Antiatherothrombotic effects of dipeptidyl peptidase inhibitors.

Atherothrombotic cardiovascular events are a leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). A number of factors beyond hyperglycemia contribute to this increased risk of cardiovascular events in T2D, including elevated blood pressure, dyslipidemia, inflammation, endothelial dysfunction, and enhanced platelet activation. Importantly, most currently available antihyperglycemic treatments for T2D do not address these additional mechanisms. Indeed, we posit that this may explain why more intensive treatment of hyperglycemia has not contributed to a reduced incidence of cardiovascular events in subjects with T2D. Incretin-targeted therapies, such as dipeptidyl peptidase 4 inhibitors, are a relatively new class of antidiabetic treatments, and preclinical as well as small mechanistic clinical studies suggest that they exert beneficial cardiovascular effects. This review focuses specifically on the potential antiatherothrombotic effects of dipeptidyl peptidase 4 inhibitors.

Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis.

Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas. Incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in MEG-01 cells, and exenatide significantly inhibited thrombin-, ADP-, and collagen-induced platelet aggregation. Incubation with exenatide also inhibited thrombus formation under flow conditions in ex vivo perfusion chambers using human and mouse whole blood. In a mouse cremaster artery laser injury model, a single intravenous injection of exenatide inhibited thrombus formation in normoglycemic and hyperglycemic mice in vivo. Thrombus formation was greater in mice transplanted with bone marrow lacking a functional GLP-1R (Glp1r(-/-)), compared with those receiving wild-type bone marrow. Although antithrombotic effects of exenatide were partly lost in mice transplanted with bone marrow from Glp1r(-/-) mice, they were undetectable in mice with a genetic deficiency of endothelial nitric oxide synthase. The inhibition of platelet function and the prevention of thrombus formation by GLP-1R agonists represent potential mechanisms for reduced atherothrombotic events.

GLP-1 receptor agonists: a clinical perspective on cardiovascular effects.

The active incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) is a 30-amino acid peptide that exerts glucoregulatory and insulinotropic actions by functioning as an agonist for the GLP-1 receptor (GLP-1R). In addition to its anti-diabetic effects, GLP-1 has demonstrated cardioprotective actions. Here we review the cardiovascular effects of the GLP-1 analogues currently approved for the treatment of type 2 diabetes, namely exenatide and liraglutide. We discuss their anti-hyperglycaemic efficacy, and offer a clinical perspective of their effects on cardiovascular risk factors such as body weight, blood pressure, heart rate and lipid profiles, as well as their potential consequences on cardiovascular events, such as arrhythmias, heart failure, myocardial infarction and death. Lastly, we briefly review additional GLP-1R agonists in clinical development.

Platelets in thrombosis and hemostasis: old topic with new mechanisms.

Platelets are small anucleate cells generated from megakaryocytes in the bone marrow. After being released into the circulation, platelets play key roles in the surveillance of vascular injury, and can quickly adhere and aggregate at the site of injury, which are critical events for vascular repair and hemostasis. However, the same biological processes of platelet adhesion and aggregation may also cause thrombotic disorders. The formation of a platelet plug at sites of atherosclerotic lesion rupture is the most common mechanism leading to myocardial or cerebral infarction. Platelet-related deep vein thrombosis is also one of the leading causes of mortality worldwide. The contribution of several platelet receptors and their ligands has been highlighted in these processes. In platelet adhesion, particularly at high shear stress, GPIbα-von Willebrand factor (VWF) interaction may initiate this event, which is followed by GPVI signalling and firm platelet adhesion mediated by members of the integrin family, such as ß3 (αIIbß3) and ß1 (α2ß1, α5ß1) integrins. In platelet aggregation, although GPIbα-VWF, P selectin-sulfatides, and other molecules, may be involved, the process is mainly mediated by ß3 (αIIbß3) integrin and its ligands, such as fibrinogen and VWF. It is intriguing that platelet adhesion and aggregation still occur in mice lacking both fibrinogen and VWF, suggesting that other unforeseen molecule(s) may also be important in these processes. Identification and characterization of these molecules will enrich our knowledge in the basic science of hemostasis and thrombosis, and may lead to the development of new therapies against bleeding disorders and thrombotic diseases.