PCSK9 inhibition with alirocumab decreases plasma lipoprotein(a) concentration by a dual kinetic mechanism of action

Abstract

Abstract Background Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle, covalently bound to apolipoprotein(a) [apo(a)]. Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab, decrease plasma Lp(a) levels and risk of atherosclerotic cardiovascular disease (ASCVD). The kinetic mechanism for lowering Lp(a) by PCSK9 inhibitors may differ according to pre-treatment apo(a) levels. Purpose We investigated the effect of alirocumab on Lp(a) metabolism in 21 long-term statin-treated patients [Lp(a) >0.5 g/L in all] with moderate-high (n=10) and high (n=11) apo(a) concentrations according to a cutoff of median apo(a) levels of 145 nmol/L. Methods Apo(a) kinetics were studied before and after 12-week treatment with alirocumab (150 mg subcutaneously fortnightly). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. Results The plasma concentration and PR of apo(a) were significantly higher in patients with high apo(a) than in patients with moderate-high apo(a) levels (273±30 nmol/L vs 130±4.7 nmol/L and 6.0±0.69 nmol/kg/day vs 2.6±0.15 nmol/kg/day, respectively; P<0.001). The FCR of apo(a) was not significantly different between two groups (0.48±0.02 pools/day vs 0.45±0.01 pools/day, P>0.05). In patients with moderate-high apo(a) levels, alirocumab significantly lowered plasma apo(a) levels (−17%, P<0.01) and increased the FCR of apo(a) (+26%, P<0.001), but did not alter apo(a) PR. In contrast, alirocumab significantly lowered plasma apo(a) concentrations (−31%, P<0.001) via a dual mechanism that increased apo(a) FCR (+31%, P<0.001) and lowered PR (−9%, P<0.05) in patients with high apo(a) levels. The reductions in apo(a) concentration and PR with alirocumab in the high apo(a) group remained significant after adjusting for background statin when compared with patients with moderate-high apo(a) levels (P<0.05). Conclusions In statin-treated patients with elevated Lp(a), alirocumab may lower elevated plasma Lp(a) concentrations by a dual mechanism of increasing the catabolism and decreasing the production of Lp(a) particles, specifically in patients with relatively high apo(a) concentrations. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This independent research was funded by an Investigator Initiated Study Concept Research Grant from Regeneron Pharmaceuticals and Sanofi (Protocol No. LPS 14508). Figure 1Figure 2