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 that could impact on cholesterol efflux capacity (CEC). METHODS: We conducted a 2‐by‐2 factorial trial of the effects of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg 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 < .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 > .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 = .339, p < .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 = .487, p < .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.