Clinical Medicine Reviews in Vascular Health

Type 2 diabetes mellitus (T2DM) is a major public health problem that affects an increasingly larger number of individuals worldwide. Metformin, unless contraindicated, is the recommended first line pharmacological treatment as it can achieve good glycemic control without weight gain or hypoglycemia and with evidence for cardioprotection. T2DM is a progressive disease, and consequently further therapeutic agents are needed in order to maintain good glycemic control and prevent long-term complications. These drugs are commonly associated with undesirable side effects such as weight gain and hypoglycaemia. Moreover, none have been proven to slow or prevent the progression of T2DM (which is mainly due to progressive β-cell failure). As a result, new agents based on newer therapeutic targets are needed. Incretin based therapy is the latest addition to the currently available anti diabetes treatment and includes two groups of agents: glucagon-like peptide-1 (GLP-1) analogues/mimetics and dipeptidyl peptidase-4 (DPP-4) inhibitors. These agents act either by supplying exogenous GLP-1 (GLP-1 analogues/mimetics) or by preventing the degradation of endogenous GLP-1 (DPP-4 inhibitors). GLP-1 is a gut hormone that is mainly secreted secondary to oral glucose ingestion and results in glucose-dependent insulin secretion and glucose-dependant glucagon suppression which in turn improve fasting and post-prandial glucose levels. GLP-1 is rapidly inactivated by the DPP-4 enzyme. There are several DPP-4 inhibitors currently available, including sitagliptin, vildagliptin and saxagliptin while others are in development. Due to their mechanism of action, DPP-4 inhibitors are associated with low risk of hypo - glycemia and are weight neutral. As a result, they are attractive agents particularly in combination with metformin therapy. In this article we will examine the potential use of saxagliptin as an add-on therapy to metformin in patients with T2DM.