diabetes mellitus ( dm ) is associated with macrovascular and microvascular complications ( coronary artery disease , ischemic stroke , peripheral arterial disease , nephropathy , and retinopathy ) [ 1 , 2 ] . platelets have a  key role  in atherogenesis and its thrombotic complications in subjects with dm , and the concomitant presence of multiple  classical  cardiovascular risk factors ( arterial hypertension , cigarette smoking , and hyperlipidemia ) in diabetic subjects contributes to enhanced atherothrombotic risk . platelets from subjects with dm , particularly from those with type 2 diabetes , exhibit increased reactivity . factors that may contribute to this greater platelet reactivity are not completely elucidated and include metabolic abnormalities as hyperglycemia , hyperlipidemia , insulin resistance , and conditions as oxidative stress , inflammation , and endothelial dysfunction . a close relationship between poor glycemic control and increased platelet activity ( estimated by measuring mean platelet volume mpv  as part of whole blood count ) in patients with type 2 dm has been suggested . mpv is considered a marker of platelet function and activation : larger platelets are more reactive and aggregable . they contain denser granules , secrete more serotonin and -thromboglobulin , produce more thromboxane a2 and have more adhesion molecules ( like p - selectin and platelet glycoprotein it is also increased in hypercholesterolemia , metabolic syndrome , acute myocardial infarction , acute ischemic stroke , preeclampsia , and renal artery stenosis . available antiplatelet agents , such as cyclooxygenase-1 ( cox-1 ) inhibitors ( aspirin ) , adp p2y12 receptor antagonists , and gp iib / iiia receptor inhibitors , are effective and save in the treatment and prevention of thrombotic events , these drugs interfere with the platelet activation process , including adhesion , release , and aggregation . however , although the currently available treatments have proven to be useful in reducing ischemic events , diabetic patients continue to have a higher risk of adverse events compared with those in non - diabetic patients . the role of novel and more potent antiplatelet strategies , currently under clinical development , seems attractive in diabetic patients . cardiovascular ( cv ) diseases are the leading cause of morbidity and mortality in diabetic patients . large clinical trials have shown that antiplatelet agents are effective in the prevention of recurrent cardiovascular events in diabetes . the most prescribed agents are aspirin and clopidogrel , two cornerstones of the antiplatelet therapy [ 79 ] . the food and drug administration has not approved aspirin for use in primary prevention , and the benefit of aspirin among diabetic patients with no previous cardiovascular events is still controversial . in 2007 the american diabetic association ( ada ) and the american heart association ( aha ) recommended low doses of aspirin ( 75162  mg / day ) in primary prevention in diabetics at high cardiovascular risk [ 11 , 12 ] ( i.e. , those > 40 years of age or with additional risk factors : family history of cv disease , arterial hypertension , cigarette smoking , dyslipidemia , or albuminuria ) . in contrast , in the european guidelines aspirin is recommended in primary prevention   of ischemic stroke . the results of two recent randomized controlled trials in patients with diabetes raised questions about the efficacy of aspirin in primary prevention [ 15 , 16 ] . the japanese primary prevention of atherosclerosis with aspirin for diabetes ( jpad ) trial was the first prospective trial to evaluate the use of aspirin ( 81 or 100  mg ) in the primary prevention of ischemic events in diabetic type 2 patients ( n = 2,539 ) , aged 3085 years , in japan . in this trial aspirin did not reduce the risk of events in diabetic patients , unless they are aged 65 years and above ( p = .047 for patients > 65 years ) . however , aspirin was well tolerated , and there was no significant increase in hemorrhagic complications and hemorrhagic strokes . the prevention of progression of arterial disease and diabetes ( popadad ) randomized trial failed to show any benefit of aspirin ( 100  mg ) or antioxidant substances in primary prevention of vascular events in diabetic patients ( n = 1,276 ) aged > 40 years with an ankle - brachial index   0.99 , but no symptomatic cv disease . however , this should not be considered a primary prevention trial because the subjects studied had some degree of peripheral arterial disease ( pad ) . moreover , a clear benefit of aspirin ( versus placebo ) in primary prevention of major cardiovascular events or mortality in diabetes was unconfirmed in a meta - analysis . finally , the decision to give aspirin must be taken on an individual patient basis , after a careful evaluation of the balance between the expected benefits and the risk of major bleedings [ 1820 ] . two clinical trials are currently underway , which will provide insights to the usefulness of aspirin in primary prevention in diabetes : a study of cardiovascular events in diabetes ( ascend ; aspirin 75  mg versus omega-3 fatty acids 1  g ) , and aspirin and simvastatin combination for cardiovascular events prevention trial in diabetes ( accept - d ; simvastatin 2040  mg versus aspirin 100  mg , or simvastatin alone ) . in secondary prevention ada recommends low - dose aspirin ( 75162  mg / d ) in diabetic patients affected by vascular events . this position is supported by the results of two large meta - analyses by the antithrombotic trialists ' collaboration ( atc ) , which showed aspirin to be protective in patients at high cardiovascular risk , including those with diabetes [ 22 , 23 ] . a valid option for patients with aspirin intolerance is represented by ticlopidine and clopidogrel , thienopyridines which affect the adenosine diphosphate ( adp ) pathway , by blocking the platelet adp receptor p2y12 . retrospectively analyzed a subgroup of diabetic patients ( 20% of the study population ) in the clopidogrel versus aspirin in patients at risk of ischemic events ( caprie ) study . clopidogrel was significantly more effective than aspirin in reducing the risk of ischaemic events in diabetic patients with a history of atherothrombosis [ 25 , 26 ] . american diabetes association guidelines currently recommend the use of clopidogrel in very high - risk diabetic patients , or as an alternative strategy in aspirin - intolerant patients . the clopidogrel in unstable angina to prevent recurrent events ( cure ) study ( aspirin plus clopidogrel , versus aspirin alone , in patients with unstable angina or non - st elevation myocardial infarction ) confirmed the efficacy of the drug in acute coronary syndromes ( acs ) , with similar results in diabetic patients . moreover , the study showed that the event rate was much higher in the diabetic than in non - diabetic group , despite the adjunctive use of clopidogrel . numerous trials have shown clinical benefits for the gp iib / iiia antagonists ( abciximab , eptifibatide , and tirofiban ) . these drugs significantly reduce the mortality after percutaneous coronary intervention ( pci ) in all subgroups of patients considered , including diabetics . these results support the use of gp iib / iiia receptor antagonists in high risk acs patients , in particular those with diabetes . there is a reduced clinical efficacy (  aspirin resistance  ) of aspirin in diabetic compared with a non - diabetic population . increased glycation of platelets and coagulation factors may interfere with acetylation by aspirin [ 2935 ] . this may explain the greater effectiveness of clopidogrel in preventing vascular events in diabetes , as compared with low - dose aspirin . clopidogrel resistance  is a well - described phenomenon   in diabetic as well as in   non - diabetic patients , with severe clinical consequences ( e.g. , thromboembolic complications after coronary stent implantation ) [ 36 , 37 ] . insulin , which interacts with its own receptor on platelet surface , reduces platelet reactivity , by suppressing camp and by inhibiting p2y12 signalling . platelets of diabetic patients are affected by the insulin resistance , which results in an upregulation of the p2y12 pathway and in an increased platelet reactivity . low and high doses of aspirin demonstrate similar reduction in cardiovascular endpoints [ 22 , 23 ] . whether the use of higher - doses aspirin in diabetes reduces cardiovascular morbidity is still uncertain [ 39 , 40 ] , but this approach is actually unjustifiable and even unsafe in diabetes , for the increased hemorrhagic and gastrointestinal risk . the available evidence does not consider aspirin doses > 100  mg daily as either effective or safe . moreover , aspirin given once daily might be insufficient for patients with increased platelet turnover , as are diabetic patients . multiple daily doses ,  rather than an increase in a once - daily dose , might be more beneficial in these patients [ 4244 ] , as we firstly showed about 30 years ago . the association between aspirin and other antiplatelet drugs in some categories of diabetic patients at high thrombotic risk may be considered . in high - risk categories