You are on page 1of 12

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


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: movaheda@mail.ecu.edu (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.
doi:10.1016/j.ijcard.2003.07.039
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.
Obesity
Smoking and more advanced atherosclerotic lesions in middle-aged
Sedentary life style subjects are correlated with total cholesterol (TC), LDL-C
Diabetes
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
a
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
a
Derived from Adult Treatment Panel III (ATP III); HDL: high-density compared with placebo. These changes in the lipoprotein
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.
c
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
Diltiazem
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
Fluconazole
patients with atherogenic dyslipidemia with elevated LDL-C
Itraconazole
Ketoconazole levels.
Protease inhibitors
Amprenavir 5.3. Fibric acid derivatives (fibrates)
Indinavir
Nelfinavir
The currently available fibrates, gemfibrozil, fenofibrate,
Ritonavir
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-
Cilostazol
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
LDL-C, apolipoprotein B, TC, TGL, HDL-C, and the
subfraction of HDL-C, HDL [3] ( p < 0.01). [1] http://www.cdc.gov/health/cardiov.htm.
The efficacy and safety of adding ezetimibe to ongoing [2] AHA 2002. Heart and stroke statistical update. Dallas, TX: AHA,
2001. pp. 4 5.
statin therapy in patients with primary hypercholesterolemia
[3] Haust MD, More RH. Development of modern theories on the path-
was also evaluated in a randomized, double-blinded, place- ogenesis of atherosclerosis. In: Wissler RW, Geer JC, editors. The
bo-controlled study [157]. The study group included 769 pathogenesis of atherosclerosis. Baltimore, MD: Williams and Wil-
adults (aged z 18 years) with primary hypercholesterolemia kins, 1972. pp. 1 19.
who had not achieved NCEP/ATP II goals with dietary [4] Thannhauser SJ, Magendantz H. The different clinical groups of
alteration and statin monotherapy. Patients receiving a stable xanthomatous disease: a clinical physiological study of 22 cases.
Ann Intern Med 1938;11:1662 746.
dose of a statin for >6 weeks were randomized to receive [5] Kannel WB, Castelli WP, Gordon T, McNamara PM. Serum choles-
concurrent treatment with placebo (n = 390) or ezetimibe terol, lipoproteins, and the risk of coronary heart disease. Ann Intern
(n = 379), 10 mg/day, in addition to continuing their open- Med 1971;74:1 12.
label statin for 8 weeks. Ongoing statin therapy plus [6] Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA,
ezetimibe led to changes of 25.1% for LDL-C (HDL-C et al. Primary prevention of acute coronary events with lovastatin in
men and women with average cholesterol levels: results of AFCAPS/
+ 2.7%; TGL 14.0%) compared with LDL-C 3.7% TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention
( p < 0.001), HDL-C + 1.0% ( p < 0.05), and TGL 2.9% Study. JAMA 1998;279:1615 22.
( p < 0.001) for placebo added to ongoing statin therapy. [7] Randomized trial of cholesterol lowering in 4444 patients with cor-
Among patients not at LDL-C goal at on-statin baseline, onary heart disease: the Scandinavian Simvastatin Survival Study
71.5% receiving statin plus ezetimibe vs. 18.9% receiving (4S). Lancet 1994;344:1383 9.
[8] The Scandanavian Simvastatin Survival Study (4S) study group.
statin plus placebo reached their goal at end point (odds Neaton JD, Wentworth D. Serum cholesterol, blood pressure, ciga-
ratio 23.7; p < 0.001). The co-administration of ezetimibe rette smoking, and death from coronary heart disease. Overall find-
statins was well tolerated and caused a significant additive ings and differences by age for 316,099 white men. Multiple Risk
reduction in LDL-C in other RCTs [158]. Ezetimibe has Factor Intervention Trial Research Group. Arch Intern Med
been used in more than 4700 patients without any major 1992;152:56 64.
[9] Wilson PW, Garrison RJ, Castelli WP, Feinleib M, McNamara PM,
adverse events. The common side effects were fatigue Kannel WB. Prevalence of coronary heart disease in the Framing-
(2.2%), abdominal pain (3.0%), diarrhea (3.7%), back pain ham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol
(4.1%), arthralgia (3.8%), and coughing (2.3%) [68]. No 1980;46:649 54.
major drug interaction was seen with concomitant use of [10] Bays HE, Moore PB, Drehobl MA, Rosenblatt S, Toth PD, Dujovne
CA, et al. Effectiveness and tolerability of ezetimibe in patients with
ezetimibe and other lipid-lowering agents [154].
primary hypercholesterolemia: pooled analysis of two phase II stud-
ies. Clin Ther 2001;23:1209 30.
[11] Stein E. The lower the better? Reviewing the evidence for more
6. Conclusion aggressive cholesterol reduction and goal attainment. Atheroscler
Suppl 2002;2:19 25.
