The Plavix Use for Treatment Of Diabetes (PLUTO-Diabetes) Trial

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The Plavix Use for Treatment Of Diabetes (PLUTO-Diabetes) Trial

Abstract and Introduction


Background: Clopidogrel is widely used in diabetic patients after vascular events; however, the ability of this thienopyridine to yield additional antiplatelet protection on top of aspirin has never been explored in a controlled study with comprehensive assessment of platelet activity. The objective of this study was to compare the antiplatelet profiles of clopidogrel + aspirin in combination (C + ASA) versus aspirin alone (ASA) in patients with type 2 diabetes mellitus.
Methods: Seventy patients with documented diabetes already treated with antecedent aspirin were randomly assigned to receive C + ASA or ASA in the PLUTO-Diabetes trial. Platelet studies included adenosine diphosphate-, collagen-, and arachidonic acid-induced aggregometry; PFA-100 (Dade-Behring, Miami, FL) and Ultegra (Accumetrics, San Diego, CA) analyzers; and expression of 6 major receptors by flow cytometry at baseline and at day 30 after randomization.
Results: There were no differences in the baseline clinical and platelet characteristics between the C + ASA and ASA groups, or subsequent significant changes in platelet biomarkers in the ASA group, except for diminished collagen-induced aggregation (P = .02). In contrast, when compared with the ASA group, therapy with C + ASA resulted in significant inhibition of platelet activity assessed by adenosine diphosphate aggregation (P = .0001); closure time prolongation (P = .0003) and reduction of platelet activation units with Ultegra (P = .0001); and expression of platelet/endothelial cell adhesion molecule 1 (P = .002), glycoprotein IIb/IIIa antigen (P = .0002), and activity (P = .0001).
Conclusion: Treatment with C + ASA for 1 month provides significantly greater inhibition of platelet activity than ASA alone in diabetic patients in this small randomized trial. However, despite dual antiplatelet regimen, diabetic patients exhibit high residual activity of some platelet biomarkers, including unaffected protease-activated receptor 1 receptor expression.


Diabetes is one the major causes of morbidity and mortality in the Western world. Recent reports indicate an increase of diabetes incidence and prevalence in the United States. There are presently at least 15.7 million patients with type 2 diabetes mellitus (>5% of the US population). Diabetes-associated costs account for 12% of the total US health care expenditures. The total cost of diabetes treatment in 1997 in the United States was $54.1 billion. Moreover, it has been estimated that 5.4 million people are affected by undiagnosed diabetes, a factor that would further increase the estimates of health care costs.

Platelet activation has been shown to play a major role in a broad range of vascular ischemic events, and, therefore, is likely to contribute to the progression of diabetes in general and its vascular complications in particular. Platelet hyperactivity is one of the key mechanisms implicated in the progression of diabetic retinopathy and could contribute to the development of nephropathy, especially in patients with a combination of diabetes and arterial hypertension. There are numerous reports about an amplified level of platelet activity in both type 1 and type 2 diabetic patients. Importantly, consistent platelet activation does not correlate well with adequate management of glycemic control. Alarmingly, patients with diabetes without a prior myocardial infarction are at a similar risk for coronary events as nondiabetic subjects with a prior myocardial infarction. Moreover, the prognosis after a first myocardial infarction is worsened in diabetic compared to nondiabetic patients, potentially justifying more aggressive antiplatelet strategies as an integral part of modern diabetes treatment.

The available data with regard to the benefits of various antiplatelet agents including aspirin and clopidogrel in diabetic patients are extensive and have increased markedly in the last decade. Currently, aspirin is an established medication for prevention of vascular events. The American Diabetes Association recommends using aspirin for the primary and secondary prevention of vascular diseases in patients with diabetes. The Early Treatment Diabetic Retinopathy Study established conclusively that the relative risk for myocardial infarction in the first 5 years in those randomized to aspirin therapy was reduced by 38%. Other studies have shown that aspirin therapy significantly diminishes the progression of microaneurysm growth in early diabetic retinopathy, and that effect of aspirin could be associated with the suppression of tumor necrosis factor α. However, as an inhibitor of renal prostaglandin synthesis, aspirin could increase the risk for chronic sclerotic renal disease and may impair blood pressure control in hypertensive patients.

Surprisingly, large-scale randomized outcome studies of antiplatelet agents in diabetic patients are lacking, although most studies include large diabetic cohorts. Moreover, the optimal degree of platelet inhibition is this high-risk cohort is unclear, especially for long-term maintenance regimens. Despite recent advances in platelet function assessment by cartridge-based analyzers, and with flow cytometric techniques expanding our knowledge of platelet physiology beyond conventional aggregometry, the antiplatelet profiles of aspirin as a monotherapy versus clopidogrel in combination with aspirin alone (ASA) were never directly compared head-to-head in a the controlled study. Therefore, we designed and conducted the randomized PLUTO-Diabetes study to compare changes in multiple platelet activation biomarkers with 2 antiplatelet strategies over a treatment period of 30 days.

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