CLINICAL

An Overview of Cholesterol Management

Robyn A. Burns Schaiff, PharmD, BCPS; Richard M. Moe, MD, PhD; Daniel W. Krichbaum, PharmD

Cardiovascular disease is the leading cause of death worldwide. Elevated cholesterol (hyper-
cholesterolemia) and abnormal lipid profiles (dyslipidemia) are important risk factors for the
development of cardiovascular disease. This article discusses the role of cholesterol in the
body and the relationship between different cholesterol fractions and the risk of cardiovas-
cular disease. The guidelines for assessment and treatment of dyslipidemia from the National
Cholesterol Education Program are outlined, and cholesterol targets and goals of therapy are
discussed. The mechanism of action, place in therapy (eg, first-line, second-line, or add-on),
and common side effects are also discussed for each of the available classes of drugs used
in the treatment of dyslipidemia. [ADHB. 2008;1(9):39-48.]

C
ardiovascular (CV) disease (CVD) is the lead- reduction of LDL-C levels for the most common forms
ing cause of mortality and one of the leading of dyslipidemia. Conversely, high levels of HDL-C are
causes of disability worldwide.1 In the United associated with decreased risk of CV events. However,
States alone, more than 80 million adults have at least clinical trials assessing the morbidity and mortality
one type of CVD, with hypertension, coronary heart benefits of drug therapies that raise HDL-C levels have
disease (CHD), stroke, and heart failure among the had varied results. HDL-C–modifying trials with niacin
most common forms of the disease. Elevated levels of have demonstrated CV event reduction.3,4 Conversely,
cholesterol (hypercholesterolemia) and abnormal lipid other treatments that raise HDL-C, including hormone
profiles (dyslipidemia) are important risk factors for replacement therapy5 and torcetrapib,6 have not
CVD. The American Heart Association (AHA) esti- decreased CV events. Because of this, in the absence of
mates that more than 100 million Americans have ele- large clinical outcome trials, therapies that elevate HDL
vated cholesterol levels (>200 mg/dL) and 34 million cannot be assumed to produce clinical event reduction.
have cholesterol levels that necessitate treatment.2
Cholesterol is an essential component of cell mem- Approach to Patient Assessment, Treatment
branes and steroid hormones. The body synthesizes The National Cholesterol Education Program
most of its required cholesterol with the remainder (NCEP) evaluates evidence and develops guidelines for
coming from the diet. Since cholesterol is mostly lipid management. The approach to patient manage-
insoluble in blood, it is packaged with proteins and ment provided here comes primarily from the guide-
phospholipids to form lipoprotein complexes that cir- lines published in 2001 and updated in 2004.7,8
culate in the bloodstream. The types of cholesterol- Since the primary goal of lipid management is to
containing lipoproteins are high-density lipoproteins decrease the risk of CV events and death, the first step
(HDL-C), low-density lipoproteins (LDL-C), very low- in management is to assess the patient’s overall CV
density lipoproteins (VLDL-C), and chylomicrons. risk. To make this assessment, a fasting lipoprotein
High levels of LDL-C are associated with increased analysis should be obtained to determine the patient’s
CV risk in epidemiologic studies. In addition, numer- LDL-C. Optimal levels for LDL-C and total cholesterol
ous clinical studies using a variety of therapies have are <100 mg/dL and <200 mg/dL, respectively. The
demonstrated decreased CV events and mortality with NCEP guidelines recommend that a fasting lipid
LDL reduction. Therefore, the first goal of therapy is panel be drawn at least every 5 years in all adults older
than 20 years.7
Dr Burns Schaiff is Senior Director, Regional Medical & In addition to LDL-C levels, the presence or
Research Specialist, Pfizer, Inc, New York, NY; Dr Moe is absence of CHD or CHD-equivalent conditions must
Clinical Associate Professor, University of Missouri-Kansas be assessed. CHD-equivalent conditions listed by the
City, Kansas City, MO; Dr Krichbaum is Senior Director NCEP include diabetes mellitus, peripheral vascular
Team Leader, Regional Medical & Research Specialist, disease, abdominal aortic aneurysm, symptomatic
Pfizer, Inc, New York, NY. carotid disease, and a 10-year CV risk of less than 20%

