Aims; Heterozygous familial hypercholesterolaemia (HeFH) is one of the most frequent monogenic disorders in the world, leading to premature atherosclerotic cardiovascular diseases. The aim of this meta-analysis was to evaluate the efficacy and safety of lipid-lowering therapy (LLT) and achievement of low density lipoprotein cholesterol (LDL-C) goal in children with HeFH.

Methods and results: The main endpoint was efficacy of goal achievement for LDL-C and other lipid parameters: total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), apolipoprotein B, and lipoprotein(a), and the LLT safety [adverse events (AEs), including endocrine function, and growth indices]. The secondary endpoint was an effect of LLT on attainment of LDL-C goal treatment (<3.5 mmol/L/130 mg/dL). A total of 41 studies with 4667 paediatric patients at mean age 12.08 ± 2.4 years were included. Seventeen reported the efficacy and safety of LLT therapy compared to control, while the remaining assessed LLT through pre- and post-treatment. At median follow-up of 18.8 months, the group on LLT had significantly higher mean reductions of TC, LDL-C, TG, and increased HDL-C compared to control [−1.75 mmol/L (−67.7 mg/dL), −1.84 mmol/L (−71.2 mg/dL), −0.11 mmol/L (−9.74 mg/dL), 0.08 mmol/L (3.1 mg/dL), respectively, P < 0.001 for all]. In the subgroup analysis according to different types of LLT, we observed a significantly higher mean reduction of LDL-C by statin combined with ezetimibe treatment, followed by statins in monotherapy, PCSK9 inhibitors, and monotherapy with ezetimibe [−2.48 mmol/L (−95.9 mg/dL), −2.16 mmol/L (−83.5 mg/dL), −2.03 mmol/L (−78.5 mg/dL), and −1.50 mmol/L (−58 mg/dL), respectively, test for overall effect: P < 0.001]. The pooled LDL-C was reduced by 33.44% [−2.14 mmol/L (−82.8 mg/dL), P < 0.001] and failed to reach the goal treatment (<3.5 mmol/L) by 12.6% (95% CI, 12.4-12.9%). A total of 38.7% of children achieved the LDL-C goal, 23.9% fell short by up to 10%, 10.7% experienced moderate failure (were over the LDL-C target between >10% and 20%), and 26.7% failed by more than 20% to reach the LDL-C target. When comparing different regions, only Sweden and Greece achieved the LDL-C goal < 3.5 mmol/L in the follow-up. Netherlands, Norway, Poland, USA, UK, France, Spain, Belgium, and Austria required 2.2%, 3.4%, 3.5%, 8.9%, 10.2%, 11.2%, 11.2%, 15%, and 19.4% additional reduction in LDL-C respectively to achieve the LDL-C goal of < 3.5 mmol/L. All other countries required over 20% additional reduction in LDL-C to achieve the LDL-C goal. For other investigated countries, over 20% mean LDL-C reduction was required. All parameters related to endocrine function and demographic indices were unaffected by LLT therapy (P > 0.05). The AEs were not reported significantly higher when compared to the control, and the prevalence of therapy discontinuation was only 0.8%.

Conclusion: Despite the efficacy of LLT in children with HeFH and the low occurrence of discontinuation-related adverse events, achieving LDL-C treatment goals was relatively rare, with large differences between the investigated countries. These results underscore the importance of considering early combination therapy of statins and ezetimibe, and PCSK9 inhibitors (if available) to attain LDL-C goals effectively.