Effect of a PCSK9 Inhibitor and a Statin on Cholesterol Efflux Capacity: a Limitation of Current Cholesterol-Lowering Treatments?

Background: Cellular cholesterol efflux is a key step in reverse cholesterol transport that may impact on atherosclerotic cardiovascular risk. The process may be reliant on the availability of apolipoprotein (apo) B-100 containing lipoproteins to accept cholesterol from high-density lipoprotein. Evolocumab and atorvastatin are known to lower plasma apoB-100-containing lipoproteins which could impact on cholesterol efflux capacity (CEC). Methods: We conducted a 2-by-2 factorial trial of the effects of subcutaneous evolocumab (420mg every 2 weeks) and atorvastatin (80mg daily) for 8 weeks on CEC in 81 healthy, normolipidaemic men. The capacity of whole plasma and apoB-depleted plasma, including ATP binding cassette transporter A1 (ABCA1)-mediated and passive diffusion, to efflux cholesterol was measured. Results: Evolocumab and atorvastatin independently decreased whole plasma CEC (main effect P<0.01 for both). However, there were no significant effects of evolocumab and atorvastatin on apoB-depleted plasma, ABCA1-mediated and passive diffusion-mediated CEC (P>0.05 in all). In the three intervention groups combined, the reduction in whole plasma CEC was significantly correlated with the corresponding reduction in plasma apoB-100 concentration (r =0.339, P<0.01). In the evolocumab monotherapy group, the reduction in whole plasma CEC was also significantly correlated with the corresponding reduction in plasma lipoprotein(a) concentration (r =0.487, P<0.05). Conclusions: In normolipidaemic men, evolocumab and atorvastatin decrease the capacity of whole plasma to efflux cellular cholesterol. These effects may be chiefly owing to a fall in the availability of apoB-100 containing lipoproteins. Reduction in circulating lipoprotein(a) may also contribute to the decrease in whole plasma cholesterol efflux with evolocumab monotherapy.