International Journal of Cardiology 97 (2004) 355 366

www.elsevier.com/locate/ijcard

Review
Optimal management of hyperlipidemia in primary prevention
of cardiovascular disease
Jaffar Ali Raza, Joseph D. Babb, Assad Movahed *
Department of Medicine, Section of Cardiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834-4354, USA
Received 24 April 2003; received in revised form 14 July 2003; accepted 25 July 2003
Available online 9 April 2004

Abstract

Cardiovascular disease (CVD) in the developed countries continues to grow at an epidemic proportion. There are a significant number of
young adults with no clinical evidence of CVD, but who have two or more risk factors that predispose them to CV events and death. Many of
these risk factors are modifiable, and by controlling these factors, the CVD burden can be decreased significantly. Recent statistics have
shown that, if all major forms of CVD were eliminated, the life expectancy would rise by almost 7 years. Hence it is imperative that primary
prevention efforts should be initiated at a young age to avert decades of unattended risk factors. Hyperlipidemia has been linked to CVD
almost a century ago. Since then various clinical trials have not only supported this link, but have also shown the CV benefits in aggressively
treating patients with hyperlipidemia. In this generation, we have various therapeutic agents that are capable of reducing the elevated lipid
levels. With drugs like statins, we are able to reduce the risk of CVD by about 30% and avoid major adverse events. Newer drugs are being
researched and introduced in the treatment of hyperlipidemia in humans. These can be used in combination therapy resulting in optimal levels
of lipids. The new National Cholesterol Education Program (NCEP)/Adult Treatment Panel III (ATP III) guidelines have come as a wake-up
call to clinicians about primary prevention of CVD through strict lipid management and multifaceted risk management approach in the
prevention of CVD.
D 2003 Elsevier Ireland Ltd. All rights reserved.

Keywords: Primary prevention; Cardiovascular disease; Hyperlipidemia; Statins; Ezetimibe

1. Introduction However, though treating patients with hyperlipidemia with

Heart disease and stroke, the principal components of
cardiovascular disease (CVD), are the first and third leading
causes of death in the United States (US), accounting for
more than 40% of all deaths [1]. In the US alone there are
nearly a million deaths due to CVD [2]. The relationship
between elevated serum cholesterol and CVD was recog-
nized nearly a century ago by investigators [3 5]. Since
then, multiple clinical and epidemiological studies have
further established this relationship beyond reasonable
doubt [6 10]. The relationship between the cholesterol
level and coronary heart disease (CHD) mortality has a
linear approximation, with each 20 mg/dl (0.5 mmol/l)
increase in total cholesterol resulting in a 12% increase in
CHD mortality [11]. This led to the belief that decreasing
serum cholesterol level will decrease the CVD mortality.
* Corresponding author. Tel.: +1-252-744-4651; fax: +1-252-744-
5884.
E-mail address: movaheda@mail.ecu.edu (A. Movahed).
agents like bile acid sequestrants, nicotinic acid and fibrates
resulted in decrease in cholesterol level, no decrease in the
rates of CHD mortality or total mortality was seen [12,13].
This could probably be related to the identification of low-
density lipoprotein (LDL-C) as the main atherogenic com-
ponent of serum cholesterol, or the fact that these agents
were not able to decrease the cholesterol level adequately
enough to decrease the CVD risk [8,9,14].
The introduction of 3-hydroxy-3-methylglutaryl coen-
zyme A reductase inhibitors (statins) in the late 1980s was
a major breakthrough in the treatment of hyperlipidemia and
CVD [15]. Since then various multicenter clinical trials have
shown a decrease in total cholesterol and LDL-C levels with
statins and a resulting reduction in the CVD mortality
[6,7,16,17]. These trials have examined the effectiveness
of lipid-lowering therapy in both the primary and secondary
prevention of CVD. These trials have shown that the
reduction in serum cholesterol levels leads to reduced
cardiovascular events irrespective of whether there is al-
ready established CVD [6 9,14,16,17]. More patients are

0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2003.07.039
356 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366
Table 1
Risk factors for CVD
Non-modifiable
Increasing age
Male sex
Family history
Modifiable
Raised LDL levels
Low HDL levels
Raised TGL levels
HTN
Obesity
Smoking
Sedentary life style
Diabetes
Atherogenic diet
CVD: cardiovascular disease; LDL: low-density lipoprotein; HDL: high-
density lipoprotein; TGL: triglycerides; HTN: hypertension.
now eligible based on the new National Cholesterol Edu-
cation Program (NCEP) guidelines, for intensive lipid-
lowering therapy [18]. The NCEP estimates that the number
of Americans who qualify for dietary treatment of hyper-
lipidemia will increase from 52 million to 65 million, and
those who are candidates for drug therapy will nearly
triplefrom 13 million to 36 million. In this review, we
will discuss the benefits of treating hyperlipidemia in the
primary prevention of CVD.
