Physicians' Academy for Cardiovascular Education

LDL-receptor expression correlates with the reduction in LDL-c in patients with homozygous FH on PCSK9 inhibitor treatment

Homozygous Familial Hypercholesterolemia Patients With Identical Mutations Variably Express the LDLR (Low-Density Lipoprotein Receptor) Implications for the Efficacy of Evolocumab

Literature - Thedrez A, Blom DJ, Ramin-Mangata S, et al. - Arterioscler Thromb Vasc Biol. 2017;published online ahead of print


Statins and ezetimibe reduce LDL-c levels by ~25% in homozygous familial hypercholesterolemia (HoFH) patients, leading to a delay of CV events and to life prolongation, although therapeutic targets cannot be achieved with these lipid-lowering therapies in this condition [1,2]. The PCSK9 inhibitor evolocumab yields an additional 20-30% reduction in LDL-c in HoFH patients, unless they totally lack the LDL-receptor (LDLR) [3,4]. The response to evolocumab is extremely variable, even among homozygous carriers of identical LDLR genetic defects [5].

In this study, levels of LDLR expression of HoFH patients were measured at the lymphocyte surface by mean fluorescence intensity (MFI) using flow cytometry, and the effects of statins, recombinant PCSK9, and a monoclonal antibody targeting PCSK9, on LDLR expression were investigated. For this purpose, lymphocytes isolated from 1 normolipemic control donor, 1 ligand-defective apoB (LDB) HoFH patient, 5 HeFH patients, and 21 HoFH patients with LDLR genetic defects were incubated sequentially with increasing concentrations of mevastatin, recombinant PCSK9 (rPCSK9), and the PCSK9 inhibitor mAb1/31H4 (mAb1).

Main results


//Ex vivo// LDLR expression is inversely associated with the plasma levels of LDL-c and apoB in HoFH patients. Residual LDLR expression seems to drive the individual response to evolocumab in these patients.


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