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International Journal of Cardiology 97 (2004) 355 366

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


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

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

0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved.
356 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366

Table 1 Table 2
Risk factors for CVD ATP III classification of total cholesterol and LDL cholesterola
Non-modifiable Category Total cholesterol LDL cholesterol
Increasing age
Optimal < 200 < 100
Male sex Near optimal N/A 100 129
Family history Borderline high 200 239 130 159
Modifiable High >240 160 190
Raised LDL levels
Very high N/A >190
Low HDL levels a
Raised TGL levels Derived from Adult Treatment Panel III (ATP III); LDL: low-density
HTN lipoprotein; N/A: not applicable.
Smoking and more advanced atherosclerotic lesions in middle-aged
Sedentary life style subjects are correlated with total cholesterol (TC), LDL-C
Atherogenic diet
levels, and apolipoprotein B [25,26]. Angiographic studies
have also proved this relationship [27 29]. The pathophys-
CVD: cardiovascular disease; LDL: low-density lipoprotein; HDL: high-
density lipoprotein; TGL: triglycerides; HTN: hypertension. 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
now eligible based on the new National Cholesterol Edu- from an early age in the form of dietary modifications,
cation Program (NCEP) guidelines, for intensive lipid- increased physical activity, smoking cessation and, if nec-
lowering therapy [18]. The NCEP estimates that the number essary, drug therapy.
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 3. Screening
triplefrom 13 million to 36 million. In this review, we
will discuss the benefits of treating hyperlipidemia in the Though the benefits of lipid-lowering agents in the
primary prevention of CVD. secondary prevention of CVD in patients with lipid dis-
orders have been well documented, primary prevention
trials have reached mixed conclusions about the benefits
2. Atherosclerosis of lipid-lowering on mortality from CVD and on all cause
mortality [30,31]. However, recent systematic reviews and
Atherosclerosis was relatively uncommon until the 20th large subsequent randomized control trials (RCT) have
century, when factors such as reduced infectious disease found that lowering cholesterol in people at high risk of
mortality combined with high-fat diet, sedentary life styles, ischemic coronary events substantially reduces overall
cigarette smoking and urbanization resulted in the increased mortality, cardiovascular mortality, and nonfatal cardiovas-
prevalence of hyperlipidemia and CVD in the developed cular events [32 34]. Caution against drug treatment in
nations [19]. The process of atherogenesis begins early in patients with low to moderate risk of death from CHD has
life as documented by the autopsy results of US soldiers also been proposed because of the possible increase in all
killed in the Korean War [20]. The investigators found that cause mortality with treatment [35]. Systematic review of
about 35% of the soldiers who died had fibrous coronary long-term statin trials by La Rosa et al. [36] found no
arterial plaque with no significant narrowing, 12% had significant difference between statins and placebo in terms
more than 50% occlusion of one or more vessels and 3% of non-CV mortality, cancer incidence, asymptomatic ele-
had complete occlusion of one or more vessels. Similar vation of creatine kinase ( > 10 times upper reference limit),
results were also seen in US soldiers who died in the or elevation of transaminases (>3 times upper reference
Vietnam War [21]. This data has been recently confirmed limit) during a mean of 5.4 years of treatment. All these
by the Pathobiological Determinants of Atherosclerosis in suggest that the benefits of treatment of lipid abnormalities
Youth (PDAY) Research, in which autopsy was done on far outweigh any adverse effects that may result from the
individuals between the age of 15 and 34 who had medical therapy. High-risk patients can be identified using
traumatic deaths [22,23]. All of the aortas and about half the assessment tool from the Framingham Heart Study
of the right coronary arteries in the youngest age group (15
through 19 years) had lesions. The mean percent intimal
Table 3
surface involved by lesions, in 5-year age groups, increased New ATP III classification triglyceride levelsa
from 15 through 34 years. Recently, Tuzcu et al. have . Normal: less than 150 mg/dl
demonstrated via intravascular ultrasound that coronary . Borderline high: 150 199 mg/dl
atherosclerosis begins at a young age and that atheroscle- . High: 200 499 mg/dl
rotic lesions are present in 1 of 6 teenagers [24]. The . Very high: 500 mg/dl or higher
presence of atherosclerotic fatty streaks in young subjects Derived from Adult Treatment Panel III (ATP III).