VOL. 1 NO. 9 www.AHDBonline.com 39

 CLINICAL

KEY POINTS Goals of Therapy

For patients with CHD or CHD-equivalent disease,
▲ Cholesterol is an essential component of cell membranes the NCEP recommends the LDL-C goal of ≤100
and steroid hormones. mg/dL, with <70 mg/dL a therapeutic option for
▲ Hypercholesterolemia and dyslipidemia are important risk patients considered at very high risk for CV events.8
factors for cardiovascular disease, which affects more than For patients with 2 or more CV risk factors but with a
80 million Americans. 10-year Framingham risk of less than 20%, the LDL-C
▲ Evidence shows that high levels of LDL-C are associated goal is <130 mg/dL, with <100 mg/dL a therapeutic
with increased cardiovascular risk; reducing LDL levels has option. Finally, for patients with 0 to 1 risk factors, the
been associated with significant reduction in mortality. LDL-C target is <160 mg/dL.8
▲ The first goal of therapy in hypercholesterolemia is reduc-
tion of LDL-C levels. Therapeutic Lifestyle Changes
▲ Statins are considered the most effective lipid-lowering The NCEP Adult Treatment Panel III guidelines
agents available, both in lowering LDL levels and in the recommend that therapeutic lifestyle changes be
prevention of cardiovascular events. implemented for all patients at risk for CVD.7 These
changes include reducing intake of saturated fats and
cholesterol while increasing soluble fiber intake and
physical activity. Optimization of weight, moderation
Table 1 Major Risk Factors (Exclusive of LDL-C) that Modify of alcohol consumption, and cessation of smoking are
LDL Goals* also encouraged. If drug therapy is needed, it should be
Cigarette smoking used as an addition to, rather than a substitute for, ther-
Hypertension (blood pressure ≥140/90 mm Hg or on
apeutic lifestyle changes.
antihypertensive medication)
Treatment Initiation
Low HDL-C (<40 mg/dL)† Since the clinical evidence of benefit is greatest
Family history of premature CHD (CHD in male first-degree with the statin drug class, the American College of
relative <55 y, CHD in female first-degree relative <55 y) Cardiology (ACC) recommends drug therapy begin
Age (men ≥45 y; women ≥55 y) with a statin and that titration to goal or the maximal-
* ly tolerated dose of a statin be achieved before consid-
Diabetes is regarded a CHD risk equivalent.
HDL cholesterol ≥60 mg/dL counts as a negative risk factor; its presence
† eration of adding other agents.11 Regardless of the ini-
removes 1 risk factor from the total count. tial treatment chosen, it is critical that the patient be
LDL-C indicates low-density lipoprotein cholesterol; HDL-C, high-density reevaluated and therapy titrated or added until the goal
lipoprotein cholesterol; CHD, coronary heart disease. LDL-C is attained.
Reprinted with permission from Expert Panel on Detection, Evaluation, and For patients with 0 to 1 risk factors and no CHD,
Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
treatment is initiated with therapeutic lifestyle changes
with reassessment after 6 weeks. If goal LDL of <160
calculated with the Framingham risk calculator.7 mg/dL is not reached at 6 weeks, lifestyle changes
Although not addressed by the NCEP, the National should be intensified and reinforced and a visit with
Kidney Foundation also considers chronic kidney dis- a dietitian considered. If after 12 weeks of therapeutic
ease (glomerular filtration rate <60 mL/min) to be a lifestyle changes the patient is not at the LDL-C goal
high-risk state and recommends that this patient group of <160 mg/dL, drug therapy, usually a statin, should
be treated as having a CHD-equivalent disease.9 be added.
Likewise, the AHA and the American Stroke For patients at moderate risk, with 2 or more risk fac-
Association recommend the use of a statin with inten- tors and a 10-year CV risk of less than 20%, treatment
sive lipid-lowering effects in patients with atheroscle- begins with therapeutic lifestyle changes. Drug therapy,
rotic stroke or transient ischemic attack, even in the usually a statin, can be initiated concurrently if the
absence of known CHD.10 LDL is >100 mg/dL at baseline or if LDL-C remains
In the absence of CHD or CHD-equivalent condi- >100 mg/dL after a 6-week trial of lifestyle changes.
tions, CVD risk factors (Table 1) should be carefully For the highest risk patients with CHD or equivalent
assessed using the Framingham risk score to determine conditions, statin therapy and therapeutic lifestyle
the patient’s 10-year risk of CV events (Table 2).7 changes should be initiated simultaneously for all

40 AMERICAN HEALTH & DRUG BENEFITS November/December 2008 VOL. 1 NO. 9

 Cholesterol Management

Table 2 An Overview of Cholesterol Management

HDL indicates high-density lipoprotein; BP, blood pressure.

Reprinted with permission from Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