There are still many unanswered questions in the area of [12] Levine GN, Keaney Jr. JF, Vita JA. Cholesterol reduction in cardio-
vascular disease. Clinical benefits and possible mechanisms. N Engl
primary prevention of CVD. The RCTs done to date have J Med 1995;332:512 21.
not included all subgroups of population. Large proportions [13] Lipid Research Clinics Program JA. The lipid research clinics cor-
of dyslipidemic patients who are being treated do not onary primary prevention trial results: I. Reduction in incidence of
achieve the NCEP target levels [159,160]. The Lipid Treat- coronary heart disease. JAMA 1984;251:351 64.
ment Assessment Project (L-TAP) study showed that only [14] Verschuren WM, Jacobs DR, Bloemberg BP, Kromhout D,
Menotti A, Aravanis C, et al. Serum total cholesterol and long-
38% of the patients treated in primary care settings attained term coronary heart disease mortality in different cultures. Twenty-
LDL-C target levels or values lower than the goals [161]. five-year follow-up of the seven countries study. JAMA 1995;274:
Another unanswered question is how low the TC and LDL- 131 6.
J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366 363

[15] Hoeg JM, Brewer Jr HB. 3-Hydroxy-3-methylglutaryl-coenzyme A [31] Howes LG, Simons LA. Efficacy of drug intervention for lipids in
reductase inhibitors in the treatment of hypercholesterolemia. JAMA the prevention of coronary artery disease. Aust N Z J Med 1994;24:
1987;258:3532 6. 107 12.
[16] Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane [32] Heart Protection Study collaboration group. MRC/BHF Heart Pro-
PW, et al. Prevention of coronary heart disease with pravastatin in tection Study of cholesterol lowering with simvastatin in 20,536
men with hypercholesterolemia. West of Scotland Coronary Preven- high-risk individuals: a randomized placebo-controlled trial. Lancet
tion Study Group. N Engl J Med 1995;333:1301 7. 2002;360:7 22.
[17] The Long-Term Intervention with Pravastatin in Ischaemic Disease [33] Bucher HC, Griffith LE, Guyatt G. Systematic review on the risk
(LIPID) Study Group. Prevention of cardiovascular events and and benefit of different cholesterol-lowering interventions. Arterios-
death with pravastatin in patients with coronary heart disease and cler Thromb Vasc Biol 1999;19:187 95.
a broad range of initial cholesterol levels. N Engl J Med 1998;339: [34] Miettinen TA, Pyorala K, Olsson AG, Musliner TA, Cook TJ, Fae-
1349 57. rgeman O, et al. Cholesterol-lowering therapy in women and elderly
[18] The Scandanavian Simvastatin Survival Study (4S) study group. patients with myocardial infarction or angina pectoris: findings from
Third report of the expert panel on detection, evaluation, and treat- the Scandinavian Simvastatin Survival Study (4S). Circulation
ment of high blood cholesterol in adults (Adult Treatment Panel III, 1997;96:4211 8.
or ATP III) final report. Circulation 2002;106:3143 420. [35] Smith GD, Song F, Sheldon TA. Cholesterol lowering and mortality:
[19] The Scandanavian Simvastatin Survival Study (4S) study group. the importance of considering initial level of risk. [correction
Summary of the second report of the National Cholesterol Education appears in BMJ 306 (1993) 1648] BMJ 1993;306:1367 73.
Program (NCEP) expert panel on detection, evaluation, and treat- [36] LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary
ment of high blood cholesterol in adults (Adult Treatment Panel II). disease: a meta-analysis of randomized controlled trials. JAMA
JAMA 1993;269:3015 23. 1999;282:2340 6.
[20] Enos WF, Holmes RH, Beyer J. Coronary disease among United [37] http://www.nhlbi.nih.gov/guidelines/cholesterol/chap_3.pdf.
States soldiers killed in action in Korea. Preliminary report. By Wil- [38] Wilson PWF, DAgostino RB, Levy D, Belanger AM, Silbershatz H,
liam F. Enos, Robert H. Holmes and James Beyer. JAMA 1986;256: Kannel WB. Prediction of coronary heart disease using risk factor
2859 62. categories. Circulation 1998;97:1837 47.
[21] McNamara JJ, Molot MA, Stremple JF, Cutting RT. Coronary artery [39] Expert Panel on Detection, Evaluation, and Treatment of High Blood
disease in combat casualties in Vietnam. JAMA 1971;216:1185 7. Cholesterol in Adults. Executive summary of the third report of the
[22] The Pathobiological Determinants of Atherosclerosis in Youth National Cholesterol Education Program (NCEP) Expert Panel on
(PDAY) Research Group. Relationship of atherosclerosis in young Detection, Evaluation, and Treatment of High Blood Cholesterol in
men to serum lipoprotein cholesterol concentrations and smoking. A Adults (Adult Treatment Panel III). JAMA 2001;285:2486 97.
preliminary report from the Pathobiological Determinants of Ath- [40] Sawayama Y, Shimizu C, Maeda N, Tatsukawa M, Kinukawa N,
erosclerosis in Youth (PDAY) Research Group. JAMA 1990;264: Koyanagi S, et al. Effects of probucol and pravastatin on common
3018 24. carotid atherosclerosis in patients with asymptomatic hypercholes-
[23] The Pathobiological Determinants of Atherosclerosis in Youth terolemia. Fukuoka Atherosclerosis Trial (FAST). J Am Coll Cardiol
(PDAY) Research Group. Natural history of aortic and coronary 2002;39:610 6.
atherosclerotic lesions in youth. Findings from the PDAY Study. [41] Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for
Pathobiological Determinants of Atherosclerosis in Youth (PDAY) primary prevention of coronary heart disease: meta-analysis of ran-
Research Group. Arterioscler Thromb 1993;13:1291 8. domized trials. BMJ 2000;321:983 6.
