Cilostazol attenuates the severity of peripheral arterial occlusive disease in patients with type 2 diabetes: the role of plasma soluble receptor for advanced glycation end-products

Abstract

Recent studies have demonstrated that the plasma soluble receptor for advanced glycation end-products (sRAGE) play a major role in developing macrovascular complications of type 2 diabetes, including peripheral arterial occlusion disease (PAOD). Cilostazol is an antiplatelet, antithrombotic agent, which has been used for the treatment of PAOD. We hypothesized that cilostazol attenuates the severity of PAOD in patients with type 2 diabetes through the augmentation of plasma sRAGE. Ninety type 2 diabetic patients with PAOD defined as intermittent claudication with ankle-brachial index (ABI) ≦0.9 were recruited for an open-labeled, placebo-controlled study for 52 weeks with oral cilostazol 100 mg twice daily (n = 45) or placebo (n = 45). Fasting plasma sRAGE, endothelial variables of E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), and inflammatory markers of high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α) were determined. After completely the 52-week treatment program, the ABI values were elevated in cilostazol group (P < 0.001). The plasma sRAGE was significantly increased (P = 0.007), and hsCRP, sVCAM, and E-selectin concentrations were significantly decreased (P = 0.028, <0.001 and <0.001, respectively) with cilostazol treatment. In a partial correlation analysis with adjustments for sex and age, the net change of sRAGE significantly correlated with the change of ABI in the cilostazol group (P = 0.043). In a stepwise multiple regression model, only the change with regards to sRAGE was significantly associated with the change of ABI (P = 0.046). Our results suggest that cilostazol may effectively attenuate the severity of PAOD in patients with type 2 diabetes. Plasma sRAGE plays a role as an independent predictor for improving the index of PAOD.

Oxidative stress and antioxidant treatment in patients with peripheral artery disease

“…Cilostazol, an antiplatelet, antithrombotic agent that is used in the treatment of PAD, has been shown to attenuate the severity of PAD through augmentation of the decoy receptor soluble RAGE (sRAGE) (Liu et al. ). In addition to using AGEs as a biomarker, lowering of AGEs may also be a potential therapeutic target for PAD patients (Fig.…”

“…Additionally, in a 5-year prospective cohort study, higher SAF was independently associated with increased risk for all-cause mortality and fatal or nonfatal major adverse cardiovascular events (de Vos et al 2014), and SAF was a predictor for amputation in patients with PAD independent from the presence of DM and Fontaine stage (de Vos et al 2015). Cilostazol, an antiplatelet, antithrombotic agent that is used in the treatment of PAD, has been shown to attenuate the severity of PAD through augmentation of the decoy receptor soluble RAGE (sRAGE) (Liu et al 2015b). In addition to using AGEs as a biomarker, lowering of AGEs may also be a potential therapeutic target for PAD patients (Fig.…”

Effect of cilostazol in treating diabetes-associated microvascular complications

“…Results of the study suggest that renal deterioration resulting from an upregulated immune response mediated by NF-ĸB-induced inflammatory and endothelial markers may be suppressed with cilostazol by inhibiting NF-ĸB [15][16][17]. Additionally, as supported by another study, cilostazol may ameliorate peripheral arterial occlusion disease, a macro-vascular complication of diabetes mellitus, in patients with type 2 diabetes mellitus by attenuating pro-inflammatory markers [18].…”

The use of Cilostazol in Diabetic Patients

“…It has been suggested that cilostazol may effectively attenuate the severity of peripheral arterial disease (PAD) in patients with type 2 diabetes [5]. Thus, cilostazol may increase skin oxygen supply assessed by transcutaneous oxygen pressure measurement, enhance collateral blood flow,* and promote angiogenesis** in diabetic patient with lower limb ischemia [6].…”