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Comparison of Effects of Ezetimibe/Simvastatin Versus SimvastatinVersus Atorvastatin in Reducing C-Reactive Protein

and Low-Density Lipoprotein Cholesterol LevelsThomas Pearson, MD, PhDa,*, Christie Ballantyne, MDb, Christine Sisk, BSc, Arvind Shah, PhDc,

Enrico Veltri, MDd, and Darbie Maccubbin, PhDc

The lowering effects of ezetimibe/simvastatin combination therapy on low-density lipoprotein(LDL) cholesterol and high-sensitivity C-reactive protein (CRP) were compared with those ofsimvastatin or atorvastatin monotherapy in a large cohort of patients with primary hypercho-lesterolemia. To compare ezetimibe/simvastatin with simvastatin, data were combined from 3identical, prospective 12-week trials in which patients were randomized to receive placebo;ezetimibe 10 mg; ezetimibe 10 mg added to simvastatin 10, 20, 40, or 80 mg; or simvastatin 10,20, 40, or 80 mg. To compare ezetimibe/simvastatin with atorvastatin, data were analyzed froma phase III double-blind, active-controlled study in which patients were randomized equally toreceive ezetimibe/simvastatin 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80mg for 6 weeks. When averaged across doses, ezetimibe/simvastatin produced significantlygreater reductions compared with simvastatin alone in LDL cholesterol (52.5% vs 38.0%,respectively) and CRP levels (31.0% vs 14.3%, respectively). At each individual simvastatindose, co-administration with ezetimibe produced significant further CRP reductions versussimvastatin alone. Ezetimibe/simvastatin was significantly more effective at lowering LDLcholesterol than atorvastatin when pooled across doses (53.4% vs 45.3%, respectively) and ineach milligram-equivalent dose comparison. Reductions in CRP of similar magnitude wereobserved with ezetimibe/simvastatin and atorvastatin when averaged across doses and at eachmilligram-equivalent statin dose comparison. In conclusion, the lipid-modulating and anti-in-flammatory effects of ezetimibe/simvastatin provide additional benefits not realized by statin mono-

therapy alone. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1706–1713)

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zetimibe is a novel agent that potently inhibits the intes-inal absorption of cholesterol from dietary and biliary

aUniversity of Rochester School of Medicine and Dentistry, Rochester,ew York; bMethodist DeBakey Heart Center and Baylor College of Medi-

ine, Houston, Texas; cMerck & Company, Rahway, New Jersey; and dSchering-lough Research Institute, Kenilworth, New Jersey. Manuscript received Octo-er 13, 2006; revised manuscript received and accepted January 29, 2007.

Table 2 for this article is available online at www.AJConline.org.These studies were supported by Merck & Co., Inc, North Wales, Penn-

ylvania. Dr. Pearson has received consulting fees/honoraria from Bristol-yers Squibb, New York, New York; Bayer, Wayne, New York; Johnson &

ohnson/Merck, Merck/Schering-Plough, North Wales, Pennsylvania; Sanofi/ventis, Bridgewater, New Jersey; and Forbes/Meditech, Vancouver, Britisholombia, Canada; and is on the speaker’s bureau for Abbott, Abbott Park,

llinois; AstraZeneca, New Castle County, Delaware, Bayer; Bristol-Myers/quibb; Kos, Miami, Florida; Pfizer, New York City, New York; and Merck/chering-Plough and Merck & Co., Inc. Whitehouse Station, New Jersey; andas received research grants from Kos; Merck & Co., Inc.: Pfizer; and Sanofi/ventis. Dr. Ballantyne has received consulting fees/honoraria from Merck &o. Inc.; and Reliant, Liberty Corner, New Jersey; research grants fromstraZeneca; diaDexus, South San Francisco, California, Gene Logic, Gaith-

rsburg, Maryland; GlaxoSmithKline, Brentford, London, United Kingdom;os; Merck & Co., Inc.; Novartis, Basel, Switzerland; Pfizer; Roche, Nutley,ew Jersey; Sankyo Pharma, Chuo-ku, Tokyo, Japan; Sanofi-Synthelabo,ew York City, New York, Schering-Plough, Kennilworth, New Jersey, andakeda, Deerfield, Illinois; Merck/Schering-Plough; AstraZeneca; Pfizer; andlaxoSmithKline.

*Corresponding author: Tel: 585-275-2191; fax: 585-756-7775.

bE-mail address: thomas_pearson@urmc.rochester.edu (T. Pearson).

002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.01.062

ources by blocking the Niemann-Pick C1–Like 1 proteinor cholesterol transport across the intestinal wall withoutffecting the absorption of bile acids, fatty acids, fat-solubleitamins, or triglycerides (TGs).1–6 Unlike 3-hydroxy-3-ethylglutaryl coenzyme A reductase inhibitors (i.e., sta-

ins), the metabolic effects of ezetimibe appear to be limitedo the liver and intestine; the target of ezetimibe (the sterolransporter Niemann-Pick C1–Like 1 protein) has little oro distribution outside the intestines and/or portal system.2,4

revious studies have shown that, in addition to the favor-ble effects on lipid levels, combined therapy withzetimibe plus a statin produced significant reductions in-reactive protein (CRP) relative to statin monotherapy. Toore fully explore this observation, we conducted the

resent analysis to compare the anti-inflammatory and lipid-odifying effects of ezetimibe/simvastatin therapy with

hose of simvastatin and atorvastatin monotherapy acrosshe marketed doses in a large number of patients withypercholesterolemia.

