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

Abstract

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.

Keywords: Atherosclerosis; Biomarkers; Pharmacology, Clinical.

Figure 1. PRISMA flow diagram of study screening and selection. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2. LDL-C was statistically significantly reduced with PCSK9 targeting therapies when compared with control group (placebo on the background of standard lipid-lowering therapy) (p<0.00001). FH, familial hypercholesterolaemia; HoFH, homozygous FH; LDL-C, low-density lipoprotein cholesterol; MD, mean difference; RCT, randomised controlled trial.

Figure 3. Apolipoprotein B was statistically significantly reduced with PCSK9 targeting therapies when compared with control group (placebo on the background of standard lipid-lowering therapy) (p<0.00001). FH, familial hypercholesterolaemia; HoFH, homozygous FH; MD, mean difference; RCT, randomised controlled trial.

Figure 4. Lipoprotein (a) was statistically significantly reduced with PCSK9 targeting therapies when compared with control group (placebo on the background of standard lipid-lowering therapy) (p<0.00001). FH, familial hypercholesterolaemia; HoFH, homozygous FH; MD, mean difference; RCT, randomised controlled trial.

Figure 5. Injection site adverse effects caused by subcutaneous injections periodically were statistically increased in the PCSK-9 targeting therapies group when compared with the control group (p<0.00001). FH, familial hypercholesterolaemia; HoFH, homozygous FH; M-H, Mantel-Haenszel; RCT, randomised controlled trial.

Figure 6. Mechanism of action of PCSK9 inhibitors. Left panel: Without PCSK9 inhibitors, PCSK9 binds to LDL receptors (LDLR) on hepatocytes, promoting receptor degradation and reducing LDL clearance, leading to elevated LDL blood levels. Right panel: PCSK9 inhibitors block PCSK9 from binding to LDLR, promoting LDLR recycling and an increase in LDL clearance, resulting in lower LDL-C levels in the bloodstream. Image created with BioRender. LDL-C, low-density lipoprotein cholesterol.

Figure 7. Mechanism of action of Inclisiran for hypercholesterolaemia. Inclisiran, a small interfering RNA (siRNA) with a GalNAc tail, binds to asialoglycoprotein receptors (ASGPR) on hepatocytes, facilitating its uptake. Inside the cell, Inclisiran forms a RISC complex that binds to PCSK9 mRNA, leading to its degradation and reduced PCSK9 production. Lowered PCSK9 levels result in increased LDL receptor recycling and enhanced clearance of LDL from the bloodstream, causing reduction in LDL-C levels. Image created with BioRender. LDL-C, low-density lipoprotein cholesterol.