J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366 357

Table 4 decrease of 10% in serum TC, 14% in non-HDL-C (non-

ATP III classification of HDL cholesterola
HDL-C includes all known potential atherogenic lipid
. High HDL cholesterol >60 mg/dl
particles), 11% in LDL-C, 35% in TGL, and a mean
. Low HDL cholesterol < 40 mg/dl
increase of 11% in HDL-C level from baseline levels as
Derived from Adult Treatment Panel III (ATP III); HDL: high-density 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
(FHS) [37,38]. Aggressive risk factor modifications includ- myocardial infarction, and fatal myocardial infarction over
ing diet modification, lifestyle changes, increasing physical the 5-year study period.
activity, and smoking cessation should be recommended to The West of Scotland Coronary Prevention Study
these persons at young age. The current NCEP recommen- (WOSCOPS) was a primary prevention trial designed to
dation is to screen all patients older than 20 years of age demonstrate the effectiveness of pravastatin in reducing
and to undergo cholesterol testing at least every 5 years morbidity and mortality from CHD in hypercholesterolemic
[39]. The Adult Treatment Panel III (ATP III) guidelines men [16]. These patients were considered to be at a very risk
recommend a more comprehensive assessment, including for the development of CVD with a fasting LDL-C >252
measurements of fasting TC, LDL-C, high-density lipopro- mg/dl before diet and >155 mg/dl after 4 weeks of diet. In
tein cholesterol (HDL-C), and triglyceride (TGL) levels 6595 hypercholesterolemic men with mean cholesterol level
[18] (Tables 1, 2, 3, and 4). 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
4. Primary prevention trials improvement in the lipid parameters resulted in 33%
( p = 0.03) reduction in the death from myocardial infarction
The role of primary prevention of CVD has been a and 31% ( p < 0.001) reduction in nonfatal myocardial
subject of considerable debate. This question has been infraction. There was also a 22% ( p = 0.05) reduction in
addressed in various clinical trials. The treatment of athero- all cause mortality. However, this trial did not include
genic dyslipidemia (atherogenic dyslipidemia consists of women or patients older than 65 years.
raised TGL, small LDL-C particles, and low HDL-C) results The Air Force/Texas Coronary Atherosclerosis Preven-
in decreased CVD morbidity and mortality. However, the tion Study (AFCAPS/TexCAPS) trial also looked at the
major RCTs done so far have predominantly targeted beneficial effect of statins in generally healthy individuals
towards the treatment of LDL-C and outcome. The major (average TC and LDL-C and below-average HDL-C, as
RCTs that assessed the benefits in the treatment of dyslipi- characterized by lipid percentiles for an age- and sex-
demia in the primary prevention of CVD are discussed matched cohort without cardiovascular disease from Na-
below. tional Health and Nutrition Examination Survey
The Lipid Research Clinics Coronary Primary Prevention (NHANES) III) with low to moderate risk for CHD [6].