ethodsDesign of pooled simvastatin factorial studies: Results

ere analyzed from 3 similar phase III randomized, multi-enter, double-blind, placebo-controlled, 10-arm, parallel-roup studies designed to evaluate the efficacy and safetyrofile of ezetimibe/simvastatin relative to ezetimibe andimvastatin monotherapy. The design of the 3 studies has

een previously reported.7–9 After a 4-week single-blind

www.AJConline.org

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1707Preventive Cardiology/Comparison of LDL Cholesterol/CRP Lowering Agents

lacebo lead-in period, patients with primary hypercholes-erolemia (plasma low-density lipoprotein [LDL] choles-erol concentration of �145 to �250 mg/dl and TG levels

350 mg/dl) were randomized in equal numbers to 1 of 10aily treatments for 12 weeks: ezetimibe/simvastatin 10/10,0/20, 10/40, or 10/80 mg; simvastatin 10, 20, 40, or 80 mg;zetimibe 10 mg; or placebo. Individual tablets of ezetimibend simvastatin were co-administered in 2 of the studies7,8

nd a single co-granulated tablet (ezetimibe/simvastatin)as administered in the third.9 Bioequivalence between

o-administered ezetimibe and simvastatin and the singleo-granulated ezetimibe/simvastatin tablet was demon-trated in a previous study.10 Patients were required to havelanine aminotransferase and aspartate aminotransferaseevels �2 times the upper limit of normal (ULN) with noctive liver disease and creatine kinase levels �1.5 timeshe ULN. Patients with uncontrolled or unstable cardiac,ndocrine, hepatic, renal, or metabolic conditions or whoere taking nonstatin lipid-lowering drugs, immunosup-ressants, corticosteroids, or potent cytochrome P-450 3A4nhibitors were ineligible to participate. All lipid-alteringrugs were discontinued for 6 weeks (for statins) or 8 weeksfor fibrates) before randomization. Patients were instructedo maintain a cholesterol-lowering diet throughout the du-ation of the trial. Blood samples were collected at weeks4 and �2 for an assay of qualifying parameters and ateeks 0 (i.e., baseline), 2, 4, 8, and 12 for assay of lipid

fficacy variables. Plasma concentrations of CRP were mea-ured at baseline and end point (or the last available lipidetermination in patients who discontinued study treatmentrematurely).

Design of atorvastatin factorial study: The atorvastatinactorial study was a phase III, multicenter, double-blind,andomized, active-controlled, 8-arm parallel-group studyesigned to evaluate the efficacy and safety profiles of

able 1atient characteristics and baseline lipid variables in the pooled simvastat

ariable Pooled Simvastati

Placebo(n � 257*)

Ezetimibe 10 mg(n � 246*)

ge (yrs) 57 � 11 57 � 11�65 72.8% 74.8%�65 27.2% 25.2%en (%) 43.6% 42.7%aucasian (%) 90.3% 90.2%ody mass index (kg/m2) 28 � 5 29 � 5oronary heart disease (%) 19.5% 21.1%etabolic syndrome (%) 25.7% 27.6%iabetes mellitus (%) 9.7% 6.9%RP (mg/L), median � SD 2 � 4 2 � 4otal cholesterol (mg/dl) 262 � 28 266 � 28DL cholesterol (mg/dl) 177 � 23 180 � 24G (mg/dl), median � SD 152 � 76 157 � 92polipoprotein B (mg/dl) 163 � 24 166 � 23DL (mg/dl) 52 � 12 52 � 12

Data are presented as mean � SD or percentage, except where otherwi* Number of patients with baseline and post treatment CRP measureme

zetimibe/simvastatin and atorvastatin monotherapy. The s

tudy design has been reported previously.11 After a 4-weekingle-blind placebo run-in period, patients with primaryypercholesterolemia who were not at their LDL cholesteroloal as defined by the Third Report of the National Cho-esterol Education Program Adult Treatment Panel guide-ines were randomized in equal numbers to 8 treatmentrms: ezetimibe/simvastatin at doses of 10/10, 10/20, 10/40,r 10/80 mg or atorvastatin monotherapy at doses of 10, 20,0, or 80 mg for 6 weeks. Patients were eligible for enroll-ent if they met prespecified criteria with regard to coro-

ary heart disease (CHD) or CHD risk and/or LDL choles-erol levels. Other criteria included fasting serum TG level

350 mg/dl; alanine aminotransferase, aspartate amino-ransferase, or creatine kinase level �1.5 times ULN; serumreatinine level �1.5 mg/dl; and hemoglobin A1c �9.0% inatients with diabetes. Randomization was stratified accord-ng to LDL cholesterol levels at visit 2: �130 and �160g/dl, �160 and �190 mg/dl, and �190 mg/dl. Patients

iscontinued fibrate therapy 9 weeks before the start of thetudy and all other lipid-lowering therapy 7 weeks beforehe start of the study. Patients were instructed to maintain aholesterol-lowering diet throughout the duration of therial. Blood specimens were collected at weeks �4, �1, and, day 1; and week 6 or at discontinuation.

