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CLINICAL RESEARCH

Insulin Therapy Is Associated With Platelet Dysfunction in Patients With Type 2 Diabetes Mellitus on Dual Oral Antiplatelet Treatment

Dominick J. Angiolillo, MD, PhD, FACC^_*,_*, Esther Bernardo, BSc, Celia Ramírez, BSc, Marco A. Costa, MD, PhD, FACC^_*, Manel Sabaté, MD, PhD, Pilar Jimenez-Quevedo, MD, Rosana Hernndez, MD, PhD, Raul Moreno, MD, Javier Escaned, MD, PhD, Fernando Alfonso, MD, PhD, Camino Bañuelos, MD, Theodore A. Bass, MD, FACC^_*, Carlos Macaya, MD, PhD and Antonio Fernandez-Ortiz, MD, PhD

^_* Division of Cardiology, University of Florida, Shands Jacksonville, Jacksonville, Florida
Cardiovascular Institute, San Carlos University Hospital, Madrid, Spain

Manuscript received February 3, 2006; revised manuscript received March 10, 2006, accepted March 20, 2006.

^_* Reprint requests and correspondence: Dr. Dominick J. Angiolillo, Division of Cardiology, University of Florida, Shands Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209 (Email: dominick.angiolillo{at}jax.ufl.edu).

OBJECTIVES: This study sought to assess the influence of type 2 diabetes mellitus (T2DM) and the impact of hypoglycemic treatment (insulin vs. noninsulin) on platelet function profiles in patients treated with dual oral antiplatelet therapy.

BACKGROUND: Insulin inhibits platelet aggregation by suppressing the P2Y₁₂ pathway. However, T2DM patients have a loss of responsiveness to insulin that leads to upregulation of the P2Y₁₂ pathway, increased platelet reactivity, and reduced responsiveness to antiplatelet agents. Patients with insulin-treated diabetes mellitus (ITDM) have a more advanced disease status and higher atherothrombotic risk compared with non-ITDM (NITDM). However, the impact of insulin therapy on platelet dysfunction in patients treated with P2Y₁₂ antagonists is unknown.

METHODS: A total of 201 T2DM and 65 nondiabetic patients with coronary artery disease in a steady phase of aspirin and clopidogrel treatment were studied. Platelet aggregation was assessed using agonists specific (6 and 20 µM adenosine diphosphate [ADP]) and nonspecific (6 µg/ml collagen and 20 µM epinephrine) for the P2Y₁₂ pathway. High shear-induced platelet reactivity was assessed by means of the PFA-100 system (Dade-Behring International, Miami, Florida).

RESULTS: The T2DM patients had platelet aggregation and shear-induced platelet function significantly increased compared with nondiabetic patients using all assays. Platelet aggregation was increased in ITDM (n = 68) compared with NITDM (n = 133) patients after P2Y₁₂-specific stimuli. Insulin treatment was the strongest predictor of ADP-induced aggregation. Platelet function profiles were similar between ITDM and NITDM using assays nonspecific to the P2Y₁₂ pathway. Platelet dysfunction was independent of glycemic control and inflammatory status.

CONCLUSIONS: The P2Y₁₂-dependent and -independent pathways of platelet reactivity are altered in T2DM compared with nondiabetic patients, and ITDM have greater ADP-induced platelet aggregation compared with NITDM.

Abbreviations and Acronyms   ADP = adenosine diphosphate   CADP = collagen/ADP   CEPI = collagen/epinephrine   CT = closure time   HbA1C = hemoglobin A1C   ITDM = insulin-treated diabetes mellitus   NITDM = noninsulin-treated diabetes mellitus   PPP = platelet-poor plasma   PRP = platelet-rich plasma   T2DM = type 2 diabetes mellitus

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