Younger age, higher body mass index and lower adiponectin concentration predict higher serum thromboxane B2 level in aspirin-treated patients with type 2 diabetes: an observational study

Cardiovascular Diabetology Younger age, higher body mass index and lower adiponectin concentration predict higher serum thromboxane B level in aspirin-treated patients 2 with type 2 diabetes: an observational study Agnieszka Kaplon-Cieslicka 0 Marek Postula 1 2 Marek Rosiak 2 Michal Peller 0 Agnieszka Kondracka 4 Agnieszka Serafin 0 Ewa Trzepla 3 Grzegorz Opolski 0 Krzysztof J Filipiak 0 0 1st Chair and Department of Cardiology, Medical University of Warsaw, Public Central Teaching Hospital in Warsaw , 1a Banacha St., Warsaw 02-097 , Poland 1 Department of Experimental and Clinical Pharmacology, Medical University of Warsaw , Warsaw , Poland 2 Department of Noninvasive Cardiology and Hypertension, Central Clinical Hospital, the Ministry of the Interior , Warsaw , Poland 3 Medical Centre, Medical University of Warsaw , Warsaw , Poland 4 Chair and Department of Internal Diseases and Endocrinology, Medical University of Warsaw , Warsaw , Poland Background: Evidence from the literature suggests diminished acetylsalicylic acid (ASA) treatment efficacy in type 2 diabetes (DM2). High on-aspirin platelet reactivity (HAPR) in DM2 has been linked to poor glycemic and lipid control. However, there are no consistent data on the association between HAPR and insulin resistance or adipose tissue metabolic activity. The aim of this study was to assess the relationship between laboratory response to ASA and metabolic control, insulin resistance and adipokines in DM2. Methods: A total of 186 DM2 patients treated with oral antidiabetic drugs and receiving 75 mg ASA daily were included in the analysis. Response to ASA was assessed by measuring serum thromboxane B2 (TXB2) concentration and expressed as quartiles of TXB2 level. The achievement of treatment targets in terms of glycemic and lipid control, insulin resistance parameters (including Homeostatic Model Assessment-Insulin Resistance, HOMA-IR, index), and serum concentrations of high-molecular weight (HMW) adiponectin, leptin and resistin, were evaluated in all patients. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of serum TXB2 concentration above the upper quartile and above the median. Results: Significant trends in age, body mass index (BMI), HOMA-IR, HMW adiponectin concentration, C-reactive protein concentration and the frequency of achieving target triglyceride levels were observed across increasing quartiles of TXB2. In a multivariate analysis, only younger age and higher BMI were independent predictors of TXB2 concentration above the upper quartile, while younger age and lower HMW adiponectin concentration were predictors of TXB2 concentration above the median. Conclusions: These results suggest that in DM2, the most important predictor of HAPR is younger age. Younger DM2 patients may therefore require total daily ASA doses higher than 75 mg, preferably as a twice-daily regimen, to achieve full therapeutic effect. Higher BMI and lower HMW adiponectin concentration were also associated with less potent ASA effect. This is the first study to demonstrate an association of lower adiponectin concentration with higher serum TXB2 level in patients treated with ASA. Aspirin; Platelet aggregation; Diabetes mellitus; Insulin resistance; Adipokines - Background Treatment with acetylsalicylic acid (ASA) has proven effective in the reduction of cardiovascular morbidity and mortality. Type 2 diabetic (DM2) patients are known to be at a very high cardiovascular risk, therefore it could be anticipated that they should potentially benefit the most from ASA treatment [1]. However, results of the Antithrombotic Trialists' Collaboration's meta-analysis of 195 clinical trials with over 135,000 patients, including almost 5000 diabetic patients, suggest that ASA therapy in diabetic patients may be less effective in cardiovascular prevention than in normoglycemic individuals [2]. Concomitant DM2 also increases the risk of high on-aspirin platelet reactivity (HAPR), defined as inadequate inhibition of platelet function, assessed in vitro with laboratory tests [3-9]. According to the position paper of the Working Group on Antiplatelet Drugs Resistance, endorsed by the Working Group on Thrombosis of the European Society of Cardiology, laboratory response to ASA treatment should be assessed with aspirin-specific tests evaluating the degree of cyclooxygenase 1 (COX-1) inhibition, either directly, by measuring serum concentration of thromboxane B2 (TXB2) - a stable metabolite of thromboxane A2 (COX-1 product) or indirectly, by assessing platelet aggregation induced by arachidonic acid (COX-1 substrate) [10]. Patients with DM2 exhibit abnormalities of both platelet and plasma hemostasis, and differ from other patients in terms of thrombus structure and kinetics [11]. The pathomechanism of HAPR in patients with DM2 is complex and, so far, not entirely understood [12,13]. It is hypothesized that under hyperglycemic conditions nonenzymatic glycation of COX-1 may competitively inhibit its acetylation by ASA [14]. In addition, nonenzymatic glycation of platelet membrane proteins may result in reduced membrane fluidity, increasing the propensity of platelets to activate [15]. Other possible mechanisms leading to enhanced platelet reactivity under hyperglycemia include osmotic effect of glucose, increased activation of protein kinase C and decreased activation of nitric oxide (NO) - cyclic guanosine monophosphate (cGMP) - cGMP-dependent protein kinase pathway [15-17]. These assumptions are supported by clinical studies demonstrating relationship between HAPR and inadequate glycemic control, as well as in vitro studies showing enhanced platelet activation, assessed using flow cytometry, with increasing glucose concentrations despite incubation with ASA [6,7,18-23]. Alongside with poor glycemic control, HAPR in DM2 patients has been linked to high triglyceride, total cholesterol and low-density lipoprotein (LDL) concentrations, as well as low highdensity lipoprotein (HDL) concentration [18,20,24]. Hyperglycemia and hyperlipidemia induce oxidative stress, which, in turn, leads to fatty acids peroxidation and, consequently, formation of products that may change physicochemical properties of platelet plasma membrane or - as described for isoprostanoids - act as ligands for platelet membrane receptors, triggering platelet activation and aggregation via alternative pathways [25]. Furthermore, oxidative stress may also augment platelet reactivity indirectly, as it results in endothelial dysfunction, diminished endothelial synthesis of NO and prostacyclin, and attenuation of biological effects of NO [15]. Much as the relationship of HAPR with glycemic and lipid control of DM2 has been well documented, only few small studies regarding the association of platelet reactivity with insulin resistance and adipokine concentrations have been conducted so far [5,26-28]. Among 60 healthy women, a lower insulin (...truncated)