All study protocols were reviewed and approved by theppropriate institutional review boards or independent eth-cs committees. Patients provided written informed consentefore initiation of any study procedure.

Laboratory methods: In each study, lipid levels werenalyzed from fasting plasma samples at Medical Researchaboratories International (Highland Heights, Kentucky) asescribed previously.7 LDL cholesterol concentrations (inilligrams per deciliter) were calculated according to theriedewald equation: LDL cholesterol � total cholesterol �igh-density lipoprotein (HDL) cholesterol � (TG/5).12 As-

rial and atorvastatin factorial studies

rial Studies Atorvastatin Factorial Study

imvastatinonotherapy� 1,031*)

Ezetimibe �Simvastatin

(n � 1,007*)

AtorvastatinMonotherapy

(n � 917*)

Ezetimibe �Simvastatin(n � 915*)

55 � 11 57 � 11 58 � 10 59 � 1076.5% 73.7% 70.1% 68.5%23.5% 26.3% 29.9% 31.5%47.9% 47.4% 52.5% 51.9%88.4% 90.5% 86.2% 86.1%29 � 5 28 � 5 30 � 6 30 � 517.8% 19.9% 19.4% 20.5%31.2% 31.9% 51.8% 52.4%4.4% 5.9% 21.5% 23.0%2 � 3 2 � 3 2 � 3 2 � 3

262 � 28 262 � 28 265 � 42 264 � 42177 � 24 176 � 24 179 � 38 178 � 38158 � 80 160 � 89 168 � 93 170 � 95164 � 23 163 � 23 165 � 29 165 � 2951 � 12 51 � 13 49 � 12 49 � 13

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1708 The American Journal of Cardiology (www.AJConline.org)

rchived plasma samples stored during the study at �70°Cnd then batch-processed together in a treatment-blindedashion. CRP was measured by high-sensitivity immunon-phelometry (Dade Behring, Deerfield, Illinois), as previ-usly described.13

Statistical analysis: Analyses of LDL cholesterol andRP were performed on a modified intent-to-treat popu-

ation, which included all randomized patients who hadalid baseline and end point measurements for LDL cho-esterol and CRP. Analysis of variance (ANOVA) modelsere used to obtain the within-treatment estimates andetween-treatment comparisons for LDL cholesterol andRP. For the LDL cholesterol analyses, the ANOVAodel included terms for study and treatment (10 treat-ent groups) in the pooled simvastatin factorial studies

nd terms for treatment (8 treatment groups) and LDLholesterol stratum at visit 2 in the atorvastatin factorialtudy. Because the distribution of CRP measurementsollows a log-normal distribution, logarithms of the ratiosf end point to baseline values (i.e., log-ratio) wereodeled through ANOVA. The geometric mean percent-

ge changes from baseline in CRP levels were calculatedased on back-transformation via exponentiation of theodel-based least-squared means obtained from theNOVA model with the terms for treatment (i.e., dose

ombinations), baseline CRP, baseline LDL cholesterol,nd baseline HDL. Various Spearman’s correlation coef-cients were calculated within each treatment group totudy the relations between LDL cholesterol and CRParameters.

The geometric mean percentage change from baseline inRP (�SE) was examined for various patient subgroups.he ANOVA model for the subgroup analyses included

erms for treatment, baseline CRP, baseline LDL choles-erol, baseline HDL, subgroup, and treatment-by-subgroup

Mea

n %

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PBOEZE 10mgSIMVAEZE/SIMVA

PooledSIMVA

PooledEZE/

SIMVA

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EZE/SIMVA(mg/mg) ____________________

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*p<0.001 vs. PBO

**p<0.001 vs corresponding dose of SIMVA

***p<0.001 vs. pooled SIMVA

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igure 1. Mean percentage change from baseline levels in LDL cholesterolfter 12 weeks of treatment with placebo (PBO), ezetimibe (EZE), simva-tatin (SIMVA), or ezetimibe/simvastatin.

nteraction. e

The percentage of patients in whom defined single andual LDL cholesterol levels (�70 and �100 mg/dl) andRP levels (�1 and �2 mg/L) were achieved, without

egard to patients’ baseline CHD risk, were examinedcross the individual and pooled treatment groups. Theifferences between the pooled groups were tested forignificance with Fisher’s exact test. A model-based anal-sis was also performed using logistic regression for thechievement of single and dual LDL cholesterol/CRPevels with terms for treatment, baseline CRP, baselineDL cholesterol, and baseline HDL cholesterol levels.or both analyses, between-group comparisons forzetimibe/simvastatin versus statin monotherapy wereerformed for only the pooled treatment groups to control

igure 2. Mean percentage change from baseline levels in LDL cholesterolfter 6 weeks of treatment with atorvastatin (ATORVA) or ezetimibe/imvastatin. Other abbreviations as in Figure 1.

igure 3. Geometric mean percentage change from baseline levels in CRPfter 12 weeks of treatment with placebo, ezetimibe, simvastatin, orzetimibe/simvastatin Abbreviations as in Figure 1.

xperiment-wise error rate.

