Cardiovascular disease, particularly coronary artery dis-ease resulting from accelerated atherosclerosis, is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM). 1 Of note, DM patients without a history of coronary artery disease have overall the same cardiac risk as non-DM patients with a history of myocardial infarction (MI). 2 Furthermore, patients with DM also have a higher risk of cardiovascular complications and recurrent atherothrombotic events than non-DM patients. 3 In fact, in the setting of acute coronary syndromes (ACS), the presence of DM is a strong independent predictor of short-term and long-term recurrent ischemic events, including mortality. 4, 5 The concomitant presence of cardiovascular risk factors and comorbidities that negatively affect the outcomes of ACS is higher in DM patients. 6 The negative impact of DM on outcomes is maintained across the ACS spectrum, including unstable angina and non–ST-elevation MI (NSTEMI), 7 ST-elevation MI (STEMI) treated medically, 8 and ACS undergoing percutaneous coronary intervention (PCI). 9, 10 Platelets of DM patients are characterized by dysregulation of several signaling pathways, both receptor (eg, increased expression) and intracellular downstream signaling abnormalities, which leads to increased platelet reactivity. 11–15 This may play a role not only in the higher risk of developing ACS and the worse outcomes observed in DM, but also in the larger proportion of DM patients with inadequate response to antiplatelet agents compared with non-DM subjects, 13, 16–18 which may also contribute to the impaired outcomes observed in DM patients despite compliance with recommended antiplatelet treatment regimens.

The aim of this article is to provide an overview of the current status of knowledge on platelet abnormalities that characterize DM patients, to analyze the benefits and limitations of currently available antiplatelet agents used in ACS, focusing on drawbacks of these therapies in DM patients, and to describe potential future directions to overcome these limitations, which include new agents and treatment strategies.