Efficacy and safety of PCSK9 inhibitors for children and adolescents with heterozygous familial hypercholesterolaemia: Systematic review and meta-analysis of randomised controlled trials

Background Statins and ezetimibe are the preferred lipid-lowering therapies (LLTs) for children with heterozygous familial hypercholesterolaemia (HeFH). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are newer add-on therapies for individuals not achieving low-density lipoprotein-cholesterol (LDL-C) targets. We evaluated the efficacy and safety of PCSK9i in children aged <18 years with HeFH. Methods Systematic review and pairwise meta-analyses of randomised-controlled trials (RCTs) of evolocumab, alirocumab and inclisiran. Comprehensive bibliographic searches were conducted in February 2026. Risk of bias was assessed with Cochrane RoB 2. Results Of 2798 unique records screened, three RCTs were included (n=451, mean age 13 years, follow-up 24 to 47 weeks). Each trial evaluated either evolocumab, alirocumab or inclisiran against placebo as add-on to baseline LLT. Participants had elevated LDL-C (>3.4 mmol/L [130 mg/dL]) despite stable LLT. Overall risk of bias was low. PCSK9i reduced LDL-C by an average of 35.44% (95% CI -41.74 to -29.14, I2=50.8%) and by 1.63 mmol/L [62.93 mg/dL] (95% CI -1.86 to -1.39, I2=18.6%) compared with placebo. There was no evidence of differences between PCSK9i and placebo in tolerability, growth and maturation, and overall incidence of adverse events. Conclusions PCSK9i add-on therapy leads to substantial reductions in LDL-C in paediatric patients with HeFH failing to achieve LDL-C targets with standard LLT. While the findings of this review support the use of PCSK9i in a subset of children and young people with HeFH, limited trial numbers and short follow-up periods underscore the need for future high-quality studies evaluating long-term safety, effectiveness and cost-effectiveness.