred, whereas use with niacin or fibrates is contraindicated
in patients who have chronic liver disease.

Cholesterol absorption inhibitors

Cholesterol 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 the
cholesterol content of bile in the enterohepatic circulation leads to decreased
intrahepatic cholesterol, which in turn promotes the synthesis of the LDL
receptors. This upregulation of the number of LDL receptors leads to the
enhanced clearance of LDL cholesterol from the systemic circulation, and
1048 EATON

thus to lower plasma cholesterol levels. Ezetimide is available in a 10 mg

dose, and averages 18% LDL lowering in clinical trials. 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.
Ezetimide is synergistic with other lipid-lowering agents, including statins,
whereby an additional 9% to 14% LDL lowering has been found. Ezetimide
is relatively safe, with limited evidence of myopathy or liver dysfunction to
date. Gemfibrozil increases the level of ezetimide with unclear clinical impli-
cations. Fenofibrate has been used safely in combination with ezetimide.

Bile acid sequestrants

Bile 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 bind
bile acids in the terminal ileum, preventing the reabsorption of biliary cho-
lesterol, and thus (similar to ezetimide) lower the intrahepatic cholesterol
levels, leading via the negative feedback loop to enhanced LDL receptor
synthesis. 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 and
constipation limit compliance. BAS decrease the absorption of fat-soluble
vitamins, and may interfere with other drugs, so that a multivitamin is rec-
ommended, and other medications should not be taken concomitantly, but
rather 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 in
combination therapy when higher doses of statins lead to increased side ef-
fects or risk of toxicity when moderate LDL lowering is the goal.

Fibrates
Fibrates 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 the
drug of choice for triglyceride dominant lipid disorder, and a reasonable
choice for mixed lipid disorders and diabetic dyslipidemia, when non-
HDL cholesterol lowering is an important goal of therapy. Fibrates lower
triglycerides 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 clearance
of VLDL by the stimulation of LPL, and downregulation of Apo C-III
gene. The HDL raising associated with fibrates is associated with the direct
 HYPERLIPIDEMIA 1049

stimulation of the synthesis of Apo A-I and A-II, increased transfer of Apo
A-I from HDL to VLDL, and reduced inhibition by lower levels of VLDL
on the hepatic synthesis of Apo A-I. Gemfibrozil and fenofibrate are fibrates
that are available in the United States. Absolute contraindications include
severe renal disease and severe liver disease. Potential side effects include
such GI side-effects as dyspepsia, nausea, bloating and cramping, gallstones,
liver toxicity, and myopathy. Most GI side effects can be diminished if the
patient takes the medicine with meals, and gradually increases the dose.
Most side effects dissipate
Fibrates in combination with statins and with cyclosporine are associated
with 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 not
extensively metabolized by the cytochrome P-450 3A4 system (CYP3A4 sys-
tem), are used, but this is uncertain [15]. Gemfibrozil potentiates the action
of warfarin, and therefore monitoring prothrombin time and using a lower
dose 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.

Niacin
Niacin or nicotinic acid is available in several formulations and is effec-
tive in treating patients who have LDL dominant lipid disorders, mixed lipid
disorder, and isolated low HDL cholesterol. Niacin has been shown to lower
LDL cholesterol 10% to 25%, raise HDL cholesterol 15% to 35%, and re-
duce triglycerides 25% to 30% in a dose-response manner. Nicotinic acid
inhibits 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% by
an unknown mechanism [16]. Effective doses for niacin range from 1.5 g
per day to 3 g per day. Short-acting preparation or crystalline niacin is given
three times daily, whereas sustained-release preparations can be given once
daily. Frequent side effects limit the tolerability of niacin despite its thera-
peutic efficacy. The side effects and tolerability can be improved with careful
slow titration of crystalline niacin and pretreatment with aspirin. It is rec-
ommended that crystalline niacin be started at 100 mg three times a day
with meals, and increased in 2-week intervals by 100 mg per dose until
500 mg three times a day is reached. 80 mg baby aspirin given 30 minutes
before each dose will decrease the flushing side-effects. Use of a sustained-
release preparation reduced flushing significantly. Liver toxicity is relatively
common, and periodic liver function testing is recommended. Onset of he-
patic injury is not predictable, and thus liver function testing is required
for the duration of therapy. Niacin can induce insulin resistance and thus
worsen glucose control, as well as induce hyperuricemia and gout. Niacin
1050 EATON

can also raise homocysteine levels, and some experts have suggested routine
screening 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 inhibitors

High levels of CETP are correlated with low levels of HDL cholesterol.
Recently, a randomized controlled trial [18] has demonstrated that the
CETP inhibitor, torcetrapib, raised HDL cholesterol 46% and, in combina-
tion with atorvastatin, raised HDL cholesterol 61%. HDL2 was raised more
than HDL3, and torcetrapib increased the size of the HDL particles and
Apo A-I levels. Torcetrapib also lowered LDL cholesterol and Apo B levels,
and increased LDL size. Although this class of drugs looks promising, it is
not yet available for clinical use. HDL raising appears to be beneficial in
concert with LDL lowering in statin plus niacin trials [19]. Ultimately, the
benefits of CETP inhibition on reducing coronary heart disease need to be
shown before this class of drugs can uniformly recommended.

