PCSK9 and ANGPTL3 Inhibitors in Homozygous Familial Hypercholesterolemia: A Meta-analysis of Randomized Clinical Trials

The aim of this meta-analysis was to compare the efficacy of PCSK9 and ANGPTL3 inhibitors in patients with homozygous familial hypercholesterolemia (HoFH).

We systematically searched selected electronic databases until 30 November 2024. Main end point was the effect of lipid lowering therapy on lipid profile: total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and lipoproteins levels. The secondary end point was adverse clinical effects.

A total of 12 trials involving 392 patients with HoFH, were finally included in the meta-analysis. At a median follow-up of 12 months, ANGPTL3 inhibitors achieved greater reductions in TC (− 49.9% versus − 21.2%; p _{for subgroup} < 0.001), LDL-C (− 50.77% versus − 17.88%; p _{for subgroup} < 0.001) and TG (− 48.9% versus − 8.2%; p _{for subgroup} < 0.001) compared with PCSK9 inhibitors, but had a smaller impact on HDL-C (− 28.9% versus + 5.2%; p _{for subgroup} = 0.001). Apolipoprotein B decreased more with ANGPTL3i (− 26.9% versus − 13.2%; p _{for subgroup} < 0.001), while lipoprotein(a) reductions were similar between groups, and apolipoprotein A remained unaffected with PCSK9i but slightly decreased with ANGPTL3i. In meta-regression, ANGPTL3i produced a greater LDL-C reduction in the negative LDL receptor (LDLR) genotype (− 34.5%; p = 0.04) and showed a trend toward significance in the defective genotype (− 23.1%; p = 0.07), with no significant difference in the heterozygous type. The rates of adverse events and discontinuations were not significantly different between the groups.

PCSK9 inhibitors have lower efficacy in reducing lipid levels in HoFH compared with ANGPTL3 inhibitors, with the greatest difference seen in patients with the negative LDLR genotype. Further studies are needed to clarify efficacy across LDLR functional variants.

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