[24] Tuzcu EM, Kapadia SR, Tutar E, Ziada KM, Hobbs RE, McCarthy [42] Lloyd-Jones DM, ODonnell CJ, DAgostino RB, Massaro J, Silber-
PM, et al. High prevalence of coronary atherosclerosis in asymp- shatz H, Wilson PW. Applicability of cholesterol-lowering primary
tomatic teenagers and young adults: evidence from intravascular prevention trials to a general population: the Framingham heart
ultrasound. Circulation 2001;103:2705 10. study. Arch Intern Med 2001;161:949 54.
[25] Newman WP, Freedman DS, Voors AW, Gard PD, Srinivasan SR, [43] The Post Coronary Artery Bypass Graft Trial Investigators. The
Cresanta JL, et al. Relation of serum lipoprotein levels and systolic effect of aggressive lowering of low-density lipoprotein cholesterol
blood pressure to early atherosclerosis: the Bogalusa Heart Study. levels and low-dose anticoagulation on obstructive changes in sa-
N Engl J Med 1986;314:138 44. phenous-vein coronary-artery bypass grafts. N Engl J Med 1997;
[26] Holme I, Solberg LA, Weissfeld L, Helgeland A, Hjermann I, Leren 336:153 62.
P, et al. Coronary risk factors and their pathway of action through [44] Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM,
coronary raised lesions, coronary stenoses and coronary death: mul- et al. Aggressive lipid-lowering therapy compared with angioplasty
tivariate statistical analysis of an autopsy series: the Oslo Study. Am in stable coronary artery disease. Atorvastatin versus Revasculariza-
J Cardiol 1985;55:40 7. tion Treatment Investigators. N Engl J Med 1999;341:70 6.
[27] Romm PA, Green CE, Reagan K, Rackley CE. Relation of serum [45] Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ,
lipoprotein cholesterol levels to presence and severity of angiograph- Stalenhoef AF. Effect of aggressive versus conventional lipid low-
ic coronary artery disease. Am J Cardiol 1991;67:479 83. ering on atherosclerosis progression in familial hypercholesterolae-
[28] Kempen HJ, van Gent CM, Buytenhek R, Buis B. Association of mia (ASAP): a prospective, randomised, double-blind trial. Lancet
cholesterol concentrations in low-density lipoprotein, high-density 2001;357:577 81.
lipoprotein, and high-density lipoprotein subfractions, and of apoli- [46] Pedersen TR. Aggressive lipid-lowering therapy: a clinical impera-
poproteins AI and AII, with coronary stenosis and left ventricular tive. Eur Heart J 1998;19:M15 21 [Suppl. M].
function. J Lab Clin Med 1987;109:19 26. [47] Pedersen TR, Kjekshus J, Olsson AG, Cook TJ. 4S results support
[29] Dahlen GH, Guyton JR, Attar M, Farmer JA, Kautz JA, Gotto Jr. AHA guidelines to reduce LDL-cholesterol to less than 100 mg/dl
AM. Association of levels of lipoprotein Lp(a), plasma lipids, and inpatients with CHD. Circulation 1997;96:717 [Suppl. I].
other lipoproteins with coronary artery disease documented by an- [48] Wannamethee SG, Shaper AG, Walker M. Physical activity and
giography. Circulation 1986;74:758 65. mortality in older men with diagnosed coronary heart disease. Cir-
[30] Manninen V, Elo MO, Frick MH, Haapa K, Heinonen OP, Hein- culation 2000;102:1358 63.
salmi P, et al. Lipid alterations and decline in the incidence of [49] Leon AS, Connett J. Physical activity and 10.5 year mortality in the
coronary heart disease in the Helsinki Heart Study. JAMA 1988; Multiple Risk Factor Intervention Trial (MRFIT). Int J Epidemiol
260:641 51. 1991;20:690 7.
364 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366

[50] Rosengren A, Wilhelmsen L. Physical activity protects against cor- [68] Plenge JK, Hernandez TL, Weil KM, et al. Simvastatin lowers C-
onary death and deaths from all causes in middle-aged men. Evi- reactive protein within 14 days: an effect independent of LDL cho-
dence from a 20-year follow-up of the primary prevention study in lesterol reduction. Circulation 2002;106:1447 52.
Goteborg. Ann Epidemiol 1997;7:69 75. [69] Albert MA, Danielson E, Rifai N, for PRINCE Investigators. Effect
[51] Kokkinos PF, Fernhall B. Physical activity and high density lipo- of statin therapy on C-reactive protein levels: the pravastatin inflam-
protein cholesterol levels: what is the relationship? Sports Med mation/CRP evaluation (PRINCE). A randomized trial and cohort
1999;28:307 14. study. JAMA 2001;286:64 70.
