SISANews

Evolocumab riduce la lipoproteina (a)

Gli anticorpi anti PCSK9, come l'evolocumab, oltre a ridurre il colesterolo LDL stimolando l'attività recettoriale, riducono del 20-30% anche la lipoproteina (a) con un meccanismo ancora non chiaro. Sono stati supposti vari meccanismi, come la riduzione della sintesi di apo B, la diminuzione della disponibilità delle lipoproteine contenenti apo B per il legame con l'apo (a), un aumento della rimozione della Lp(a) attraverso il recettore LDL o altri recettori epatici. Gli anticorpi monoclonali anti PCSK9 hanno un'azione mirata sulla via recettoriale delle LDL per cui l'ipotesi che la riduzione della Lp(a) fosse in qualche modo legata al meccanismo recettoriale è sempre stata considerata possibile anche se finora si è pensato che la rimozione della Lp(a) dal plasma non avvenisse attraverso questa via. I risultati in vivo e in vitro dello studio di Raal e Coll. suggeriscono tuttavia che evolocumab promuove la riduzione di Lp(a) con lo stesso meccanismo con cui riduce le LDL.

PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor's role

Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Blom D, Seidah NG, Honarpour N, Lira A, Xue A, Chiruvolu P, Jackson S, Di M, Peach M, Somaratne R, Wasserman SM, Scott R, Stein EA

J Lipid Res 2016;57:1086-1096

Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced.

J Lipid Res 2016;57:1086-1096