Efficacy of PCSK9 inhibitors on pediatric patients with heterozygous familial hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials

Background and purpose: Pediatric patients with heterozygous familial hypercholesterolemia (HeFH) are at heightened risk for early-onset cardiovascular events because of elevated low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as promising agents for safely lowering LDL-C levels, especially when traditional lipid-lowering therapies fail. This systematic review and meta-analysis aims to evaluate the efficacy of PCSK9 inhibitors in pediatric patients with HeFH. Methods: The study protocol was registered in PROSPERO (CRD42024595391). We systematically identified randomized controlled trials (RCTs) evaluating the efficacy and safety of PCSK9 inhibitors in pediatric patients with HeFH from nine major electronic databases and clinical trial registries (Proquest, PubMed, Ovid MEDLINE, Ovid Embase, Scopus, Web of Science, Cochrane CENTRAL, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform). Clinical trial registries were used to retrieve unpublished studies. The risk of bias was evaluated using the Revised Cochrane risk-of-bias tool for randomized trials. The fixed-effects model was used to estimate the pooled mean difference (MD) and risk ratio (RR) with 95% confidence intervals (95% CIs). Simultaneously, heterogeneity was evaluated using Cochran's Q test and the I-2 statistic. Results: Two RCTs, comprising 236 pediatric patients, were included. All studies were rated as having a low risk of bias. PCSK9 inhibitors significantly reduced LDL-C levels after 24 weeks compared with placebo (MD: -62.64 mg/dL; 95% CI: -74.53 to -50.74; P < 0.01). Adverse event rates were similar between the two groups (RR: 0.93; 95% CI: 0.75-1.15; P = 0.49). Furthermore, PCSK9 inhibitors showed consistent reductions in other lipid parameters, including non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein (a). Moderate heterogeneity was found, though not statistically significant. Conclusions: This meta-analysis demonstrates that PCSK9 inhibitors are an effective and safe therapeutic option for improving lipid profiles in pediatric patients with HeFH. However, the inclusion of only two RCTs with limited follow-up underscores the need for larger and longer studies to strengthen these findings.