Efficacy of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Patients with Heterozygous Familial Hypercholesterolemia: A Meta-analysis.

Background: Patients with heterozygous familial hypercholesterolemia (HeFH) are at high risk of major adverse cardiovascular events (MACE) and mortality. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), including monoclonal antibodies (alirocumab, evolocumab) and small interfering RNA (inclisiran), substantially reduce lipid levels. This meta-analysis aimed to evaluate the efficacy of both types of PCSK9i specifically in patients with HeFH.

Methods: A librarian-assisted systematic search of MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov was performed from 2013 to 2023. Randomized controlled trials of PCSK9i versus control in patients with HeFH were included. No language restrictions were applied. Cochrane Risk-of-Bias tool 2 was used to assess quality of evidence. Meta-analyses were performed using Cochrane ReviewManager. Outcomes included change in atherogenic lipids, MACE, and all-cause death.

Results: Seven trials were included (N = 2196). Overall risk of bias was mostly low or with some concerns. Median follow-up was 24 weeks. PCSK9i had an uncertain effect on MACE (odds ratio [OR] 1.25, 95% confidence interval [CI] 0.69-2.26) and all-cause death (OR 2.47, 95% CI 0.33-18.26) due to the low event rate and short follow-up. However, PCSK9i significantly reduced low-density lipoprotein cholesterol (LDL-C) by 54% (95% CI 49-58), apolipoprotein B by 43% (95% CI 37-49), and lipoprotein(a) by 20% (95% CI 13-28).

Conclusions: In patients with HeFH, PCSK9i significantly reduced atherogenic lipids (LDL-C, apolipoprotein B, and lipoprotein[a]). Despite this, the effect on MACE or all-cause death was unclear. Larger-scale randomized controlled trials of longer duration are needed to validate whether this short-term reduction in lipid levels translates into a reduction in clinically meaningful outcomes.