VOL. 1 NO. 9 www.AHDBonline.com 41

 CLINICAL

patients with LDL-C >100 mg/dL. Drug therapy may C–related anti-inflammatory mechanism.
also be considered in very high-risk patients with LDL- Adverse events, relatively uncommon with this
C <100 mg/dL targeted to achieve the optional goal of class, include gastrointestinal (GI) disturbances, mus-
<70 mg/dL.8 cle aches, and asymptomatic transaminasemia. Rare
serious adverse events may include myopathy and rhab-
Pharmacotherapy Options domyolysis. FDA-approved labeling recommends
A variety of lipid-lowering agents are available, assessment of liver function at baseline, after 12 weeks
including 3-hydroxy-3-methylglutaryl coenzyme A of therapy, after dose escalation, and twice yearly there-
(HMG-CoA) reductase inhibitors, bile acid seques- after. However, the National Lipid Association has sug-
trants, cholesterol absorption inhibitors, fibrates, nico- gested that this practice does not increase the safety of
tinic acid derivatives, and omega-3 fatty acids. Dosage statin therapy, but merely increases cost.14
ranges, US Food and Drug Administration (FDA) indi-
cations, evidence of clinical outcome benefit, and side Bile Acid Sequestrants
effects are highlighted in Table 3. Bile acid sequestrants bind to bile acids in the intes-
tine, reducing absorption of cholesterol and other lipids.
The resultant decrease in available cholesterol causes
an increase in the number of LDL receptors on hepato-
These are the most prescribed drugs in the cytes, further promoting clearance of LDL-C from the
world and are considered the most effective blood. Bile acid sequestrants are recommended as sec-
ond-line therapy for patients with elevated cholesterol,
lipid-lowering agents available. but not elevated TGs, as both VLDL-C and TG con-
centrations may increase during therapy. Agents in this
class lower LDL-C by 15% to 30% and increase HDL-C
HMG-CoA Reductase Inhibitors (Statins) by 3% to 5% on average.9 Patient adherence with these
HMG-CoA reductase inhibitors, or statins, are the agents is frequently poor due to the need for frequent
recommended first-line therapy for most patients. dosing, poor palatability, and frequent GI side effects.
These are the most prescribed drugs in the world and Since these drugs remain in the GI tract, systemic
are considered the most effective lipid-lowering agents adverse effects are minimal; however, these agents can
available, both in lowering LDL-C levels and in the interfere with absorption of concomitantly adminis-
prevention of CV events. Statins are similar in struc- tered drugs as well as fat-soluble vitamins.
ture to HMG-CoA, a precursor of cholesterol, and act
as competitive inhibitors of HMG-CoA reductase, the Nicotinic Acid Derivatives
last regulated enzymatic step in cholesterol synthesis. Niacin reduces synthesis of VLDL-C in the liver and
Therefore, statins reduce the rate of synthesis of choles- therefore reduces LDL-C production. Pharmacologic
terol. The liver responds by increasing the number of doses of niacin (1.5-2 g/day) lower LDL-C and TGs by
LDL receptors, which increases hepatic uptake and 15% to 20% and 30% to 40%, respectively, and
catabolism of circulating LDL-C. Statins reduce LDL-C increase HDL-C by 15% to 25%. Niacin is used as sec-
by 24% to 60% and decrease triglycerides (TGs) by 5% ond-line therapy in concert with other lipid-lowering
to 50% (percentages are based on the various package agents. The most common adverse events include
inserts), depending on the agent selected and the base- vasodilation with flushing and pruritis, which frequent-
line lipid profile. HDL-C levels are usually increased. ly is dose-limiting. Other adverse events include dys-
The effects on HDL are a class effect and are small rel- pepsia, gastric ulceration, hyperuricemia, palpitations,
ative to the effects on LDL-C and TGs. In addition, and, rarely, peripheral neuropathy.
statins have a variety of anti-inflammatory effects that Niacin-induced hyperglycemia may be problematic
are independent of the LDL-C lowering, which may for patients with diabetes mellitus or with impaired glu-
contribute to the clinical benefit in CVD, especially cose tolerance, particularly in the first 6 months of
early in therapy.12 However, a recent meta-analysis of 23 therapy, but long-term clinical benefits have been
lipid-lowering trials demonstrated that the majority demonstrated in these patients.15 The most serious side
(89%-98%) of the anti-inflammatory effects of lipid- effect is hepatotoxicity; cases of fatal fulminant hepat-
lowering therapy is related to the degree of LDL reduc- ic failure have been associated with niacin administra-
tion,13 which suggests a limited influence of a non-LDL- tion, particularly with older formulations.16

42 AMERICAN HEALTH & DRUG BENEFITS November/December 2008 VOL. 1 NO. 9

 Table 3 Pharmacotherapy for Lipid Disorders
Populations w/ Cost,
demonstrated Primary effect Side effects 30-day

VOL. 1
Drug Dosage range Available doses Indications event reduction† on lipids (most often reported) supply

Questran * 8-24 g/d, Questran Light: packets •Adjuct therapy of Men with primary LDL-C↓ Abdominal discomfort, $$$$
(cholestyramine) 2 divided and powder (each 5 g hypercholesterolemia hypercholesterolemia 10%-30% constipation, flatulence,

NO. 9
doses contain 4 g anhydrous •Pruritis due to partial biliary (LRC-CTTP1) nausea and vomiting,
cholestyramine resin) obstruction vitamin A, D deficiency
Questran: powder and
packets (each 9 g
contain 4 g anhydrous
cholestyramine resin)

Welchol 3.75 g/d 625-mg tablets •Adjuct therapy of hypercholesterolemia LDL-C↓ Asthenia, constipation, $$$$
(colesevelam) •Adjunct therapy to improve 10%-18% indigestion, pharyngitis,
glycemic control in type 2 DM myalgia

Colestid* 2-16 g/d 1-g tablets Adjunct therapy for primary LDL-C↓ Abdominal distension, ab- $$$
(colestipol) 2 divided hypercholesterolemia 10%-20% dominal pain, constipation,
doses musculoskeletal pain, headache

