title: Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery disease.
abstract: BACKGROUND
  Several studies have shown that patients with diabetes mellitus (DM) exhibit an impaired response to clopidogrel. This may contribute to their increased risk of recurrent atherothrombotic events, despite the use of dual-antiplatelet therapy. The mechanisms for impaired clopidogrel response in DM patients have not been fully elucidated.
  
  
  OBJECTIVE
  The aim of this study was to explore the mechanisms for impaired clopidogrel-mediated platelet inhibition in patients with DM using a comprehensive methodological approach embracing both pharmacokinetic (PK) and pharmacodynamic (PD) assessments as well as ex vivo and in vitro investigations.
  
  
  METHODS
  Patients (DM, n = 30; non-DM, n = 30) with stable coronary artery disease taking aspirin 81 mg/day and P2Y12 antagonist naive were enrolled. Blood was collected before and at various times (0.5, 1, 2, 4, 6, and 24 h) after a 600-mg loading dose of clopidogrel. PD assessments included vasodilator-stimulated phosphoprotein, light transmission aggregometry, and VerifyNow P2Y12 ex vivo, before and after dosing and following in vitro incubation with escalating concentrations (1, 3, and 10 μM) of clopidogrel's active metabolite (Clop-AM). Exposure to Clop-AM was also determined.
  
  
  RESULTS
  PD assessments consistently showed that during the overall 24-h study time course, residual platelet reactivity was higher in DM patients compared with non-DM patients. In vitro incubation with Clop-AM revealed altered functional status of the P2Y12 signaling pathway in DM platelets as measured by vasodilator-stimulated phosphoprotein, but not with other PD assays. Clop-AM exposure was ∼40% lower in DM patients than in non-DM patients.
  
  
  CONCLUSIONS
  The present study suggests that among DM patients, impaired P2Y12 inhibition mediated by clopidogrel is largely attributable to attenuation of clopidogrel's PK profile. This is characterized by lower plasma levels of Clop-AM over the sampling time course in DM patients compared with non-DM patients and only modestly attributed to altered functional status of the P2Y12 signaling pathway.
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida. Electronic address: dominick.angiolillo@jax.ufl.edu.
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Ferreiro
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Antonio
authors.initials: A
authors.lastname: Tello-Montoliu
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rollini
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Francesco
authors.initials: F
authors.lastname: Franchi
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ueno
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Andrew
authors.initials: A
authors.lastname: Darlington
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Bhaloo
authors.initials: B
authors.lastname: Desai
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Moser
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Guzman
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Bass
mesh_terms: D000328:Adult; D000368:Aged; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use; D000077144:Clopidogrel; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D010979:Platelet Function Tests; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D012016:Reference Values; D018570:Risk Assessment; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin
keywords: coronary disease; diabetes mellitus; platelets