Original Investigation
Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations

https://doi.org/10.1016/j.jacc.2017.06.058Get rights and content
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Abstract

Background

Homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder, is characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerotic cardiovascular disease. Statin treatment starts at diagnosis, but no statin has been formally evaluated in, or approved for, HoFH children.

Objectives

The authors sought to assess the LDL-C efficacy of rosuvastatin versus placebo in HoFH children, and the relationship with underlying genetic mutations.

Methods

This was a randomized, double-blind, 12-week, crossover study of rosuvastatin 20 mg versus placebo, followed by 12 weeks of open-label rosuvastatin. Patients discontinued all lipid-lowering treatment except ezetimibe and/or apheresis. Clinical and laboratory assessments were performed every 6 weeks. The relationship between LDL-C response and genetic mutations was assessed by adding children and adults from a prior HoFH rosuvastatin trial.

Results

Twenty patients were screened, 14 randomized, and 13 completed the study. The mean age was 10.9 years; 8 patients were on ezetimibe and 7 on apheresis. Mean LDL-C was 481 mg/dl (range: 229 to 742 mg/dl) on placebo and 396 mg/dl (range: 130 to 700 mg/dl) on rosuvastatin, producing a mean 85.4 mg/dl (22.3%) difference (p = 0.005). Efficacy was similar regardless of age or use of ezetimibe or apheresis, and was maintained for 12 weeks. Adverse events were few and not serious. Patients with 2 defective versus 2 negative LDL receptor mutations had mean LDL-C reductions of 23.5% (p = 0.0044) and 14% (p = 0.038), respectively.

Conclusions

This first-ever pediatric HoFH statin trial demonstrated safe and effective LDL-C reduction with rosuvastatin 20 mg alone or added to ezetimibe and/or apheresis. The LDL-C response in children and adults was related to underlying genetic mutations. (A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia [HYDRA]; NCT02226198)

Key Words

apheresis
low-density lipoprotein cholesterol
low-density lipoprotein receptor
pediatrics
statins

Abbreviations and Acronyms

apo B
apolipoprotein B
ARH
autosomal recessive hypercholesterolemia
CVD
cardiovascular disease
HeFH
heterozygous familial hypercholesterolemia
HoFH
homozygous familial hypercholesterolemia
LDL-C
low-density lipoprotein cholesterol
LDLR
low-density lipoprotein receptor
PCSK9
proprotein convertase subtilisin/kexin type 9

Cited by (0)

The study was funded by AstraZeneca Pharmaceuticals LP. AstraZeneca was responsible for study conduct, data collection, and analysis. The study was designed by AstraZeneca in conjunction with Drs. Stein and Kastelein. The initial drafts of the manuscript were done by Dr. Stein, Prof. Raal, and Dr. Kastelein, who had full access to the study data. All authors reviewed and had input to the final draft. The academic authors vouch for the validity of the data in the final manuscript. Dr. Stein has received consultant and expert witness fees from AstraZeneca regarding statins. Dr. Gaudet has served as a consultant or advisor for AstraZeneca, Regeneron, Sanofi, Amgen, Aegerion, Chiesi, Gemphire, Novartis, Ionis, Cymabay, Uniqure, and Catabasis; and has received research funding from AstraZeneca. Dr. Sokal has received consultant and expert witness fees from AstraZeneca regarding statins and from Promethera Biosciences, Abbvie, Alexion, and Shire not related to statins; and is chief science officer of Promethera Biosciences. Dr. Mohamed has received consultant and advisor fees from AstraZeneca. Drs. Raichlen, Sundén, and Carlsson are employees of AstraZeneca. Prof. Raal has received research grants and consultant or lecture fees from AstraZeneca, Merck, Pfizer, Regeneron, Sanofi, and Amgen. Dr. Kastelein has received grant support from AstraZeneca, Pfizer, Roche, Novartis, Merck, Merck/Schering-Plough, Ionis, Genzyme, and Sanofi; lecture fees from AstraZeneca, GlaxoSmithKline, Pfizer, Novartis, Merck/Schering-Plough, Roche, Ionis, and Boehringer Ingelheim; and consulting fees from AstraZeneca, Abbott, Pfizer, Ionis, Genzyme, Roche, Novartis, Merck, Merck/Schering-Plough, and Sanofi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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