Zetia 10 mg/d 10-mg tablets •Primary hyperlipidemia LDL-C↓ Headache, diarrhea, $$$
(ezetimibe) •Mixed dyslipidemia 10%-20% abdominal pain, arthralgia,
•Homozygous familial hypercholesterolemia backache, myalgia, sinusitis
•Homozygous sitosterolemia

Antara* 43-130 mg/d 43-, 130-mg capsules •Hypertriglyceridemia TG↓ Rash, diarrhea, flatulence, $$
(fenofibrate) •Primary hyperglyceridemia 20%-50% nausea and vomiting,
•Mixed dyslipidemia myalgia, rhinitis

Lipofen* (fenofibrate) 50-150 mg/d 50-, 150-mg capsules

Lofibra* (fenofibrate) 54-200 mg/d 54-, 160-mg tablets

67-,134-, 200-mg capsules

TriCor* (fenofibrate) 48-145 mg/d 48-, 145-mg tablets

Triglide (fenofibrate) 50-160 mg/d 50-, 160-mg tablets

Lopid* (gemfibrozil) 600-1200 mg/d, 600-mg tablets •Reducing CHD risk in patients w/type 2b •Men w/primary TG↓ Rash, abdominal pain, $
2 divided doses dyslipidemia and inadequate response to dyslipidemia (Helsinki 25%-45% diarrhea, flatulence,
TLC, other drug therapy, who have Heart Study2) indigestion, xerostomia,
high LDL, low HDL, high TG •Men w/CHD and low myalgia
•Familial type IV or V hyperlipidemia HDL-C (VA Hit3)

Lipitor 10-80 mg/d 10-, 20-, 40-, 80-mg •Primary prevention of MI, stroke in •Patients w/hypertension and LDL-C↓ Abdominal pain, $$$
(atorvastatin) tablets patients w/type 2 DM and other CHD ≥3 CHD risk factors (ASCOT4) 39%-60% constipation,
risk factors •Patients w/type 2 DM and no flatulence, indigestion,
•Primary prevention of MI, stroke, history of CVD (CARDS5) increased liver enzymes,
revascularization, hospitalization for •Patients w/stable CHD (TNT,6 headache, myalgia
heart failure and angina in patients IDEAL,7 ALLIANCE,8 and
w/clinically evident CAD and AVERT 9)
•Primary hypercholesterolemia or •Patients w/atherosclerotic
mixed dyslipidemia stroke or TIA w/o documented

www.AHDBonline.com
•Hypertriglyceridemia CHD (SPARCL10)
•Primary dysbetalipoproteinemia •Patients w/ACS (PROVE-IT,11
•Homozygous FH in adolescents MIRACL12)
•Heterozygous FH in adolescents

43
Continued
 Table 3 Pharmacotherapy for Lipid Disorders Continued

44
Populations w/ Side effects Cost,
demonstrated Primary effect (most often 30-day
Drug Dosage range Available doses Indications event reduction† on lipids reported) supply

Lescol (fluvastatin) 20-80 mg/d 20-, 40-mg •Reduce coronary revascularization in CHD Patients with CHD who had LDL-C↓ Abdominal pain, diarrhea, $$$
capsules •Reduce progression of coronary coronary intervention (LIPS13) 20%-35% dyspepsia, nausea, headache,
atherosclerosis in CHD myalgia
•Hypercholesterolemia
•Heterozygous FH in adolescents

Lescol XL 80-mg mg/d 80-mg extended- $$$$

(fluvastatin ER) release tablets

Mevacor* 10-80 mg/d 10-, 20-, 40-mg •Primary prevention of MI, unstable High risk (elevated LDL-C LDL-C↓ Abdominal pain, constipation, $$
(lovastatin) tablets angina, coronary revascularization w/low HDL-C) patients w/o 25%-45% diarrhea, nausea, headache,
•To slow progression of coronary clinical CHD myalgia, increased hepatic
atherosclerosis in CHD (AFCAPS-TexCaps14) transaminase levels
•Hypercholesterolemia
•Heterozygous FH in adolescents

Pravachol* 10-80 mg/d 10-, 20-, 40-, 80-mg •Primary prevention of MI, revasculari- •Men w/o history of MI LDL-C↓ Diarrhea, flatulence, heart- $$

AMERICAN HEALTH & DRUG BENEFITS

(pravastatin) tablets zation, and CV mortality w/elevated LDL (WOSCOPS15) 25%-40% burn, nausea, vomiting,
•Reduction in total mortality by •Patients w/MI in preceding asthenia, headache, myalgia
reducing coronary death, MI, 3-20 mo (CARE16)
revascularization, stroke, and to slow •Patients w/MI or unstable
progression of coronary atherosclerosis in angina in previous 3-36 mo
patients with CHD (LIPID17)
•Hypercholesterolemia
•Heterozygous FH in adolescents

Crestor 5-40 mg/d 5-, 10-, 20-, 40-mg •Primary hyperlipidemia Men ≥55 and women ≥65 LDL-C↓ Abdominal pain, constipation, $$$$
(rosuvastatin) tablets and mixed dyslipidemia w/LDL ≤130 mg/dL and CRP 45%-60% nausea, arthralgia, asthenia,
•Primary hypertriglyceridemia ≥2 mg/L (JUPITER18) headache, myalgia, increased
•Homozygous familial hypercholesterolemia hepatic transaminase levels