Trial (LRC-CPPT) was a multicenter, randomized, double- This study included women and also patients up to age
blind study that evaluated the efficacy of cholestyramine in 73. The mean TC level was 5.71 mmol/l (221 mg/dl),
the primary prevention of CHD [13]. In this study, 3806 mean LDL-C level was 3.89 mmol/l (150 mg/dl), mean
middle-aged men at risk for coronary artery disease were HDL-C level was 0.94 mmol/l (36 mg/dl) for men and
treated with either dietary modification and cholestyramine 1.03 mmol/l (40 mg/dl) for women, respectively, and
(24 g/day) or dietary modification and placebo. The mean median TGL levels were 1.78 mmol/l (158 mg/dl). The
TC was 7.55 mmol/l (292 mg/dl) and the LDL-C level was subjects received lovastatin (20 40 mg daily) or placebo
5.59 mmol/l (216 mg/dl) at baseline. The patients were in addition to a low-saturated fat, low-cholesterol diet. In
followed for a mean of 7.4 years. The combination of diet a 5.2-year follow-up of 6605 subjects (5608 men and 997
and cholestyramine group experienced an average TC and women), lovastatin (20 40 mg daily) reduced LDL-C by
LDL-C reductions of 13.4% and 20.3%, respectively, as 25% to 2.96 mmol/l (115 mg/dl) and increased HDL-C
compared to 5.0% and 8.6% ( p < 0.001), respectively, in the by 6% to 1.02 mmol/l (39 mg/dl). This resulted in a
placebo group. With an average of 7.4 years of follow-up, decrease in the incidence of first acute major coronary
the cholestyramine-treated group, as compared with the diet- events (183 vs. 116 first events; p < 0.001), myocardial
only group, had a 19% ( p < 0.05) reduction in nonfatal infarction (95 vs. 57 myocardial infarctions; p = 0.002),
myocardial infarctions and a 24% reduction in deaths from unstable angina (87 vs. 60 first unstable angina events;
CHD death. p = 0.02), coronary revascularization procedures (157 vs.
The Helsinki Heart Study (HHS) was a randomized 5- 106 procedures; p = 0.001), coronary events (215 vs. 163
year double-blind trial that involved 4081 men between the coronary events; p = 0.006), and CV events (255 vs. 194
ages of 40 and 55 years [30]. Subjects were randomly CV events; p = 0.003).
assigned to receive either gemfibrozil (600 mg twice a The Fukuoka Atherosclerosis Trial (FAST) was a RCT
day) or placebo. Gemfibrozil therapy produced a mean 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 isolated hypertriglyceridemia or low HDL-C in primary
[40]. This study is a primary prevention trial on high-risk prevention. Lloyd-Jones et al. [42] used the eligibility
individuals, as they already had documented carotid ath- criteria of the major primary prevention trials in the FHS
erosclerosis. It included 246 asymptomatic men with subjects and found that 40% of men and 80% of women had
hyperlipidemia and investigated the effect of reducing lipid profiles that have not been studied in large trials to
serum lipids on carotid artery intima-media thickness date. They also observed a large number of CHD events in
(IMT). It compared three treatments: diet alone, diet with these ineligible subjects in whom hypertriglyceridemia
pravastatin, and diet with probucol. A total of 246 asymp- was common. New trials looking at these questions are
tomatic hypercholesterolemic patients (mean age 66 years) essential to better understand the metabolic differences
were randomized to receive either probucol (500 mg/day) among the subgroups and the role of lipid-lowering therapy
or pravastatin (10 mg/day) or to enter a control group (diet vs. other strategies for primary prevention in the general
alone); they were followed for 2 years. Over the 2-year population (Tables 3 and 4).
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, 5. Treatment
and p < 0.05, respectively). After 2 years, the probucol and
pravastatin groups showed a significant reduction in IMT Aggressive treatment of TC and LDL-C has shown to
( 13.9% and 13.9% and p < 0.01 and p < 0.01, respec- decrease the incidence of CVD. This has been shown in
tively), but there was significant IMT thickening (23.2%; patients with established CHD and in families with hyper-
p < 0.05) in the diet alone group. CV events were also cholesterolemia, where aggressive reduction in the lipid
reduced by pravastatin (absolute risk [AR] for any CV levels resulted in decreased CVD incidence [43 45]. The
event 4.8% with pravastatin vs. 13.6% with diet alone, p Simvastatin Survival Study (4S) and the AFCAPS/Tex-
value not provided) and probucol (l2.4% with probucol vs. CAPS trials also has demonstrated that there is no thresh-
13.6% with diet alone; p = 0.0136) after 2 years. old for LDL-C reduction in primary prevention beyond
The Heart Protection Study (HPS) examined the effect of which additional reduction in CVD events would not be
lipid-lowering in patients with simvastatin [32]. This study achieved [46]. In the 4S trial CVD event rates were
included 20,536 patients considered high risk for CHD. reduced progressively with increasing reduction in the
Patients were randomly allocated to receive 40 mg simvas- LDL-C levels. There was a 18.2% event rate with < 34%
tatin daily or matching placebo. A subset of these patients reduction in LDL-C level from baseline, 13.8% even rate
had a low-density lipoprotein cholesterol (LDL-C) levels with reduction between 34 44% and 10.6% event rate in
not normally considered to be elevated. In these patients those with 44 70% reduction [47]. All these evidence
who had baseline LDL-C level of 116 mg/dl or lower, suggest aggressive lowering of LDL-C and TC level with
further lowering LDL-C by 39 mg/dl resulted in a 25% risk all the available modalities to achieve maximum CV
reduction for CHD. Over a 5-year treatment period, the benefits. Based on their risk factors, patients can be scored
study demonstrated that 40 mg of simvastatin reduced the according to the modified Framingham scoring and based
risk of nonfatal myocardial infarction. There were signifi- on these scores, the aggressiveness of treatment can be
cant reductions in the first event rate for nonfatal myocardial modified [37] (Table 5).
