Incretin-based Therapies (Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase - 4 Inhibitors) for the Treatment of Type 2 Diabetes

Abstract

Since the publication of the 2008 guidelines, a number of new agents have been approved in Canada, all in the incretin class. Because our next set of guidelines will not be published until 2013, it was felt that an interim position statement should be developed. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1) are incretin hormones secreted by cells of the gastrointestinal (GI) tract in response to food ingestion (1). GIP is secreted from K-cells, located primarily in the duodenum. GLP-1 is secreted from the L-cells, located primarily in the distal ileum but also found in the rest of the small and large intestine, pancreatic alpha-cells and central nervous system (2). Secretion of the incretin hormones results in glucose-dependent stimulation of insulin secretion. GLP-1 also inhibits glucagon secretion by stimulating insulin release from beta-cells and via somatostatin secretion from the D-cells (3e6). Other actions of GLP-1 include inhibition of gastric emptying, and reduction in appetite and food intake (6). Incretin hormones are secreted within minutes of nutrient intake, suggesting a mechanism controlled by a combination of neural and endocrine stimulatory factors (1). Subsequent direct nutrient contact with GLP-1esecreting L cells in the distal small bowel and colon also stimulates GLP-1 secretion (3). The circulating levels of intact GLP-1 decrease rapidly by enzymatic inactivation mediated by dipeptidyl peptidase-4 (DPP-4), and by renal clearance (7e9). DPP-4 is found on endothelial and epithelial cells throughout the vascular beds, and is widely distributed. DPP-4 enzymatic removal of the N-terminal dipeptides results in a very short circulating half-life of 2 minutes for native GLP-1 (5,10). The incretin effect is significantly reduced in type 2 diabetes. Recent studies suggest that the defective incretin action in type 2 diabetes results from loss or decreased responsiveness of beta-cells to insulinotropic action of GIP, even though GLP-1 secretion and activity is maintained (11e14). The lack of responsiveness to GIP is mainly related to a decrease in beta-cell mass (15). To overcome the rapid degradation of native GLP-1, DPP-4degradation-resistant GLP-1 receptor agonists (GLP-1RA) have