Ezetimibe/Simvastatin (Vytorin): A Dual Approach to Treating Hyperlipidemia
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DRUG FORECAST
Ezetimibe/Simvastatin (Vytorin ): ®
A Dual Approach to Treating
Hyperlipidemia
Katrina Touchstone, PharmD Candidate, Laura Stark, PharmD Candidate, Marlon Honeywell,
PharmD, Marvin Scott, PharmD, and Evans Branch III, PharmD
INTRODUCTION levels of one or more of the following: ial hypercholesterolemia (HoFH), the
Hyperlipidemia is commonly diag- cholesterol, cholesterol esters, phospho- initial recommended dose of ezetimibe/
nosed each year. There is a strong cor- lipids, or triglycerides.2 The causes of simvastatin (E/S) is 10/20 mg. Primary
relation between hypercholesterolemia high serum lipid levels are divided into hypercholesterolemia, the most common
and coronary heart disease.1 Lowering two categories. Primary hyperlipidemia form of hyperlipidemia, is defined as a
lipid levels has been shown to decrease is caused by a defect in an inherited gene. total cholesterol level of 240 to 350
the risk of coronary artery disease and to Secondary hyperlipidemia may develop mg/dl. This condition is caused by a
help prevent additional coronary events. as a result of high dietary fat intake mutation of DNA (e.g., guanine to cyto-
Our continuing improvement in under- (especially trans fatty acids and saturated sine) on the LDL receptor, and it is
standing the body and cholesterol syn- fats), excessive alcohol consumption, or greatly affected by excessive consump-
thesis has allowed for the development of systemic diseases (e.g., diabetes melli- tion of saturated fats and high intakes of
increasingly effective treatment options. tus, hypothyroidism, pancreatitis, cholesterol and trans fatty acids. HoFH is
Five categories of drugs are used to nephro- sis, and systemic lupus erythe- an inherited disorder that causes eleva-
treat hyperlipidemia: matosus). tions in total cholesterol and LDL-
cholesterol (LDL-C) levels. Early screen-
• 3-hydroxy-3-methylglutaryl coenzyme PATHOGENESIS ing is recommended if a primary relative
A reductase inhibitors (HMG–CoA Cholesterol is a naturally occurring sub- of the patient has had this condition.
reductase inhibitors), or statins stance produced by the body. It is neces- Studies have shown that aggressive treat-
• fibric acid derivatives sary for the synthesis of bile acids and ments to lower LDL levels can improve
• bile acid sequestrants steroid hormones, and it helps to form morbidity and mortality and can often
• intestinal absorption inhibitors cell membranes. However, the cholesterol reduce the severity of adverse coronary
• niacin level is also heavily influenced by diet. events.3–5
Cholesterol can be subdivided into Treatment of hypercholesterolemia
A newly approved combination of two very-low-density lipoproteins (VLDLs), should be implemented with therapeutic
lipid-altering drugs, ezetimibe (Zetia®, low-density lipoproteins (LDLs), and lifestyle changes that include exercise
Merck/Schering-Plough) and simva- high-density lipoproteins (HDLs). and a diet low in saturated fat and
statin (Zocor®, Merck), is now available LDLs make up the main component of cholesterol. The National Cholesterol
as Vytorin® (Merck/Schering-Plough). cholesterol (65% or greater). Therefore, Education Program (NCEP) Adult Treat-
the risk for the development of cardio- ment Panel III (ATP III) guidelines sug-
ETIOLOGY vascular disease is strongly related to gest aggressive treatment for men and
Hyperlipidemia is defined as elevated the degree of cholesterol and LDL ele- women 18 to 80 years of age with coro-
vation in a graded, continuous fashion. If nary heart disease (CHD) or a CHD risk-
the LDL level is greatly elevated, athero- equivalent disease with LDL-C at or
Ms. Touchstone and Ms. Stark are students
sclerosis may ensue. Atherosclerosis is above 130 mg/dl and a triglyceride level
in the Center for Excellence at Florida A&M
caused by soft deposits of fat and fibrin at 350 mg/dl or below.
University’s College of Pharmacy in Talla-
on the wall of the arteries that accumu- These guidelines are based on evi-
hassee, Florida. Dr. Honeywell is Associate
late and harden over time; these plaques dence from randomized, controlled trials
Professor of Pharmacy Practice, and
may also lead to coronary events. To pre- on the management of high cholesterol.
