title: The effect of clopidogrel on platelet activity in patients with and without type-2 diabetes mellitus: a comparative study.
abstract: BACKGROUND
  Although antiplatelet therapy involving clopidogrel is a standard treatment for preventing cardiovascular events after coronary stent implantation, patients can display differential responses. Here, we assessed the effectiveness of clopidogrel on platelet function inhibition in subjects with and without type-2 diabetes and stable coronary artery disease. In addition, we investigated the correlation between platelet function and routine clinical parameters.
  
  
  METHODS
  A total of 64 patients with stable coronary heart disease were enrolled in the study. Among these, 32 had known type-2 diabetes, whereas the remaining 32 subjects were non-diabetics (control group). A loading dose of 300 mg clopidogrel was given to clopidogrel-naïve patients (13 patients in the diabetes group and 14 control patients). All patients were given a daily maintenance dose of 75 mg clopidogrel. In addition, all patients received 100 mg ASA per day. Agonist-induced platelet aggregation measurements were performed on hirudin-anticoagulated blood using an impedance aggregometer (Multiple Platelet Function Analyzer, Dynabyte, Munich, Germany). Blood samples were drawn from the antecubital vein 24 h after coronary angiography with percutaneous coronary intervention. The platelets were then stimulated with ADP alone or ADP and prostaglandin-E (ADP and ADP-PGE tests, respectively) in order to evaluate clopidogrel-mediated inhibition of platelet function. The effectiveness of ASA was measured by stimulation with arachidonic acid (ASPI test). In addition, maximal platelet aggregation was assessed via stimulation with thrombin receptor-activating peptide (TRAP test).
  
  
  RESULTS
  Patients with diabetes exhibited significantly less inhibition of platelet function than patients without diabetes (ADP-PGE test p = 0.003; ASPI test p = 0.022). Administering a clopidogrel loading dose of 300 mg did not result in a lower level of ADP-PGE-induced platelet reactivity in comparison to the use of a 75 mg maintenance dose. Moreover, we observed that ADP-PGE-induced platelet inhibition was positively correlated with fasting blood glucose and HbA1c (p < 0.01).
  
  
  CONCLUSIONS
  Patients with type-2 diabetes exhibited increased platelet reactivity compared to patients without diabetes despite combined treatment with clopidogrel and ASA. Using a loading dose of clopidogrel rather than small daily doses was not sufficient for adequately overcoming increased platelet reactivity in patients with type-2 diabetes, highlighting the need for more effective anti-platelet drugs for such patients.
authors: Department of Internal Medicine/Cardiology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. claudia.schuette@charite.de.
authors: Claudia
authors: C
authors: Schuette
authors: Department of Internal Medicine/Cardiology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. daniel.steffens@charite.de.
authors: Daniel
authors: D
authors: Steffens
authors: Department of Internal Medicine/Cardiology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. marco.witkowski@charite.de.
authors: Marco
authors: M
authors: Witkowski
authors: Department of Internal Medicine/Cardiology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. caroline.stellbaum@charite.de.
authors: Caroline
authors: C
authors: Stellbaum
authors: Department of Internal Medicine/Cardiology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. peter.bobbert@charite.de.
authors: Peter
authors: P
authors: Bobbert
authors: Department of Internal Medicine/Cardiology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. heinz-peter.schultheiss@charite.de.
authors: Heinz-Peter
authors: HP
authors: Schultheiss
authors: Department of Internal Medicine/Cardiology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. ursula.rauch@charite.de.
authors: Ursula
authors: U
authors: Rauch
mesh_terms: D000368:Aged; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine
references: Cardiovasc Diabetol. 2005;4:18
references: 16321162
references: Semin Vasc Med. 2003 May;3(2):147-62
references: 15199478
references: Cardiovasc Diabetol. 2012;11:82
references: 22805289
references: Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):746-51
references: 18258814
references: Diabetes Care. 2013 Aug;36(8):2211-6
references: 23491524
references: Thromb Haemost. 2007 Jan;97(1):9-10
references: 17200763
references: Haemostasis. 1997;27 Suppl 1:12-8
references: 9439753
references: Diabetes. 2005 Aug;54(8):2430-5
references: 16046311
references: J Thromb Haemost. 2006 Dec;4(12):2566-8
references: 16938125
references: J Cardiovasc Pharmacol. 2007 Nov;50(5):555-62
references: 18030066
references: JAMA. 2002 Nov 20;288(19):2411-20
references: 12435254
references: Am J Cardiol. 2000 Jul 15;86(2):246-9
references: 10913498
references: Cardiovasc Ther. 2013 Apr;31(2):115-23
references: 22212466
references: Cardiovasc Revasc Med. 2012 May-Jun;13(3):159-66
references: 22503564
references: J Am Coll Cardiol. 2001 Nov 1;38(5):1307-12
references: 11691500
references: Am Heart J. 2010 Sep;160(3):543-51
references: 20826265
references: N Engl J Med. 2009 Sep 10;361(11):1045-57
references: 19717846
references: Platelets. 1998;9(3-4):237-40
references: 16793709
references: J Am Coll Cardiol. 2004 Jul 7;44(1):20-4
references: 15234399
references: Diabetes Res Clin Pract. 2008 Nov;82(2):179-84
references: 18778866
references: Cardiovasc Diabetol. 2014;13:112
references: 25123549
references: Diabetes. 2006 Mar;55(3):780-4
references: 16505243
references: Circulation. 2003 Jun 17;107(23):2908-13
references: 12796140
references: Cardiol J. 2013;20(5):545-51
references: 24469880
references: Curr Pharm Des. 2012;18(33):5344-61
references: 22724409
references: Cytokine. 2011 Nov;56(2):332-7
references: 21733717
references: Circulation. 2001 Nov 6;104(19):2266-8
references: 11696462
references: J Am Coll Cardiol. 2008 Dec 9;52(24):1968-77
references: 19055987
references: Thromb Haemost. 2014 Feb;111(2):273-8
references: 24154787
references: Cardiovasc Diabetol. 2013;12:14
references: 23311535
references: Diabet Med. 1999 Oct;16(10):848-52
references: 10547212
references: Biochim Biophys Acta. 2006 Feb;1760(2):207-15
references: 16442234
references: Diabetes Care. 2007 Feb;30(2):372-4
references: 17259513
references: Eur Heart J. 2011 Apr;32(7):838-46
references: 21252171
references: Thromb Res. 2010 Oct;126(4):e318-22
references: 20451957
references: N Engl J Med. 1997 Apr 3;336(14):973-9
references: 9077376
references: J Am Coll Cardiol. 2007 Mar 13;49(10):1035-42
references: 17349882
references: Thromb Haemost. 2004 Sep;92(3):614-20
references: 15351859
references: Clin Res Cardiol. 2010 Nov;99(11):743-52
references: 20526607
references: Horm Metab Res. 1997 Dec;29(12):631-5
references: 9497901
references: J Thromb Haemost. 2010 May;8(5):923-33
references: 20156305