[52] Kokkinos PF, Holland JC, Narayan P, Colleran JA, Dotson CO, [70] Mabuchi H, Haba T, Tatami R, Miyamoto S, Sakai Y, Wakasugi T,
Papademetriou V. Miles run per week and high-density lipoprotein et al. Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coen-
cholesterol levels in healthy, middle-aged men. A dose response zyme A reductase on serum lipoproteins and ubiquinone-10 levels in
relationship. Arch Intern Med 1995;155:415 20. patients with familial hypercholesterolemia. N Engl J Med
[53] Stefanick ML, Mackey S, Sheehan M, Ellsworth N, Haskell WL, 1981;305:478 82.
Wood PD. Effects of diet and exercise in men and postmenopausal [71] Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J,
women with low levels of HDL cholesterol and high levels of LDL Isaacsohn JL, Weiss SR, et al. Efficacy and safety of a new
cholesterol. N Engl J Med 1998;339:12 20. HMG-CoA reductase inhibitor, atorvastatin, in patients with hyper-
[54] Davignon J, Montigny M, Dufour R. HMG-CoA reductase inhibi- triglyceridemia. JAMA 1996;275:128 33.
tors: a look back and a look ahead. Can J Cardiol 1992;8:843 64. [72] Davidson MH, Stein EA, Dujovne CA, Hunninghake DB, Weiss SR,
[55] Reihner E, Rudling M, Stahlberg D, Berglund L, Ewerth S, Bjor- Knopp RH, et al. The efficacy and six-week tolerability of simvas-
khem I, et al. Influence of pravastatin, a specific inhibitor of HMG- tatin 80 and 160 mg per day. Am J Cardiol 1997;79:38 42.
CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med [73] Crouse III JR, Frohlich J, Ose L, Mercuri M, Tobert JA. Effects of
1990;323:224 8. high doses of simvastatin and atorvastatin on high-density lipoprotein
[56] Arad Y, Ramakrishnan R, Ginsberg HN. Effects of lovastatin therapy cholesterol and apolipoprotein A-I. Am J Cardiol 1999;83: 1476 7.
on very-low-density lipoprotein triglyceride metabolism in subjects [74] Kastelein JJ, Isaacsohn JL, Ose L, Hunninghake DB, Frohlich J,
with combined hyperlipidemia: evidence for reduced assembly and Davidson MH, et al. Comparison of effects of simvastatin versus
secretion of triglyceride-rich lipoproteins. Metabolism 1992;41: atorvastatin on high-density lipoprotein cholesterol and apolipopro-
487 93. tein A-I levels. Am J Cardiol 2000;86:221 3.
[57] Sacks FM, Pfeiffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole [75] Salonen R, Nyyssonen K, Porkkala-Sarataho E, Salmen JJ. The
TG, et al. The effect of pravastatin on coronary events after myo- Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravas-
cardial infarction in patients with average cholesterol levels: choles- tatin treatment on lipids, oxidation resistance of lipoproteins, and
terol and recurrent events trial investigators. N Engl J Med 1996; atherosclerotic progression. Am J Cardiol 1995;76:34 9.
335:1001 9. [76] Dupuis J, Tardif JC, Theroux P. Cholesterol reduction rapidly
[58] Packard CJ. Influence of pravastatin and plasma lipids on clinical improves endothelial function after acute coronary syndromes. The
events in the West of Scotland Coronary Prevention Study RECIFE (Reduction of Cholesterol in Ischemia and Function of the
(WOSCOPS). Circulation 1998;87:1440 5. Endothelium) trial. Circulation 1999;99:3227 33.
[59] Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methyl- [77] Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW. Pravastatin
glutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc sodium activates endothelial nitric oxide synthase independent of its
Biol 2001;21:1712 9. cholesterol-lowering actions. J Am Coll Cardiol 1999;33:234 41.
[60] McFarlane SI, Muniyappa R, Francisco R, Sowers JR. Clinical review [78] Dangas G, Badimon JJ, Smith DA, Unger AH, Levine D, Shao JH.
145: pleiotropic effects of statins: lipid reduction and beyond. J Clin Pravastatin therapy in hyperlipidemia effects on thrombus formation
Endocrinol Metab 2002;87:1451 8. and the systemic hemostatic profile. J Am Coll Cardiol 1999;33:
[61] Liao JK, Bettmann MA, Sandor T, Tucker JI, Coleman SM, Creager 1294 304.
MA. Differential impairment of vasodilator responsiveness of pe- [79] Kempen HJM, Vermeer M, de Wit E, Havekes LM. Vastatins inhibit
ripheral resistance and conduit vessels in humans with atherosclero- cholesterol ester accumulation in human monocyte-derived macro
sis. Circ Res 1991;68:1027 34. phages. Arterioscler Thromb 1991;11:146 53.