Dr. Scott is Assistant Professor of Pharmacy
vent these life-threatening situations, an Therapy with the use of a single agent,
Practice, both at Florida A&M University in
attempt must be made to lower choles- such as a statin alone, or with other med-
Tallahassee. Dr. Branch is Associate Pro-
terol levels, especially LDL, by diet and, ications (fibric acid derivatives, bile acid
fessor of Pharmacy Practice at Florida A&M
commonly, by medications. sequestrants) often does not result in
University in Miami, Florida. Drug Forecast
attainment of LDL-C treatment goals, as
is a regular department coordinated by Alan TREATMENT AND INDICATIONS defined by the NCEP ATP III guidelines.
Caspi, PhD, PharmD, MBA, President of
For patients with primary hyper- Consequently, these patients remain at
Caspi & Associates in New York.
cholesterolemia and homozygous famil- an increased risk for coronary events.
320 P&T® • June 2005 • Vol. 30 No. 6DRUG FORECAST
PHARMACOLOGY reductase. Eleven percent of ezetimibe patients (with CHD or CHD risk-equiva-
Two different mechanisms enable E/S and 13% of simvastatin are excreted lent disease, according to NCEP ATP III
to reduce cholesterol levels. Ezetimibe is renally; 78% of ezetimibe and 60% of guidelines) to achieve a LDL-C goal of
presently the only medication in a new simvastatin are excreted fecally. This less than 100 mg/dl.
category of cholesterol-lowering agents includes absorbed drug equivalents Of 1,609 patients screened, 710
that inhibits small-intestinal absorption excreted in the bile. patients were randomly assigned to one
and decreases lipoproteins associated The average half-life of E/S is 22 hours of four daily treatment groups. The
with high total cholesterol, LDL-C, apo- in healthy individuals. patients received simvastatin 20 mg or
lipoprotein B (the major component of ezetimibe 10 mg plus simvastatin 10, 20,
LDL-C), and triglycerides. 6 It also PHARMACODYNAMICS or 40 mg. The ezetimibe arm was com-
directly inhibits the passage of dietary Significant drug interactions may pletely blinded, and the daily dose of 10
and biliary cholesterol across the brush occur, primarily because of simvastatin’s mg/day remained constant throughout
border of the small intestine. hepatic elimination via the CYP450 3A4 the study; the simvastatin arm was only
Simvastatin belongs to another class of (CYP3A4) pathway. Many drugs are partially blinded. The patients continued
cholesterol-lowering agents, the statins. potent inhibitors of CYP3A4 and can their initial doses of simvastatin for the
Statins work by inhibiting the first step increase the risk of myopathy. Inhibitors first six weeks of the study and returned
involved in cholesterol synthesis. They of the CYP3A4 pathway include amio- for assessment at the fifth week of each
competitively block HMG–CoA reduc- darone, human immunodeficiency virus subsequent six-week period. In every
tase and lower the amount of cholesterol (HIV) protease inhibitors, clarithromycin group, the simvastatin doses were dou-
that is synthesized by the body. This is (Biaxin®, Abbott), cyclosporine (Neo- bled at weeks six, 12, and 18, up to a
the rate-limiting enzyme in the liver nec- ral®, Sandimmune®, Novartis) digoxin maximum dose of 80 mg/day.
essary for cholesterol production.7 (Lanoxin®, GlaxoSmithKline), diltiazem The percentage of patients who
(e.g., Cardizem®, Biovail), fluconazole achieved LDL-C goals of less than 100
PHARMACOKINETICS (Diflucan®, Pfizer), itraconazole (Spora- mg/dl after five weeks with E/S co-
A peak response is seen in healthy sub- nox®, Janssen), ketoconazole (Nizoral®, administration was significantly higher
jects with hypercholesterolemia when Janssen), propranolol (Inderal®, than that in the simvastatin 20-mg group.
they take E/S orally for two weeks. This Wyeth), telithromycin (Ketek®, Aven- The mean plasma levels of LDL-C were
maximal response is maintained while tis), verapamil (Calan®, Pfizer), and war- also reduced significantly more by E/S
therapy continues. The plasma drug con- farin (Coumadin®, Bristol-Myers doses than by simvastatin 20 mg after
centrations attained are equivalent to Squibb). There is also an interaction five weeks (P < .0001 for all three
those achieved when ezetimibe and sim- noted with grapefruit juice. Patients comparisons) (Table 1). Both primary
vastatin are administered concurrently should avoid grapefruit and these prod- and secondary efficacy variables were
as separate agents. ucts while taking E/S, especially at statistically significant between treat-
Steady-state plasma concentrations of higher doses, to prevent an increased ment groups. At the endpoint, signifi-
ezetimibe are reached in one to two hours risk of myopathy. cantly more patients in the three E/S
following administration. Maximum con- The risk of myopathy is also increased groups reached LDL goals than patients
centrations are seen within four to 12 if E/S is administered with other lipid- in the simvastatin monotherapy group
hours after a single dose of ezetimibe. lowering medications. Bile acid seques- (Table 2).
