Altered calcium and magnesium homeostasis

plasminogen activator inhibitor type-I, and reduced tissue plasminogen activator levels.

The details of these various coagulation pathway abnormalities have been extensively covered in a recent paper by Sobel [54]. The authors of this article believe it is important to emphasize the role of platelet dysfunction in the setting of diabetes mellitus with a view toward practical implications of antiplatelet therapy.

Multiple biochemical and functional abnormalities in the platelet function have been documented in type 1 and type 2 diabetes and are noted in Box 1. Together these abnormalities lead to increased platelet aggregability and adhesiveness. The correction of this increased platelet aggregability and adhesiveness with antiplatelet agents such as aspirin should logically reduce CV events in diabetics. Although there are no prospective studies designed for investigating the therapeutic role of aspirin in the diabetic cohort, several lines of evidence support its use in reducing CV risk in diabetic patients. In the recently completed Primary Prevention Project study, efficacy of low-dose aspirin (100 mg/d) in primary prevention of CV events was studied in individuals with one or more of the following risk factors: hypertension, hypercholes-terolemia, diabetes, obesity, family history of premature myocardial infarction, or advanced age. After a mean follow-up of 3.6 years, there was significantly lower frequency of mortality from CV and of total CV events in the group treated with aspirin [37]. The United States Physicians' Health Study was a 5-year primary prevention trial in nearly 23,000 healthy men that included 533 men with diabetes. Among the diabetic men, 4% of those treated with aspirin (325 mg every other day) had a myocardial infarction, versus 10.1% of those who received placebo (RR, 0.39).

Based on the data from these studies and other collaborative trial data, the ADA recommends the use of enteric-coated aspirin as a primary prevention strategy in patients with diabetes who are classified as high risk [38]. The American Heart Association issued similar recommendations recently, with a dose of 75 to 160 mg/d as primary prevention strategy in individuals with a 10-year coronary heart disease risk of more than 10% [39]. The indications for aspirin use for primary prevention in high-risk diabetic patients are



Cigarette smoking

Family history of coronary heart disease

Micro- or microalbuminuria

Atherogenic dyslipidemia

The efficacy of aspirin for secondary prevention of CV events is suggested by a meta-analysis of secondary prevention trials by the Antithrom-botic Trialists' Collaboration (ATC). The ATC meta-analysis included 287 trials with total involvement of 212,000 high-risk patients [40]. In more than 4500 patients with diabetes, the incidence of vascular events was reduced from 23.5% with control treatment to 19.3% with antiplatelet therapy (P < 0.01). Although the overall incidence of vascular events in the diabetic subgroup was much higher than in the nondia-betic group, the benefit of antiplatelet therapy was comparable in the diabetic and nondiabetic patients. In the HOT study, half of the 1501 patients with diabetes mellitus included in each target group were randomly allocated to receive aspirin. CV events were reduced by 15%, and myocardial infarctions were reduced by 36% compared with placebo. The relative effects of aspirin were similar in nondiabetic and diabetic subjects [27].

Ticlopidine and clopidogrel are thienopyridine antiplatelet agents that inhibit the binding of ADP to the platelet type 2 purinergic receptor, preventing the activation of the GpIIb-IIIa receptor and the subsequent binding of fibrinogen. Thus these agents prevent platelet aggregation. An analysis of the diabetic subgroup in the Clopidogral versus Asprin in Patients at Risk of Ischemic Events study was recently reported [41]. Of 1914 diabetic patients randomly assigned to clopidogrel, 15.6% had the composite vascular primary endpoint, versus 17.7% of 1952 diabetic patients randomly assigned to aspirin therapy (P = 0.042). Thus clopidogrel is an effective antiplatelet agent for secondary prevention in diabetic patients, although it is much more expensive than aspirin. Future prospective studies are needed to examine the relative benefits of treatment with clopidogrel versus aspirin in diabetic patients.

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