infarction or coronary death ( p < 0.0001) compared to Dietary changes and risk factor modifications (smoking
placebo. cessation, weight control, hypertension (HTN) control,
Meta-analysis of the primary prevention trials showed increased physical activity, diabetes mellitus (DM) control)
that active treatment of hyperlipidemia was associated with is strongly recommended in patients with hyperlipidemia.
a 34% risk reduction ( p < 0.001) in major coronary events. Various studies have shown a correlation between increased
Compared with controls, active treatment was associated physical activities with decreased CV mortality [48 50].
with a lower risk of coronary disease mortality ( p = 0.09), Though regular exercise has been shown to increase the
CV mortality ( p = 0.01), and all-cause mortality ( p = 0.18)
in the primary prevention trials [36]. However, Pignone et Table 5
al. [41] in a meta-analysis of four randomized controlled Drug therapy for primary preventiona
trials found that, although treatment of patients with no Risk category 10-year Level to Goal of
previous history of CHD with lipid-lowering agents (statins, CHD riskb consider therapyc therapyc
cholestyramine, gemfibrozil) decreased CV events, they did Multiple (2+) >20% >100 mg/dl < 100 mg/dl
not significantly decrease CHD mortality. risk factors 10 20% >130 mg/dl < 130 mg/dl
< 10% >160 mg/dl < 130 mg/dl
Although these studies have addressed various issues, 0 1 Risk < 10% >190 mg/dl < 160 mg/dl
there are still questions about the primary prevention of factors
CVD. There have been patient groups (elderly, women, a
Derived from Adult Treatment Panel III (ATP III).
diabetic) who were not adequately represented in these b
Framingham Score.
trials. Thus far no study has evaluated the effect of treating Low-density cholesterol level, CHD: coronary heart disease.
J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366 359

HDL-C levels, it has minimal effect on the LDL-C levels dyslipidemic. Hypertensive patients (10,305) with TC
[51,52]. Patients who follow the NCEP Step 2 diet have concentrations 6.5 mmol/l or less were randomly assigned
decreased fat intake, but have failed to lower LDL-C level in to receive atorvastatin 10 mg or placebo in addition to
men or women with high-risk lipoprotein levels [53]. Hence their antihypertensive agent. Treatment was stopped after
diet and exercise in spite of being helpful in patients with a median follow-up of 3.3 years. The total CV events
hyperlipidemia are seldom successful in meeting the desired (389 vs. 486, p = 0.0005), and total coronary events (178
or recommended lipid goals. Most patients need to have vs. 247, p = 0.0005) were significantly lower in the
additional drug therapy for adequate reduction in their lipid atorvastatin group as compared to the placebo group
levels. There are various agents in the market currently [95]. Regression analysis of all the major statin trials
available in treatment of patients with lipid abnormalities done by Jackson et al. [96] found that mortality benefits
(Table 5). of statins outweigh risks in people with a 10-year CHD
risk of more than 13%. La Rosa et al. [36] found that,
5.1. HMG-coA reductase inhibitors (statins) after 4 6 years of treatment for primary prevention,
statins compared with placebo did not significantly reduce
The 3-hydroxy-3-methylglutaryl coenzyme A reductase all cause mortality or CHD mortality, but did reduce
inhibitors commonly known as statins are the most often major coronary events and CV mortality (all cause
prescribed lipid-lowering agents in the US. Recent clinical mortality: OR 0.87, 95% CI 0.71 1.06; CHD mortality