The maximal response of simvastatin trants, such as cholestyramine (Ques- No treatment-related adverse drug
occurs at 9.88 hours. Steady-state plasma tran®, Par), colesevelam (Welchol®, events (ADEs) were classified as seri-
concentrations of simvastatin are highest Sankyo Pharma), and colestipol ous. The number of patients who dis-
at four hours after a single dose. Because (Colestid®, Pfizer) should not be given continued the study because of ADEs
the drug undergoes extensive first-pass concomitantly with E/S. These agents was similar for all treatment groups.
metabolism, less than 5% reaches the decrease the mean area-under-the-curve
general circulation. E/S may be given (AUC) concentration by 55% and can The Ballantyne Study8
without regard to food intake. decrease the lipid-lowering effects sig- A 28-week multicenter, active-
Both ezetimibe and simvastatin are nificantly. If bile acid sequestrants are controlled, double-blinded study, similar
extensively bound to protein (90% and needed, E/S should be given two hours to the Feldman trial,3 was conducted to
95%, respectively). This is also true for beforehand or four hours afterward. compare the efficacy and safety of co-
their active metabolites. The volume of administered E/S with that of atorva-
distribution following oral administration EFFICACY statin (Lipitor®, Pfizer) monotherapy in
of E/S is approximately 105.3 liters. Eze- The Feldman Study3 adults with hypercholesterolemia. Seven
timibe is metabolized primarily in the Ezetimibe, coadministered with simva- hundred eighty-eight patients were
small intestines and the liver and shows statin, was analyzed in this randomized, randomly divided into three treatment
only a minimal likelihood of interaction parallel-group, 23-week study conducted groups. In each group, the dose was
with cytochrome P450 (CYP450) sub- at 48 centers in the U.S. The objective of titrated over four six-week treatment
strates. this study was to assess whether the periods (Table 3).
Simvastatin is hydrolyzed in the liver coadministration of ezetimibe and sim- At the end of the first treatment period
to an active inhibitor of HMG–CoA vastatin monotherapy allowed high-risk (week six), coadministration of E/S
continued on page 327
322 P&T® • June 2005 • Vol. 30 No. 6DRUG FORECAST
continued from page 322
Table 1 Percentage Change in Lipid Parameters after the First Treatment Period of
Ezetimibe/Simvastatin Therapy
Least Square Mean (SE)% Change from Baseline after First Treatment Period
No. S20 No. E10 + S10 mg No. E10 + S20 No. E10 + S40
LDL-C 246 –38 (0.8) 242 –47 (0.8)* 108 –53 (1.2%)* 96 –59 (1.3)*
Total cholesterol (TC) 248 –27 (0.7) 245 –33 (0.6)* 109 –38 (0.9)* 97 –42 (1.0)*
Non–HDL-C 248 –34 (0.8) 245 –42 (0.8)* 109 –48 (1.1)* 97 –53 (1.2)*
Apolipoprotein B 241 –30 (0.8) 237 –36 (0.8)* 105 –41 (1.1)* 95 –47 (1.2)*
Triglycerides† 248 –19 (0.9) 245 –19 (1.5) 109 –25 (2.7)‡ 97 –30 (2.6)*
HDL-C 248 5.1 (0.7) 245 6.2 (0.7) 109 8.0 (1.0)‡ 97 7.4 (1.1)
Apolipoprotein A1 241 3.0 (0.8) 237 3.0 (0.8) 105 2.3 (1.1) 95 1.2 (1.2)
TC : HDL-C 248 –30 (0.7) 245 –37 (0.7)* 109 –42 (1.0)* 97 –45 (1.1)*
LDL-C : HDL-C 246 –41 (0.8) 242 –50 (0.8)* 108 –56 (1.2)* 96 –61 (1.3)*
E = ezetimibe; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; S = simvastatin.
* P < .001 versus simvastatin 20 mg (S20).
† Values are medians (SE for medians).
‡ P < .050 versus S 20 mg.
