Abstract 12325: Diabetes Mellitus, CYP2C19 Genotype, and Pharmacodynamic Response to Clopidogrel Dosing: Insights From the ELEVATE-TIMI 56 Trial
Background: Both diabetes mellitus (DM) and CYP2C19 loss-of-function alleles are associated with high on-treatment platelet reactivity with standard doses of clopidogrel. We investigated whether escalating doses (up to 300 mg daily) improves the response to clopidogrel in the setting of DM, the CYP2C19*2 allele, or both.
Methods: ELEVATE-TIMI 56 genotyped 333 patients with coronary artery disease and an indication for clopidogrel treatment, 35.4% of whom had DM. They were randomized to different series of maintenance doses of clopidogrel. We examined on-treatment platelet reactivity [P2Y12 reaction units (PRU)] stratified by the presence or absence of DM and CYP2C19*2.
Results: The presence of the CYP2C19*2 allele was similar among patients with or without DM (P=0.52). Both DM and CYP2C19*2 were associated with higher on-treatment platelet reactivity with clopidogrel 75 mg daily (P≤0.01 for each). With 75 mg, on-treatment platelet reactivity was progressively higher going from non-DM/non-carriers, to DM/non-carriers, to non-DM/CYP2C19*2 carriers, to DM/CYP2C19*2 carriers (Figure, left). Notably, with 75 mg, non-DM/CYP2C19*2 carriers had significantly higher PRU values than DM/non-carriers (P=0.0068). To achieve low on-treatment platelet reactivity similar to that seen with clopidogrel 75 mg in non-DM/non-carriers, the following doses were required: 150 mg in DM/non-carriers, 225 mg in non-DM/CYP2C19*2 carriers, and 300 mg in DM/CYP2C19*2 carriers (Figure, right).
Conclusion: Both DM and CYP2C19*2 genotype influence on-treatment platelet reactivity with standard 75 mg doses of clopidogrel, with the *2 allele leading to higher PRU values than DM. Doubling the maintenance dose of clopidogrel to 150 mg daily in patients with DM achieved levels of platelet reactivity similar to that seen with the standard 75 mg dose in patients without DM; notably, among patients with both DM and the CYP2C19*2 allele, a quadrupling to 300 mg was needed.
- © 2013 by American Heart Association, Inc.