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1709Preventive Cardiology/Comparison of LDL Cholesterol/CRP Lowering Agents

esultsDemographics: Paired baseline and post-treatment CRP

easurements were available for 2,541 patients in the co-ort from the pooled simvastatin factorial studies and 1,832atients from the atorvastatin factorial study. The treatmentroups were generally well balanced in terms of patientemographics, baseline CRP levels, and baseline lipid pa-ameters within and between studies, with the exception thatatients in the atorvastatin factorial study had slightlyigher median TG levels compared with patients in theimvastatin factorial studies (Table 1). In addition, thereere larger proportions of patients with diabetes and met-

bolic syndrome in the atorvastatin factorial study than inhe simvastatin factorial studies (Table 1).

Effects on LDL cholesterol in pooled simvastatin fac-orial studies: After 12 weeks of treatment, ezetimibeonotherapy was significantly more effective at reducingDL cholesterol compared with placebo (�18.3% vs0.5%, respectively; p �0.001). Averaged across all doses,

ooled ezetimibe/simvastatin produced significantly greaterean percentage reductions from baseline in LDL choles-

erol compared with pooled simvastatin monotherapy�52.5% vs �38.0%, respectively; p �0.001; Figure 1). Atach dose tested, ezetimibe/simvastatin was significantlyore effective at lowering LDL cholesterol compared with

ach milligram-equivalent dose of simvastatin monotherapyp �0.001 for all comparisons; Figure 1).

Effects on LDL cholesterol in atorvastatin factorialtudy: After 6 weeks of treatment, pooled ezetimibe/sim-

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igure 4. Geometric mean percentage difference between treatment groupepresent the number of patients in the pooled simvastatin and pooled ezetimas p �0.15 for all subgroups, indicating consistency of the treatment ef

astatin was significantly more effective at lowering LDL d

holesterol than pooled atorvastatin (�53.4% vs �45.3%,espectively; p �0.001; Figure 2). At each dose tested, theDL cholesterol reductions achieved with ezetimibe/sim-astatin were significantly greater compared with eachilligram-equivalent dose of atorvastatin monotherapy

p �0.001 for all comparisons; Figure 2).

Effects on CRP in pooled simvastatin factorial studies:n the fitted model predicting log ratio of CRP as a measuref CRP change, the terms for treatment, baseline CRP, andaseline LDL cholesterol were significant (p �0.0001, p0.0001, and p � 0.0146, respectively), whereas baselineDL was not a significant predictor (p � 0.4833). Medianaseline CRP values were similar across individual treat-ent groups. Relative to placebo, treatment with ezetimibe

0 mg for 12 weeks did not produce significant reductionsrom baseline in CRP (Figure 3). When averaged across alloses, ezetimibe/simvastatin demonstrated significantlyreater reductions in CRP compared with simvastatin (p0.001; Figure 3). The geometric mean percentage reduc-

ions from baseline in CRP were 31.0% for pooledzetimibe/simvastatin and 14.3% for pooled simvastatin,eading to an incremental reduction of 16.7% (95% confi-ence interval 11.7% to 21.7%) in favor of ezetimibe/sim-astatin therapy (Figure 3). A nonparametric analysisielded similar results; the median percentage reductionsrom baseline in CRP were 33.3% for ezetimibe/simvastatinnd 15.4% for simvastatin averaged across doses.

The CRP-lowering effects of ezetimibe/simvastatin andimvastatin were compared across each of the simvastatin

MetabolicSyndromeCHD

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RP levels from baseline across patient subgroups. Values in parenthesesvastatin groups, respectively. The treatment-by-subgroup interaction term

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1710 The American Journal of Cardiology (www.AJConline.org)

ge reductions in CRP were achieved with ezetimibe/sim-astatin compared with each corresponding dose of simva-tatin monotherapy (p �0.01 for ezetimibe/simvastatin0/10 vs simvastatin 10 mg, ezetimibe/simvastatin 10/20 vsimvastatin 20 mg, ezetimibe/simvastatin 10/40 vs simva-tatin 40 mg, and ezetimibe/simvastatin 10/80 vs simvasta-in 80 mg; Figure 3).

The relation between simvastatin and ezetimibe/simva-tatin dose and CRP response was examined in this poolednalysis through pairwise comparisons (Figure 3). The re-uctions in CRP associated with placebo, ezetimibe 10 mg,nd simvastatin 10 mg were not significantly different fromero (p �0.10 for each between-group comparison). Addi-ionally, simvastatin 10 mg did not produce significant re-uctions from baseline in CRP relative to placebo (�4.0%s 7.4%, respectively; p � 0.0859) or ezetimibe alone�4.0% vs �2.8%, respectively; p � 0.8406). Relative toimvastatin 10 mg, significantly greater reductions in CRPere observed with simvastatin 20 mg (�4.0% vs �16.2%,

espectively; p �0.05), 40 mg (�4.0% vs �17.3%, respec-ively; p �0.05), and 80 mg (�4.0% vs �18.4%, respec-ively; p �0.05). However, there were no significant dif-erences in CRP-lowering response among simvastatin0, 40, and 80 mg (p �0.05 for each between-groupomparison). For ezetimibe/simvastatin at every doseevel, significant reductions in CRP were observed rela-ive to zero, placebo, and ezetimibe alone (p �0.006 forach between-group comparison). The geometric mean per-entage reduction in CRP associated with ezetimibe/simva-tatin 10/10 mg was significantly lower than those ofzetimibe/simvastatin 10/20 mg (�19.0% vs �30.3%, re-pectively; p �0.05), 10/40 mg (�19.0% vs �35.0, respec-ively; p �0.001), and 10/80 mg (�19.0% vs �37.8%, respec-ively; p �0.0001). However, there were no significantifferences in CRP-lowering response among ezetimibe/sim-astatin 10/20, 10/40, and 10/80 mg (p �0.05 for eachetween-group comparison).