2. Atherosclerosis
Atherosclerosis was relatively uncommon until the 20th
century, when factors such as reduced infectious disease
mortality combined with high-fat diet, sedentary life styles,
cigarette smoking and urbanization resulted in the increased
prevalence of hyperlipidemia and CVD in the developed
nations [19]. The process of atherogenesis begins early in
life as documented by the autopsy results of US soldiers
killed in the Korean War [20]. The investigators found that
about 35% of the soldiers who died had fibrous coronary
arterial plaque with no significant narrowing, 12% had
more than 50% occlusion of one or more vessels and 3%
had complete occlusion of one or more vessels. Similar
results were also seen in US soldiers who died in the
Vietnam War [21]. This data has been recently confirmed
by the Pathobiological Determinants of Atherosclerosis in
Youth (PDAY) Research, in which autopsy was done on
individuals between the age of 15 and 34 who had
traumatic deaths [22,23]. All of the aortas and about half
of the right coronary arteries in the youngest age group (15
through 19 years) had lesions. The mean percent intimal
surface involved by lesions, in 5-year age groups, increased
from 15 through 34 years. Recently, Tuzcu et al. have
demonstrated via intravascular ultrasound that coronary
atherosclerosis begins at a young age and that atheroscle-
rotic lesions are present in 1 of 6 teenagers [24]. The
presence of atherosclerotic fatty streaks in young subjects
Table 2
ATP III classification of total cholesterol and LDL cholesterola
Category Total cholesterol LDL cholesterol
Optimal < 200 < 100
Near optimal N/A 100 129
Borderline high 200 239 130 159
High >240 160 190
Very high N/A >190
a
Derived from Adult Treatment Panel III (ATP III); LDL: low-density
lipoprotein; N/A: not applicable.
and more advanced atherosclerotic lesions in middle-aged
subjects are correlated with total cholesterol (TC), LDL-C
levels, and apolipoprotein B [25,26]. Angiographic studies
have also proved this relationship [27 29]. The pathophys-
iology of the development of atherosclerosis is beyond the
scope of this article. Information such as this, however,
suggests that management of the dyslipidemias should start
from an early age in the form of dietary modifications,
increased physical activity, smoking cessation and, if nec-
essary, drug therapy.
3. Screening
Though the benefits of lipid-lowering agents in the
secondary prevention of CVD in patients with lipid dis-
orders have been well documented, primary prevention
trials have reached mixed conclusions about the benefits
of lipid-lowering on mortality from CVD and on all cause
mortality [30,31]. However, recent systematic reviews and
large subsequent randomized control trials (RCT) have
found that lowering cholesterol in people at high risk of
ischemic coronary events substantially reduces overall
mortality, cardiovascular mortality, and nonfatal cardiovas-
cular events [32 34]. Caution against drug treatment in
patients with low to moderate risk of death from CHD has
also been proposed because of the possible increase in all
cause mortality with treatment [35]. Systematic review of
long-term statin trials by La Rosa et al. [36] found no
significant difference between statins and placebo in terms
of non-CV mortality, cancer incidence, asymptomatic ele-
vation of creatine kinase ( > 10 times upper reference limit),
or elevation of transaminases (>3 times upper reference
limit) during a mean of 5.4 years of treatment. All these
suggest that the benefits of treatment of lipid abnormalities
far outweigh any adverse effects that may result from the
medical therapy. High-risk patients can be identified using
the assessment tool from the Framingham Heart Study
Table 3
New ATP III classification triglyceride levelsa
. Normal: less than 150 mg/dl
. Borderline high: 150 199 mg/dl
. High: 200 499 mg/dl
. Very high: 500 mg/dl or higher
a
Derived from Adult Treatment Panel III (ATP III).
 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366
Table 4
ATP III classification of HDL cholesterola
. High HDL cholesterol >60 mg/dl
. Low HDL cholesterol < 40 mg/dl
a
Derived from Adult Treatment Panel III (ATP III); HDL: high-density
lipoprotein.
(FHS) [37,38]. Aggressive risk factor modifications includ-
ing diet modification, lifestyle changes, increasing physical
activity, and smoking cessation should be recommended to
these persons at young age. The current NCEP recommen-
dation is to screen all patients older than 20 years of age
and to undergo cholesterol testing at least every 5 years
[39]. The Adult Treatment Panel III (ATP III) guidelines
recommend a more comprehensive assessment, including
measurements of fasting TC, LDL-C, high-density lipopro-
tein cholesterol (HDL-C), and triglyceride (TGL) levels
[18] (Tables 1, 2, 3, and 4).
4. Primary prevention trials
The role of primary prevention of CVD has been a
subject of considerable debate. This question has been
addressed in various clinical trials. The treatment of athero-
genic dyslipidemia (atherogenic dyslipidemia consists of
raised TGL, small LDL-C particles, and low HDL-C) results
in decreased CVD morbidity and mortality. However, the
major RCTs done so far have predominantly targeted
towards the treatment of LDL-C and outcome. The major
RCTs that assessed the benefits in the treatment of dyslipi-
demia in the primary prevention of CVD are discussed
below.