[62] Rikitake Y, Kawashima S, Takeshita S, Yamashita T, Azumi H, Yasu- [80] Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhib-
hara M, et al. Anti-oxidative properties of fluvastatin, an HMG-CoA itors decrease CD11b expression and CD11b-dependent adhesion of
reductase inhibitor, contribute to prevention of atherosclerosis in cho- monocytes to endothelium and reduce increased adhesiveness of
lesterol-fed rabbits. Atherosclerosis 2001;154: 87 96. monocytes isolated from patients with hypercholesterolemia. J Am
[63] Lopez S, Peiretti F, Bonardo B, Juhan-Vague I, Nalbone G. Effect of Coll Cardiol 1997;30:1212 7.
atorvastatin and fluvastatin on the expression of plasminogen acti- [81] Negre-Aminou P, van Vliet AK, van Erck M, van Thiel GC, van
vator inhibitor type-1 in cultured human endothelial cells. Athero- Leeuwen RE, Cohen LH. Inhibition of proliferation of human
sclerosis 2000;152:359 66. smooth muscle cells by various HMG-CoA reductase inhibitors;
[64] Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pas- comparison with other human cell types. Biochim Biophys Acta
cuala R, Hernandez G, Diaz C, et al. Effects of the 3-hydroxy-3-meth- 1997;1345:259 68.
ylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on [82] Igarashi M, Takeda Y, Mori S, Ishibashi N, Kamatsu E, Takahashi K.
the expression of endothelin-1 and endothelial nitric oxide synthase in Suppression of neointimal thickening by a newly developed HMG-
vascular endothelial cells. J Clin Invest 1998;101: 2711 9. CoA reductase inhibitor, BAYw6228, and its inhibitory effect on
[65] Tamai O, Matsuoka H, Itabe H, Wada Y, Kohno K, Imaizumi T. vascular smooth muscle cell growth. Br J Pharmacol 1997;120:
Single LDL apheresis improves endothelium-dependent vasodilata- 1172 8.
tion in hypercholesterolemic humans. Circulation 1997;95:76 82. [83] Notarbartolo A, Davi G, Averna M, Barbagallo CM, Ganci A, Giam-
[66] Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial marresi C. Inhibition of thromboxane biosynthesis and platelet func-
nitric oxide synthase by HMG CoA reductase inhibitors. Circulation tion by simvastatin in type IIa hypercholesterolemia. Arterioscler
1998;97:1129 35. Thromb Vasc Biol 1995;15:247 51.
[67] Essig M, Nguyen G, Prie D, Escoubet B, Sraer JD, Friedlander G. [84] Mayer J, Eller T, Brauer P, Solleder EM, Schafer RM, Keller F.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in- Effects of long-term treatment with lovastatin on the clotting system
crease fibrinolytic activity in rat aortic endothelial cells: role of and blood platelets. Ann Hematol 1992;64:196 201.
geranylgeranylation and Rho proteins. Circ Res 1998;83:683 90. [85] Sandset PM, Lund H, Norseth J, Abildgaard U, Ose L. Treatment with
J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366 365

hydroxymethylglutaryl coenzyme A reductase inhibitors in hyper [103] Davidson MH, Stein EA, Hunninghake DB, Ose L, Dujovne CA,
cholesterolemia induces changes in the components of the extrinsic Insull Jr W, et al. Lipid-altering efficacy and safety of simvastatin 80
coagulation system. Arterioscler Thromb 1991;11: 138 45. mg/day: worldwide long-term experience in patients with hypercho-
[86] Velussi M, Cemigi AM, Tortal C, Merni M. Atorvastatin for the lesterolemia. Nutr Metab Cardiovasc Dis 2000;10:253 62.
management of type 2 diabetic patients with dyslipidemia. A mid- [104] Backes JM, Howard PA. Association of HMG-CoA reductase inhib-
term (9 months) treatment experience. Diabetes Nutr Metab itors with neuropathy. Ann Pharmacother 2003;37:274 8.
1999;12:407 12. [105] Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of
[87] Tsuda Y, Satoh K, Kitadai M, Takahashi T, Izumi Y, Hasomi N. the HMG-CoA reductase inhibitors. Similarities and differences.
Effects of pravastatin sodium and simvastatin on plasma fibrinogen Clin Pharmacokinet 1997;32:403 25.
level and blood rheology in type II hyperlipoproteinemia. Athero- [106] Spach DH, Bauwens JE, Clark CD, Burke WG. Rhabdomyolysis
sclerosis 1996;122:225 33. associated with lovastatin and erythromycin use. West J Med
[88] Koenig W, Hehr R, Ditshuneit H, Kuhn K, Ernst E, Rosenthal J. 1991;154:213 5.
Lovastatin alters blood rheology in primary hyperlipoproteinemia: [107] Neuvonen PJ, Jalava KM. Itraconozole drastically increases plasma
dependence on lipoprotein (a)? J Clin Pharmacol 1992;32:539 45. concentration of lovastatin and lovastatin acid. Clin Pharmacol Ther
[89] Isaacsohn JL, Setaro JF, Nicholas C, Davey JA, Diotalevi LJ, Chris- 1996;60:54 61.
tianson DS. Effects of lovastatin therapy on plasminogen activator [108] Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconozole on the
inhibitor-1 antigen levels. Am J Cardiol 1994;73:5 7. pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998;64:
[90] Puccetti L, Pasqui AL, Pastorelli M, Bova G, Cercignani M, Palaz- 58 65.
zuoli A, et al. Time-dependent effect of statins on platelet function in [109] Hanston PD, Horn JR. Drug interactions with HMG Co A reductase
hypercholesterolaemia. Eur J Clin Invest 2002;32:901 8. inhibitors. Drug Interact Newsl 1998;64:103 6.