The enhanced CRP-lowering efficacy of ezetimibe/simva-

igure 5. Effect of baseline CRP levels at clinically meaningful cut-offoints (�1, 1 to 3, �3) on CRP efficacy with placebo, ezetimibe, simva-tatin monotherapy (pooled across doses), and ezetimibe/simvastatinpooled across doses). Shown are median percentage changes from base-ine in CRP level. Bars, SE. Abbreviations as in Figure 1.

tatin was consistent across patient subgroups based on age c

�65 vs �65 years), gender, race (Caucasian versus non-aucasian), body mass index (BMI; �30 vs �30 kg/m2), andaseline presence of diabetes, CHD, and metabolic syn-rome status (Figure 4). Median percentage changes in CRParied across baseline CRP levels, with the greatest reduc-ions observed in the patients with the highest baseline CRPevels (Figure 5). However, the trend in CRP response wasimilar to that observed in the entire cohort, with ezetimibe/imvastatin being more effective in reducing CRP thanimvastatin or ezetimibe alone.

Spearman’s correlation coefficients for placebo, ezetimibe0 mg, simvastatin, and ezetimibe/simvastatin demonstratedinimal associations (most coefficients �0.2) between baselineDL cholesterol and percentage change in CRP, percentage

igure 6. Geometric mean percentage change from baseline level in CRPfter 6 weeks of treatment with atorvastatin and ezetimibe/simvastatin.bbreviations as in Figures 1 and 2.

igure 7. Effect of baseline CRP levels at clinically meaningful cut-offoints (�1, 1 to 3, �3 mg/L) on CRP efficacy with atorvastatin (pooledcross doses) and ezetimibe/simvastatin (pooled across doses). Medianercentage changes from baseline levels in CRP are shown. Bars, SE.bbreviations as in Figures 1 and 2.

hange in LDL cholesterol and percentage change in CRP, per-

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1711Preventive Cardiology/Comparison of LDL Cholesterol/CRP Lowering Agents

entage change in LDL cholesterol and change in CRP, andhange in LDL cholesterol and change in CRP across the indi-idual treatment groups (Table 2, online only).

Effects on CRP in atorvastatin factorial study: In thetted model, predicting log ratio of CRP, the term foraseline CRP was significant (p �0.0001), whereas theerms for treatment, baseline LDL cholesterol, and baselineDL cholesterol were not significant (p � 0.20, p � 0.62,

nd p � 0.22, respectively). Median baseline CRP valuesere similar across the individual treatment groups. After 6eeks of treatment, the geometric mean percentage reduc-

ions from baseline in CRP were 25.1% for pooledzetimibe/simvastatin and 24.8% for pooled atorvastatin,esulting in a between-group difference of 0.3% (95% con-dence interval, �5.14 to 5.82; Figure 6). Similar resultsere observed in a nonparametric analysis; the median per-

entage reductions from baseline in CRP were 26.5% fortorvastatin averaged across doses and 26.7% for ezetimibe/imvastatin averaged across doses. Because the treatment termn the fitted model was not significant, pairwise testing amonghe treatment groups was not performed. This finding indicatedhat reductions in CRP of similar magnitude were observedith ezetimibe/simvastatin and atorvastatin when averaged

cross doses and at each milligram-equivalent statin doseomparison.

Because the treatment term in the fitted model was notignificant, the relation between ezetimibe/simvastatin andtorvastatin dose and CRP response could not be examinedhrough pairwise comparisons. However, the geometric meanercentage reductions from baseline CRP levels observed withtorvastatin 10, 20, 40, and 80 mg and ezetimibe/simvastatin0/10, 10/20, 10/40, and 10/80 mg were significantly differenthan zero (p �0.0001 for each comparison; Figure 6). There-

able 3ercentage* of patients achieving individual and dual low-density lipopro�1, �2 mg/L) levels after 12 weeks’ treatment with placebo, ezetimibe,

reatmentLDL Cholesterol

�100 mg/dl �70 mg/dl �2

lacebo 0 0 1zetimibe 10 mg 1.6 0 1imvastatin 10 mg 20.8 0.4 2zetimibe/simvastatin 10/10 mg 63.3 10.4 2imvastatin 20 mg 30.3 1.2 2zetimibe/simvastatin 10/20 mg 74.4 28.0 3imvastatin 40 mg 50.6 3.4 2zetimibe/simvastatin 10/40 mg 87.1 49.8 3imvastatin 80 mg 69.3 17.4 3zetimibe/simvastatin 10/80 mg 90.6 59.2 4ooled simvastatin 43.1 5.7 2ooled ezetimibe/simvastatin 78.9† 37.0† 3

p Values are based on the Fisher’s exact test.Between-treatment group comparisons were only performed on pooled

rrors.* Expressed as number of patients achieving level/number of patients a

atients had to be above the stated LDL cholesterol and/or CRP level at b† One-sided p value �0.001 versus corresponding dose of simvastatin m‡ One-sided p value �0.050 versus corresponding dose of simvastatin m

ore, although ezetimibe/simvastatin and atorvastatin produced s

ignificant reductions in CRP, there were no differences in theRP-lowering response across the individual ezetimibe/sim-astatin and atorvastatin doses.

