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.

Diverse Effects of Cilostazol on Proprotein Convertase Subtilisin/Kexin Type 9 between Obesity and Non-Obesity

“…A previous study demonstrated the diverse effects of adipoR activation on PCSK9 expression in apoE-deficient (apoE −/− ) mice and wild-type mice [ 17 ]. The current clinical data, along with the contradictory results of a previous clinical study [ 35 ], imply that different clinical settings may determine the diverse effects of cilostazol treatment on PCSK9 expression, which may partly explain the inconclusive results regarding the effects of cilostazol on TC and LDL-C levels in previous clinical studies [ 19 , 20 , 34 , 35 , 36 ]. Despite the obesity-dependent effects of cilostazol on PCSK9 expression, we observed similar effects on the expression of AMPKα and PPARγ, suggesting that mechanisms beyond AMPK/PPARγ activation may be at play.…”

“…Circulating adiponectin concentrations are reduced in obese individuals, and this reduction has been proposed to play a crucial role in the pathogenesis of atherosclerosis and cardiovascular diseases associated with obesity and lipid metabolism [ 33 ]. We and others have demonstrated that cilostazol treatment can increase plasma adiponectin levels in patients with PAD [ 12 , 34 ]; however, the mechanisms of action were unknown. In the present study, we demonstrated that cilostazol treatment can enhance adiponectin expression in hepatocytes and that the adiponectin/adipoR/AMPK axis plays an important role in cilostazol-induced PCSK9 expression under normal conditions.…”

“…However, our data showed that cilostazol treatment could modulate PCSK9 expression rather than by SREBP-2/SRE pathway. This entanglement of signaling pathways could further explain the inconclusive results regarding the effects of cilostazol on TC and LDL-C levels [ 19 , 20 , 34 , 35 , 36 ]. Nevertheless, in agreement with previous studies [ 17 ], our findings demonstrate that cilostazol has an anti-atherosclerotic effect, particularly in obese conditions.…”

Plasma PCSK9 predicts microvascular function but not arterial stiffness in African-Americans with well controlled type 2 diabetes

“…Unexpectedly, in this study we found that plasma PCSK9 levels were reduced in poorly controlled patients as compared to well controlled patients. This finding could be partially explained by number of medications that could influence levels of plasma PCSK9 [27][28][29]. Several studies reported elevation of PCSK9 levels in diabetic patients [17,30].…”

A Randomized Controlled Trial Evaluating Outcome Impact of Cilostazol in Patients with Coronary Artery Disease or at a High Risk of Cardiovascular Disease

“…Nevertheless, a meta-analysis comparing triple antiplatelet therapy with dual therapy in patients with DM after PCI reported that triple therapy was associated with a lower risk of MACE despite MACE not being the primary endpoint in these trials [ 39 ]. Recently, we and other researchers have found that this compound has beneficial effects on metabolic parameters and vasculo-angiogenesis functions in diabetes, either bench or bedside [ 1 , 2 , 40 ]. Taken together, the DM subgroup analysis from our study, along with the results of previous studies in diabetes, implied that cilostazol might be a good choice of antiplatelet agent for diabetic patients with CAD or at a high risk of CV disease.…”