Antiplatelet Therapy in Patients With Diabetes Mellitus and Acute Coronary Syndrome

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp iabetes mellitus (DM) represents a major public health concern because of its prevalence and the poorer cardiovascular prognosis of patients with this disease; thus, strategies aimed at improving cardiovascular outcomes in patients with DM may have relevant epidemiological, economic and clinical effects. Previous investigations in diabetic patients with acute coronary syndrome (ACS) showed a 1.8-fold increase in cardiovascular deaths and a 1.4-fold increase in myocardial infarctions (MI) at 2 years compared with nondiabetics. 1 Moreover, a gradient in the incidence of these events according to diabetes type has been demonstrated, as patients with insulin-dependent DM (IDDM) have a worse prognosis than those with non-IDDM. 2 Randomized evidence in the setting of ACS indicates that an invasive strategy with systematic coronary angiography and, when indicated, coronary revascularization, compared with a conservative strategy, is associated with more pronounced benefit in patients with vs. those without DM (27% vs. 13% risk reduction of events at 6 months in the TACTICS-TIMI 18 trial, although in that study the P-value for interaction was not significant). 3 Nevertheless, despite diabetic patients gaining the greatest advantage from an invasive strategy, after ACS in the real world they undergo early cardiac catheterization and percutaneous coronary intervention (PCI) less frequently than non-DM patients; 2 it is notable that rates of receiving an invasive approach are the lowest for ACS patients with IDDM. Biological Bases of Platelet Hyperreactivity in Patients With DMDifferent systems involved in the maintenance of vascular integrity and patency are impaired in DM, such as platelet and endothelial function, coagulation pathways and fibrinolysis. 4 Notably, platelets of patients with DM have been proven to be hyperreactive, which leads to intensified adhesion, activation and aggregation. 5, 6 Several mechanisms are involved in this platelet dysfunction (Figure 1): hyperglycemia enhances platelet aggregation by inducing P-selectin expression, 7 by activating protein kinase C (a mediator of platelet activation) 8 and by glycating platelet surface proteins, with consequent decrease in membrane fluidity and amplification of platelet adhesion. 9 Moreover, insulin resistance and/or deficiency in diabetic patients have been associated with impairment in the response to antithrombotic molecules (such as prostacyclin) 10 and contribute to platelet dysfunction by insulin receptor substrate-dependent effects, causing a rise in the intracellular calcium concentration and subsequent enhanced platelet degranulation. 11 Upregulation of glycoprotein (GP) IIb/IIIa surface receptors, 12 amplification of P2Y12 signaling, 13 and overproduction of reactive oxygen species 14 also contribute to the platelet dysfunction of diabetic patients; finally, metabolic conditions frequently associated with DM (ie, obesity, dyslipidemia and systemic i...

Efficacy and Safety of Adjusted-Dose Prasugrel Compared With Clopidogrel in Japanese Patients With Acute Coronary Syndrome

“…The incidence of MACE in patients in the clopidogrel group with and without diabetes mellitus was 9.7% and 12.9%, respectively, which was quite different from previous reports. 6,13, 14 However, in the prasugrel group, the incidence of MACE in patients with diabetes mellitus was similar to that described in previous studies, including the TRITON-TIMI 38 study. 6 Although it is difficult to provide a clear explanation for these findings, we suspect the small sample size of the subgroups may have contributed.…”

Safety and efficacy of nonvitamin K antagonist oral anticoagulants versus warfarin in diabetic patients with atrial fibrillation: A study‐level meta‐analysis of phase III randomized trials

“…The presence of DM carries a higher risk of cardiovascular events and cardiovascular mortality, as well as of AF‐related thromboembolic events, especially in patients not receiving long‐term anticoagulation; this is mediated by a prothrombotic milieu because of enhanced platelet reactivity, impaired response to antiplatelet agents, changes in vascular function, more pronounced coagulation mechanisms (ie, higher levels and activity of coagulation factors), and impaired fibrinolysis . Of note, this prothrombotic status is particularly enhanced in patients with long‐lasting disease or in those receiving insulin therapy .…”

Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs

“…A lower rate of MACE was observed with the combination of clopidogrel and aspirin regardless of diabetic status; although no significant interaction was present, the relative reduction of adverse cardiovascular events at 1 year with clopidogrel in the 2,840 patients with diabetes was numerically lower than the reduction in those without diabetes (14% versus 20% relative risk reduction). This finding might be a result of the more pronounced interindividual variability of clopidogrel responsiveness in diabetes, resulting in a higher prevalence of HPR [77][78][79] .…”