PCSK9 targeting therapies for familial hypercholesterolaemia: a meta-analysis of efficacy on lipid biomarkers and safety in adults and children across 23 RCTs

Background Familial hypercholesterolaemia (FH) is a hereditary disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels, substantially increasing the risk of atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting therapies, including monoclonal antibodies and small interfering RNA (siRNA) agents, have emerged as effective lipid lowering therapies. Objective To assess the efficacy and safety of PCSK9-targeting therapy on lipid biomarkers and adverse events in patients with FH, compared with placebo on the background of standard lipid-lowering therapy. Methods A systematic review and meta-analysis were conducted, incorporating data from 23 randomised controlled trials involving adult and paediatric FH patients treated with PCSK9 inhibitors (PCSK9i) or siRNA, including alirocumab, bococizumab, evolocumab, tafolecimab and inclisiran. Eligible studies reported changes in LDL-C, apolipoprotein B (ApoB), lipoprotein a (Lp(a)), triglycerides (TGL) and adverse effects. Pooled mean differences (MDs) and ORs with 95% CIs were calculated using random-effects models, and heterogeneity was assessed with I² statistic. This meta-analysis was registered on PROSPERO (CRD42025631510). Results A total of 4282 patients were included. PCSK9-targeting therapies significantly reduced LDL-C levels compared with control therapies (MD=−46.64%; 95% CI −50.77% to –42.52%; p<0.00001) and TGL (MD=−15.18%; 95% CI –19.34% to –11.03%; p<0.00001). Significant reductions were also observed for ApoB (MD=−34.94%; 95% CI –40.89% to –28.99%; p<0.00001) and Lp(a) (MD=−22.7%; 95% CI −25.95% to –19.44%; p<0.00001). LDL-C, TGL and ApoB reduction were more significant in heterozygous FH patients than in homozygous patients. The safety profile of these therapies was favourable, with adverse event rates comparable to those of the controls. Conclusions PCSK9i and Inclisiran demonstrate significant and sustained reductions in LDL-C, ApoB, Lp(a) and TGL in FH patients, especially in heterozygous FH patients. These agents are generally well-tolerated and represent effective treatment options for FH patients inadequately controlled by standard lipid-lowering therapies.