Platelets and diabetes: A complex association

• Diabetes mellitus
• platelet
• drugs
• hyperactivity
• glycaemia

It is well established that type 2 diabetes mellitus (T2DM) is associated with an increased risk of vascular events [1]. There is evidence that platelet hyperactivity contributes to this risk but the pathogenesis of abnormal platelet function in patients with T2DM is complex and involves several mechanisms [1]. Describing these processes in detail is beyond the scope of this editorial; however, it is clear that the quality of glycaemic control plays a role. For example, the synthesis of prostacyclin (PGI₂) [2] and its bioavailability [3] are decreased in the presence of an excess of free fatty acids (FFAs), as would occur in poorly controlled T2DM. High levels of FFAs also damage the endothelium and decrease the activity of ADPase [4]. Both PGI₂ and ADPase are involved in inhibiting platelet activation. Also, postprandial glucose levels may be relevant to platelet function [5]. It follows that good glycaemic control may result in the normalization of platelet function.

This issue of the journal features a paper [6] reporting that sitagliptin, a relatively new agent that is used to control glycaemia, can inhibit platelet function (in vitro as well as in vivo). This leads to the question do other drugs used to treat patients with T2DM influence platelet function?. Actually, there is considerable evidence supporting such effects. Briefly, the most commonly used glucose-lowering drugs like metformin, sulphonylureas (e.g. glimepiride, gliclazide, gliquidone and glibenclamide) and insulin, have all been shown to exert beneficial effects on platelets [1, 7–11]. Among the relatively more recent drugs, there is evidence for glucagon-like peptide-1 receptor agonists, glitazones and other classes of drugs [10, 12]. These effects do not necessarily depend on correcting glycaemia and any associated metabolic abnormalities. They may also involve direct action on platelets and other determinants of platelet activity, (e.g. nitric oxide (NO) and oxidative stress).

In addition to drugs aimed at glycaemic control, patients with T2DM are likely to receive antiplatelet drugs, lipid lowering agents (mainly statins) and antihypertensives. In the context of drugs that inhibit platelet activity, there is evidence of a decreased pharmacological response in patients with T2DM. This topic was recently reviewed elsewhere [13]. This diminished response possibly underlines the relevance of other drugs that may have antiplatelet actions such as those described above. In the context of lipid lowering agents, it is know that statins exert antiplatelet as well as other antithrombotic actions [14]. The same applies to some blood pressure lowering drugs [15]. Smoking exerts several adverse vascular effects [16]. It follows that every effort should be made to encourage patients with T2DM to quit smoking.

T2DM is associated with microvascular complications (e.g. retinopathy and nephropathy). There is evidence that platelets play a role in the pathogenesis of these complications [17–20].

Clearly, more research is urgently needed in order to unravel the links between platelet function, T2DM, the drugs used to treat T2DM and lifestyle factors (e.g. smoking and obesity). This study should include identifying and evaluating the clinical relevance of potentially adverse drug interactions in terms of platelet inhibition (e.g. clopidogrel and sulphonylureas) [21]. We also need to establish whether the effects of these variables on platelet function translates into a decreased risk of macrovascular (e.g. myocardial infarction and stroke) [22, 23] and microvascular complications known to be associated with T2DM.

Declaration of interest: This editorial was written independently; no company or institution supported the authors financially or by providing a professional writer. DPM has given talks, attended conferences and participated in trials and advisory boards sponsored by MSD, Genzyme and Abbott.