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

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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 &lt;18 years with HeFH.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> 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 (&gt;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, I <jats:sup>2</jats:sup> =50.8%) and by 1.63 mmol/L [62.93 mg/dL] (95% CI −1.86 to −1.39, I <jats:sup>2</jats:sup> =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. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Abstract Figure</jats:title> <jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"> <jats:label>GRAPHICAL ABSTRACT</jats:label> <jats:caption> <jats:title>PCSK9 inhibitors for children and adolescents with HeFH</jats:title> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="26359681v1_ufig1" position="float" orientation="portrait"/> </jats:fig> </jats:sec>