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