The Lipid Research Clinics Coronary Primary Prevention
Trial (LRC-CPPT) was a multicenter, randomized, double-
blind study that evaluated the efficacy of cholestyramine in
the primary prevention of CHD [13]. In this study, 3806
middle-aged men at risk for coronary artery disease were
treated with either dietary modification and cholestyramine
(24 g/day) or dietary modification and placebo. The mean
TC was 7.55 mmol/l (292 mg/dl) and the LDL-C level was
5.59 mmol/l (216 mg/dl) at baseline. The patients were
followed for a mean of 7.4 years. The combination of diet
and cholestyramine group experienced an average TC and
LDL-C reductions of 13.4% and 20.3%, respectively, as
compared to 5.0% and 8.6% ( p < 0.001), respectively, in the
placebo group. With an average of 7.4 years of follow-up,
the cholestyramine-treated group, as compared with the diet-
only group, had a 19% ( p < 0.05) reduction in nonfatal
myocardial infarctions and a 24% reduction in deaths from
CHD death.
The Helsinki Heart Study (HHS) was a randomized 5-
year double-blind trial that involved 4081 men between the
ages of 40 and 55 years [30]. Subjects were randomly
assigned to receive either gemfibrozil (600 mg twice a
day) or placebo. Gemfibrozil therapy produced a mean
357
decrease of 10% in serum TC, 14% in non-HDL-C (non-
HDL-C includes all known potential atherogenic lipid
particles), 11% in LDL-C, 35% in TGL, and a mean
increase of 11% in HDL-C level from baseline levels as
compared with placebo. These changes in the lipoprotein
profile were associated with a 34% reduction in the com-
bined end point of death from cardiac disease, nonfatal
myocardial infarction, and fatal myocardial infarction over
the 5-year study period.
The West of Scotland Coronary Prevention Study
(WOSCOPS) was a primary prevention trial designed to
demonstrate the effectiveness of pravastatin in reducing
morbidity and mortality from CHD in hypercholesterolemic
men [16]. These patients were considered to be at a very risk
for the development of CVD with a fasting LDL-C >252
mg/dl before diet and >155 mg/dl after 4 weeks of diet. In
6595 hypercholesterolemic men with mean cholesterol level
of 272 mg/dl (7.03 mmol/l), treatment with 40 mg/day of
pravastatin reduced TC by 20% and LDL-C level by 26%.
The patients had a median follow-up of 4.9 years. The
improvement in the lipid parameters resulted in 33%
( p = 0.03) reduction in the death from myocardial infarction
and 31% ( p < 0.001) reduction in nonfatal myocardial
infraction. There was also a 22% ( p = 0.05) reduction in
all cause mortality. However, this trial did not include
women or patients older than 65 years.
The Air Force/Texas Coronary Atherosclerosis Preven-
tion Study (AFCAPS/TexCAPS) trial also looked at the
beneficial effect of statins in generally healthy individuals
(average TC and LDL-C and below-average HDL-C, as
characterized by lipid percentiles for an age- and sex-
matched cohort without cardiovascular disease from Na-
tional Health and Nutrition Examination Survey
(NHANES) III) with low to moderate risk for CHD [6].
This study included women and also patients up to age
73. The mean TC level was 5.71 mmol/l (221 mg/dl),
mean LDL-C level was 3.89 mmol/l (150 mg/dl), mean
HDL-C level was 0.94 mmol/l (36 mg/dl) for men and
1.03 mmol/l (40 mg/dl) for women, respectively, and
median TGL levels were 1.78 mmol/l (158 mg/dl). The
subjects received lovastatin (20 40 mg daily) or placebo
in addition to a low-saturated fat, low-cholesterol diet. In
a 5.2-year follow-up of 6605 subjects (5608 men and 997
women), lovastatin (20 40 mg daily) reduced LDL-C by
25% to 2.96 mmol/l (115 mg/dl) and increased HDL-C
by 6% to 1.02 mmol/l (39 mg/dl). This resulted in a
decrease in the incidence of first acute major coronary
events (183 vs. 116 first events; p < 0.001), myocardial
infarction (95 vs. 57 myocardial infarctions; p = 0.002),
unstable angina (87 vs. 60 first unstable angina events;
p = 0.02), coronary revascularization procedures (157 vs.
106 procedures; p = 0.001), coronary events (215 vs. 163
coronary events; p = 0.006), and CV events (255 vs. 194
CV events; p = 0.003).
The Fukuoka Atherosclerosis Trial (FAST) was a RCT
based on the fact that carotid atherosclerosis is a strong
358 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366
and independent predictor of CV morbidity and mortality
[40]. This study is a primary prevention trial on high-risk
individuals, as they already had documented carotid ath-
erosclerosis. It included 246 asymptomatic men with
hyperlipidemia and investigated the effect of reducing
serum lipids on carotid artery intima-media thickness
(IMT). It compared three treatments: diet alone, diet with
pravastatin, and diet with probucol. A total of 246 asymp-
tomatic hypercholesterolemic patients (mean age 66 years)
were randomized to receive either probucol (500 mg/day)
or pravastatin (10 mg/day) or to enter a control group (diet
alone); they were followed for 2 years. Over the 2-year
period, serum LDL-C was significantly reduced in the
pravastatin group (36%), the probucol group (29%),
and the diet alone group (12%) ( p < 0.0001, p < 0.0001,
and p < 0.05, respectively). After 2 years, the probucol and
pravastatin groups showed a significant reduction in IMT
( 13.9% and 13.9% and p < 0.01 and p < 0.01, respec-
tively), but there was significant IMT thickening (23.2%;
p < 0.05) in the diet alone group. CV events were also
reduced by pravastatin (absolute risk [AR] for any CV
event 4.8% with pravastatin vs. 13.6% with diet alone, p
value not provided) and probucol (l2.4% with probucol vs.