[91] Puccetti L, Bruni F, Bova G, Cercignani M, Palazzuoli A, Console [110] Olbricht C, Wanner C, Eisenhauer T, Kliem V, Doll R, Boddaert M,
E, et al. Effect of diet and treatment with statins on platelet-depen- et al. Accumulation of lovastatin, but not pravastatin, in the blood of
dent thrombin generation in hypercholesterolemic subjects. Nutr cyclosporine-treated kidney graft patients after multiple doses. Clin
Metab Cardiovasc Dis 2001;11:378 87. Pharmacol Ther 1997;62:311 21.
[92] Ridker PM, Rifal N, Pfeffer MA, Sacks F, Braunwald E. Long-term [111] Gruer PJ, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA. Con-
effects of pravastatin on plasma concentration of C reactive protein. comitant use of cytochrome P450 3A4 inhibitors and simvastatin.
The Cholesterol and Recurrent Events (CARE) Investigators. Circu- Am J Cardiol 1999;84:811 5.
lation 1999;100:230 5. [112] Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas
[93] Sposito AC, Mansur AP, Coelho OR, Nicolau JC, Ramires JAF. RJ, et al. Fifteen year mortality in Coronary Drug Project patients:
Additional reduction in blood pressure after cholesterol-lowering long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245 55.
treatment by statins (lovastatin or pravastatin) in hypercholesterol- [113] Knopp RH, Ginsberg J, Albers JJ, Hoff C, Ogilvie JT, Warnick GR,
emic patients using angiotensin-converting enzyme inhibitors (ena- et al. Contrasting effects of unmodified and time-release forms of
lapril or lisinopril). Am J Cardiol 1999;83:1497 9. niacin on lipoproteins in hyperlipidemic subjects: clues to mecha-
[94] Lee TM, Su SF, Tsai CH. Effect of pravastatin on proteinuria in nism of action of niacin. Metab Clin Exper 1985;34:642 50.
patients with well controlled hypertension. Hypertension 2002;40: [114] Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH,
67 73. Knopp RH, et al. Comparative effects of lovastatin and niacin in
[95] Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, primary hypercholesterolemia. A prospective trial. Arch Intern Med
et al. ASCOT investigators. Prevention of coronary and stroke events 1994;154:1586 95.
with atorvastatin in hypertensive patients who have average or lower- [115] Gibbons LW, Gonzalez V, Gordon N, Grundy S. The prevalence of
than-average cholesterol concentrations, in the Anglo-Scandinavian side effects with regular and sustained-release nicotinic acid. Am J
Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a mul- Med 1995;99:378 85.
ticentre randomised controlled trial. Lancet 2003;361:1149 58. [116] Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA,
[96] Jackson PR, Wallis EJ, Haq IU, Ramsay LE. Statins for primary Brusco OA, et al. Efficacy and safety of an extended-release niacin
prevention: at what coronary risk is safety assured? Br J Clin Phar- (Niaspan): a long-term study. Am J Cardiol 1998;82:74U 81U.
macol 2001;52:439 46. [117] Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan
[97] Gotto Jr AM. Treating hypercholesterolemia: looking forward. Clin D, et al. Effect of niacin on lipid and lipoprotein levels and glycemic
Cardiol 2003 Jan.;26 (1 Suppl. 1):I21 8. control in patients with diabetes and peripheral arterial disease: the
[98] Cheng-Lai A. Rosuvastatin: a new HMG-CoA reductase inhibitor ADMIT study: a randomized trial. Arterial Disease Multiple Inter-
for the treatment of hypercholesterolemia. Heart Dis 2003;5:72 8. vention Trial. JAMA 2000;284:1263 70.
[99] Paoletti R, Fahmy M, Mahla G, Mizan J, Southworth H. Rosuvastatin [118] McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison
demonstrates greater reduction of low-density lipoprotein cholesterol of the efficacy and toxic effects of sustained- vs. immediate-release
compared with pravastatin and simvastatin in hypercholesterolaemic niacin in hypercholesterolemic patients. JAMA 1994;271:672 7.
patients: a randomized, double-blind study. J Cardiovasc Risk [119] Morgan JM, Capuzzi DM, Guyton JR. A new extended-release ni-
2001;8:383 90. acin (Niaspan): efficacy, tolerability, and safety in hypercholesterol-
[100] Davidson M, Ma P, Stein EA, Gotto Jr. AM, Raza A, Chitra R, et al. emic patients. Am J Cardiol 1998;82:29U 34U.
