PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor's role.
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.
Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.
Frederick J
FJ
Raal
TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA.
Robert P
RP
Giugliano
TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA.
Marc S
MS
Sabatine
Jacksonville Center For Clinical Research, Jacksonville, FL.
Michael J
MJ
Koren
Division of Lipidology, University of Cape Town, Cape Town, South Africa.
Dirk
D
Blom
IRCM, University of Montreal, Montreal, QC, Canada.
Nabil G
NG
Seidah
Amgen Inc., Thousand Oaks, CA.
Narimon
N
Honarpour
Amgen Inc., Thousand Oaks, CA.
Armando
A
Lira
Amgen Inc., Thousand Oaks, CA.
Allen
A
Xue
Amgen Inc., Thousand Oaks, CA.
Padmaja
P
Chiruvolu
Amgen Inc., San Francisco, CA.
Simon
S
Jackson
Amgen Inc., San Francisco, CA.
Mei
M
Di
Amgen Inc., San Francisco, CA.
Matthew
M
Peach
Amgen Inc., Thousand Oaks, CA.
Ransi
R
Somaratne
Amgen Inc., Thousand Oaks, CA.
Scott M
SM
Wasserman
Amgen Inc., Thousand Oaks, CA.
Rob
R
Scott
Metabolic and Atherosclerosis Research Center, Cincinnati, OH ESteinMRL@aol.com.
Evan A
EA
Stein
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL / Q000378:metabolism; D002986:Clinical Trials as Topic; D056945:Hep G2 Cells; D006801:Humans; D017270:Lipoprotein(a) / Q000378:metabolism*; D008297:Male; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000276:immunology* / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; C573412:LDLR protein, human; D017270:Lipoprotein(a); D000091362:PCSK9 Inhibitors; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C577155:evolocumab
lipoprotein (a); low density lipoprotein cholesterol; low density lipoprotein receptor; proprotein convertase subtilisin/kexin type 9