November/December 2008
•To slow the progression of atherosclerosis

Zocor* 5-80 mg/d 5-, 10-, 20- 40-, 80-mg •Prevention of CHD mortality and •Existing CHD and elevated LDL-C↓ Constipation, GI $$
(simvastatin) tablets CV events in patients w/existing CHD, total cholesterol (4S19) 35%-50% irritation, headache,
history of stroke, diabetes, or peripheral •Patients at high risk of CV upper respiratory
artery disease events from existing CHD, infection, myalgia,
•Hypercholesterolemia history of stroke, other cerebro- increased hepatic
•Heterozygous FH in adolescents vascular disease, peripheral transaminase levels
artery disease, or hypertension
in men ≥65 yr (HPS20)

Slo-Niacin CR* 0.5-2 g/d Niacin CR: 250-, 500-, •Primary hypercholesterolemia or mixed Men w/history of MI (CDP21; LDL↓ Constipation, flushing, $$
(controlled-release 750-mg tablets dyslipidemia (alone or with lovastatin) immediate-release dosage form) 5%-15% pruritis, GI irritation,
niacin) •Severe hypertriglyceridemia TG↓ nausea, vomiting
•To reduce risk of recurrent MI in patients 15%-30%
w/hypercholesterolemia and history of MI HDL↑ $$$$$
Niaspan 0.5-2 g/d Niacin ER: 500-, 750-, •W/bile acid–binding resin to slow 15%-20%
(niacin ER) 1000-mg tablets progression or induce regression of coronary
atherosclerosis in patients w/CAD and

VOL. 1
hypercholesterolemia
•W/bile acid–binding resin: primary
hypercholesterolemia
Immediate-release 0.25-6 g/d, 3 500-mg tablets $

NO. 9
niacin* divided doses
 Populations w/ Cost,
demonstrated Primary effect Side effects 30-day
Drug Dosage range Available doses Indications event reduction† on lipids (most often reported) supply

VOL. 1
Omega-3 fatty acid* 2-4 g/d Various Hypertriglyceridemia (TG ≥500 mg/dL) •Hypercholesterolemic Japanese TG↓ Increased bleeding/bruising, $$
(Lovaza) patients (over statin background 25%-45% burping, indigestion,
therapy) (JELIS22) altered taste sense
•Patients w/recent MI

NO. 9
(GISSI-Prevenzione23)
Advicor Niacin-ER Niacin-ER– •Hypercholesterolemia LDL↓ 30%-45% See under $$$$
(niacin-ER/ 500 mg–lovastatin lovastatin •Mixed dyslipidemia HDL↑ 20%-30% components
lovastatin) 20 mg/d to niacin-ER 500 mg-20 mg TG↓ 30%-45%
2000 mg–lovastatin 750 mg-20 mg
40 mg/d 1000 mg-20 mg
Simcor Niacin-ER Niacin-ER– •Hypercholesterolemia LDL↓ 10%-15% $$$
(niacin-ER/ 500 mg– simvastatin •Mixed dyslipidemia HDL↑ 20%-30%
simvastatin) simvastatin 500 mg-20 mg •Hypertriglyceridemia TG↓ 15%-40%
20 mg/d to 750 mg-20 mg (all when monotherapy (from baseline
niacin-ER 1000 mg-20 mg inadequate) treatment w/
2000 mg– simvastatin
simvastatin 0-20 mg/d)
40 mg/d
Vytorin Ezetimibe 10 mg– Ezetimibe– •Primary hyperlipidemia LDL↓ $$$$
(ezetemibe/ simvastatin simvastatin or mixed hyperlipidemia 45%-60%
simvastatin) 10 mg/d to 10 mg-10 mg •Homozygous FH
ezetimibe 10 mg– 10 mg-20 mg
simvastatin 10 mg-40 mg
80 mg/d 10 mg-80 mg

*Generic available. †Studies listed in this column may not be included in FDA-approved indications.
LDL-C indicates low-density lipoprotein cholesterol; DM, diabetes mellitus; TG, triglycerides; CHD, coronary heart disease; TLC, therapeutic lifestyle changes; HDL-C, high-density lipoprotein cholesterol; MI, myocardial infarction; CAD,
coronary artery disease; FH, familial hypercholesterolemia; CVD, cardiovascular disease; TIA, transient ischemic attack; ACS, acute coronary syndrome; CV, cardiovascular; GI, gastrointestinal; CR, controlled release; ER, extended release.
1. Lipid Research Clinics Program: the lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.
2. Helsinki Heart Study. Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317:1237-1245.
3. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418.
4. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac
Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158.
5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-
controlled trial. Lancet. 2004;364:685-696.
6. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.
7. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-2445.
8. Koren MJ, Hunninghake DB; ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study. J Am Coll
Cardiol. 2004;44:1772-1779.
9. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med. 1999;341:70-76.
10. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711-1718.
11. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
12. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.
13. Serruys PW, De Feyter PJ, Benghozi R, et al. The Lescol(R) Intervention Prevention Study (LIPS): a double-blind, placebo-controlled, randomized trial of the long-term effects of fluvastatin after successful transcatheter therapy in
patients with coronary heart disease. Int J Cardiovasc Intervent. 2001;4:165-172.
14. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis
Prevention Study. JAMA. 1998;279:1615-1622.
15. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-1307.
16. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001-1009.
17. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial
cholesterol levels. N Engl J Med. 1998;339:1349-1357.
18. Ridker PM, Danielson MIA, Fonseca AH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.
19. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
20. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.