several studies have shown the benefit of triple therapy with aspirin , clopidogrel , and cilostazol ( a phosphodiesterase iii inhibitor ) , particularly in diabetic patients treated with bare - metal or drug - eluting stents . however , cilostazol therapy has side effects ( migraine , palpitations , and gastrointestinal problems ) . several studies have focused on how to overcome  clopidogrel resistance  by increasing the dose . in the optimizing antiplatelet therapy in diabetes mellitus ( optimus ) study , the use of clopidogrel 150  mg / d , chronically , resulted in greater platelet inhibition than clopidogrel 75  mg in type 2 diabetes mellitus [ 48 , 49 ] . these include prasugrel and ticagrelor , which are administered orally , and cangrelor that is administered intravenously , and elinogrel that can be administered in oral and endovenous route . between orally administered drugs , prasugrel is a third - generation thienopyridine that , like clopidogrel , exerts its antiplatelet effect by p2y12 receptor blockade . however , prasugrel has a more favourable pharmacokinetic profile because it is more efficiently transformed in its active metabolite . in the triton - timi 38 trial , comparing prasugrel ( a 60  mg loading dose and a 10  mg daily maintenance dose ) with clopidogrel ( a 300  mg loading dose and a 75  mg daily mainteinance dose ) in 13,608 patients who underwent percutaneous coronary revascularization , prasugrel significantly reduced the composite primary endpoint of   death , nonfatal myocardial infarction and nonfatal stroke ( 9.9% versus 12.1% , hr 0.81 ; 95% ci 0.730.90 ; p < .001 ) . this clinical benefit was greater in diabetic patients than among patients without diabetes ( 12.2% versus 17% ; hr 0.70 , p < .001 ) . another alternative to aspirin to prevent cardiovascular events in diabetes is considered picotamide ( thromboxane a2 synthase and thromboxane a2 receptors inhibitor ) . the drug evaluation in atherosclerotic vascular disease in diabetics ( david ) study is the first trial showing a significant reduction of overall mortality by picotamide versus aspirin in patients at high cardiovascular risk , and in diabetics with peripheral artery disease . recent findings do not support the use of aspirin in primary prevention of cardiovascular events in diabetics , at difference with secondary prevention . while we await the results of two undergoing primary prevention trials ( ascend and accept - d ) , patients with type 2 dm at high risk of cardiovascular events should be considered for low - doses of aspirin ( 75162  mg / day ) in primary prevention . a decision should be taken on an individual patient basis . the optimal control of hyperglicemia and other risk factors ( arterial hypertension , hyperlipidemia , and cigarette smoking ) is necessary to decrease platelet reactivity and to enhance the efficacy of antiplatelet drugs . recurrent cardiovascular events in diabetic patients , despite antiplatelet therapy , underscore the need of individualized antiplatelet regimens . more specific antiplatelet strategies , as more potent drugs or an association between antiplatelet drugs are warranted in diabetic patients .
diabetes mellitus ( dm ) is associated with macrovascular and microvascular complications . 
 platelets have a  key role  in atherogenesis and its thrombotic complications in subjects with dm . 
 moreover , the concomitant presence of multiple  classical  cardiovascular risk factors in diabetic subjects contributes to enhanced atherothrombotic risk . 
 antiplatelet agents are effective in primary and secondary prevention of arterial thrombosis ( cardiovascular events , ischaemic stroke , and peripheral arterial occlusive disease ) . 
 the role of chronic administration of antiplatelet drugs in primary prevention of arterial vascular events is known to be less clear than in secondary prevention , and , also in diabetic patients , the decision to give primary prophylaxis should be taken on an individual - patient basis , after a careful evaluation of the balance between the expected benefits and the risk of major bleedings . 
 although , currently , treatment has proven useful in reducing vascular events , diabetic patients continue to have a higher risk of adverse cardiovascular events compared with those in nondiabetic patients . 
 this paper reviews the role of currently available antiplatelet drugs in primary and secondary prevention of vascular events in diabetic patients and the limitations of these drugs , and it discusses the role of novel and more potent antiplatelets and of new agents currently under clinical development .