Variability of clopidogrel response in patients with type 2 diabetes mellitus

Abstract

The global prevalence of diabetes mellitus (DM) continues to climb, with a commensurate increase in the cardiovascular complications associated with DM and representing a global public health crisis.Macrovascular atherosclerotic disease, most often manifesting as coronary heart disease (CHD) and its complications, account for the majority of morbidity and mortality associated with DM, underscoring the imperative to develop more effective and specific strategies towards mitigation of the cardiovascular disease (CVD) risk associated with DM. 1 One specific therapeutic target of interest is the prothrombotic state associated with DM, involving endothelial dysfunction, impaired proteo-fibrinolytic pathways, and platelet dysfunction. 2 As perturbations of platelet function in DM have been implicated in contributing to increased CVD risk, 3 the clinical effects of antiplatelet therapies remain a focus of intense interest, both in therapeutic decision-making and ongoing drug development. The aim of this review is to summarise and discuss the aggregate evidence supporting an increased variability of responsiveness to clopidogrel associated with DM and its potential clinical implications. Platelet dysfunction in DMIncreased platelet activation and aggregation in DM have been attributed to a number of metabolic abnormalities, including hyperglycaemia, 4 insulin resistance, 5 and dyslipidaemia. 6 Furthermore, cellular abnormalities, primarily mediated through platelet and endothelial cell dysfunction, 7,8 also contribute to the DM prothrombotic milieu. As reviewed elsewhere, 3,9 platelets in DM patients have increased expression of activation markers and platelet surface receptors -such as purinergic receptor P2Y, G-protein coupled, 12 (P2Y 12 ), glycoprotein Ib (GPIb), glycoprotein IIb/IIIa (GPIIb/IIIa), and P-selectin -and increased concentrations of intracellular calcium that lead to augmented platelet degranulation and aggregation. DM is also associated with increased platelet surface area, size, AbstractThe global prevalence of diabetes mellitus (DM) continues to climb, and is accompanied by an increase in DM associated complications, most often manifesting as coronary heart disease. Platelet dysfunction has been implicated as a central contributor to the increased risk of coronary artery disease in patients with DM, and it is not surprising that the anti-platelet agent, clopidogrel, has been shown to have efficacy in both short and long term outcomes in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. However, accumulating data suggest a clinically relevant sub-optimal clopidogrel response in some patients with DM. The exact mechanism of these observations is not yet fully understood, but appears to be related to reduced concentrations of circulating clopidogrel active metabolite, with less variability in pharmacodynamic and clinical response suggested by the evaluation of newer P2Y 12 antagonists, such as prasugrel and ticagrelor. More research is needed to better under...

Association of fibrinogen level with early neurological deterioration among acute ischemic stroke patients with diabetes

“…Previous large scale trials, such as the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial [34], and the Prevention of Progression of Arterial Disease and Diabetes (POPAPAD) trial [35], have shown low efficacy of aspirin monotherapy for prevention of cardiovascular events in patients with diabetes. In addition, recent data show that responses to clopidogrel in patients with diabetes are suboptimal [36]. Such data suggest that diabetes is associated with considerable resistance to aspirin and clopidogrel therapy, and such insufficient antiplatelet responses could be an underlying causal factor for the frequent END observed in this population.…”

Aspirin in the prevention of cardiovascular events in patients with diabetes

“…[97][98][99] Another potential option for reducing CV events in patients with diabetes is the P2Y 12 inhibitor clopidogrel (Plavix; Sanofi-Aventis, Bridgewater, NJ, USA). However, a lack of antiplatelet effects similar to that observed with aspirin has been observed in patients with diabetes [100] and, in patients at high risk of a CV event (i.e. evidence of a previous occlusive event or other predisposing condition), clopidogrel alone provided no additional CV protection compared with aspirin.…”

“…[32] Because clopidogrel and aspirin exert their antiplatelet effects through two separate pathways (i.e. reduced TXA 2 production via COX inhibition with aspirin [10] and ADP-induced activation of GPIIb-GPIIIa with clopidogrel [100][101][102][103]), it was hypothesized that combination therapy with both of these antiplatelet agents might provide additional protection against CVD. In patients with type 2 diabetes, combination therapy with aspirin 81 mg/day and clopidogrel 75 mg/day for 1 month significantly reduced ADP-, epinephrine-and collagen-stimulated platelet aggregation compared with aspirin 81 mg/day alone; however, no significant difference in arachidonic acid-induced aggregation was observed between treatment groups.…”

State-of-the-Art: Hypo-responsiveness to Oral Antiplatelet Therapy in Patients with Type 2 Diabetes Mellitus

“…[79] Although Clopidogrel resistance has been studied more extensively than aspirin resistance, its prevalence estimates in patients with diabetes also varies based on assay, patient population and dose of Clopidogrel. [80] However, inter-individual variability in platelet response to Clopidogrel is now a well-established concept. Clopidogrel hypo-responsiveness is more prevalent in patients with diabetes, and is highest in insulin-treated patients.…”