Comparison of effects on low-density lipoprotein cholesterol and [120] Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP,
high-density lipoprotein cholesterol with rosuvastatin versus atorvas- Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin
tatin in patients with type IIa or IIb hypercholesterolemia. Am J therapy on coronary atherosclerosis and coronary venous bypass
Cardiol 2002;89:268 75. grafts. JAMA 1987;257:3233 40.
[101] Olsson AG, Istad H, Luurila O, Ose L, Stender S, Tuomilehto J, et al. [121] Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ.
Effects of rosuvastatin and atorvastatin compared over 52 weeks of Regression of coronary atherosclerosis during treatment of familial
treatment in patients with hypercholesterolemia. Am Heart J hypercholesterolemia with combined drug regimens. JAMA 1990;
2002;144:1044 51. 264:3007 12.
[102] Insull Jr W, Isaacsohn J, Kwiterovich P, Ra P, Brazg R, Dujovne C, [122] Carlson LA, Rosenhamer G. Reduction of mortality in the Stock-
et al. Efficacy and safety of cerivastatin 0.8 mg in patients with holm Ischaemic Heart Disease Secondary Prevention Study by com-
hypercholesterolaemia: the pivotal placebo-controlled clinical trial. bined treatment with clofibrate and nicotinic acid. Acta Med Scand
Cerivastatin Study Group. J Int Med Res 2000;28:47 68. 1988;223:405 18.
366 J.A. Raza et al. / International Journal of Cardiology 97 (2004) 355366

[123] Guyton JR, Capuzzi DM. Treatment of hyperlipidemia with com- [143] Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM,
bined niacin-statin regimens. Am J Cardiol 1998;82:82U 4U. Loh IK, et al. Effects of therapy with cholestyramine on progression
[124] Guyton JR, Goldberg AC, Kreisberg RA, Sprecher DL, Superko of coronary arteriosclerosis: results of the NHLBI Type II Coronary
HR, OConnor CM. Effectiveness of once-nightly dosing of ex- Intervention Study. Circulation 1984;69:313 24.
tended-release niacin alone and in combination for hypercholes- [144] Schectman G, Hiatt J. Evaluation of the effectiveness of lipid-low-
terolemia. Am J Cardiol 1998;82:737 43. ering therapy (bile acid sequestrants, niacin, psyllium, and lovastat-
[125] Knopp RH. Drug treatment of lipid disorders. N Engl J Med in) for treating hypercholesterolemia in veterans. Am J Cardiol
1999;34:498 511. 1993;71:759 65.
[126] Ide T, Oku H, Sugano M. Reciprocal responses to clofibrate in [145] Hunninghake DB, Stein EA, Fraser Bremner W, Greenland P,
ketogenesis and triglyceride and cholesterol secretion in isolated Demke DM, Oliphant TH. Dose response study of colestipol tab-
rat liver. Metabolism 1982;31:1065 72. lets in patients with moderate hypercholesterolemia. Am J Ther
[127] Schoonjans K, Staels B, Auwerx J. Role of the peroxisome prolif- 1995;2:180 9.
erator-activated receptor (PPAR) in mediating the effects of fibrates [146] Superko HR, Greenland P, Manchester RA, Andreadis NA, Schect-
and fatty acids on gene expression. J Lipid Res 1996;37:907 25. man G, West NH, et al. Effectiveness of low-dose colestipol therapy
[128] Auwerx J, Schoonjans K, Fruchart JC, Staels B. Regulation of tri- in patients with moderate hypercholesterolemia. Am J Cardiol
glyceride metabolism by PPARs: fibrates and thiazolidinediones 1992;70:135 40.
have distinct effects. J Atheroscler Thromb 1996;3:81 9. [147] Vecchio TJ, Linden CV, OConnell MJ, Heilman J. Comparative
[129] Fruchart JC , Brewer HB Jr., Leitersdorf E. Consensus for the use of efficacy of colestipol and clofibrate in type IIa hyperlipoproteinemia.
fibrates in the treatment of dyslipoproteinemia and coronary heart Arch Intern Med 1982;142:721 3.
disease. Fibrate Consensus Group. Am J Cardiol 1998;81:912 27. [148] Knapp HH, Schrott H, Ma P, Knopp R, Chin B, Gaziano JM, et al.
[130] Auwerx J, Schoonjans K, Fruchart JC, Staels B. Transcriptional Efficacy and safety of combination simvastatin and colesevelam in
control of triglyceride metabolism: fibrates and fatty acids change patients with primary hypercholesterolemia. Am J Med 2001;110:
the expression of the LPL and apo C-III genes by activating the 52 60.
nuclear receptor PPAR. Atherosclerosis 1996;124:S29 37 [Suppl.]. [149] Denke MA, Grundy SM. Efficacy of low-dose cholesterol-lowering
[131] Wood D, De Backer G, Faergeman O, Graham I, Mancia G, Pyor- drug therapy in men with moderate hypercholesterolemia. Arch In-
ala K. Prevention of coronary heart disease in clinical practice. tern Med 1995;155:393 9.
Summary of recommendations of the second joint task force of [150] Andrade SE, Walker AM, Gottlieb LK, Hollenberg NK, Testa MA,
european and other societies on coronary prevention. Blood Press Saperia GM, et al. Discontinuation of antihyperlipidemic drugs: do
1998;124(5 6):262 9. rates reported in clinical trials reflect rates in primary care settings?
