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CLINICAL RESEARCH: LIPID REDUCTION IN ADOLESCENTS

Efficacy and Safety of Coadministration of Ezetimibe and Simvastatin in Adolescents With Heterozygous Familial Hypercholesterolemia

Anouk van der Graaf, MD^_*, Cynthia Cuffie-Jackson, MD, Maud N. Vissers, PhD^_*, Mieke D. Trip, MD, PhD, Claude Gagné, MD^||, Genming Shi, PhD, Enrico Veltri, MD, Hans J. Avis, MD^_* and John J.P. Kastelein, MD, PhD^_*,_*

^_* Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Global Clinical Development–Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, New Jersey
Biostatistics, Schering-Plough Research Institute, Kenilworth, New Jersey
^|| Lipid Research Center (S-102), CHUL Research Center, Laval University, Quebec, Canada

Manuscript received May 26, 2008; revised manuscript received July 29, 2008, accepted September 9, 2008.

^_* Reprint requests and correspondence: Dr. John J. P. Kastelein, Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam, the Netherlands (Email: j.j.kastelein{at}amc.uva.nl).

Objectives: The study evaluated the efficacy and safety of long-term coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia (HeFH).

Background: Aggressive intervention to achieve lipid goals for adolescents with HeFH is recommended to reduce risk of premature cardiovascular disease.

Methods: In a multicenter, randomized, double-blind, placebo-controlled study, 248 male and female subjects ages 10 and 17 years with HeFH were randomized to receive: step 1: simvastatin 10, 20, or 40 mg/day plus ezetimibe 10 mg/day or placebo for 6 weeks, followed by step 2: simvastatin 40 mg/day plus ezetimibe 10 mg/day or placebo for 27 weeks; followed by step 3: all subjects received open-label simvastatin 10 or 20 mg/day (titrated to maximum 40 mg/day) plus ezetimibe 10 mg/day for 20 weeks. Safety was assessed throughout the study.

Results: Coadministered ezetimibe and simvastatin for 6 weeks (step 1) resulted in significantly greater mean reduction in low-density lipoprotein cholesterol (LDL-C) from baseline (49.5%) compared with simvastatin monotherapy (34.4%; p < 0.01) in pooled dose groups and in individual dose groups (46.7% vs. 30.4%, 49.5% vs. 34.3%, 52.1% vs. 38.6%, respectively; p < 0.01). At 33 weeks (step 2), ezetimibe-simvastatin subjects had a mean 54.0% reduction in LDL-C compared with a mean 38.1% reduction in simvastatin monotherapy subjects (p < 0.01). At 53 weeks (step 3), the pooled reduction in LDL-C was 49.1%. All treatment regimens were well tolerated throughout 53 weeks.

Conclusions: Coadministration of ezetimibe with simvastatin was safe, well tolerated, and provided higher LDL-C reduction compared with simvastatin alone in adolescents with HeFH studied up to 53 weeks. (Effects of Ezetimibe With Simvastatin in the Therapy of Adolescents With Heterozygous Familial Hypercholesterolemia; NCT00129402)

Key Words: ezetimibe • simvastatin • heterozygous familial hypercholesterolemia • efficacy • safety • pediatric

Abbreviations and Acronyms   AAP = American Academy of Pediatrics   apo B = apolipoprotein B   CPK = creatinine phosphokinase   FH = familial hypercholesterolemia   HDL-C = high-density lipoprotein cholesterol   HeFH = heterozygous familial hypercholesterolemia   IMT = intima media thickness   LDL-C = low-density lipoprotein cholesterol   NCEP = National Cholesterol Education Program   ULN = upper limit of normal

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