13.6% with diet alone; p = 0.0136) after 2 years.
The Heart Protection Study (HPS) examined the effect of
lipid-lowering in patients with simvastatin [32]. This study
included 20,536 patients considered high risk for CHD.
Patients were randomly allocated to receive 40 mg simvas-
tatin daily or matching placebo. A subset of these patients
had a low-density lipoprotein cholesterol (LDL-C) levels
not normally considered to be elevated. In these patients
who had baseline LDL-C level of 116 mg/dl or lower,
further lowering LDL-C by 39 mg/dl resulted in a 25% risk
reduction for CHD. Over a 5-year treatment period, the
study demonstrated that 40 mg of simvastatin reduced the
risk of nonfatal myocardial infarction. There were signifi-
cant reductions in the first event rate for nonfatal myocardial
infarction or coronary death ( p < 0.0001) compared to
placebo.
Meta-analysis of the primary prevention trials showed
that active treatment of hyperlipidemia was associated with
a 34% risk reduction ( p < 0.001) in major coronary events.
Compared with controls, active treatment was associated
with a lower risk of coronary disease mortality ( p = 0.09),
CV mortality ( p = 0.01), and all-cause mortality ( p = 0.18)
in the primary prevention trials [36]. However, Pignone et
al. [41] in a meta-analysis of four randomized controlled
trials found that, although treatment of patients with no
previous history of CHD with lipid-lowering agents (statins,
cholestyramine, gemfibrozil) decreased CV events, they did
not significantly decrease CHD mortality.
Although these studies have addressed various issues,
there are still questions about the primary prevention of
CVD. There have been patient groups (elderly, women,
diabetic) who were not adequately represented in these
trials. Thus far no study has evaluated the effect of treating
isolated hypertriglyceridemia or low HDL-C in primary
prevention. Lloyd-Jones et al. [42] used the eligibility
criteria of the major primary prevention trials in the FHS
subjects and found that 40% of men and 80% of women had
lipid profiles that have not been studied in large trials to
date. They also observed a large number of CHD events in
these ineligible subjects in whom hypertriglyceridemia
was common. New trials looking at these questions are
essential to better understand the metabolic differences
among the subgroups and the role of lipid-lowering therapy
vs. other strategies for primary prevention in the general
population (Tables 3 and 4).
5. Treatment
Aggressive treatment of TC and LDL-C has shown to
decrease the incidence of CVD. This has been shown in
patients with established CHD and in families with hyper-
cholesterolemia, where aggressive reduction in the lipid
levels resulted in decreased CVD incidence [43 45]. The
Simvastatin Survival Study (4S) and the AFCAPS/Tex-
CAPS trials also has demonstrated that there is no thresh-
old for LDL-C reduction in primary prevention beyond
which additional reduction in CVD events would not be
achieved [46]. In the 4S trial CVD event rates were
reduced progressively with increasing reduction in the
LDL-C levels. There was a 18.2% event rate with < 34%
reduction in LDL-C level from baseline, 13.8% even rate
with reduction between 34 44% and 10.6% event rate in
those with 44 70% reduction [47]. All these evidence
suggest aggressive lowering of LDL-C and TC level with
all the available modalities to achieve maximum CV
benefits. Based on their risk factors, patients can be scored
according to the modified Framingham scoring and based
on these scores, the aggressiveness of treatment can be
modified [37] (Table 5).
Dietary changes and risk factor modifications (smoking
cessation, weight control, hypertension (HTN) control,
increased physical activity, diabetes mellitus (DM) control)
is strongly recommended in patients with hyperlipidemia.
Various studies have shown a correlation between increased
physical activities with decreased CV mortality [48 50].
Though regular exercise has been shown to increase the
Table 5
Drug therapy for primary preventiona
Risk category 10-year Level to Goal of
CHD riskb consider therapyc therapyc
Multiple (2+) >20% >100 mg/dl < 100 mg/dl
risk factors 10 20% >130 mg/dl < 130 mg/dl
< 10% >160 mg/dl < 130 mg/dl
0 1 Risk < 10% >190 mg/dl < 160 mg/dl
factors
a
Derived from Adult Treatment Panel III (ATP III).
b
Framingham Score.
c
Low-density cholesterol level, CHD: coronary heart disease.
