PCSK9 and ANGPTL3 inhibitors in homozygous familial hypercholesterolemia: A meta-analysis of randomized clinical trials

Background: The aim of this meta-analysis was to compare the efficacy of PCSK9 and ANGPTL3 inhibitors in patients with Homozygous familial hypercholesterolemia (HoFH) Methods: We systematically searched selected electronic databases until 30th November 2024. Main endpoint 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 endpoint was adverse clinical effects. Results: 12 trials involving a total of 392 patients with HoFH, were included in the meta-analysis. At a median follow-up of 12 months, the ANGPTL3i group demonstrated a greater reduction in mean TC [–4.27 mmol/L (165.1 mg/dL) vs. –1.37 mmol/L (52.9 mg/dL); p for subgroup <0.001], LDL-C [–3.51 mmol/L (135.7 mg/dL) vs. –1.81 mmol/L (69.9 mg/dL); p for subgroup <0.001], and TG [–0.61 mmol/L (54.1 mg/dL) vs. –0.21 mmol/L (18.6 mg/dL); p for subgroup <0.001], but a smaller impact on HDL-C compared to those treated with PCSK9i. Lipids were reduced more in adults compared to children in the PCSK9i group (p<0.01) but not in the ANGPTL3i group (p=0.23). Likewise, Apo-B reduced more with ANGPTL3i compared to PCSK9i but Apo-A and Lipoprotein (a) remained comparable between the two groups. The treatment-related adverse events and discontinuation rates were not different between groups. Conclusions: PCSK9 inhibitors have lower efficacy in reducing lipid levels in HoFH patients compared to ANGPTL3 inhibitors, particularly in children. Their effectiveness in different functional variations of LDL-C receptors in HoFH patients needs to be established.