The complexity of lipoprotein (a) lowering by PCSK9 monoclonal antibodies

• Published in: Clinical science (1979) Vol. 131; no. 4; pp. 261 - 268
• Main Authors: Lambert, Gilles, Thedrez, Aurélie, Croyal, Mikaël, Ramin-Mangata, Stéphane, Couret, David, Diotel, Nicolas, Nobécourt-Dupuy, Estelle, Krempf, Michel, LeBail, Jean Christophe, Poirier, Bruno, Blankenstein, Jorg, Villard, Elise F., Guillot, Etienne
• Format: Journal Article
• Language: English
• Published: England Portland Press 01.02.2017
• Subjects: Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Humans; Hyperlipidemias - blood; Hyperlipidemias - drug therapy; Hypolipidemic Agents - pharmacology; Hypolipidemic Agents - therapeutic use; Life Sciences; Lipoprotein(a) - blood; Proprotein Convertase 9 - antagonists & inhibitors; Proprotein Convertase 9 - immunology; Receptors, LDL - physiology; Research Design; low-density lipoprotein (LDL) receptor; proprotein convertase subtilisin kexin type 9 (PCSK9); statins; lipoprotein (a); proprotein convertase subtilisin kexin type 9 (PCSK9)
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/CS20160403

Since 2012, clinical trials dedicated to proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition with monoclonal antibodies (mAbs) have unambiguously demonstrated robust reductions not only in low-density lipoprotein (LDL) cholesterol (LDL-C) but also in lipoprotein (a) [Lp(a)] levels. The scientific literature published prior to those studies did not provide any evidence for a link between PCSK9 and Lp(a) metabolism. More recent investigations, either in vitro or in vivo, have attempted to unravel the mechanism(s) by which PCSK9 mAbs reduce circulating Lp(a) levels, with some showing a specific implication of the LDL receptor (LDLR) in Lp(a) clearance whereas others found no significant role for the LDLR in that process. This elusive pathway appears clearly distinct from that of the widely prescribed statins that also enhance LDLR function but do not lower circulating Lp (a) levels in humans. So how does PCSK9 inhibition with mAbs reduce Lp(a)? This still remains to be established.