trials using statins to treat LDL-C have demonstrated OR 0.73, 95% CI 0.51 1.05; major coronary events: OR
beyond reasonable doubt that coronary events can be 0.66, 95% CI 0.57 0.76; CV mortality: OR 0.68, 95% CI
prevented by decreasing LDL-C levels [6,16,17]. Statins 0.50 0.93). The currently available statins in the US
are structurally similar to HMG-coenzyme A, which is a market are atorvastatin, fluvastatin, lovastatin, pravastatin,
precursor to cholesterol and competitively inhibit the and simvastatin. Rosuvastatin and pitavastatin are two
HMG-coA reductase that is the last step in the synthesis new statins currently in development [97]. Rosuvastatin
of cholesterol [54]. Statins also upregulate the LDL-C has been submitted for FDA approval whereas pitavastatin
receptor activity and decrease the entry of LDL-C into is now in phase II trials. Rosuvastatin is a new statin
the circulation resulting in low serum LDL-C concentration under investigation, with a number of favorable character-
[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 Table 6
Beneficial effects of statins in preventing CVD
clinical trials indicate that statin-treated individuals have
significantly less CVD than patients with comparable Lipid effects
(1) Decreases LDL-C level [70].
serum cholesterol levels [57,58]. This is probably due to (2) Lowers TGL levels [71,72].
their beneficial pleiotropic effects: improving or restor- (3) Increases HDL-C and apolipoprotein A-I (apoA-I) [73,74].
ing endothelial function, enhancing the stability of athero- (4) Decreases oxidation of LDL-C [75].
sclerotic plaques, and decreasing oxidative stress and Vascular effects
vascular inflammation [59,60]. Statins also have beneficial (5) Increases endothelium-dependent vasodilator response [76].
(6) Activates endothelial NO synthesis [77].
role in the coagulation and fibrinolytic pathways (see Table (7) Promotes plaque stabilization [78].
6). Hypercholesterolemia has been shown to impair endo- (8) Blocks the accumulation of cholesterol in macrophages [79].
thelial function, one of the earliest manifestations of (9) Reduces monocyte adhesion to endothelial cells [80].
atherosclerosis [61]. Statins improve endothelial function (10) Antiproliferative effects on smooth muscle cells [81].
by reducing oxidative stress [62], plasminogen activator (11) Suppresses neointimal thickening [82].
Antithrombotic effects
inhibitor-1 (PAI-1) expression [63], and by inhibiting the (12) Reduces thromboxane synthesis [83].
expression of endothelin-1, a potent vasoconstrictor [64]. (13) Reduces platelet aggregation [84].
Statins also improve endothelial function by increasing (14) Reduces tissue factor/extrinsic pathway inhibitor (EPI) production
nitrous oxide (NO) bioavailability by stimulating endothe- [85].
lial NO synthase (eNOS) [65,66], and by increasing the (15) Decreases plasma fibrinogen concentrations [86,87].
(16) Improves whole blood and plasma viscosity [88].
expression of tissue-type plasminogen activator [67]. Sta- (17) Reduces plasminogen activator inhibitor-1 (PAI-1) activity [89].
tins have also been noted to have a specific effect on (18) Reduces platelet-associated ox-LDL (Pox-LDL) activity [90].
lowering high-sensitivity C-reactive protein (hsCRP) lev- (19) Decreases platelet-dependent thrombin generation (PDTG) [91]
els, independent of the effects on cholesterol or other Other effects
inflammatory markers and improve the global CV risk (20) Reduces C-reactive protein levels [92].
(21) Greater reduction in mean blood pressure when used with ACEI. [93].