www.AHDBonline.com
21. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255.
22 Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized, open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.
23. Marchioli R, Schweiger C, Tavazzi L, Valagussa F. Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico.
Lipids. 2001;36(suppl):S119-S126.
Cost: $ 0-25, $$ 26-50, $$$ 51-100, $$$$ 101-200, $$$$$ >200

45
Sources: Clinical data compiled from Micromedex website. http://www.thomsonhc.com. Accessed August 22, 2008. Cost information from www.drugstore.com. Accessed August 22, 2008.
 CLINICAL

Fibrates lower risk of CV events compared with those with a

Fibric acid derivatives, or fibrates, such as gemfi- typical Western diet. Studies of omega-3 fatty acid
brozil and fenofibrate, are agonists of the peroxisome- administration have demonstrated reductions in TGs
activated receptor-α in muscle, liver, and other tissues. of up to 45% in patients with baseline TG levels >500
Fibrates can lower TG levels by up to 50% and mg/dL.23 Smaller reductions are expected in patients
are therefore considered the first-line agents in with lower baseline levels. In addition to the reduction
patients with hypertriglyceridemia (TG >400 mg/dL). in TGs, HDL-C levels may be increased by as much as
However, LDL-C reduction is variable (10%-15%), 9%. The addition of omega-3 fatty acids to statin ther-
with some patients exhibiting increased levels of LDL- apy produces further reductions in VLDL-C and TGs
C. HDL-C levels may be increased up to 25% and further elevations in HDL-C. The putative mech-
in patients with very high TG levels at baseline.17 The anisms for TG reduction with high-dose omega-3 fats
most common adverse events are rash and dyspepsia include increased beta oxidation. ■
for fenofibrate and GI disturbances for gemfibrozil.
All fibrates may increase the risk of gallstones. In addi- Conclusion
tion, gemfibrozil has been shown to increase plasma Elevated cholesterol level is a major risk factor for
concentration of statins, thereby increasing the risk of CVD, the leading cause of death worldwide. Reduction
muscle toxicity.18 of LDL-C has been shown to decrease the risk of CV
events in a large number of clinical trials. Because they
Ezetimibe are the best studied, have a favorable risk/benefit pro-
As with bile acid sequestrants, ezetimibe inhibits the file, and have been demonstrated to produce clinical
absorption of cholesterol. However, since it does not benefits in many large trials, statins are the first-line
interfere with the absorption of other dietary fats, it is treatment for patients with hypercholesterolemia.
better tolerated. Ezetimibe localizes at the brush border
of the small intestine, where it binds to a critical medi- Disclosure Statement
Dr Moe is on the Speakers’ Bureau for Pfizer, BMS, Novartis,
ator of cholesterol absorption, the Niemann-Pick C1-
Abbott, and GlaxoSmithKline. Drs Burns Schaiff and Krichbaum are
like 1 protein on the GI tract epithelial cells19 and liver employees of Pfizer, Inc. Limited editorial support was provided by
cells. Like the bile acid sequestrants, by reducing the Paul Lane, PhD, at Envision Pharma, Ltd, and was funded by
availability of LDL-C, ezetimibe also induces LDL Pfizer, Inc.
receptor upregulation leading to increased uptake of
LDL-C into cells, further lowering circulating LDL-C
levels. While ezetimibe effectively lowers LDL-C, stud- References
1. Mensah GA, Brown DW. An overview of cardiovascular disease bur-
ies assessing clinical event reduction are lacking. In a den in the United States. Health Aff (Millwood). 2007;26:38-48.
recent study, no additional decrease in the carotid inti- 2. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statis-
tics—2008 update: a report from the American Heart Association
ma-media thickness was demonstrated with ezetimibe- Statistics Committee and Stroke Statistics Subcommittee. Circulation.
simvastatin combination therapy compared with sim- 2008;117:e25-146.
vastatin alone, despite significantly greater reduction 3. The Lipid Research Clinics Coronary Primary Prevention Trial
Results. I. Reduction in incidence of coronary heart disease. JAMA.
in LDL-C in the combination group.20 1984;251:351-364.
In addition, in another study, an increased risk of 4. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery dis-
cancer death was observed in the simvastatin-ezetimibe ease as a result of intensive lipid-lowering therapy in men with high lev-
els of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.
group compared with the placebo group,21 but an analy- 5. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the
sis of more than 20,000 patients in ongoing randomized risk of coronary heart disease. N Engl J Med. 2003;349:523-534.
trials revealed no increase in cancer risk in patients 6. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in pa-
tients at high risk for coronary events. N Engl J Med. 2007;357:2109-2122.
receiving ezetimibe compared with placebo.22 However, 7. Expert Panel on Detection, Evaluation, and Treatment of High Blood
given the lack of documented outcome benefit with Cholesterol in Adults. Executive Summary of the Third Report of the
this agent, the ACC recommends that it be reserved National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in
for patients who cannot reach LDL-C goal with maxi- Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
mal dose statins.11 8. Grundy SM, Cleeman JI, Bailey Merz CN, et al. Implications of
recent clinical trials for the National Cholesterol Education Program
Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
Omega-3 Fatty Acids 9. National Kidney Foundation. K/DOQI Clinical practice guidelines
Epidemiologic studies have demonstrated that peo- for managing dyslipidemias in chronic kidney disease. Part 3: treating
ple who have diets rich in omega-3 fatty acids have a dyslipidemias. Am J Kidney Dis. 2003;41(4 suppl 3):S39-S58.

