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for the Simvastatin in Children Study GroupBackground-A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol-lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH). Methods and Results-A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2.Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (Ϫ41%), total cholesterol (Ϫ31%), apolipoprotein B (Ϫ34%), VLDL cholesterol (Ϫ21%), and triglyceride (Ϫ9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group. Conclusions-Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.

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available. It is known that combining lipid lowering agents with different modes of action may enhance the lipid altering effect, but the impact of the combined treatment effects on the major cholesterol balance mechanisms is only poorly understood.In addition to newer medications meant to treat hypercholesterolemia, there have been major improvements in the development of methods of measuring cholesterol balance. The use of nonradiolabeled isotope enrichment of tracer cholesterol and the nonabsorbed marker sitostanol and multiple selective ion monitoring gas chromatographymass spectroscopy (GC-MS) have made it possible to make repeated treatments within a study, whereas, previously, the number of treatments and measurements was limited by exposure to radiation and/or the ability to detect the isotopes. Numerous studies of cholesterol absorption have demonstrated that there are wide interindividual variations in the fraction of cholesterol absorbed with a range of about 15-70% in normal healthy individuals ( 1-5 ).This study investigated the infl uence of simvastatin and ezetimibe and the combination of simvastatin and ezetimibe on cholesterol balance by assessing fractional cholesterol absorption from the gastrointestinal tract by measuring the absorption of isotopic cholesterol compared with the nonabsorbed marker sitostanol ( 6 ) as well as cholesterol synthesis by mass balance ( 7 ).Simvastatin and ezetimibe are approved cholesterol lowering medications that are prescribed individually or together in patients in need of plasma cholesterol reduction. Simvastatin has been previously characterized as an inhibitor of HMG-CoA reductase and as an LDL receptor enhancer ( 8 ), and ezetimibe, an inhibitor of cholesterol absorption from the gastrointestinal tract, has been characterized as an inhibitor of the Niemann-Pick C1-Like 1 Abstract This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively ( P < 0.001 for both relative to placebo). Simvastatin did not signifi cantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively ( P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated.The decreases in net cholesterol synthesis and increased fecal sterol e...

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In patients with homozygous sitoserolemia, long-term treatment with ezetimibe 10 mg/day for 2 years was effective in reducing plasma plant sterol concentrations with an overall favourable safety and tolerability profile.