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...