46 AMERICAN HEALTH & DRUG BENEFITS November/December 2008 VOL. 1 NO. 9

 Cholesterol Management

10. Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA 17. Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic
recommendations for the prevention of stroke in patients with stroke agent. Ann Pharmacother. 1999;33:1083-1103.
and transient ischemic attack. Stroke. 2008;39:1647-1652. 18. Noé J, Portmann R, Brun ME, Funk C. Substrate-dependent drug-
11. American College of Cardiology. ACC Statement on ENHANCE drug interactions between gemfibrozil, fluvastatin and other organic
Trial. January 15, 2008. http://www.acc.org/enhance_statement.htm. anion-transporting peptide (OATP) substrates on OATP1B1,
Accessed October 10, 2008. OATP2B1, and OATP1B3. Drug Metab Dispos. 2007;35:1308-1314.
12. Libby P. Current concepts of the pathogenesis of atherosclerosis. 19. Garcia-Calvo M, Lisnock J, Bull HG, et al. The target of ezetimibe
Circulation. 2001;104:365-372. is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci. 2005;102:
13. Kinlay S. Low density lipoprotein-dependent and independent 8132-8137.
effects of cholesterol lowering therapies on C-reactive protein: a meta- 20. Kastelein JP, Akdim F, Stroes ES, et al. Simvastatin with or without eze-
analysis. J Am Coll Cardiol. 2007;49:2003-2009. timibe in familial hypercholesterolemia. N Engl J Med. 2008;358: 1431-1443.
14. Cohen DE, Anania FA, Chalasani N; National Lipid Association 21. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering
Statin Safety Task Force Liver Expert Panel. An assessment of statin with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;
safety by hepatologists. Am J Cardiol. 2006;97(8A):77C-81C. 359:1343-1356.
15. Canner PL, Furberg CD, Terrin ML, McGovern ME. Benefits of 22. Peto R, Emberson J, Landray M, et al. Analysis of cancer data from
niacin by glycemic status in patients with healed myocardial infarction three ezetimibe trials. N Engl J Med. 2008;359:1357-1366.
(from the Coronary Drug Project). Am J Cardiol. 2005;95:254-257. 23. Kris-Etherton PM, Harris WS, Appel LJ; American Heart
16. Ferenchick G, Rovner D. Hepatitis and hematemesis complicating Association. Nutrition Committee. Fish consumption, fish oil, omega-3
nicotinic acid use. Am J Med Sci. 1989;298:191-193. fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-2757.

Stakeholder Perspectives
Experts Debate Meaning of JUPITER for Clinical Practice
PHYSICIANS/PAYERS: Should the indications for study who had an elevation of CRP without other
statins be expanded? This was the question that had risk factors, and this group had a benefit from rosu-
many cardiovascular (CV) experts talking, but with vastatin as well.” Of those who fit the profile of the
little consensus, in light of the findings from the study population, 25 patients would need to be treat-
JUPITER (Justification for the Use of Statins in ed to prevent 1 CV event, which is “smaller than we
Primary Prevention: An Intervention Trial Evaluating anticipated,” said Dr Ridker.
Rosuvastatin) study released in November 2008 at the Steve Nissen, MD, Chairman of the Department
American Heart Association annual meeting and of Cardiovascular Medicine at the Cleveland Clinic,
then published in the New England Journal of is a believer in CRP testing and is already using it to
Medicine.1 The results have also created a buzz among guide treatment decisions. He noted that the reduc-
P & T Committee members: Should they change plan tion in death and major CV events with rosuvastatin
benefits for statins? Will physicians begin to prescribe was larger than in any other trial of a statin, and he
the drugs to a new patient population even off-label? was impressed that it occurred after only an average
JUPITER showed that apparently healthy indi- of 1.9 years of treatment (the study had been
viduals with unremarkable levels of low-density planned to last 5 years but was terminated early
lipoprotein cholesterol (LDL-C) but with elevated because of the large benefit found).
levels of high-sensitivity C-reactive protein (hs- According to Dr Nissen, applying the findings
CRP)—2.0 mg/L or more—had a dramatic reduc- from JUPITER to the US population could add 10
tion in the risk for CV events by taking rosuvastatin million persons who could benefit from statins.
(Crestor) compared with placebo. Critics point out that although the magnitude of
The large benefit of rosuvastatin—a 44% relative the 44% relative reduction in risk was large, the
reduction in CV risk—surpassed the expectations of absolute risk reduction was rather small—only 0.9%
the lead investigator, Paul Ridker, MD, Director of (1.8% in the placebo group had an event compared
the Center for Cardiovascular Disease Prevention at with 0.9% in the rosuvastatin group). Of note, sub-
Brigham and Women’s Hospital, who has champi- jects enrolled in the trial were at low risk at baseline,
oned the use of hs-CRP to estimate CV risk for quite and this low risk accounted for the small reduction
some time. “Getting CRP down appears to have in absolute risk. Only 157 of 8901 subjects taking
incremental benefit to lowering LDL cholesterol,” placebo had an event compared with 83 of 8901 ran-
Dr Ridker said. “There was a large number in our domized to rosuvastatin.

