Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus

Phase 4

Completed

Conditions: Chronic Kidney Disease (CKD)
Type 2 Diabetes Mellitus (T2DM)
Coronary Artery Disease (CAD)

Interventions: Drug: Clopidogrel
Drug: Clopidogrel active metabolite

Registration Number: NCT03774394

Lead Sponsor: University of Florida

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 61

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Diabetes Mellitus patients with Chronic Kidney Disease	Clopidogrel active metabolite	Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours. Blood samples collected at baseline will be incubated with clopidogrel active metabolite.
Diabetes Mellitus patients without Chronic Kidney Disease	Clopidogrel active metabolite	Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours. Blood samples collected at baseline will be incubated with clopidogrel active metabolite.
Diabetes Mellitus patients with Chronic Kidney Disease	Clopidogrel	Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours. Blood samples collected at baseline will be incubated with clopidogrel active metabolite.
Diabetes Mellitus patients without Chronic Kidney Disease	Clopidogrel	Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours. Blood samples collected at baseline will be incubated with clopidogrel active metabolite.

Primary Outcome Measures

Name	Time	Method
Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50%	6 hours	Comparison of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD

Secondary Outcome Measures