A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia

Langslet G, Breazna A, Drogari E.
Journal of Clinical Lipidology 2016. Published online: June 7, 2016

Background

Individuals with the autosomal dominant lipid disorder familial hypercholesterolaemia (FH) show reduced clearance of LDL-c from the circulation, and consequently elevated LDL-c levels, as a result of mutations interfering with the LDL-receptor metabolism [1,2]. About 1 in 200-250 people in most populations are affected by heterozygous FH (HeFH) [3]. In addition to the higher risk of coronary heart disease (CHD) associated with FH [3-5], children with FH have been shown to have greater carotid intima media thickness than their unaffected siblings [6,7].

Early CHD may be prevented with early intervention with cholesterol-lowering treatment, primarily statins and some evidence on the efficacy and safety of statins in young subjects is available. However, statins have not been evaluated in children on the longer run, and although statins are now considered in children with HeFH younger than 10 years of age, few studies have evaluated their use in this age group.

This 3-year open-label, multicentre, prospective study that enrolled ~250 subjects aged 6-15 years with genetically confirmed HeFH and LDL-c>4.0 mmol/L (154 mg/dL) evaluated the long-term efficacy and safety of atorvastatin, assessed its impact on growth and development. Subjects aged 6 to <10 years initiated therapy on atorvastatin 5 mg/day and older ones initiated with 10 mg/day, and doses were titrated based on LDL-c target of <3.35 mmol/L (<130 mg/dL). Subjects were divided into Tanner stage 1 (TS1) and stage >2 (TS>2). 27.3% of participants were between the ages of 6 and 8, and 51.7% were younger than 10 years at baseline. Mean duration of treatment was 1085 days (IQR: 1035-1099).

Main results

• Mean LDL-c was reduced by ~35% from month 1 in all subject groups, with a further reduction to ~45% at month 3, with little differences between the whole group and TS 1 or >2. LDL-c levels were then maintained at this level until month 30.
• 52% of subjects younger than 10 years old attained the LDL-c target of <3.35 mmol/L at month 3. Goal attainment was >50% throughout the whole study.
• Mean percentage reductions from baseline in total cholesterol, non-HDL-c and apoB at month 36/early termination were comparable for subjects at TS1 and TS>2.
• Different effects were seen for TS1 and TS>2 for HDL-c levels from baseline to month 36/early termination (1.1% decrease vs. 1.6% increase) and triglycerides (larger mean percentage reduction in TS>2: -7.76 vs. -0.70% in TS1, but baseline TG levels were higher in TS>2 : 0.980 vs. 0.880 mmol/L).
• The overall incidence of all-causality adverse effects (AEs) was very similar in both TS categories (81.3% in TS1 vs. 79.5% in TS>2).
• 21 patients (7.7%) reported a serious AE (14 TS1, 7 TS>2). 6 subjects (2.2%) discontinued due to treatment-related AEs.
• No evidence was seen of a dose-related increase in the overall incidence of AEs or disconintunations/dose reductions of study medication.
• Creatine kinase >2xULN was more often seen in TS>2 (12.9%) than in TS1 (4.4%).

Conclusion

This 3-year study showed that atorvastatin was well tolerated and efficacious in very young subjects with HeFH. No evidence was seen that atorvastatin therapy had any clinically relevant effect on growth or maturation, as the TS shift seen in this trial was consistent with the normal trajectory, and mean height of both male and female subjects fitted on gender-specific WHO height for age charts. The LDL-c lowering effect was similar in both categories based on TS, or in subjects aged <10 vs. >10 years.
The EAS consensus statements on FH and the clinical guidance of the NLA recommend that lipid-lowering therapy should be considered in children along with lifestyle changes, and initiated at 8-10 years of age. Although this study did not include an active comparator, the data suggest that atorvastatin 5-40 mg is effective and can be used in children as young as 6 years old.


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