 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366
HDL-C levels, it has minimal effect on the LDL-C levels
[51,52]. Patients who follow the NCEP Step 2 diet have
decreased fat intake, but have failed to lower LDL-C level in
men or women with high-risk lipoprotein levels [53]. Hence
diet and exercise in spite of being helpful in patients with
hyperlipidemia are seldom successful in meeting the desired
or recommended lipid goals. Most patients need to have
additional drug therapy for adequate reduction in their lipid
levels. There are various agents in the market currently
available in treatment of patients with lipid abnormalities
(Table 5).
5.1. HMG-coA reductase inhibitors (statins)
The 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors commonly known as statins are the most often
prescribed lipid-lowering agents in the US. Recent clinical
trials using statins to treat LDL-C have demonstrated
beyond reasonable doubt that coronary events can be
prevented by decreasing LDL-C levels [6,16,17]. Statins
are structurally similar to HMG-coenzyme A, which is a
precursor to cholesterol and competitively inhibit the
HMG-coA reductase that is the last step in the synthesis
of cholesterol [54]. Statins also upregulate the LDL-C
receptor activity and decrease the entry of LDL-C into
the circulation resulting in low serum LDL-C concentration
[55,56]. The anti-ischemic benefits seen with statin therapy
cannot be solely accounted by the reduction in the LDL-C
levels seen with statin therapy. Subgroup analyses of large
clinical trials indicate that statin-treated individuals have
significantly less CVD than patients with comparable
serum cholesterol levels [57,58]. This is probably due to
their beneficial pleiotropic effects: improving or restor-
ing endothelial function, enhancing the stability of athero-
sclerotic plaques, and decreasing oxidative stress and
vascular inflammation [59,60]. Statins also have beneficial
role in the coagulation and fibrinolytic pathways (see Table
6). Hypercholesterolemia has been shown to impair endo-
thelial function, one of the earliest manifestations of
atherosclerosis [61]. Statins improve endothelial function
by reducing oxidative stress [62], plasminogen activator
inhibitor-1 (PAI-1) expression [63], and by inhibiting the
expression of endothelin-1, a potent vasoconstrictor [64].
Statins also improve endothelial function by increasing
nitrous oxide (NO) bioavailability by stimulating endothe-
lial NO synthase (eNOS) [65,66], and by increasing the
expression of tissue-type plasminogen activator [67]. Sta-
tins have also been noted to have a specific effect on
lowering high-sensitivity C-reactive protein (hsCRP) lev-
els, independent of the effects on cholesterol or other
inflammatory markers and improve the global CV risk
[68,69].
The recently published Anglo-Scandinavian Cardiac
Outcomes Trial (ASCOT) assessed the benefits of cho-
lesterol lowering in the primary prevention of CHD in
hypertensive patients who are not conventionally deemed
359
dyslipidemic. Hypertensive patients (10,305) with TC
concentrations 6.5 mmol/l or less were randomly assigned
to receive atorvastatin 10 mg or placebo in addition to
their antihypertensive agent. Treatment was stopped after
a median follow-up of 3.3 years. The total CV events
(389 vs. 486, p = 0.0005), and total coronary events (178
vs. 247, p = 0.0005) were significantly lower in the
atorvastatin group as compared to the placebo group
[95]. Regression analysis of all the major statin trials
done by Jackson et al. [96] found that mortality benefits
of statins outweigh risks in people with a 10-year CHD
risk of more than 13%. La Rosa et al. [36] found that,
after 4 6 years of treatment for primary prevention,
statins compared with placebo did not significantly reduce
all cause mortality or CHD mortality, but did reduce
major coronary events and CV mortality (all cause
mortality: OR 0.87, 95% CI 0.71 1.06; CHD mortality
OR 0.73, 95% CI 0.51 1.05; major coronary events: OR
0.66, 95% CI 0.57 0.76; CV mortality: OR 0.68, 95% CI
0.50 0.93). The currently available statins in the US
market are atorvastatin, fluvastatin, lovastatin, pravastatin,
and simvastatin. Rosuvastatin and pitavastatin are two
new statins currently in development [97]. Rosuvastatin
has been submitted for FDA approval whereas pitavastatin
is now in phase II trials. Rosuvastatin is a new statin
under investigation, with a number of favorable character-
Table 6
Beneficial effects of statins in preventing CVD
Lipid effects
(1) Decreases LDL-C level [70].
(2) Lowers TGL levels [71,72].
(3) Increases HDL-C and apolipoprotein A-I (apoA-I) [73,74].
(4) Decreases oxidation of LDL-C [75].
Vascular effects
(5) Increases endothelium-dependent vasodilator response [76].
(6) Activates endothelial NO synthesis [77].
(7) Promotes plaque stabilization [78].
(8) Blocks the accumulation of cholesterol in macrophages [79].
(9) Reduces monocyte adhesion to endothelial cells [80].
(10) Antiproliferative effects on smooth muscle cells [81].
(11) Suppresses neointimal thickening [82].
Antithrombotic effects
(12) Reduces thromboxane synthesis [83].
(13) Reduces platelet aggregation [84].
(14) Reduces tissue factor/extrinsic pathway inhibitor (EPI) production
[85].
(15) Decreases plasma fibrinogen concentrations [86,87].
(16) Improves whole blood and plasma viscosity [88].