Adapted from Feldman T, Koren M, Insull W, et al. Am J Cardiol 2004;93:1481–1486. Copyright 2004, with permission from Excerpta Medica,
Inc.3
resulted in a statistically significant the baseline, compared with atorvastatin ing atorvastatin monotherapy.
decrease in the difference of LDL-C from 80 mg. Other lipid parameters (HDL-C, total
the baseline compared with atorvastatin For all of the dose ranges, the mean cholesterol, apolipoprotein B, apolipopro-
10 mg (Table 4). At the endpoint assess- percentage decrease in LDL-C showed tein A1, apolipoprotein B/apolipoprotein
ment (week 24), treatment with E/S a greater statistically significant differ- A1 and non–HDL-C) were also signifi-
10/80 mg resulted in a significantly ence in E/S coadministration groups of cantly improved with the E/S combina-
greater mean decrease in LDL-C from patients compared with patients receiv- tion compared with atorvastatin.
Table 2 Low-Density Lipoprotein-Cholesterol (LDL-C) Goal Attainment after the First Treatment
Period (Week 5) and at End of Study of Ezetimibe/Simvastatin Therapy
After First Treatment Period
S20 (n = 246) E10 + S10 (n = 242) E10 + S20 (n = 108) E10 + S40 (n = 96)
No. (%) of patients attaining 112 (46%) 181 (75%)† 90 (83%)† 84 (87%)†
LDL-C goal (DRUG FORECAST
Table 3 Ezetimibe/Simvastatin Therapy Plan by Six-Week Treatment Periods
Period 1 Period 2 Period 3 Period 4
(Weeks 1–6) (Weeks 7–12) (Weeks 13–18) (Weeks 19–24)
Treatment group 1 Atorvastatin 10 mg Atorvastatin 20 mg Atorvastatin 40 mg Atorvastatin 80 mg
Treatment group 2 Ezetimibe 10 mg + Ezetimibe 10 mg + Ezetimibe 10 mg + Ezetimibe 10 mg +
simvastatin 10 mg simvastatin 20 mg simvastatin 40 mg simvastatin 80 mg
Treatment group 3 Ezetimibe 10 mg + Ezetimibe 10 mg + Ezetimibe 10 mg + Ezetimibe 10 mg +
simvastatin 20 mg simvastatin 40 mg simvastatin 40 mg simvastatin 80 mg
From Ballantyne C, Blazing M, King T, et al. Am J Cardiol 2004;93:1487–1494. Copyright 2004, with permission from Excerpta Medica, Inc.8
Table 4 Summary of Efficacy Results of Ezetimibe/Simvastatin Therapy in the Modified Intent-to-Treat
Population (Mean ± [SE] Percent Change from Baseline)*
Total Apo B/
Treatment Cholesterol LDL-C Apo B HDL-C TG† Non–HDL-C Apo A1 Apo A1
Week 6
Atorvastatin 10 mg‡ –28.1 (0.6) –37.2 (0.8) –31.7 (0.7) 5.1 (0.8) –22.5 (1.8) –35.1(0.7) 1.6 (0.7) –32.2 (0.7)
Ezetimibe + simvastatin –33.9 (0.6)¶ –46.1 (0.8)¶ –37.7 (0.7)¶ 8.0 (0.8)¶ –26.3 (1.5) –42.7 (0.7)¶ 4.1 (0.7)¶ –39.7 (0.7)¶
10/10 mg§
Ezetimibe + simvastatin –36.2 (0.6)¶ –50.3 (0.8)¶ –41.2 (0.7)¶ 9.5 (0.8)¶ –24.6 (2.0) –46.2 (0.7)¶ 4.6 (0.7)¶ –43.2 (0.7)¶
10/20 mg
Week 12
Atorvastatin 20 mg ‡ –33.1 (0.6) –44.3 (0.9) –37.7 (0.7) 6.9 (0.9) –28.4 (1.7) –41.6 (0.8) 2.0 (0.7) –38.5 (0.8)
Ezetimibe + simvastatin –36.5 (0.6)¶ –50.2 (0.8)¶ –40.6 (0.7)¶ 9.0 (0.9) –27.7 (1.9) –46.2 (0.8)¶ 5.4 (0.7)¶ –43.2 (0.8)¶
10/20 mg§
Ezetimibe + simvastatin –39.2 (0.6)¶ –54.3 (0.8)¶ –44.9 (0.7)¶ 12.4 (0.9) –30.8 (1.7) –50.3 (0.8)¶ 6.0 (0.7)¶ –47.4 (0.8)¶
10/40
Week 18
Atorvastatin 40 mg‡ –37.0 (0.7) –49.1 (0.9) –42.3 (0.8) 7.8 (1.0) –31.2 (1.8) –46.5 (0.8) 1.3 (0.8) –42.2 (0.8)
Ezetimibe + simvastatin –40.5 (0.5)¶ –55.6 (0.6)¶ –45.3 (0.5)¶ 11.4 (0.7)¶ –32.0 (1.3) –51.6 (0.5)¶ 4.9 (0.6)¶ –47.3 (0.6)¶
10/40 mg§#
Week 24
Atorvastatin 80 mg ‡ –40.2 (0.7) –52.5 (1.0) –45.2 (0.8) 6.5 (1.0) –34.8 (1.9) –50.3 (0.9) –1.2 (0.8) –44.1 (0.8)
Ezetimibe + simvastatin –43.3 (0.5)¶ –59.4 (0.7)¶ –48.6 (0.6)¶ 12.3 (0.7)¶ –35.3 (1.2) –55.3 (0.6)¶ 4.7 (0.6)¶ –50.5 (0.6)¶
10/80 mg§#
Apo = apolipoprotein; E = ezetimibe; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol;
S = simvastatin; TG = triglycerides.
