A new DPP-4
Inhibitor for the Treatment of Type 2 Diabetes
Vildagliptin is a highly selective, reversible and competitive inhibitor of
dipeptidyl peptidase-4 (DPP-4). In this review, the authors discuss the
characteristics and clinical experience with vildagliptin.
Asia is in the midst of an epidemic of type 2 diabetes. The key to reducing the burden of diabetes and its complications lies in attaining optimal glycaemic control as well as reduction of other cardiovascular risk factors, including blood pressure, hypercholes-terolaemia and microalbuminuria. Whilst there are a variety of glucoselowering agents available for the treatment of type 2 diabetes with differing mechanisms of action, side effects, including weight gain and the risk of hypoglycaemia, have been the main obstacles against achievement of glycaemic targets, especially among overweight patients. This treatment. gap is highlighted by the recent controversy surrounding the outcome of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, in which subjects who received intensive glucose control had increased weight gain, increased risk of hypoglycaemia and an increased risk of death during the study. New treatments based on the incretin pathway have recently emerged, and encouraging data have accumulated to suggest that agents in this class may provide a much-needed treatment alternative, as well as address an important clinical need.
The Incretin Pathway as a Therapeutic Target in Type 2 Diabetes
'The incretin effect refers to the observation that insulin secretion is augmented following orally administered glucose compared to identical plasma glucose levels achieved by intravenous glucose infusion. 'This is now known to be mediated by two gut peptides, glucagon-like peptide-1 (GLP-1), produced by the L cells of the ileum, and the glucose-dependent insulinotropic polypeptide (GIP), produced by the K cells in the duodenum and jejunum. Among these, GLP-1 has been explored as a therapeutic strategy in the treatment of type 2 diabetes, as the insulinotropic effects of GLP-1 persist in patients with type 2 diabetes, compared to GIP, which has minimal glucose-lowering effects in subjects with type 2 diabetes.
In addition to enhancing glucosedependent insulin secretion, GLP-1 also suppresses glucagon secretion in a glucose-dependent manner. This has additional beneficial effects, including lowering fasting glucose, improving postprandial glycaemic control and improving hepatic insulin resistance. Other beneficial properties include delayed gastric emptying arid
gut motility, which further reduces postprandial glucose excursion, and reducing appetite, food intake and weight. (Figure 1)
The main obstacle against the use of GLP-1 as a potential treatment for type 2 diabetes is its rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), which cleaves off the N-terminal dipeptides (His-Ala) from GLP-1 (7-36), thereby inactivating it, resulting in its short half-life of only 2 minutes.
There are currently several agents developed to target the incretin pathway as therapeutic agents in type 2 diabetes. These include the GLP-1 mimetics, such as exenatide and liraglutide, and orally administered inhibitors of DPP-4, such as sitagliptin, vildagliptin and saxagliptin. in general, the metabolic benefits, including lowering of blood glucose and weight loss, are greater with GLP-1 mimetics compared with the DPP-4 inhibitors, presumably due to the higher levels of GLP-1 achieved. However, certain gastrointestinal side effects of GLP-1 mimetics such as nausea and vomiting are usually not seen in patients treated with DPP-4 inhibitors, likewise due to the lower GLP-1 levels achieved. Whilst sitagliptin is the first DPP-4 inhibitor available in most countries, vildagliptin
is now available in many countries in Europe. This current article will review the characteristics and clinical experience with this DPP-4 inhibitor.