title: Racial differences in resistance to P2Y12 receptor antagonists in type 2 diabetic subjects.
abstract: Although resistance to the P2Y12 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 P2Y12 receptor function we applied the direct P2Y12 antagonist 2-methylthio-AMP (2-methylthioadenosine 5'-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 αIIbβ3 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 P2Y12 pharmacodynamic defects among diabetic patients. Inhibition of thrombin-mediated αIIbβ3 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 P2Y12 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, P2Y12 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.
authors: Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania (M.H.) john.cleator@vanderbilt.edu heidi.hamm@vanderbilt.edu.
authors: John H
authors: JH
authors: Cleator
authors: Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania (M.H.).
authors: Matthew T
authors: MT
authors: Duvernay
authors: Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania (M.H.).
authors: Michael
authors: M
authors: Holinstat
authors: Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania (M.H.).
authors: Nancy E
authors: NE
authors: Colowick
authors: Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania (M.H.).
authors: Willie J
authors: WJ
authors: Hudson
authors: Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania (M.H.).
authors: Yanna
authors: Y
authors: Song
authors: Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania (M.H.).
authors: Frank E
authors: FE
authors: Harrell
authors: Department of Medicine and Division of Cardiovascular Medicine (J.H.C.), Department of Pharmacology (J.H.C., M.T.D., M.H., N.E.C., W.J.H., H.E.H.), and Department of Biostatistics (Y.S., F.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania (M.H.) john.cleator@vanderbilt.edu heidi.hamm@vanderbilt.edu.
authors: Heidi E
authors: HE
authors: Hamm
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D001741:Black or African American; D001792:Blood Platelets / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D044465:White People
chemical_list: C000593020:2-methylthioadenosine 5'-monophosphate; D058921:Purinergic P2Y Receptor Antagonists; D000249:Adenosine Monophosphate