Effects of pioglitazone on platelet P2Y12-mediated signalling in clopidogrel-treated patients with type 2 diabetes mellitus

Summary

Patients with type 2 diabetes mellitus (T2DM) have impaired clopidogrel-induced antiplatelet effects, which may be in part attributed to their reduced sensitivity to insulin and consequently, results in upregulation of the P2Y₁₂ signalling pathway. It has been hypothesised that insulin sensitising strategies may enhance clopidogrel-mediated P2Y₁₂ inhibitory effects. The aim of this pilot pharmacodynamics (PD) study was to assess the impact of pioglitazone on clopidogrel-mediated P2Y₁₂ inhibitory effects in patients with T2DM. This was a prospective, randomised, double-blind, placebo-controlled, cross-over PD study. Patients with T2DM and stable coronary artery disease on maintenance aspirin and clopidogrel were randomised to receive either pioglitazone 30 mg or matching placebo daily for 14 days. PD assessments were measured at baseline, 14 days after randomisation, at the end of the wash-out period, and 14 days after cross-over. The primary endpoint measure was maximal platelet aggregation (MPA) to 20 μM adenosine diphosphate (ADP) as assessed by light transmittance aggregometry (LTA). Flow cytometric analysis of vasodilator-stimulated phosphoprotein phosphorylation (VASP-PRI), and VerifyNow P2Y₁₂ testing were also performed. A total of 15 randomised patients completed the study. MPA to 20 μM ADP (primary endpoint) was not significantly different with pioglitazone compared with placebo (49.53 ± 4.76 vs. 52.52 ± 3.89%; p = 0.594). Similarly, other PD measures did not differ significantly between the groups. In conclusion, in patients with T2DM on maintenance aspirin and clopidogrel therapy, the adjunctive use of pioglitazone does not result in enhanced inhibition of platelet P2Y₁₂ mediated signalling.

Keywords

Diabetes Mellitus - platelet function - pioglitazone

• References

• 1 Levine GN, Bates ER, Blankenship JC. et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011; 58: e44-e122.
• 2 Wright RS, Anderson JL, Adams CD. et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol 2011; 57: e215-e367.
• 3 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Variability in individual responsiveness to clopidogrel: clinical implications, management and future perspectives. J Am Coll Cardiol 2007; 49: 1505-1516.
• 4 Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: Current status and future directions. Thromb Haemost 2009; 102: 7-14.
• 5 Bonello L, Tantry US, Marcucci R. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
• 6 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005; 54: 2430-2435.
• 7 Angiolillo DJ, Bernardo E, Ramirez C. et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006; 48: 298-304.
• 8 Angiolillo DJ, Shoemaker SB, Desai B. et al. A randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007; 115: 708-716.
• 9 van Werkum JW, Topcu Y, Postma S. et al. Effects of diabetes mellitus on platelet reactivity after dual antiplatelet therapy with aspirin and clopidogrel. Thromb Haemost 2008; 99: 637-639.
• 10 Serebruany V, Pokov I, Kuliczkowski W. et al. Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thromb Haemost 2008; 100: 76-82.
• 11 Mangiacapra F, Patti G, Peace A. et al. Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 2010; 106: 619-623.
• 12 Angiolillo DJ, Badimon JJ, Saucedo JF. et al. A pharmacodynamics comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. Eur Heart J 2011; 32: 838-846.
• 13 Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 2011; 123: 798-813.
• 14 Ferroni P, Basili S, Falco A. et al. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2: 1282-1291.
• 15 Ferreira IA, Mocking AI, Feijge MA. et al. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 2006; 26: 417-422.
• 16 Ueno M, Ferreiro JL, Tomasello SD. et al. Functional profile of the platelet P2Y12, receptor signalling pathway in patients with type 2 diabetes mellitus and coronary artery disease. Thromb Haemost 2011; 105: 730-732.
• 17 Ferreira IA, Eybrechts KL, Mocking AI. et al. IRS-1 mediates inhibition of Ca2+ mobilization by insulin via the inhibitory G-protein Gi. J Biol Chem 2004; 279: 3254-3564.
• 18 Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351: 1106-1118.
• 19 Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47: 507-514.
• 20 Sidhu JS, Cowan D, Tooze JA. et al. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces platelet activity in patients without diabetes mellitus who have coronary artery disease. Am Heart J 2004; 147: e25.
• 21 Akbiyik F, Ray DM, Gettings KF. et al. Human bone marrow megakaryocytic and platelets express PPARgamma and PPARgamma agonists blunt platelet release of CD40 ligand and thromboxanes. Blood 2004; 104: 1361-1368.
• 22 Li D, Chen K, Sinha N. et al. The effects of PPARgamma ligand pioglitazone on platelet aggregation and arterial thrombus formation. Cardiovas Res 2005; 65: 907-912.
• 23 Bodary P, Vargas FB, King SAD. et al. Pioglitazone protects against thrombosis in a mouse model of obesity and insulin resistance. J Thromb Haemost 2005; 3: 2149-2153.
• 24 Khanolkar MP, Morris RH, Thomas AW. et al. Rosiglitalozone produces a greater reduction in circulating platelet activity compared with glicazide in patients with type 2 diabetes mellitus-an effect probably mediated by direct platelet PPARgamma activation. Atherosclerosis 2008; 197: 718-724.
• 25 Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med 1998; 15: 539-553.
• 26 Peters RJ, Mehta SR, Fox KA. et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108: 1682-1687.
• 27 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
• 28 Price MJ, Berger PB, Teirstein PS. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc 2011; 305: 1097-1105.
• 29 Campo G, Parrinello G, Ferraresi P. et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011; 57: 2474-2483.
• 30 Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract 2004; 10: 307-312.
• 31 Miyazaki Y, Mahankali A, Matsuda M. et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001; 24: 710-719.
• 32 Tonelli J, Li W, Kishore P. et al. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes 2004; 53: 1621-1629.
• 33 Haffner S, Greenberg AS, Weston WM. et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679-684.
• 34 Bell DSH. Dyslipidemia in type 2 diabetes and the effects of thiazolidinediones. Endocrinologist 2003; 13: 496-504.
• 35 Mohanty P, Aljada A, Ghanim H. et al. Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab 2004; 89: 2728-2735.
• 36 Pfutzner A, Marx N, Lubben G. et al. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. J Am Coll Cardiol 2005; 45: 1925-1931.
• 37 Granberry MC, Fonseca VA. Cardiovascular risk factors associated with insulin resistance: effects of oral antidiabetic agents. Am J Cardiovasc Drugs 2005; 5: 201-209.
• 38 Martens FM, Visseren FL, Lemay J. et al. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002; 62: 1463-1480.
• 39 Natali A, Baldeweg S, Toschi E. et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care 2004; 27: 1349-1357.
• 40 Gerstein HC, Ratner RE, Cannon CP. et al. Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial. Circulation 2010; 121: 1176-1187.
• 41 Chokesuwattanaskul W, Yaqub Y, Suarez JA. et al. Effect of pioglitazone on platelet aggregation in a healthy cohort. Cardiology 2010; 116: 253-256.