Statin treatment effective in pediatric patients with homozygous FH
Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations
Background
Rosuvastatin reduces significantly LDL-C levels in adults with homozygous familial hypercholesterolemia (HoFH), but data in pediatric patients are limited [1]. There is also a lack of data regarding the use of lomitapide, mipomersen and evolocumab, as well as apheresis in young HoFH children [2,3].
In this global study, the efficacy and safety of rosuvastatin on LDL-C and other lipids, lipoproteins, and apolipoproteins was evaluated compared with placebo, in 13 children and adolescents aged < 18 years with HoFH. Moreover, the association between HoFH genotypes and the LDL-C response to rosuvastatin was assessed in a broader HoFH population of both children and adults.
Patients with at least 1 of the following were eligible for the study:
- genetic confirmation of 2 mutated alleles of either the LDLR, apo B, or PCSK9 genes
- phenotype with untreated LDL-C >500 mg/dL and triglycerides <400 mg/dL and 1 or more of the following
- tendon or cutaneous xanthoma before the age of 10 years
- HeFH diagnosed by genetic or clinical criteria in both parents
Eligible patients discontinued all lipid-lowering therapy except ezetimibe and/or apheresis, and received rosuvastatin 10 mg daily for 4 weeks in the lead-in phase. Subsequently, they were randomized 1:1 to a double-blind, 12-week crossover period of rosuvastatin 20 mg daily versus placebo, followed by a 12-week, open-label rosuvastatin 20 mg maintenance phase.
Main results
- Mean ± SD LDL-C level on placebo was 481 ± 185 mg/dL, whereas mean LDL-C on rosuvastatin 20 mg was 396 ± 196 mg/dL, representing a mean absolute reduction in LDL-C of 85.4 mg/dL and a least-squares mean relative difference versus placebo of -22.3% (95% CI: -33.5% to -9.1%; P = 0.005).
- During the maintenance period, the least-squares mean reduction in LDL-C was 19.3% (P = 0.009).
- Reductions in apoB, and other apoB-containing lipoproteins, paralleled those for LDL-C, with mean absolute reductions of 33 mg/dL (17.1%) in apoB (P = 0.024) and 93.2 mg/dL (22.9%) in non-HDL-C (P = 0.003).
- Mean absolute reductions in triglycerides of 39.6 mg/dL (30.4%; P = 0.004) were seen with rosuvastatin 20 mg compared with placebo.
- Non-statistically significant increases in HDL-C of 1.8 mg/dL (7.4%; P = 0.314) occurred with rosuvastatin 20 mg versus placebo during the crossover phase together with a nominally significant 11.2% increase during the maintenance phase (P = 0.026).
- The largest mean reductions in LDL-C with rosuvastatin were seen in the subgroup with the most residual LDLR activity, that is, in those with 2 defective LDLR mutations: 23.5% (P = 0.0044) and 21.3% (P = 0.0001) in the children and all patients, respectively.
- The subgroup with 1 defective and 1 negative mutation in the LDLR demonstrated a mean reduction in LDL-C of 17.0% (P = 0.014).
- The lowest reductions in LDL-C were seen in the subgroup with 2 negative LDLR mutations: 12.9% (P = 0.022) and 14.0% (P = 0.038) in the children and all patients, respectively.
- Rosuvastatin 20 mg daily was well tolerated, with no patient terminating the trial. There were neither drug discontinuations due to treatment-related adverse events, nor serious adverse events.
Conclusion
In children and adolescents with HoFH, rosuvastatin 20 mg alone or in combination with ezetimibe and/or apheresis led to an effective LDL-C reduction, and was well tolerated. Consequently, rosuvastatin is approved for the treatment of HoFH pediatric patients 7 to 17 years of age. The LDL-C response to rosuvastatin was related to the underlying mutations and was consistent with that seen in adults.
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