(17) Reduces plasminogen activator inhibitor-1 (PAI-1) activity [89].
(18) Reduces platelet-associated ox-LDL (Pox-LDL) activity [90].
(19) Decreases platelet-dependent thrombin generation (PDTG) [91]
Other effects
(20) Reduces C-reactive protein levels [92].
(21) Greater reduction in mean blood pressure when used with ACEI. [93].
(22) Decreases proteniuria. [94].
(23) Anti-oxidant effect [62]
CVD: cardiovascular disease; LDL-C: low density lipoprotein cholesterol;
HDL-C: high-density lipoprotein cholesterol; TGL: triglycerides; NO: nitric
oxide; ACEI: angiotensin-converting enzyme inhibitor.
360 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366
istics, which include low lipophilicity, high hepatocyte
selectivity, minimal metabolism, and a low propensity for
cytochrome P-450 drug interactions (see Table 7). In
comparative clinical trials, rosuvastatin given at 5 10
mg/day reduced LDL to a significantly greater extent
(39 60%) than atorvastatin 10 mg/day, pravastatin 20
mg/day, and simvastatin 20 mg/day. Rosuvastatin also
has beneficial effects on HDL and TGL [98 101].
Statin therapy has been proven to be safe without major
adverse effects [36,102,103]. The common side effects are
elevated liver transaminase level and myopathy. Serious
side effects like rhabdomyolysis and peripheral neuropathy
have been reported, though they are extremely rare [104
108]. The incidence of serious adverse effects are increased
in patients who use concomitant drugs like gemfibrozil,
macrolide antibiotics, itraconazole, cyclosporin, nicotinic
acid, and any other medications that interfere with the
cytochrome P-450 drug metabolism pathway [109 111].
Caution should be exercised when these agents are used (see
Table 7). If myopathy is strongly suspected or if there is
elevation of the serum transaminase levels >3 times the
upper limit of normal, statins should be discontinued. The
current ATP III recommendation is to consider statins as the
first line of treatment in the treatment of elevated LDL-C
levels [18].
5.2. Nicotinic acid (niacin)
Niacin is the oldest agent in the lipid-lowering group of
drugs that had been shown to decrease CVD mortality [112].
Niacin inhibits the mobilization of free fatty acids from the
peripheral tissues and hence reduces the synthesis of TGL
[113]. It also inhibits the secretion of VLDL and the
conversion of VLDL to LDL [113]. One of the important
effects of niacin in the treatment of lipid disorders is its
Table 7
Drugs that inhibit cytochrome P-3A4
Calcium channel blockers
Verapamil
Diltiazem
Macrolide antibiotics
Azithromycin
Clarithromycin
Erythromycin
Azole antifungals
Fluconazole
Itraconazole
Ketoconazole
Protease inhibitors
Amprenavir
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Grapefruit juice (>1 quart/day)
Nefazadone
Cyclosporine
Cilostazol
ability to increase the HDL-C and HDL-C levels [2] by 26%
and 36%, respectively, at a dose of 3 g/day, greater than any
other agent available [113]. Other than estrogen, niacin is
the only drug that has been shown to lower elevated levels
of lipoprotein (a) [Lp(a)], which has been shown to increase
risk for CVD [114]. Niacin (1.5 g/d) reduced Lp(a) levels by
35% at 26th week of treatment.
The major disadvantage in the use of niacin is the
adverse effects [115]. Niacin treatment causes significant
flushing and pruritis. This has lead to significant problem
with noncompliance among patients. Forty-three percent of
individuals given regular nicotinic acid and forty-two per-
cent of those given sustained-release nicotinic acid discon-
tinued the medication because of side effects. Starting at a
low dose and titrating to desired dose could reduce the
flushing. Taking aspirin or other non-steroidal anti-inflam-
matory drugs about 30 min prior to taking niacin also
minimizes flushing [116]. Other adverse effects include
gastrointestinal complaints like nausea, dyspepsia, flatu-
lence, vomiting, diarrhea, and activation of peptic ulcer
disease [115]. Hyperuricemia and gout can occur and
worsening of hyperglycemia may be seen in patients with
diabetes [117]. Hepatotoxicity has been reported and this
risk seems to be higher in patients who take sustained
release niacin [118]. Hence liver enzymes need to be
monitored periodically in patients who take nicotinic acid
compounds. The risk of hepatotoxicity with Niaspan is
however less as compared to other sustained released
niacins [119].
Nicotinic acid has is most effective in preventing CVD
when give in combination with resins [120,121] or fibrates
[122] or stains [123]. Guyton et al. [124] studied the
combination of Niaspan and statin. They found that the
Niaspan plus statin combination lowered LDL-C (32%),
apolipoprotein B (26%), TC (23%), triglycerides (30%), and
Lp(a) (19%), and increased HDL cholesterol (26%). Myop-
athy, rhabdomyolysis, and substantial transaminase eleva-
tions can occur with this combination [123]. Hence, careful
attention should be given to niacin formulation and dosing,
liver functions be monitored periodically, and patients
should be educated to recognize symptoms of myopathy
[123]. The current ATP III recommendation is to use
nicotinic acid as a single agent in high-risk patients with
atherogenic dyslipidemia without substantial elevation in
the LDL-C levels [18]. It can also be used in combination in
patients with atherogenic dyslipidemia with elevated LDL-C
levels.
