Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment

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 P2Y(12) pathway. However, T2DM patients have a loss of responsiveness to insulin that leads to upregulation of the P2Y(12) 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 P2Y(12) 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 mu M adenosine diphosphate [ADP]) and nonspecific (6 mu g/ml collagen and 20 mu M epinephrine) for the P2Y(12) 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 P2Y(12)-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 P2Y(12) pathway. Platelet dysfunction was independent of glycemic control and inflammatory status. CONCLUSIONS The P2Y(12)-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.