Beyond Hyperglycemia in Diabetes: Role of Statin Treatment on Thrombogenesis Triggered by Inflammation

Abstract

Type 2 diabetes mellitus (T2D) constitutes a growing global public health problem and its prevalence is estimated to increase during the next decades, especially in the developing countries. To date, 15 % of the whole population is considered at high risk to develop T2D [1]. T2D is associated with a decrease of health-related quality of life and overall life expectancy, mainly due to an increased risk for cardiovascular disorders. Indeed, T2D is commonly associated with both microvascular and macrovascular complications [2]. Macrovascular complications manifest themselves as accelerated atherosclerosis, clinically resulting in premature coronary artery disease, increased risk of cerebrovascular disease, and severe peripheral vascular disease [2]. Patients with T2D have a a two-to four-fold increase in the risk of coronary artery disease (CAD) and patients with DM but without previous myocardial infarction (MI) carry the same level of risk for subsequent acute coronary events as non-diabetic patients with previous MI [3,4] so that T2D has been defined a CAD equivalent.T2D is associated with a prothrombotic state characterized by a number of changes in thrombotic and fibrinolytic coagulation factor level/activity, which together increase the risk of thrombus formation. Both glucose and insulin seem to play a role in the pathogenesis of this prothrombotic state [5]. In vitro induced thrombin generation is increased in platelet-rich plasma from diabetics compared with that from healthy subjects and a significant elevation of thrombin levels can be demonstrated in T2D patients in poor metabolic control when compared with well controlled patients [6]. Moreover, a significant correlation can be observed between improved glycemic control and blood thrombogenicity, as reflected by a reduction in ex-vivo thrombus formation in a Badimon perfusion chamber [7]. Improved glycemic control is the only significant predictor of a decrease in blood thrombogenicity, irrespective of treatment allocation [7]. Enhanced levels of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes (TAT) have been shown in T2D patients in comparison with healthy subjects [8].A hypercoagulable state, detected by thrombin generation tests, was reported in patients with T2D, explaining, at least partially, the high incidence of vascular events in these patients [9].Platelets of patients with DM are characterized by dysregulation of several signaling pathways, leading to an hyperreactive phenotype with enhanced adhesion, aggregation, and activation [10]. Chronic hyperglycemia has been clearly identified as a causal factor for in vivo platelet activation [11]. Our group firstly demonstrated enhanced thromboxane (TX) biosynthesis in T2D, providing evidence for its platelet origin. Moreover, tight metabolic control led to reduction of TX metabolite urinary levels [11]. Interestingly, inflammatory mediators (such as CD40L) derived from platelets expand the functional repertoire of platelets from players of hemostasis and thrombosis to powerful a...

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