* Baseline – on no lipid-lowering drug.
† For triglycerides, median percent change from baseline, with robust SE = (interquartile range/1.0575)/number.
‡ Atorvastatin: 10 mg starting dose titrated to 20 mg, 40 mg, and 80 mg through weeks 6, 12, 18, and 24.
§ Ezetimibe + simvastatin: 10/10 mg starting dose titrated to 10/20 mg, 10/40 mg, and 10/80 mg through weeks 6, 12, 18, and 24.
Ezetimibe + simvastatin: 10/20 mg starting dose titrated to 10/40 mg, 10/40 mg, and 10/80 mg through weeks 6, 12, 18, and 24.
¶ P ≤ .05 for difference with atorvastatin in the specified week.
# Data pooled for common doses of ezetimibe + simvastatin at weeks 18 and 24.
Adapted from Ballantyne C, Blazing M, King T, et al. Am J Cardiol 2004;93:1487–1494. Copyright 2004, with permission from Excerpta Medica, Inc.8
328 P&T® • June 2005 • Vol. 30 No. 6DRUG FORECAST
Table 5 Least Squares Mean Percent Change in Efficacy Parameters from Baseline to Endpoint
Presented by Pooled Treatment Group
Least Squares Comparison Pooled Eze/Simva
Mean (SE) Change, % versus Pooled Simva
Pooled Incremental
Efficacy Placebo Eze Pooled Simva* Eze/Simva† Least Squares
Parameter (n = 140–146) (n = 143–148) (n = 595–612) (n = 566–604) Mean Change, %‡ P Value
LDL-C –2.2 (1.2) –18.9 (1.2) –39.0 (0.6) –53.0 (0.6) –14.0 (0.8)DRUG FORECAST
continued from page 329
work and electrocardiograms. fore be used with caution in women of
The treatment groups were generally childbearing age. Steps involved in the
dichotomous, and LDL-C reductions biosynthesis of cholesterol are also
with pooled E/S tablets were determined involved in proper fetal development.
to be greater in mean percent from base- Nursing mothers should avoid taking
line than pooled simvastatin or ezetimibe E/S.
10 mg alone (Table 5). Generally, the
observed ADE profiles were similar for CONCLUSION
all treatment groups, and the results of E/S has proved to be an effective and
this study were similar to those of Feld- a well-tolerated option for the manage-
man3 and Ballantyne.8 ment of hyperlipidemia. The combined
action of this medication has allowed
ADVERSE DRUG REACTIONS individuals to meet LDL-C goals without
Patients experienced some ADEs the high-dose side-effect profile associ-
while taking E/S (Table 6). The most ated with simvastatin. E/S is an effi-
commonly reported events were cacious and a pharmocoeconomically
headache, influenza, upper respiratory desirable form of therapy that can help
tract infection, myalgia, and pain in the reduce the risk of coronary events.
extremities.9
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with moderate-to-severe hepatic insuffi- Hill; 2002.
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ciency or active liver disease. The effects Treatment of high-risk patients with eze-
of E/S on these patients are unknown at timibe plus simvastatin co-administra-
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effect and should immediately inform primary hypercholesterolemia. Clin Ther
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administered with simvastatin compared
The use of E/S is contraindicated in with atorvastatin in adults with hyper-
pregnancy, primarily because simva- cholesterolemia. Am J Cardiol 2004;93:
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