Racial Differences in Resistance to P2Y₁₂Receptor Antagonists in Type 2 Diabetic Subjects

Abstract

Although resistance to the P2Y 12 antagonist clopidogrel is linked to altered drug metabolism, some studies suggest that these pharmacokinetic abnormalities only partially account for drug resistance. To circumvent pharmacokinetic complications and target P2Y 12 receptor function we applied the direct P2Y 12 antagonist 2-methylthio-AMP (2-methylthioadenosine 59-monophosphate triethylammonium salt) to purified platelets ex vivo. Platelets were purified from healthy and type 2 diabetes mellitus (T2DM) patients and stimulated with thrombin or the selective protease-activated receptor agonists, protease-activated receptor 1-activating peptide (PAR1-AP), or PAR4-AP. Platelet activation as measured by a IIb b 3 activation, and P-selectin expression was monitored in 141 subjects. Our results demonstrate that, compared with healthy subjects, platelets from diabetic patients are resistant to inhibition by 2-methylthio-AMP, demonstrating P2Y 12 pharmacodynamic defects among diabetic patients.Inhibition of thrombin-mediated a IIb b 3 activation by 2-methylthio-AMP was lower in diabetic platelets versus healthy platelets. Subgroup analysis revealed a racial difference in the resistance to 2-methylthio-AMP. We found no resistance in platelets from diabetic African Americans; they were inhibited by 2-methylthio-AMP equally as well as platelets from healthy African Americans. In contrast, platelets from Caucasian patients with diabetes were resistant to P2Y 12 antagonism compared with healthy Caucasians. Multivariable analysis demonstrated that other variables, such as obesity, age, or gender, could not account for the differential resistance to 2-methylthio-AMP among races. These results suggest that in addition to altered drug metabolism, P2Y 12 receptor function itself is altered in the Caucasian diabetic population. The racial difference in platelet function in T2DM is a novel finding, which may lead to differences in treatment as well as new targets for antiplatelet therapy.

Hypoxia and Ischemia Promote a Maladaptive Platelet Phenotype

“… 17 , 29 , 30 Resistance to antiplatelet therapeutic agents has been described in diabetics, in MI, and in patients with PAD. 31 Explanations for such treatment failure may include metabolic comorbidities which alter the inflammatory environment, the metabolism of antiplatelet agents, and interactions of antiplatelet agents with other drugs. 32 – 36 Comparing differences in the platelet phenotype between clinical groups is challenging given the difficulty in exactly matching control human populations in a complex disease group such as PAD, where the clinical pathology leading to the vascular injury is multifactorial.…”