5.3. Fibric acid derivatives (fibrates)
The currently available fibrates, gemfibrozil, fenofibrate,
and clofibrate in the US resemble short chain fatty acids in
their structure [125]. Fibrates increase peripheral fatty acid
uptake and oxidation in the liver [126]. They enhance
lipoprotein lipase (LPL) enhanced catabolism of very low-
density lipoprotein (VLDL). The major role of fibrates in
 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366
atherogenic dyslipidemia is its ability to decrease the TGL
levels. Recent research has shown the fibrates to be agonist
for the nuclear transcription factor, peroxisome proliferator-
activated receptor (PPAR)-alpha [127]. The hypotriglyceri-
demic actions of fibrates seem to involve PPAR mechanism
with increased hydrolysis of plasma triglycerides due to
induction of LPL and reduction of apoC-III expression
[128]. They also stimulate cellular fatty acid uptake and
conversion to acetyl-CoA derivatives. They also increase
the PPAR mediated activation of apolipoprotein Al gene and
downregulate the apolipoprotein CIII gene [129]. There is
increased peroxisomal and mitochondrial beta-oxidation and
decreased synthesis of fatty acids and triglycerides resulting
in decreased production of VLDL [130]. Fibrates exert their
hypolipidemic effect by enhancing the catabolism of tri-
glyceride-rich particles and reducing secretion of VLDL
particles. Increased risk of CVD seen with elevated fibrin-
ogen level is reduced by fibrates like benzafibrate and
fenofibrate (not available in US) by decreasing the fibrino-
gen levels [131,132].
In two large primary prevention trials; World Health
Organization (WHO) clofibrate trial and the HHS gemfi-
brozil trial, treatment with clofibrate and gemfibrozil has
been shown to decrease the risk of fatal and nonfatal
myocardial infarction [133,134]. The Veterans Affairs Co-
operative Studies Program High-Density Lipoprotein Cho-
lesterol Intervention Trial [VA-HIT] was a secondary
prevention trial comparing gemfibrozil (1200 mg/day) with
placebo in 2531 men with coronary heart disease, an HDL
cholesterol level of 40 mg/dl (1.0 mmol/l) or less, and an
LDL cholesterol level of 140 mg/dl (3.6 mmol/l) or less
[135]. They hypothesized that therapy aimed at raising HDL
cholesterol levels and lowering levels of triglycerides would
reduce the incidence of death from CHD. One year after
randomization, the mean HDL-C level was 6% higher in the
gemfibrozil group than in the placebo group (34 vs. 32 mg/
dl, p < 0.001); the mean TC level was 4% lower (170 vs. 177
mg/dl, p < 0.001); and the mean TGL level was 31% lower
(115 vs. 166 mg/dl, p < 0.001). Gemfibrozil therapy was
associated with a 22% reduction in the rate of death from
CHD or nonfatal myocardial infarction ( p = 0.006).
Fibrates are generally well tolerated by patients. The
common side effects are usually gastrointestinal symptoms
like diarrhea, abdominal pain, constipation, and dyspepsia.
These drugs also increase the lithogenecity of the bile and
may result in the formation of gall stones [136]. The fibrates
bind with serum albumin very strongly and may displace
other albumin binding drugs like warfarin and increase their
serum levels [137]. In patients with hypertriglyceridemia,
fibrate therapy may increase the LDL-C levels [138,139].
Hence LDL-C levels should be closely monitored. In
patients who have elevated LDL levels, fibrates can be
cautiously used in combination with statins, being aware of
the fact that this combination can increase the risk of
myopathy and rhabdomyolysis [109]. The fibrates are able
to reduce the triglycerides level by 25 50% [139]. The
361
higher the initial triglyceride level, the greater the reduction
noted. The current ATP III recommendation on the use of
fibrates is to use these agents in patients with very high TGL
level that may increase their risk for pancreatitis [18]. They
have also been recommended in people with dysbetalipo-
proteinemia (elevated beta-VLDL), low LDL-C atherogenic
dyslipidemia, and in combination with statin in elevated
LDL-C atherogenic dyslipidemia.
5.4. Bile acid sequestrants (resins)
Resins decrease serum cholesterol level by disrupting the
enterohepatic circulation of the bile acids, causing the
shunting of cholesterol into bile acid syntheses in the liver
[140,141]. The available agents in this group are cholestyr-
amine, colestipol and colesevelam. The resins are able to
reduce the LDL-C levels, and increase HDL-C levels
[142,143]. The TGL levels, which are initially elevated with
treatment, by about 5 20% with bile acid sequestrant
therapy, tend to be transient and are typically related to
high baseline TG levels or dysbetalipoproteinemia
[144,145]. Although the LDL-C response was dosage-de-
pendent, there seemed to be nonlinear response with bile
acid sequestrants [144,146,147]. Currently resins are mostly
used as an adjunctive to statins in the treatment of hyper-
lipidemia. While doubling the dose of statins resulted only
in 6% further reduction in LDL-C, adding a small dose of
resins resulted in lowering of LDL-C levels by 12 16%
[148,149].
