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

Ibadete Bytyçi1,2, Michael Y Henein3,4, Sefer Bytyqi5

  • 1Medical Faculty, University of Prishtina, Prishtina, Kosovo.

Drugs
|January 7, 2026
PubMed

Insights

ANGPTL3 inhibitors demonstrate superior efficacy in lowering lipid levels for patients with homozygous familial hypercholesterolemia (HoFH) compared to PCSK9 inhibitors. This difference is most pronounced in individuals with the negative LDL receptor (LDLR) genotype.

Area of Science:

  • Cardiovascular Medicine
  • Genetics
  • Pharmacology

Background:

  • Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C).
  • Current treatments aim to reduce lipid levels, but many patients remain inadequately controlled.
  • PCSK9 inhibitors have shown efficacy, but novel therapeutic targets like ANGPTL3 are emerging.

Purpose of the Study:

  • To conduct a meta-analysis comparing the efficacy of ANGPTL3 inhibitors versus PCSK9 inhibitors in patients with HoFH.
  • To evaluate the impact of these inhibitors on lipid profiles and identify potential differences based on genetic variants.

Main Methods:

  • Systematic literature search of electronic databases up to November 30, 2024.
  • Inclusion of 12 trials with 392 HoFH patients.
  • Primary endpoint: effect on lipid profile (TC, TG, LDL-C, HDL-C). Secondary endpoint: adverse clinical effects.

Main Results:

  • ANGPTL3 inhibitors achieved significantly greater reductions in total cholesterol (TC), LDL-C, and triglycerides (TG) compared to PCSK9 inhibitors.
  • ANGPTL3 inhibitors led to a greater decrease in HDL-C and apolipoprotein B, while apolipoprotein A was unaffected or slightly decreased.
  • Greater LDL-C reduction with ANGPTL3 inhibitors was observed in patients with the negative LDL receptor (LDLR) genotype.

Conclusions:

  • ANGPTL3 inhibitors exhibit higher efficacy in reducing lipid levels in HoFH patients than PCSK9 inhibitors.
  • The superior efficacy of ANGPTL3 inhibitors is particularly evident in patients with the negative LDLR genotype.
  • Further research is warranted to elucidate efficacy across different LDLR functional variants.
Abstract

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