Enhanced post‐clopidogrel platelet reactivity in diabetic patients is independently related to plasma fibrinogen level but not to glycemic control

Diabetes mellitus increases the risk of first and recurrent vascular events. Recently, evidence has grown that diabetic patients may be predisposed to inadequate platelet responses to clopidogrel [1,2]. However, mechanisms underlying this reduced effect in diabetes remain broadly unexplored. Hyperglycemia, insulin resistance, adipokines and inflammation are all potential candidates. A mechanistic link between hyperglycemia and platelet activation has already been suggested [3,4]. Nevertheless, whether or not poor glycemic control is involved in this suboptimal response remains unknown [2,5–7]. The present study was designed to determine the clinical or biochemical factors potentially associated with suboptimal clopidogrel response in diabetic patients. The relationship between glycemic control, adiponectin, fibrinogen and platelet function testing was investigated in two settings: in a welldefined diabetic cohort receiving standard clopidogrel treatment, and in a subpopulation of poorly controlled diabetics subjected to 1 week of insulin pump for glycemic optimization. We measured the maximal intensity of platelet aggregation induced by 10 lmol L ADP (ADP-Ag), and the platelet reactivity index of vasodilator-stimulated phosphoprotein (PRI-VASP) in a cohort of 124 diabetic patients (112 type 2 and 12 type 1) treated with clopidogrel 75 mg day for at least 1 month and no aspirin. Seventy five per cent of the patients were treated with insulin. Type 2 diabetes patients who were poorly controlled on admission (mean daily capillary blood glucose ‡ 2.50 g L) received intensive insulin therapy with continuous subcutaneous insulin infusion (CSII) (Paradigm 512/712; Medtronic Minimed pump; Medtronic Minimed, Northridge, CA, USA). Platelet tests were repeated for this subgroup 1 week after optimal glycemic control had been achieved. No correlation was observed between ADP-Ag or PRIVASPandglycemic control parameters (fastingplasmaglucose, fasting blood glucose, or glycated hemoglobin). In the 15 poorly controlled type 2 diabetic patients, optimal glycemic control achieved with CSII did not modify platelet test results: ADPAg, 53.5% ± 24.6% vs. 52.8% ± 21.1% (P = 0.72); and PRI-VASP, 64.5% ± 17.7%vs. 66.9% ± 17.6%(P = 0.99). Interestingly, type of diabetes mellitus was found to interfere with the platelet function testing. Patients with type 2 diabetes had a higher maximal intensity of ADP-Ag than those with type 1 diabetes: 49% ± 19% vs. 33% ± 19% (P = 0.008). PRI-VASP was also higher in patients with type 2 diabetes than in those with type 1 diabetes: 62% ± 16% vs. 48% ± 27% (P = 0.02). After adjustment for potential confounders [i.e. age, time since diagnosis, body mass index (BMI), triglycerides, fibrinogen], ADP-Ag but not PRI-VASP remained statistically associated with type of diabetes (P = 0.007 and P = 0.11, respectively). No significant difference was observed between patients who were treated with insulin, statins and sartans/angiotensinconverting enzyme (ACE) inhibitors and those who were not. Platelet parameters did not differ between patients with or without macrovascular complications. Among all the parameters investigated (Table 1), only fibrinogen displayed a positive independent correlation with ADP-Ag (r = 0.38, P = 0.0005). There was no relationship between ADP-Ag or PRI-VASP and gender, duration of the disease, BMI, hypertension, lipid profile, creatinine level, microalbuminuria, high sensitive C-reactive protein, adiponectin, or von Willebrand factor. Clopidogrel non-responders, defined as havingADP-Ag> 70%, as previously proposed [8], had higher plasma fibrinogen levels than clopidogrel responders: 8.2 ± 0.5 g L vs. 3.8 ± 0.1 g L (P < 0.0001). In contrast, PRI-VASP was not associated with fibrinogen level (P = 0.39). To assess the effectiveness of plasma fibrinogen level at differentiating clopidogrel responders and nonresponders, receiver operating characteristic curve analysis was performed. A threshold value of 3.57 g L was obtained, leading to a sensitivity of 84.6%, a specificity of 52.2%, and a negative predictive value of 94.7%. To assess whether fibrinogen has a direct effect on ADP-Ag, purified fibrinogen was added to platelet-rich plasma (PRP) obtained from three Correspondence: Bénédicte Gaborit, Inserm, U626, Marseille, F-13385 France; 27 boulevard Jean Moulin, 13385 Marseille cedex 05, France. Tel. : +33 491324504; fax: +33 491254336. E-mail: benedicte.gaborit@ap-hm.fr