Continued

VOL. 1 NO. 9 www.AHDBonline.com 47

 CLINICAL

Continued

Using Crestor to prevent 1 death in persons with Evidence indicates that all the statins reduce CRP,
elevated CRP levels has been estimated at $500,000, but to different degrees.
a cost that may be too high. Some suggest that pre-
1. Ridker PM, Danielson E, Fonseca FAH, et al, for the JUPITER Study
scribing Crestor to reduce CRP could add $8.9 bil- Group. Rosuvastatin to prevent vascular events in men and women
lion to the cost of treatment in this country. But this with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.
cost would be reduced to about $25,000 to prevent 1
death, using a generic statin, if generic statins are as Wayne Kuznar
effective as the brand drug at reducing CRP levels. Medical Writer

Cholesterol Management: The Complexity of Multiple Effectives Treatments

PAYERS: High levels of serum cholesterol have dation issued in 2008 by the American Academy of
long been recognized as a significant risk factor for Pediatrics is much more aggressive with regard to
the development and progression of atherosclerosis. screening, and even treatment, of children with cer-
Lowering cholesterol has been shown to effectively tain risk factors.1
reduce mortality and morbidity associated with acute This complexity is further increased with the pub-
coronary syndromes and stroke—2 of the top 3 caus- licity related to the early termination of the
es of death in the United States. As our understand- JUPITER trial (see previous page), which was pub-
ing of the role of cholesterol has evolved, we have lished in November 2008.2 In JUPITER, patients
come to realize the individual effects that low-densi- without a history of cardiovascular disease, with LDL
ty lipoprotein (LDL) and high-density lipoprotein levels <130 mg/dL but with high-sensitivity C-reac-
can have in risk assessment and modification. tive protein levels of 2.0 mg/L or more, were ran-
As the authors of this article highlight, a large domized to receive rosuvastatin or placebo. The trial
number of effective treatments are available. The was ended early because patients in the treatment
availability of multiple agents adds to the complexi- group showed very significant reductions in myocar-
ty of their use: Are all these agents equal in their dial infarction, stroke, arterial revascularization, hos-
ability to affect lipid levels? Are they equal in their pitalization for unstable angina, or death from car-
ability to influence outcomes? For an individual diovascular causes. This study will raise questions
patient with a specific set of risk factors and a specif- regarding the thresholds that must be met to initiate
ic lipid profile, which agents will best affect their therapy. It will also raise issues concerning the rela-
lipid panel and their overall risk of cardiovascular or tive effectiveness of various agents, depending on
cerebrovascular complications? their ability to affect “inflammation” as a separate
The availability of several effective treatments risk factor for atherosclerosis.
also raises questions about thresholds for screening Until the evidence becomes clearer, we must
and treatment. A number of organizations have pro- empower clinicians facing these decisions with as
vided such guidance, including the American Heart many options as possible. They must be able to per-
Association, the National Cholesterol Education sonalize therapy—the best agent for the individual
Program, the United States Preventive Services Task patient—without undue restrictions.
Force (USPSTF), and the American Academy of
Pediatrics. As is often the case for the clinician 1. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening
and cardiovascular health in childhood. Pediatrics. 2008;122:198-
attempting to determine the best recommendation 208.
for a given patient, or for the patient attempting to 2. Ridker PM, Danielson E, Fonseca FAH, et al, for the JUPITER
participate in decision-making—the rapid develop- Study Group. Rosuvastatin to prevent vascular events in men and
women with elevated C-reactive protein. N Engl J Med. 2008;
ment of new science and research and the conflict- 359:2195-2207.
ing guidance of expert panel recommendations can
compound the confusion. For example, the USPSTF
currently recommends screening of patients older Thomas McCarter, MD, FACP
than 20 years, citing insufficient evidence for screen- Chief Clinical Officer
ing younger populations. Meanwhile, a recommen- Executive Health Resources

48 AMERICAN HEALTH & DRUG BENEFITS November/December 2008 VOL. 1 NO. 9