Effect of cilostazol on plasma levels of proprotein convertase subtilisin/kexin type 9

Abstract

The protein complex proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as an important target for the prevention and treatment of atherosclerosis and lipid homeostasis. This study investigated the effect of cilostazol on plasma PCSK9 concentrations. We performed a post hoc analysis of two prospective, double-blind, randomized controlled trials including 115 patients of whom 61 received cilostazol 200 mg/day and 54 received placebo for 12 weeks. Linear regression analysis was performed to determine the associations between several parameters and changes in PCSK9 levels. Use of cilostazol, but not placebo, significantly increased plasma PCSK9 concentrations, high-density lipoprotein cholesterol levels, and number of circulating endothelial progenitor cells (EPCs), and decreased triglyceride levels with a trend toward an increase in total cholesterol (TC) levels. A reduction in hemoglobin A1C and an increase in plasma vascular endothelial growth factor and adiponectin levels with cilostazol treatment were also found. Changes in the number of circulating EPCs were positively correlated and the TC concentrations were inversely correlated with changes in the PCSK9 levels. After adjusting for changes in levels of TC and numbers of circulating EPCs and history of metabolic syndrome, use of cilostazol remained independently associated with changes in plasma PCSK9 levels. In conclusion, cilostazol treatment was significantly and independently associated with an increase in plasma PCSK9 levels in patients with peripheral artery disease or at a high risk of cardiovascular disease regardless of background statin use and caused an improvement in some metabolic disorders and levels of vasculo-angiogenic biomarkers.

Keywords: cilostazol; lipids; peripheral artery disease; proprotein convertase subtilisin/kexin type 9.

Figure 1. Participant flow diagram

AE, adverse event. SAE, serious adverse event.

Figure 2. Effects of cilostazol on proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations, lipid parameters, and circulating number and functions of endothelial progenitor cells (EPCs)

Our data revealed the effects of cilostazol treatment in (A) PCSK9 concentrations, (B) total cholesterol (TC) levels, (C) triglyceride levels, (D) high-density lipoprotein cholesterol (HDL-C) levels, (E) circulating number of EPCs, and (F) migrated EPCs. Values are expressed as mean ± standard deviation or median (interquartile range), as appropriate.