How PCSK9 antibodies lower Lp(a) remains unexplained, unlike statins which raise LDL receptor activity without lowering Lp(a), a review since 2012 (Clin Sci (Lond) 2017)

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

Clin Sci (Lond) · 1 February 2017 · 5

Lambert G, Thedrez A, Croyal M, Ramin-Mangata S, Couret D, Diotel N, Nobécourt-Dupuy E, Krempf M, LeBail JC, Poirier B, Blankenstein J, Villard EF et al.

This review by Lambert and colleagues examines the unresolved mechanism behind PCSK9 monoclonal antibodies (mAbs) robust reduction of both LDL cholesterol and Lp(a), first demonstrated in clinical trials since 2012, despite no prior literature linking PCSK9 to Lp(a) metabolism. Subsequent in vitro and in vivo studies have given conflicting results on whether the LDL receptor mediates PCSK9 mAb-driven Lp(a) clearance, with the pathway appearing distinct from statins, which also enhance LDL receptor function but do not lower circulating Lp(a) in humans. The authors conclude the mechanism by which PCSK9 inhibition with monoclonal antibodies reduces Lp(a) still remains to be established.

Original abstract

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.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.