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Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying
Evan A Stein1, Eldad J Dann2, Albert Wiegman3
1Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio.
Insights
Rosuvastatin effectively reduced LDL-C in children with homozygous familial hypercholesterolemia (HoFH). This first pediatric statin trial showed safety and efficacy, with results linked to genetic mutations.
Area of Science:
- Cardiology
- Genetics
- Pediatrics
Background:
- Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder causing extremely high LDL-C and early cardiovascular disease.
- Current statin treatments are not approved for HoFH children, necessitating evaluation of pediatric treatment options.
Purpose of the Study:
- To assess the efficacy of rosuvastatin in reducing LDL-C in children with HoFH.
- To explore the relationship between rosuvastatin's LDL-C lowering effect and specific genetic mutations in HoFH patients.
Main Methods:
- A 12-week, randomized, double-blind, crossover study comparing rosuvastatin 20 mg to placebo in HoFH children.
- Patients continued ezetimibe and/or apheresis. Genetic mutation analysis was performed using data from a prior HoFH rosuvastatin trial.
Main Results:
- Rosuvastatin reduced mean LDL-C by 85.4 mg/dl (22.3%) compared to placebo (p=0.005).
- Efficacy was consistent across age groups and with concomitant ezetimibe/apheresis use.
- LDL-C reduction varied based on genetic mutations, with greater reduction in patients with 2 defective LDL receptor mutations (23.5%) versus 2 negative mutations (14%).
Conclusions:
- Rosuvastatin 20 mg is safe and effective for lowering LDL-C in pediatric HoFH patients, alone or with ezetimibe/apheresis.
- The study is the first pediatric statin trial for HoFH, demonstrating significant LDL-C reduction.
- LDL-C response to rosuvastatin is influenced by underlying genetic mutations in both children and adults.
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).
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