Drug-resistant patients
The 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 beginning
with a statin. Many patients do not reach their LDL goals with this ap-
proach. Combination therapy is recommended. If the patient has not
reached 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 the
secondary goal of non-HDL is not reached because of elevated triglycerides,
then combination therapy with fibrate or the addition of fish oils can be
tried. 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. In general, statins plus fibrates are associated with
a 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% to
30% triglyceride lowering and, at 1.5 g per day, have been shown to reduce
recurrent CHD in European trials [20].

Low-density lipoprotein apheresis

LDL 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 severe
hypercholesterolemia such as homozygous familial hypercholesterolemia,
or heterozygous hypercholesterolemia that fails to respond to combination
 HYPERLIPIDEMIA 1051

dietary plus pharmacologic interventions. Liver transplantation and partial

ideal bypass surgery, although used in the past, have been abandoned as
therapy in refractory patients in favor of LDL apheresis.

Gene therapy
A 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 human
trials, 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 concerns
have limited this approach.

Hospital setting
Lipid-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 have
been 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 not
been tested in effectiveness trials. Concerns about inaccurate lipid levels
caused by acute phase response should not prevent initiating statin therapy,
but rather follow-up lipid levels at 6 to 12 weeks will determine subsequent
dosing or withdrawal of therapy [23].

Diabetic dyslipidemia
Diabetes mellitus is considered a ‘‘CHD equivalent’’ risk for cardiovascu-
lar disease according to ATP III guidelines, and dyslipidemia of greater than
100 mg/dL should be treated to lower levels. Primary and secondary preven-
tion trials with statins have demonstrated a reduction in cardiovascular
events in both groups. The Heart Protection Study (HPS) [24] demonstrated
a significant risk reduction, even for diabetics whose initial LDL cholesterol
was less than 116 mg/ dL. As previously discussed, many type 2 diabetics
have 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 initial
step. Dietary changes focusing on limiting carbohydrates and preventing
weight gain are most important. Many patients will need combination ther-
apy. Addition of fenofibrate, niacin, ezetimibe, or fish oils may be needed to
treat hypertriglyceridemia and the elevated non-HDL cholesterol. Fatty infil-
tration of the liver, which is common in diabetics who have modest elevations
in liver function test (1.5–2.5  ULN), is not a contraindication to statin use
1052 EATON

or lipid medications. In fact, many patients’ liver function tests will improve if
lipid lowering therapy is initiated; however, careful monitoring of the liver
function test and avoidance of niacin is recommended in such situations.

Renal and cardiac transplant patients

Cardiovascular disease is a major cause of premature death, and allograft
loss in renal and cardiac transplantation and hyperlipidemia appears to play
an important role in this process. Hyperlipidemia is common in transplant
patients, 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. Cyclosporine
inhibits the CYP3A4 cytochrome pathway, which leads to increased statin
levels, 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 patients
who have LDL dominant disorders and are on cyclosporine therapy.

Human immunodeficiency virus

Dyslipidemia is associated with the treatment of HIV infection, particu-
larly with protease inhibitors (PI), which can raise total and LDL cholesterol
and triglycerides. Patients on treatment for HIV with PI are also at increased
risk 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 CYP3A4
cytochrome pathway; thus statins metabolized through this pathway may
lead to increased statin levels and, therefore, to increased risk of myopathy.
Pravastatin and fluvastatin, which are not metabolized by this pathway, are
the statins of choice in HIV patients who need PI and LDL lowering. Feno-
fibrate or gemfibrozil can be used for triglyceride elevations, but combination
therapy of gemfibrozil and statins in HIV patients requiring PI therapy is
contraindicated because of this increased risk of myopathy. An alternative
approach is to change the HIV therapy to a regimen not using PI therapy.

Elderly
The 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 the
population attributable risk also increases, suggesting that lipid-lowering
therapy is beneficial. Until recently, few clinical trials demonstrating the
benefits of lipid lowering therapy in the primary and secondary prevention
of cardiovascular disease have included the elderly. Data from the Scandi-
navian Simvastatin Survival Study (4S) [25], Cholesterol and Recurrent
Events (CARE) trial [26], Long-term Intervention with Pravastatin in Ische-
mic Disease (LIPID) [27], HPS [28], Prospective Study of Pravastatin in the
 HYPERLIPIDEMIA 1053

Elderly at Risk (PROSPER) [29], and Cardiovascular Health Study (CHS)

[30] all show benefit in the elderly, including patients up to age 82 in the
PROSPER study. Thus the preponderance of the evidence now suggests
that lipid-lowering therapy is indicated in the elderly. Given these facts,
the risks versus the benefits of lipid-lowering therapy in the elderly should
be weighed carefully. Clearly patients who have malnutrition and limited
life expectancies should not be treated with low fat diets and aggressive
lipid-lowering therapy. 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 interac-
tions, and that both the cost of medication and the complexity of the drug
regimens 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. These
factors should be taken into account when prescribing statin therapy in the
elderly.

Step 6: Follow-up with the patient

Medication and lifestyle adherence is a significant problem in clinical
practice. 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]. Patient education, discussion of the pros and cons of taking the
medication, concomitant focus on diet and lifestyle, and pharmacotherapy
and periodic office visits will help with adherence. The ATP III cholesterol
guidelines recommend re-evaluating patients every 6 weeks until the patient
is at goal, which is usually attained with four visits, and then twice yearly
thereafter.

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