[132] Spencer CM, Barradell LB. Gemfibrozil, A reappraisal of its phar- N Engl J Med 1995;332:1125 31.
macological properties and place in the management of dyslipidae- [151] Hunninghake DB, Stein EA, Fraser Bremner W, Greenland P, Demke
mia. Drugs 1996;51:982 1018. DM, Oliphant TH. Dose response study of colestipol tablets in
[133] Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. patients with moderate hypercholesterolemia. Am J Ther 1995;2:
Helsinki Heart Study: primary-prevention trial with gemfibrozil in 180 9.
middle-aged men with dyslipidemia. Safety of treatment, changes in [152] Dorr AE, Gundersen K, Schneider Jr. JC, Spencer TW, Martin WB.
risk factors, and incidence of coronary heart disease. N Engl J Med Colestipol hydrochloride in hypercholesterolemic patients: effect on
1987;317:1237 45. serum cholesterol and mortality. J Chronic Dis 1978;31:5 14.
[134] Anonymous P. A co-operative trial in the primary prevention of [153] Davidson MH, Dillon MA, Gordon B, Jones P, Samuels J, Weiss S,
ischaemic heart disease using clofibrate. Report from the Committee et al. Colesevelam hydrochloride (cholestagel): a new, potent bile
of Principal Investigators. Br Heart J 1978;40:1069 118. acid sequestrant associated with a low incidence of gastrointestinal
[135] Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, side effects. Arch Intern Med 1999;159:1893 900.
et al. The veterans affairs high-density lipoprotein cholesterol inter- [154] Ezetimibe (Zetia) prescribing information. Merck/Schering-plough
vention Trial Study Group. Gemfibrozil for the secondary prevention pharmaceuticals, North Wales PA 19454. October 2002.
of coronary heart disease in men with low levels of high-density [155] Sudhop T, von Bergmann K. Cholesterol absorption inhibitors for the
lipoprotein cholesterol. N Engl J Med 1999;341:410 8. treatment of hypercholesterolaemia. Drugs 2002;62:2333 47.
[136] Palmer RH. Effects of fibric acid derivatives on biliary lipid com- [156] Dujovne CA, Ettinger MP, McNeer JF, Lipka LJ, LeBeaut AP,
position. Am J Med 1987;83:37 43. Suresh R, et al. Efficacy and safety of a potent new selective cho-
[137] Bays HE, Dujovne CA. Drug interactions of lipid-altering drugs. lesterol absorption inhibitor, ezetimibe, in patients with primary
Drug Saf 1998;19:355 71. hypercholesterolemia. Am J Cardiol 2002;90:1092 7.
[138] Pauciullo P, Marotta G, Rubba P, Cortese C, Caruso MG, Gnasso A, [157] Gagne C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, et al.
et al. Serum lipoproteins, apolipoproteins and very low density li- Efficacy and safety of ezetimibe added to ongoing statin therapy for
poprotein subfractions during 6-month fibrate treatment in primary treatment of patients with primary hypercholesterolemia. Am J Car-
hypertriglyceridaemia. J Intern Med 1990;228:425 30. diol 2002 Nov.;90(15):1084 91.
[139] Leaf DA, Connor WE, Illingworth DR, Bacon SP, Sexton G. The [158] Kosoglou T, Meyer I, Veltri EP, Statkevich P, Yang B, Zhu Y, et al.
hypolipidemic effects of gemfibrozil in type V hyperlipidemia. A Pharmacodynamic interaction between the new selective cholesterol
double-blind, crossover study. JAMA 1989;262:3154 60. absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol
[140] Grundy SM, Ahrens EH, Salen G. Interruption of the enterohepatic 2002;54:309 19.
circulation of bile acids in man: comparative effects of cholestyr- [159] Braun LT, Davidson MH. Cholesterol-lowering drugs bring benefits
amine and ileal exclusion on cholesterol metabolism. J Lab Clin to high-risk populations even when LDL is normal. J Cardiovasc
Med 1971;178:94 121. Nurs 2003;18:44 9.
[141] Shepherd J, Packard CJ, Bicker S, Lawrie TDV, Morgan HG. Cho- [160] Pearson TA. The undertreatment of LDL-cholesterol: addressing the
lestyramine promotes receptor-mediated low-density-lipoprotein ca- challenge. Int J Cardiol 2000;74(Suppl. 1):S23 8.
tabolism. N Engl J Med 1980;302:1219 22. [161] Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment
[142] Wiklund O, Angelin B, Fager G, Eriksson M, Olofsson SO, Berglund assessment project (L-TAP): a multicenter survey to evaluate the
L, et al. Treatment of familial hypercholesterolaemia: a controlled trial percentages of dyslipidemic patients receiving lipid-lowering thera-
of the effects of pravastatin or cholestyramine therapy on lipoprotein py and achieving low-density lipoprotein cholesterol goals. Arch
and apolipoprotein levels. J Intern Med 1990;228: 241 7. Intern Med 2000;160:459 67.