The similar CRP-lowering efficacy of ezetimibe/simva-tatin and atorvastatin was consistent among subgroupsased on age (�65 vs �65 years), gender, race (Caucasians non-Caucasian), BMI (�30 vs �30 kg/m2), and baselineresence of diabetes, CHD, and metabolic syndrome statusdata not shown). Median percentage changes in CRP variedcross baseline CRP levels, with the greatest reductionsbserved in the patients with the highest baseline CRPevels (Figure 7). However, the trend in CRP response wasimilar to that observed in the entire cohort, with ezetimibe/imvastatin and atorvastatin producing reductions in CRP ofimilar magnitude.

Spearman’s correlation coefficients for the individualzetimibe/simvastatin and atorvastatin groups demon-trated minimal association (most coefficients �0.2) be-ween baseline LDL cholesterol and percentage change inRP; percentage change in LDL cholesterol and percent-ge change in CRP; percentage change in LDL choles-erol and change in CRP; and change in LDL cholesterolnd change in CRP (Table 2, online only).

Attainment of single and dual LDL and CRP levels inooled simvastatin factorial studies: Predefined LDL,RP, and dual LDL cholesterol/CRP levels werechieved in a significantly greater proportion of patientsreated with pooled ezetimibe/simvastatin than withooled simvastatin monotherapy (p �0.05 for CRP �2g/L, p �0.001 for all other comparisons; Table 3). In

eneral, a trend toward greater LDL cholesterol, CRP,nd dual LDL cholesterol/CRP goal attainment was ob-

L) cholesterol (�70, �100 mg/dl) and C-reactive protein (CRP)tatin, and ezetimibe/simvastatin

CRPLDL Cholesterol �100

mg/dl and CRPLDL Cholesterol �70

mg/dl and CRP

�1 mg/L �2 mg/L �1 mg/L �2 mg/L �1 mg/L

7.3 0 0 0 05.1 1.7 0.3 0 09.8 7.7 3.3 0 0

17.4 36.0 21.0 5.8 4.814.0 15.0 10.0 0.3 0.320.6 43.4 24.9 15.4 9.215.9 24.7 14.6 2.0 0.724.6 53.4 36.1 28.4 18.818.8 42.7 21.5 10.2 4.322.7 58.3 34.2 38.2 22.214.7 22.2 12.2 3.2 1.321.3† 47.7† 29.0† 21.6† 13.5†

statin and pooled ezetimibe/simvastatin groups to minimize multiplicity

vel at baseline. For inclusion in the dual LDL cholesterol/CRP analysis,and have baseline and post-treatment CRP measurements.rapy.rapy.

tein (LDsimvas

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1712 The American Journal of Cardiology (www.AJConline.org)

imvastatin doses. Similar results were obtained from theodel-based analysis as well (data not shown).

Attainment of single and dual LDL and CRP levels intorvastatin factorial study: When averaged across doses,redefined LDL cholesterol and dual LDL cholesterol/CRPevels were achieved in a significantly greater proportion ofatients treated with ezetimibe/simvastatin than with ator-astatin monotherapy (p �0.002 for all comparisons; Table). The percentage of patients in whom CRP levels �1 and2 mg/L were achieved were similar between pooled

zetimibe/simvastatin and pooled atorvastatin groups. Ineneral, a trend toward greater LDL cholesterol and dualDL cholesterol/CRP goal attainment was observed across

he individual ezetimibe/simvastatin and atorvastatin doses.owever, a similar proportion of patients had CRP levels1 and �2 mg/L across these dose groups. Similar resultsere obtained from the model-based analyses as well (dataot shown).

iscussion

he present analysis showed that, when averaged across theose range and at each milligram-equivalent statin dose,zetimibe/simvastatin produced significantly greater reduc-ions in LDL cholesterol relative to simvastatin and atorva-tatin monotherapy in patients with hypercholesterolemia.he superior LDL cholesterol–lowering efficacy ofzetimibe/simvastatin was consistently observed within allrespecified patient subgroups, including age, gender, race,nd BMI, and was independent of baseline presence ofiabetes, CHD, and metabolic syndrome. In addition,zetimibe/simvastatin produced significantly greater CRPeductions relative to simvastatin monotherapy and similarRP reductions compared with atorvastatin monotherapy.

