Glucagon-Like Peptide 1 Receptor Activation and Platelet Function: Beyond Glycemic Control.

Abstract

Cardiovascular disease (CVD) associated with enhanced atherothrombosis is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) (1). Platelet hyperactivity in conjunction with endothelial dysfunction contributes to accelerated atherothrombosis in T2DM (1–3). The enhanced platelet reactivity in T2DM is caused by several factors including insulin resistance and chronic hyperglycemia (1–3). Although more intensive glycemic control has been shown to reduce the long-term risk of CVD, this treatment is often associated with weight gain and hypoglycemia (4,5). Thus, the development of novel antihyperglycemic agents without these negative side effects is needed. In this regard, incretin-based therapies have emerged as important agents in the treatment of T2DM (6). One such incretin therapy is glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) such as exenatide that provide supraphysiological concentrations of GLP-1 that stimulate GLP-1Rs (7–9). Another is dipeptidyl peptidase 4 (DPP-4) inhibitors, which prevent the proteolytic breakdown and inactivation of GLP-1 (6). Both GLP-1RAs and DDP-4 inhibitors improve glycemic control, reduce weight, and limit the risk of hypoglycemia, and thus they are regarded as therapeutic options for glycemic therapy in T2DM. The clinical trials in T2DM patients with DPP-4 inhibitors and GLP-1RAs suggest that incretin-based therapies generally have neutral CVD outcome profiles in patients with T2DM except for adverse outcomes for …