Impact of Cilostazol on Platelet Function Profiles in Diabetes and CAD
Impact of Cilostazol on Platelet Function Profiles in Diabetes and CAD
Aims: Patients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with non-diabetics following P2Y12 receptor blockade. Whether inhibition of P2Y12 signalling can be enhanced by adjunctive treatment with cilostazol in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of cilostazol in T2DM patients on standard aspirin and clopidogrel treatment.
Methods and results: This was a prospective, double-blind, double-dummy, placebo-controlled, randomized, cross-over platelet function study. T2DM patients on dual antiplatelet therapy were assigned to receive cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment assignments for another 14 days. Platelet function was performed at three time points: at baseline, 14 days after randomization, and 14 days after treatment cross-over. The P2Y12 reactivity index, determined through flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein, was the primary endpoint measure. In addition to this flow cytometric evaluation, light transmittance aggregometry and VerifyNow testing were performed. A total of 25 T2DM patients were randomized; five patients discontinued treatment due to side effects. The P2Y12 reactivity index was significantly lower following cilostazol treatment compared with placebo (36.3 ± 20 vs. 59.9 ± 16%; P = 0.0002). All other P2Y12-specific functional assessments showed enhanced inhibition of this signalling pathway following treatment with cilostazol.
Conclusion: Adjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy enhances inhibition of platelet P2Y12 signalling.
Patients with type 2 diabetes mellitus (T2DM) have reduced responsiveness to P2Y12 receptor antagonists, including clopidogrel, compared with non-diabetics as assessed by in vitro and ex vivo studies. Normally, cyclic adenosine monophosphate (cAMP) levels increase following P2Y12 receptor blockade which in turn augments the phosphorylated status of vasodilator-stimulated phosphoprotein (VASP-P), a key intraplatelet mediator of P2Y12 signalling. However, platelets from T2DM patients are characterized by reduced cAMP levels thus contributing to their lower degree of platelet inhibition compared with non-diabetics following treatment with P2Y12 receptor antagonists. These laboratory findings may explain why diabetic patients have an enhanced risk of ischaemic events, including stent thrombosis, despite the use of clopidogrel and suggest the need for more aggressive and/or tailored antiplatelet treatment regimens in these high-risk patients. Given the site of dysregulation of intraplatelet signalling, we hypothesized that intervening on pathways that increase cAMP levels can augment VASP-P and enhance inhibition of P2Y12 signalling in T2DM patients.
Cilostazol is an inhibitor of phosphodiesterase 3 (PDEIII) and leads to an increase in intraplatelet cAMP levels. In patients undergoing coronary stenting, treatment with cilostazol in adjunct to aspirin and thienopyridine therapy (‘triple antiplatelet therapy´) has been associated with a reduced risk of stent thrombosis and major adverse cardiac events compared with standard dual antiplatelet therapy. Importantly, cilostazol has been shown to be particularly effective in diabetic patients. The ever raising concerns of stent thrombosis in the current era of drug-eluting stents (DESs) has led to a more diffuse use of cilostazol in adjunct to standard aspirin and clopidogrel therapy, particularly in high-risk patients. However, whether treatment with cilostazol enhances inhibition of P2Y12 receptor signalling remains unknown.
The aim of this pilot study was to evaluate the functional impact of adjunctive treatment with cilostazol in T2DM patients with coronary artery disease (CAD) on standard dual antiplatelet therapy. Our hypothesis was that the adjunctive use of cilostazol will lead to enhanced P2Y12 inhibition compared with standard dual antiplatelet therapy in these high-risk patients.
Abstract and Introduction
Abstract
Aims: Patients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with non-diabetics following P2Y12 receptor blockade. Whether inhibition of P2Y12 signalling can be enhanced by adjunctive treatment with cilostazol in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of cilostazol in T2DM patients on standard aspirin and clopidogrel treatment.
Methods and results: This was a prospective, double-blind, double-dummy, placebo-controlled, randomized, cross-over platelet function study. T2DM patients on dual antiplatelet therapy were assigned to receive cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment assignments for another 14 days. Platelet function was performed at three time points: at baseline, 14 days after randomization, and 14 days after treatment cross-over. The P2Y12 reactivity index, determined through flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein, was the primary endpoint measure. In addition to this flow cytometric evaluation, light transmittance aggregometry and VerifyNow testing were performed. A total of 25 T2DM patients were randomized; five patients discontinued treatment due to side effects. The P2Y12 reactivity index was significantly lower following cilostazol treatment compared with placebo (36.3 ± 20 vs. 59.9 ± 16%; P = 0.0002). All other P2Y12-specific functional assessments showed enhanced inhibition of this signalling pathway following treatment with cilostazol.
Conclusion: Adjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy enhances inhibition of platelet P2Y12 signalling.
Introduction
Patients with type 2 diabetes mellitus (T2DM) have reduced responsiveness to P2Y12 receptor antagonists, including clopidogrel, compared with non-diabetics as assessed by in vitro and ex vivo studies. Normally, cyclic adenosine monophosphate (cAMP) levels increase following P2Y12 receptor blockade which in turn augments the phosphorylated status of vasodilator-stimulated phosphoprotein (VASP-P), a key intraplatelet mediator of P2Y12 signalling. However, platelets from T2DM patients are characterized by reduced cAMP levels thus contributing to their lower degree of platelet inhibition compared with non-diabetics following treatment with P2Y12 receptor antagonists. These laboratory findings may explain why diabetic patients have an enhanced risk of ischaemic events, including stent thrombosis, despite the use of clopidogrel and suggest the need for more aggressive and/or tailored antiplatelet treatment regimens in these high-risk patients. Given the site of dysregulation of intraplatelet signalling, we hypothesized that intervening on pathways that increase cAMP levels can augment VASP-P and enhance inhibition of P2Y12 signalling in T2DM patients.
Cilostazol is an inhibitor of phosphodiesterase 3 (PDEIII) and leads to an increase in intraplatelet cAMP levels. In patients undergoing coronary stenting, treatment with cilostazol in adjunct to aspirin and thienopyridine therapy (‘triple antiplatelet therapy´) has been associated with a reduced risk of stent thrombosis and major adverse cardiac events compared with standard dual antiplatelet therapy. Importantly, cilostazol has been shown to be particularly effective in diabetic patients. The ever raising concerns of stent thrombosis in the current era of drug-eluting stents (DESs) has led to a more diffuse use of cilostazol in adjunct to standard aspirin and clopidogrel therapy, particularly in high-risk patients. However, whether treatment with cilostazol enhances inhibition of P2Y12 receptor signalling remains unknown.
The aim of this pilot study was to evaluate the functional impact of adjunctive treatment with cilostazol in T2DM patients with coronary artery disease (CAD) on standard dual antiplatelet therapy. Our hypothesis was that the adjunctive use of cilostazol will lead to enhanced P2Y12 inhibition compared with standard dual antiplatelet therapy in these high-risk patients.
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