PCSK9 inhibition lowers Lp(a) concentration by a dual mechanism of action
Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics
Introduction and methods
Lipoprotein(a) [Lp(a)] has atherogenic, inflammatory, and thrombotic properties, and is a quantitative heritable trait regulated by the apo(a) (LPA) gene locus [1,2]. The role of PCSK9 in Lp(a) metabolism involves the regulation of LDL receptors, but this may not be the sole mechanism of Lp(a) lowering by PCSK9 inhibition, since statins and ezetimibe also regulate LDL receptors, but do not lower Lp(a) [3,4].
In this study, it was evaluated whether the reduction in plasma Lp(a) particle concentration with evolocumab, as monotherapy and as dual therapy with atorvastatin, involved kinetic effects on the catabolism and production of Lp(a) particles. Moreover, the effect of evolocumab on the kinetic coupling of apo(a) and apoB within Lp(a) particles was investigated.
For this purpose, 63 healthy normo-lipidemic, non-obese men aged 18–65 years were recruited, with fasting plasma LDL-c of ≥2.5 mmol/L and <4.9 mmol/L and triglycerides of <1.7mmol/L. Subjects were randomized into a double-blind, placebo-controlled, two-by-two factorial trial of the effects of oral atorvastatin 80 mg per day, or subcutaneous evolocumab 420 mg every second week, or the combination of both study treatments for 8 weeks.
The effect of intervention was determined using intravenous D3-leucine administration with serial blood samples taken after injection of the isotope, and the concentrations of apo(a) were measured by liquid chromatography mass spectrometry to estimate plasma Lp(a) particle concentration and pool size. Lp(a)-apo(a) pool size was calculated as apo(a) concentration (nmol/L) × plasma volume (L). Lp(a)-apo(a) and Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups.
- Evolocumab significantly lowered the plasma pool size of Lp(a)-apo(a) (-36%; P< 0.001 for main effect). The reductions with monotherapy (-33%; P< 0.001) and dual therapy with atorvastatin (-38%; P= 0.004) were significantly greater compared with placebo or atorvastatin alone, which did not significantly alter the plasma pool size of Lp(a)-apo(a).
- There was a statistically significant interaction (P= 0.028) between atorvastatin and evolocumab on the fractional catabolic rates (FCR) of Lp(a)-apo(a). The increase with the combination therapy (+59%; P< 0.01) was significantly greater compared with placebo and each monotherapy. Neither atorvastatin nor evolocumab alone significantly increased the FCR of Lp(a)-apo(a).
- There was a statistical significant interaction (P= 0.044) between atorvastatin and evolocumab on the production rate of Lp(a)-apo(a). The decrease with evolocumab alone (-36%; P< 0.001) was significantly greater compared with placebo, atorvastatin, and combination therapy. Neither atorvastatin nor the combination therapy significantly decreased the production rate of Lp(a)-apo(a).
- There was a highly statistically significant association (r=0.996; P < 0.001) between the interventional changes in FCR of Lp(a)-apo(a) and Lp(a)-apoB in the 16 subjects selected for this sub-study.
Evolocumab monotherapy decreased the production and in combination with atorvastatin increased the clearance of Lp(a) particles, confirming that there is a dual mechanism of action that lowers plasma Lp(a) concentration. The contribution that kinetic changes in Lp(a) makes to reduction in CV events and to future lipid guidelines requires further investigation.