The precise mechanism by which statins reduce CRPevels is not understood, but is poorly correlated with statin

able 4ercentage* of patients achieving individual and dual low-density lipopro�1, �2 mg/L) levels after 6 weeks’ treatment with atorvastatin and ezet

reatmentLDL Cholesterol

�100 mg/dl �70 mg/dl �2

torvastatin 10 mg 39.7% 3.5% 2zetimibe/simvastatin 10/10 mg 68.9% 15.9% 3torvastatin 20 mg 57.5% 11.0% 2zetimibe/simvastatin 10/20 mg 78.2% 29.3% 3torvastatin 40 mg 71.9% 19.7% 2zetimibe/simvastatin 10/40 mg 85.9% 43.2% 3torvastatin 80 mg 78.6% 33.0% 3zetimibe/simvastatin 10/80 mg 86.0% 56.5% 3ooled atorvastatin 61.9% 16.8% 2ooled ezetimibe/simvastatin 79.8%† 36.2%† 3

p Values are based on Fisher’s exact test.Between-treatment group comparisons were only performed on pooled* Expressed as number of patients achieving level/number of patients a

atients had to be above the stated LDL cholesterol and/or CRP level at b† Two-tailed p value �0.0001 versus the corresponding pooled atorvast‡ Two-tailed p value � 0.0017 versus the corresponding pooled atorvas

ffects on LDL cholesterol or other individual lipid param- a

ters in some reports,14 suggesting a direct effect on inflam-ation in peripheral tissues or on liver metabolism.zetimibe provides additional insight into this mechanism,s its direct effects are believed to be limited to inhibition ofholesterol absorption (with consequent LDL cholesterolowering) and potential direct effects on liver metabolism.he latter may be important because the liver is the primaryource of CRP synthesis. Significant CRP reductions wereot observed with ezetimibe monotherapy but rather whenzetimibe and simvastatin were co-administered; thus,zetimibe appears to potentiate the CRP-lowering effect ofimvastatin despite the low likelihood of direct effects ofzetimibe at peripheral sites. There were significant reduc-ions in CRP with simvastatin 20 mg (16.2%) and atorva-tatin 10 mg (18.1%), with respective LDL cholesterol re-uctions of 34% and 36%. One possible interpretation is thathere is a threshold effect, meaning one needs an LDL choles-erol reduction of �30% to achieve a reduction in CRP. How-ver, in the present study, there was a lack of evidence oftrong correlations between baseline LDL cholesterol level andercentage change in CRP, percentage change in LDL choles-erol and percentage change in CRP, percentage change inDL cholesterol and change in CRP, change in LDL cholesterolnd change in CRP, and baseline LDL cholesterol and baselineRP. Therefore, one possible explanation is that ezetimibeay potentiate the effects of statins on hepatic production ofRP after a threshold of LDL cholesterol reduction is

eached. This would not necessarily imply a reduction innflammation in the arterial system; therefore, the inferencehat a reduction in CRP indicates a reduction in cardiovas-ular disease risk would require verification in trials withlinical end points.

cknowledgment: We thank Hongwei Wang, PhD, andianxin Lin, MS, from Merck & Co., Inc., for computational

L) cholesterol (�70, �100 mg/dl) and C-reactive protein (CRP)imvastatin

CRPLDL Cholesterol �100

mg/dl and CRPLDL Cholesterol �70

mg/dl and CRP

�1 mg/L �2 mg/L �1 mg/L �2 mg/L �1 mg/L

9.9% 19.2% 9.8% 1.3% 0.8%18.1% 39.3% 19.2% 8.3% 5.2%15.1% 31.3% 16.5% 7.0% 4.3%18.5% 45.0% 22.8% 15.4% 9.0%18.7% 39.1% 21.3% 12.5% 7.8%17.5% 48.5% 25.5% 26.0% 14.0%19.1% 45.2% 25.6% 18.3% 10.0%19.5% 50.2% 29.6% 32.6% 17.7%15.7% 33.7% 18.3% 9.7% 5.7%18.4% 45.7%† 24.3%‡ 20.5%† 11.5%†

tatin and pooled ezetimibe/simvastatin to minimize multiplicity errors.vel at baseline. For inclusion in the dual LDL cholesterol/CRP analysis,and have baseline and post-treatment CRP measurements.notherapy.onotherapy.

tein (LDimibe/s

mg/L

8.7%2.2%8.7%5.4%3.8%3.3%6.3%0.8%9.5%3.0%

atorvasbove leaseline

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1

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1

1713Preventive Cardiology/Comparison of LDL Cholesterol/CRP Lowering Agents

1. van Heek M, France CF, Compton DS, McLeod RL, Yumibe NP,Alton KB, Sybertz EJ, Davis HR Jr. In vivo metabolism-based dis-covery of a potent cholesterol absorption inhibitor, SCH58235, in therat and rhesus monkey through the identification of the active metab-olites of SCH48461. J Pharmacol Exp Ther 1997;283:157–163.

2. van Heek M, Farley CF, Compton DS, Hoos L, Alton KB, Sybertz EJ,Davis HR Jr. Comparison of the activity and disposition of the novelcholesterol inhibitor, SCH58235, and its glucuronide, SCH60663. Br JPharmacol 2000;129:1748–1754.

3. van Heek M, Farley C, Compton DS, Hoos L, Davis HR. Ezetimibeselectively inhibits intestinal cholesterol absorption in rodents in thepresence and absence of exocrine pancreatic function. Br J Pharmacol2001;134:409–417.

4. van Heek M, Farley C, Compton DS, Hoos LM, Smith-Torhan A,Davis HR. Ezetimibe potently inhibits cholesterol absorption but doesnot affect acute hepatic or intestinal cholesterol synthesis in rats. Br JPharmacol 2003;138:1459–1464.