[68,69]. (22) Decreases proteniuria. [94].
The recently published Anglo-Scandinavian Cardiac (23) Anti-oxidant effect [62]
Outcomes Trial (ASCOT) assessed the benefits of cho- CVD: cardiovascular disease; LDL-C: low density lipoprotein cholesterol;
lesterol lowering in the primary prevention of CHD in HDL-C: high-density lipoprotein cholesterol; TGL: triglycerides; NO: nitric
hypertensive patients who are not conventionally deemed 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 ability to increase the HDL-C and HDL-C levels [2] by 26%
selectivity, minimal metabolism, and a low propensity for and 36%, respectively, at a dose of 3 g/day, greater than any
cytochrome P-450 drug interactions (see Table 7). In other agent available [113]. Other than estrogen, niacin is
comparative clinical trials, rosuvastatin given at 5 10 the only drug that has been shown to lower elevated levels
mg/day reduced LDL to a significantly greater extent of lipoprotein (a) [Lp(a)], which has been shown to increase
(39 60%) than atorvastatin 10 mg/day, pravastatin 20 risk for CVD [114]. Niacin (1.5 g/d) reduced Lp(a) levels by
mg/day, and simvastatin 20 mg/day. Rosuvastatin also 35% at 26th week of treatment.
has beneficial effects on HDL and TGL [98 101]. The major disadvantage in the use of niacin is the
Statin therapy has been proven to be safe without major adverse effects [115]. Niacin treatment causes significant
adverse effects [36,102,103]. The common side effects are flushing and pruritis. This has lead to significant problem
elevated liver transaminase level and myopathy. Serious with noncompliance among patients. Forty-three percent of
side effects like rhabdomyolysis and peripheral neuropathy individuals given regular nicotinic acid and forty-two per-
have been reported, though they are extremely rare [104 cent of those given sustained-release nicotinic acid discon-
108]. The incidence of serious adverse effects are increased tinued the medication because of side effects. Starting at a
in patients who use concomitant drugs like gemfibrozil, low dose and titrating to desired dose could reduce the
macrolide antibiotics, itraconazole, cyclosporin, nicotinic flushing. Taking aspirin or other non-steroidal anti-inflam-
acid, and any other medications that interfere with the matory drugs about 30 min prior to taking niacin also
cytochrome P-450 drug metabolism pathway [109 111]. minimizes flushing [116]. Other adverse effects include
Caution should be exercised when these agents are used (see gastrointestinal complaints like nausea, dyspepsia, flatu-
Table 7). If myopathy is strongly suspected or if there is lence, vomiting, diarrhea, and activation of peptic ulcer
elevation of the serum transaminase levels >3 times the disease [115]. Hyperuricemia and gout can occur and
upper limit of normal, statins should be discontinued. The worsening of hyperglycemia may be seen in patients with
current ATP III recommendation is to consider statins as the diabetes [117]. Hepatotoxicity has been reported and this
first line of treatment in the treatment of elevated LDL-C risk seems to be higher in patients who take sustained
levels [18]. release niacin [118]. Hence liver enzymes need to be
monitored periodically in patients who take nicotinic acid
5.2. Nicotinic acid (niacin) compounds. The risk of hepatotoxicity with Niaspan is
however less as compared to other sustained released
Niacin is the oldest agent in the lipid-lowering group of niacins [119].