The major adverse effect of the resins is gastrointestinal
upset. In the Lipid Research Clinics-Coronary Primary
Prevention Trial (LRC-CPPT), more than 1900 patients
received cholestyramine therapy at a dosage of 24 g/day.
By the end of the first year of the study, 68% of these
patients reported at least 1 gastrointestinal side effect, 39%
had constipation, 32% had abdominal gas, and 27% had
heartburn [13]. This leads to poor compliance and a very
high discontinuance rate of the resins among patients
[150 152]. Of the three resins available in the market,
colesevelam is easy to administer and is better tolerated. It
lacks the constipating effect that is typical of other bile
acid sequestrants. In a study by Davidson et al. [153] the
overall compliance with colesevelam treatment was very
high (93%). The current ATP III recommendation on the
use of resins is for patients with moderate elevation in
LDL-C levels, younger person with elevated LDL, women
who are pregnant or considering pregnancy, and for
combination therapy with statins in patients with very high
LDL-C levels [18].
5.5. Ezetimibe (Zetia)
Ezetimibe is a new class of lipid-lowering agent intro-
duced in the treatment of hypercholesterolemia. It is related
to phytoesterols and decreases the lipid levels by inhibiting
the intestinal absorption of cholesterol [154,155]. The site of
362 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366
action of ezetimibe seems to occur in the brush border of the
small intestine, where it inhibits the cholesterol absorption
[10,155]. The efficacy and safety of ezetimibe was evaluat-
ed in a randomized, double-blinded, placebo-controlled trial
of 892 patients with primary hypercholesterolemia [156].
Patients received ezetimibe 10 mg or placebo orally each
morning for 12 weeks. A total of 434 men and 458 women
(ages 18 85 years, 666 ezetimibe 10 mg, 226 placebo) were
involved in the study. Ezetimibe was found to significantly
reduce direct LDL-C by a mean of 16.9%, compared with an
increase of 0.4% with placebo ( p < 0.01). Ezetimibe effects
on LDL-C occurred early (2 weeks) and persisted through-
out the 12-week treatment period. Compared with placebo,
ezetimibe 10 mg also significantly improved calculated
LDL-C, apolipoprotein B, TC, TGL, HDL-C, and the
subfraction of HDL-C, HDL [3] ( p < 0.01).
The efficacy and safety of adding ezetimibe to ongoing
statin therapy in patients with primary hypercholesterolemia
was also evaluated in a randomized, double-blinded, place-
bo-controlled study [157]. The study group included 769
adults (aged z 18 years) with primary hypercholesterolemia
who had not achieved NCEP/ATP II goals with dietary
alteration and statin monotherapy. Patients receiving a stable
dose of a statin for >6 weeks were randomized to receive
concurrent treatment with placebo (n = 390) or ezetimibe
(n = 379), 10 mg/day, in addition to continuing their open-
label statin for 8 weeks. Ongoing statin therapy plus
ezetimibe led to changes of 25.1% for LDL-C (HDL-C
+ 2.7%; TGL 14.0%) compared with LDL-C 3.7%
( p < 0.001), HDL-C + 1.0% ( p < 0.05), and TGL 2.9%
( p < 0.001) for placebo added to ongoing statin therapy.
Among patients not at LDL-C goal at on-statin baseline,
71.5% receiving statin plus ezetimibe vs. 18.9% receiving
statin plus placebo reached their goal at end point (odds
ratio 23.7; p < 0.001). The co-administration of ezetimibe
statins was well tolerated and caused a significant additive
reduction in LDL-C in other RCTs [158]. Ezetimibe has
been used in more than 4700 patients without any major
adverse events. The common side effects were fatigue
(2.2%), abdominal pain (3.0%), diarrhea (3.7%), back pain
(4.1%), arthralgia (3.8%), and coughing (2.3%) [68]. No
major drug interaction was seen with concomitant use of
ezetimibe and other lipid-lowering agents [154].
6. Conclusion
There are still many unanswered questions in the area of
primary prevention of CVD. The RCTs done to date have
not included all subgroups of population. Large proportions
of dyslipidemic patients who are being treated do not
achieve the NCEP target levels [159,160]. The Lipid Treat-
ment Assessment Project (L-TAP) study showed that only
38% of the patients treated in primary care settings attained
LDL-C target levels or values lower than the goals [161].
Another unanswered question is how low the TC and LDL-
C should be lowered to maximize clinical benefits. This will
probably be answered by ongoing clinical trials like the
Study of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine (SEARCH), Incremental
Decrease in Endpoints through Aggressive Lipid-Lowering
(IDEAL) and Treating to New Targets (TNT), which are
specifically addressing this question. In conclusion, the
relation between dyslipidemia and CVD are real and physi-
cians should aggressively identify individuals with athero-
genic dyslipidemia for proper management to prevent CVD
morbidity and mortality.
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