Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus

Impact of Chronic Kidney Disease (CKD) on Pharmacodynamic Profiles of the P2Y12 Receptor Inhibitor Clopidogrel in the Setting of Type 2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD)

Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor in patients with coronary artery disease (CAD). However, despite its benefits, many patients still experience recurrent atherothrombotic events. The proposed study will test the central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12 inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12 signaling pathway and impaired clopidogrel metabolism.

Patients with diabetes mellitus (DM) and coexisting chronic kidney disease (CKD) are at increased risk of atherothrombotic events, underscoring the importance of secondary prevention antiplatelet therapy in these high-risk patients. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor in patients with coronary artery disease (CAD). However, despite its clinical benefits, many patients still experience recurrent atherothrombotic events. This is in part due to the impaired effects of clopidogrel in DM patients, particularly among those with coexisting CKD. However, underlying mechanism(s) leading to magnification of impaired clopidogrel response among DM patients with CKD remain unexplored. The ever growing prevalence of CKD in patients with DM and their high risk of recurrent events underscores the need to define such mechanism(s) as this may set the basis for identifying treatment regimens leading to more effective platelet inhibition and cardiovascular protection in these high-risk patients. The proposed study will test the central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12 inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12 signaling pathway and impaired clopidogrel metabolism. Comprehensive pharmacokinetic and pharmacodynamic assessments, including ex vivo and in vitro experiments, evaluating the impact of CKD on antiplatelet drug response in DM patients are proposed.

Inclusion Criteria:

• Type 2 DM, defined according to ADA definition, on treatment with oral hypoglycemic agents and/or insulin
• Angiographically documented CAD
• On treatment with low-dose aspirin (81mg/day) for ≥30 days as part of standard of care.

Exclusion Criteria:

• Use of any antiplatelet therapy (except aspirin) in prior 30 days
• Use of parenteral or oral anticoagulation
• Active bleeding
• High risk of bleeding
• Clinical indication to be on a P2Y12 receptor inhibitor
• End-stage renal disease on hemodialysis
• Any active malignancy
• Platelet count < 100x106/µl
• Hemoglobin <9 g/dl
• Severe known liver disease
• Hemodynamic instability
• Known allergy to clopidogrel
• Pregnant / lactating females (women of childbearing age must use reliable birth control).