drugs that had been shown to decrease CVD mortality [112]. Nicotinic acid has is most effective in preventing CVD
Niacin inhibits the mobilization of free fatty acids from the when give in combination with resins [120,121] or fibrates
peripheral tissues and hence reduces the synthesis of TGL [122] or stains [123]. Guyton et al. [124] studied the
[113]. It also inhibits the secretion of VLDL and the combination of Niaspan and statin. They found that the
conversion of VLDL to LDL [113]. One of the important Niaspan plus statin combination lowered LDL-C (32%),
effects of niacin in the treatment of lipid disorders is its apolipoprotein B (26%), TC (23%), triglycerides (30%), and
Lp(a) (19%), and increased HDL cholesterol (26%). Myop-
Table 7 athy, rhabdomyolysis, and substantial transaminase eleva-
Drugs that inhibit cytochrome P-3A4 tions can occur with this combination [123]. Hence, careful
Calcium channel blockers attention should be given to niacin formulation and dosing,
Verapamil liver functions be monitored periodically, and patients
should be educated to recognize symptoms of myopathy
Macrolide antibiotics
Azithromycin [123]. The current ATP III recommendation is to use
Clarithromycin nicotinic acid as a single agent in high-risk patients with
Erythromycin atherogenic dyslipidemia without substantial elevation in
Azole antifungals the LDL-C levels [18]. It can also be used in combination in
patients with atherogenic dyslipidemia with elevated LDL-C
Ketoconazole levels.
Protease inhibitors
Amprenavir 5.3. Fibric acid derivatives (fibrates)
The currently available fibrates, gemfibrozil, fenofibrate,
Saquinavir and clofibrate in the US resemble short chain fatty acids in
Grapefruit juice (>1 quart/day) their structure [125]. Fibrates increase peripheral fatty acid
Nefazadone uptake and oxidation in the liver [126]. They enhance
Cyclosporine 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 361

atherogenic dyslipidemia is its ability to decrease the TGL higher the initial triglyceride level, the greater the reduction
levels. Recent research has shown the fibrates to be agonist noted. The current ATP III recommendation on the use of
for the nuclear transcription factor, peroxisome proliferator- fibrates is to use these agents in patients with very high TGL
activated receptor (PPAR)-alpha [127]. The hypotriglyceri- level that may increase their risk for pancreatitis [18]. They
demic actions of fibrates seem to involve PPAR mechanism have also been recommended in people with dysbetalipo-
with increased hydrolysis of plasma triglycerides due to proteinemia (elevated beta-VLDL), low LDL-C atherogenic
induction of LPL and reduction of apoC-III expression dyslipidemia, and in combination with statin in elevated
[128]. They also stimulate cellular fatty acid uptake and LDL-C atherogenic dyslipidemia.
conversion to acetyl-CoA derivatives. They also increase
the PPAR mediated activation of apolipoprotein Al gene and 5.4. Bile acid sequestrants (resins)
downregulate the apolipoprotein CIII gene [129]. There is
increased peroxisomal and mitochondrial beta-oxidation and Resins decrease serum cholesterol level by disrupting the
decreased synthesis of fatty acids and triglycerides resulting enterohepatic circulation of the bile acids, causing the
in decreased production of VLDL [130]. Fibrates exert their shunting of cholesterol into bile acid syntheses in the liver
hypolipidemic effect by enhancing the catabolism of tri- [140,141]. The available agents in this group are cholestyr-
glyceride-rich particles and reducing secretion of VLDL amine, colestipol and colesevelam. The resins are able to
particles. Increased risk of CVD seen with elevated fibrin- reduce the LDL-C levels, and increase HDL-C levels
ogen level is reduced by fibrates like benzafibrate and [142,143]. The TGL levels, which are initially elevated with
fenofibrate (not available in US) by decreasing the fibrino- treatment, by about 5 20% with bile acid sequestrant
gen levels [131,132]. therapy, tend to be transient and are typically related to
In two large primary prevention trials; World Health high baseline TG levels or dysbetalipoproteinemia
Organization (WHO) clofibrate trial and the HHS gemfi- [144,145]. Although the LDL-C response was dosage-de-
brozil trial, treatment with clofibrate and gemfibrozil has pendent, there seemed to be nonlinear response with bile
been shown to decrease the risk of fatal and nonfatal acid sequestrants [144,146,147]. Currently resins are mostly
myocardial infarction [133,134]. The Veterans Affairs Co- used as an adjunctive to statins in the treatment of hyper-
operative Studies Program High-Density Lipoprotein Cho- lipidemia. While doubling the dose of statins resulted only
lesterol Intervention Trial [VA-HIT] was a secondary in 6% further reduction in LDL-C, adding a small dose of
prevention trial comparing gemfibrozil (1200 mg/day) with resins resulted in lowering of LDL-C levels by 12 16%
placebo in 2531 men with coronary heart disease, an HDL [148,149].
