Efficacy and Safety of Ezetimibe Monotherapy in Children with Heterozygous Familial or Nonfamilial Hypercholesterolemia D. Meeike Kusters, MD 1 , Maria Caceres, MS 2 , Mauricio Coll, MD 3 , Cynthia Cuffie, MD 2 , Claude Gagn  e, MD 4 , Marc S. Jacobson, MD, FAHA 5 , Peter O. Kwiterovich, MD 6,† , Raymond Lee, BS 2 , Robert S. Lowe, PhD 2 , Rachid Massaad, MS 7 , Brian W. McCrindle, MD, MPH 8 , Thomas A. Musliner, MD 2 , Joseph Triscari, PhD 2 , and John J. P. Kastelein, MD, PhD 1 Objectives To evaluate the lipid-altering efficacy and safety of ezetimibe monotherapy in young children with het- erozygous familial hypercholesterolemia (HeFH) or nonfamilial hypercholesterolemia (nonFH). Study design One hundred thirty-eight children 6-10 years of age with diagnosed HeFH or clinically important nonFH (low-density lipoprotein cholesterol [LDL-C] $160 mg/dL [4.1 mmol/L]) were enrolled into a multicenter, 12-week, randomized, double-blind, placebo-controlled study. Following screening/drug washout and a 5-week single-blind placebo-run-in with diet stabilization, subjects were randomized 2:1 to daily ezetimibe 10 mg (n = 93) or placebo (n = 45) for 12 weeks. Lipid-altering efficacy and safety were assessed in all treated patients. Results Overall, mean age was 8.3 years, 57% were girls, 80% were white, mean baseline LDL-C was 228 mg/dL (5.9 mmol/L), and 91% had HeFH. After 12 weeks, ezetimibe significantly reduced LDL-C by 27% after adjustment for placebo (P < .001) and produced significant reductions in total cholesterol (21%), nonhigh-density lipoprotein cholesterol (26%), and apolipoprotein B (20%) (P < .001 for all). LDL-C lowering response in sex, race, baseline lipids, and HeFH/nonFH subgroups was generally consistent with overall study results. Ezetimibe was well toler- ated, with a safety profile similar to studies in older children, adolescents, and adults. Conclusions Ezetimibe monotherapy produced clinically relevant reductions in LDL-C and other key lipid vari- ables in young children with primary HeFH or clinically important nonFH, with a favorable safety/tolerability profile. (J Pediatr 2015;166:1377-84). Trial registration ClinicalTrials.gov: NCT00867165. F amilial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism and the most prevalent cause for primary dyslipidemia in children. 1 Studies of FH highlight the direct link between elevated levels of low-density lipopro- tein cholesterol (LDL-C) from birth, increased risk for atherosclerosis beginning in childhood, and premature develop- ment of cardiovascular disease. 2 Recent reports from the American Academy of Pediatrics, 3 National Heart, Lung, and Blood Institute, 4 National Lipid Association, 5 and European Society of Cardiology/Eu- ropean Atherosclerosis Society 6 provide guidelines for early identification and treatment of children and adolescents at high risk for development of cardiovas- cular disease. For adolescents with high-risk dyslipidemia who do not achieve recommended lipid targets with therapeutic lifestyle/diet intervention, initiation of statin therapy is considered based on evaluation of overall cardiovascular risk. Other lipid-lowering drugs may also be used when dyslipidemia is not adequately controlled by statins alone, or when issues of statin intolerance occur. Ezetimibe is a cholesterol absorption inhibitor that lowers LDL-C and other key lipid/lipoprotein variables by selective inhibition of the NPC1L1 sterol trans- porter, thereby reducing dietary and biliary cholesterol uptake in the small intes- tines. 7 Evidence suggests that ezetimibe may also inhibit hepatic NPC1L1 transporter function and block biliary cholesterol absorption back to the liver. Coadministration of ezetimibe with statins has been evaluated in adult and adolescent patients with homozygous and heterozygous FH (HoFH, HeFH) and shown to produce significant incremental reductions in LDL-C of 15%- From the 1 Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2 Merck and Co, Inc, Whitehouse Station, NJ; 3 Centro Almirante Colon, Bogota, Colombia; 4 La Clinique des Maladies Lipidiques de Quebec, Inc, Quebec, Quebec, Canada; 5 ProHealth Care Associates, New York, NY; 6 The Johns Hopkins University, Baltimore, MD; 7 MSD Belgium, Brussels, Belgium; and 8 The Hospital for Sick Children, Toronto, Ontario, Canada †Deceased. Supported by Merck & Co, Inc, Whitehouse Station, NJ. C.G. has participated in clinical trials with AstraZeneca, Pfizer, Merck, Amgen, Regeneron, Sanofi, Genzyme, and Novartis. M.J. has received research grants from Merck. P. K. has received consulting fees/honoraria from Merck and research grants from Abbott Laboratories, GlaxoS- mithKline, Merck, and Pfizer. R. M. is an employee of MSD Belgium. B. M. received reimbursement from Merck for participation in this study; serves as a consul- tant for Bristol Myers Squibb, Eli Lilly, Genzyme, and Janssen; is a DSMB member for Medpace; and partici- pated in a trial sponsored by Astra Zeneca. J. K. has received consulting fees/honoraria from Merck. M. Ca., C. C., R. Le., R. Lo., T. M., and J. T. are employees or former employees of Merck and may own stock/stock options in the company. M. K. and M. Co. declare no conflicts of interest. Portions of the study were presented at the American Cardiology Annual Scientific sessions (March 9-11, 2013, San Fransisco, CA) and the National Lipid Association Annual Scientific Sessions (May 30-June 2, 2013, Las Vegas, Nevada). 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.02.043 AE Adverse event ALT Alanine aminotransferase AST Aspartate aminotransferase AUC Area under the curve C max Peak plasma concentration FH Familial hypercholesterolemia HDL-C High-density lipoprotein cholesterol HeFH Heterozygous FH HoFH Homozygous FH hs-CRP High-sensitivity C-reactive protein LDL-C Low-density lipoprotein cholesterol NonFH Nonfamilial hypercholesterolemia PH Polygenic hypercholesterolemia ULN Upper limit of normal 1377