Statin treatment effective in pediatric patients with homozygous FH
Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic MutationsStein EA, Dann EJ, Wiegman A, et al. - J Am Coll Cardiol. 2017;70(9):1162-1170
Rosuvastatin reduces significantly LDL-C levels in adults with homozygous familial hypercholesterolemia (HoFH), but data in pediatric patients are limited . 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.
- 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.
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.