cholesterol level of 40 mg/dl (1.0 mmol/l) or less, and an The major adverse effect of the resins is gastrointestinal
LDL cholesterol level of 140 mg/dl (3.6 mmol/l) or less upset. In the Lipid Research Clinics-Coronary Primary
[135]. They hypothesized that therapy aimed at raising HDL Prevention Trial (LRC-CPPT), more than 1900 patients
cholesterol levels and lowering levels of triglycerides would received cholestyramine therapy at a dosage of 24 g/day.
reduce the incidence of death from CHD. One year after By the end of the first year of the study, 68% of these
randomization, the mean HDL-C level was 6% higher in the patients reported at least 1 gastrointestinal side effect, 39%
gemfibrozil group than in the placebo group (34 vs. 32 mg/ had constipation, 32% had abdominal gas, and 27% had
dl, p < 0.001); the mean TC level was 4% lower (170 vs. 177 heartburn [13]. This leads to poor compliance and a very
mg/dl, p < 0.001); and the mean TGL level was 31% lower high discontinuance rate of the resins among patients
(115 vs. 166 mg/dl, p < 0.001). Gemfibrozil therapy was [150 152]. Of the three resins available in the market,
associated with a 22% reduction in the rate of death from colesevelam is easy to administer and is better tolerated. It
CHD or nonfatal myocardial infarction ( p = 0.006). lacks the constipating effect that is typical of other bile
Fibrates are generally well tolerated by patients. The acid sequestrants. In a study by Davidson et al. [153] the
common side effects are usually gastrointestinal symptoms overall compliance with colesevelam treatment was very
like diarrhea, abdominal pain, constipation, and dyspepsia. high (93%). The current ATP III recommendation on the
These drugs also increase the lithogenecity of the bile and use of resins is for patients with moderate elevation in
may result in the formation of gall stones [136]. The fibrates LDL-C levels, younger person with elevated LDL, women
bind with serum albumin very strongly and may displace who are pregnant or considering pregnancy, and for
other albumin binding drugs like warfarin and increase their combination therapy with statins in patients with very high
serum levels [137]. In patients with hypertriglyceridemia, LDL-C levels [18].
fibrate therapy may increase the LDL-C levels [138,139].
Hence LDL-C levels should be closely monitored. In 5.5. Ezetimibe (Zetia)
patients who have elevated LDL levels, fibrates can be
cautiously used in combination with statins, being aware of Ezetimibe is a new class of lipid-lowering agent intro-
the fact that this combination can increase the risk of duced in the treatment of hypercholesterolemia. It is related
myopathy and rhabdomyolysis [109]. The fibrates are able to phytoesterols and decreases the lipid levels by inhibiting
to reduce the triglycerides level by 25 50% [139]. The 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 C should be lowered to maximize clinical benefits. This will
small intestine, where it inhibits the cholesterol absorption probably be answered by ongoing clinical trials like the
[10,155]. The efficacy and safety of ezetimibe was evaluat- Study of the Effectiveness of Additional Reductions in
ed in a randomized, double-blinded, placebo-controlled trial Cholesterol and Homocysteine (SEARCH), Incremental
of 892 patients with primary hypercholesterolemia [156]. Decrease in Endpoints through Aggressive Lipid-Lowering
Patients received ezetimibe 10 mg or placebo orally each (IDEAL) and Treating to New Targets (TNT), which are
morning for 12 weeks. A total of 434 men and 458 women specifically addressing this question. In conclusion, the
(ages 18 85 years, 666 ezetimibe 10 mg, 226 placebo) were relation between dyslipidemia and CVD are real and physi-
involved in the study. Ezetimibe was found to significantly cians should aggressively identify individuals with athero-
reduce direct LDL-C by a mean of 16.9%, compared with an genic dyslipidemia for proper management to prevent CVD
increase of 0.4% with placebo ( p < 0.01). Ezetimibe effects morbidity and mortality.
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 References
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