Physicians' Academy for Cardiovascular Education

A PCSK9 inhibitor lowers LDL-c in patients with gene mutations that are causative for FH

Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Literature - Hartgers ML, Defesche JC, Langslet G, et al. - J Clin Lipidol 2018;12:390–396

Introduction and methods

Heterozygous and homozygous familial hypercholesterolemia (FH) are caused by mutations in the genes for the LDL receptor (LDLR), apolipoprotein B (APOB), and PCSK9. Both conditions are characterized by high levels of LDL-c and increased risk of CVD [1]. Residual LDLR pathway activity correlates with disease severity and response to some lipid-lowering agents, and LDL-c levels are the main determinants of CVD risk and not the genetic defect per se [2].

In this study, the treatment effect of alirocumab was evaluated in patients with FH and >1 mutation who were double heterozygotes, compound heterozygotes, or homozygotes. For this purpose, DNA samples from patients with a diagnosis of FH who were enrolled in 6 clinical trials were sequenced for mutations in genes causative for FH (LDLR, APOB, PCSK9, LDLRAP1, and signal-transducing adaptor protein 1). The trials included 1 phase 2 trial and 5 phase 3 clinical trials from the ODYSSEY program [3-7].

Clinical diagnosis was based on the Simon Broome criteria for definite FH or the World Health Organization/Dutch Lipid Network criteria [8,9]. The primary efficacy endpoint in the phase 3 trials was the percentage reduction in LDL-c from baseline to week 24.

Main results


A clinically meaningful LDL-c–lowering activity was observed in patients receiving alirocumab who are double or compound heterozygous, or homozygous for genes that are causative for FH, such as LDLR, APOB, PCSK9, and LDLRAP1. LDL-c–lowering activity of alirocumab in patients with these mutations is likely to be attributable to the presence of at least 1 partially functional allele. In the future, the impact of rare mutation types may be better assessed in specifically designed trials using a placebo-phase approach, whereby each patient acts as their own control.


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Find this article online at J Clin Lipidol 2018

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