5. Altmann SW, Davis HR, Zhu LJ, Yao X, Hoos LM, Tetzloff G, IyerSP, Maguire M, Golovko A, Zeng M, et al. Niemann-Pick C1 Like 1protein is critical for intestinal cholesterol absorption. Science 2004;303:1201–1204.

6. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, BraunMP, Crona JH, Davis HR Jr, Dean DC, Detmers PA, et al. The targetof ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl AcadSci U S A 2005;102:8132–8137.

7. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP,Suresh R, Sun S, Veltri E, on behalf of the Ezetimibe Study Group.Ezetimibe coadministered with simvastatin in patients with primaryhypercholesterolemia. J Am Coll Cardiol 2002;40:2125–2134.

8. Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB, for the

Ezetimibe Study Group. Efficacy and safety of ezetimibe coadminis-

tered with simvastatin in patients with primary hypercholesterolemia:a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc2004;79:620–629.

9. Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R, Johnson-Levonas AO, Sapre A, Donahue SR, for the Ezetimibe Study Group.A multicenter, randomized, double-blind, placebo-controlled, factorialdesign study to evaluate the lipid-altering efficacy and safety profile ofthe ezetimibe/simvastatin tablet compared with ezetimibe and simva-statin monotherapy in patients with primary hypercholesterolemia.Clin Ther 2004;26:1758–1773.

0. Migoya EM, Bergman A, Hreniuk D, Matthews N, Yi B, Roadcap B,Valesky R, Liu L, Riffel K, Groff M, et al. Bioequivalence of anezetimibe/simvastatin combination tablet and coadministration ofezetimibe and simvastatin as separate tablets in healthy subjects. IntJ Clin Pharmacol Ther 2006;44:83–92.

1. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose-comparison study of the combination of ezetimibe and simvastatin(Vytorin) versus atorvastatin in patients with hypercholesterolemia:the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J 2005;149:464–473.

2. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the con-centration of low-density lipoprotein cholesterols in plasma, with-out use of the preparative ultracentrifuge. Clin Chem 1972;18:499 –502.

3. Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automatedhigh-sensitivity C-reactive protein assay. Clin Chem 1999;45:2136–2141.

4. Devaraj S, Autret B, Jialal I. Effects of colesevelam hydrochloride(WelChol) on biomarkers of inflammation in patients with mild hy-

percholesterolemia. Am J Cardiol 2006;98:641–643.

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1713.e1 The American Journal of Cardiology (www.AJConline.org)

able 2pearman’s correlation coefficients

reatment Baseline LDL andPercent Change

in CRP

Pera

Correlation p value Co

ooled simvastatin factorial studiesPlacebo 0.08 0.20 �Ezetimibe 10 mg 0.22 0.00 �Pooled simvastatin 0.02 0.51Pooled ezetimibe/simvastatin 0.07 0.03Simvastatin 10 mg �0.03 0.62 �Ezetimibe/simvastatin 10/10 mg 0.22 0.00Simvastatin 20 mg �0.06 0.34Ezetimibe/simvastatin 10/20 mg �0.02 0.76Simvastatin 40 mg 0.09 0.14Ezetimibe/simvastatin 10/40 mg �0.01 0.91Simvastatin 80 mg 0.08 0.18Ezetimibe/simvastatin 10/80 mg 0.07 0.25Pooled atorvastatin 0.04 0.26Pooled ezetimibe/simvastatin �0.00 0.92torvastatin factorial studyAtorvastatin 10 mg 0.00 0.99Atorvastatin 20 mg 0.04 0.57Atorvastatin 40 mg 0.07 0.27 �Atorvastatin 80 mg 0.05 0.46Ezetimibe/simvastatin 10/10 mg �0.04 0.55 �Ezetimibe/simvastatin 10/20 mg �0.12 0.08Ezetimibe/simvastatin 10/40 mg �0.02 0.77Ezetimibe/simvastatin 10/80 mg 0.16 0.02

cent Change in LDLnd Percent Change

in CRP

Percent Change inLDL and Change

in CRP

Change in LDLand Change

in CRP

rrelation p value Correlation p value Correlation p value

0.07 0.25 �0.10 0.13 �0.09 0.150.07 0.27 �0.05 0.48 �0.07 0.270.11 0.00 0.07 0.02 0.05 0.080.16 0.00 0.09 0.00 0.06 0.080.10 0.11 �0.11 0.09 �0.09 0.140.12 0.06 0.09 0.17 �0.03 0.670.13 0.04 0.14 0.03 0.13 0.040.07 0.27 �0.05 0.47 0.01 0.920.03 0.60 �0.00 0.99 �0.03 0.680.05 0.46 0.04 0.54 0.02 0.730.18 0.00 0.08 0.21 0.04 0.570.18 0.00 0.12 0.06 0.05 0.430.11 0.00 0.06 0.05 0.01 0.680.12 0.00 0.08 0.02 0.06 0.07

0.02 0.73 0.04 0.55 0.04 0.510.08 0.25 0.01 0.85 �0.03 0.620.03 0.64 �0.08 0.23 �0.11 0.080.13 0.05 0.06 0.32 0.01 0.910.02 0.79 0.00 0.97 0.03 0.660.11 0.09 0.11 0.09 0.11 0.080.16 0.02 0.10 0.14 0.08 0.20