Abstract 10846: Long-term Effects of Ezetimibe Plus Statin Combination vs Double-dose Statin Therapy on Low-density Lipoprotein Cholesterol Lowering in Coronary Artery Disease Patients Pre-treated with Statins; Focus on Proprotein Convertase Subtilisin/Kexin Type 9

Abstract

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to hepatic LDL receptor, causing its subsequent degradation. Although statin therapy is known to increase concentrations of PCSK9, the relationship between long-term treatment with ezetimibe + statin and PCSK9 is not fully elucidated.

Methods: We performed a multi-center, prospective, randomized trial involving 150 patients with coronary artery disease (CAD) whose LDL-C level ≥70 mg/dL after treatment with atorvastatin 10mg/day or rosuvastatin 2.5mg/day. The patients were assigned to receive ezetimibe 10mg/day plus statin (n=78) or double-dose statin (n=75) for 52 weeks. We measured serum LDL-C levels and plasma PCSK9 concentrations by ELISA at baseline, 12 weeks and 52 weeks.

Results: Baseline patient’s characteristics did not differ in both 2 groups. Although the greater LDL-C reduction was observed from baseline to 12 weeks in the ezetimibe + statin group compared to the double-dose statin group (-28.7±19.7 mg/dL vs. -16.5±17.0 mg/dL, P<0.01), plasma PCSK9 levels increased only in the double-dose statin group and those at 12 weeks were higher in the double-dose statin group than in the ezetimibe + statin group (365.9±129.8 ng/mL vs 309.5±93.6 ng/mL, P<0.05). After 12 weeks, plasma PCSK9 levels decreased in the double-dose statin group and increased in the ezetimibe + statin group, resulting in no difference at 52 weeks (333.1±86.4 ng/mL vs 336.3±93.2 ng/mL, P=NS). However, LDL-C levels were maintained until 52 weeks in the ezetimibe + statin group and the difference in LDL-C levels between the 2 groups persisted. Plasma PCSK9 levels were more closely correlated with LDL-C levels in the double-dose statin group (r=-0.24, p<0.01) than in the ezetimibe + statin group (r=-0.17, P=0.049).

Conclusions: Although rapid increase in PCSK9 levels was observed in the double-dose statin group, PCSK9 levels unchanged in the ezetimibe + statin group in the first 12 weeks. Moreover, the ezetimibe + statin group provided a greater and stable LDL-C reduction compared to double-dose statin group despite the fact that late increase in PCSK9 levels was observed after 12 weeks. These findings may explain the advantage of combination therapy in LDL-C lowering in CAD patients pretreated with statin.