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

  • Baseline LDLR levels were on average 3.5-fold lower in lymphocytes isolated from HoFH patients (MFI: 232±109) compared with control (MFI: 811±225) and LDB (MFI: 885±73) lymphocytes. HeFH lymphocytes had intermediate baseline LDLR expression levels (MFI 572±159).
  • Mevastatin treatment significantly increased the expression of the LDLR at the surface of lymphocytes up to maximal MFI levels of 372±171 in HoFH, 1299±123 in HeFH, 1429±177 in control, and 1392±108 in LDB.
  • rPCSK9 significantly and dose-dependently reduced LDLR cell surface expression to MFI of 73±38 in HoFH, 430±97 in HeFH, 320±65 in control, and 326±83 in LDB lymphocytes.
  • Saturating concentrations of the PCSK9 inhibitor mAb1 restored LDLR expression levels to their maximal MFI levels at 353±155 in HoFH, 1129±175 in HeFH, 1341±191 in control, and 1258±169 in LDB lymphocytes.
  • In HoFH patients, there were significant negative correlations between maximal LDLR expression levels on lymphocytes and circulating levels of LDL-c at week 0 (r=−0.564; P=0.007) and after 24 weeks of evolocumab treatment (r=−0.700; P=0.0004), as well as between maximal LDLR expression levels of patients’ lymphocytes and their plasma apoB concentrations measured at week 0 (r=−0.564; P=0.007) and 24 weeks after evolocumab treatment (r=−0.667; P=0.001). This was not the case for circulating Lp(a) levels.
  • The correlation coefficients between LDLR expression and LDL-C or apoB levels were increased in HoFH patients with an apoE3/E3 genotype (n=15) compared with those observed in the entire cohort of 21 HoFH patients.
  • In a subgroup of 10 HoFH patients with identical LDLR defects (FH1/FH1), the changes in LDL-c induced by evolocumab treatment were positively correlated with basal and maximal LDLR expression on lymphocytes (r=0.775; P=0.008 and r=0.737; P=0.015, respectively).


//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.


1. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid lowering therapy. Circulation. 2011;124:2202–2207.

2. Cuchel M, Bruckert E, Ginsberg HN, et al; European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35:2146–2157.

3. Stein EA, Honarpour N, Wasserman SM, et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013;128:2113–2120.

4. Lambert G, Chatelais M, Petrides F, et al. Normalization of low-density lipoprotein receptor expression in receptor defective homozygous familial hypercholesterolemia by inhibition of PCSK9 with alirocumab. J Am Coll Cardiol. 2014;64:2299–2300.

5. Raal FJ, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017;5:280–290.

Find this article online at Arterioscler Thromb Vasc Biol

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