Incretin-based therapies: mimetics versus protease inhibitors

The physiological incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), lower blood glucose levels through multiple mechanisms, including enhancement of glucose-stimulated insulin secretion. Although of demonstrated benefit to glycemic control in patients with type 2 diabetes, particularly for GLP-1, the half-lives of these peptides are too short for practical therapeutic utility. Here, we discuss recent approaches to incretin-based therapy, including the use of long-acting GLP-1 receptor agonists, degradation-resistant GLP-1 analogs, GLP-1 analogs conjugated to albumin, non-peptide small molecules that bind to the GLP-1 receptor, and inhibitors of dipeptidyl peptidase IV, the enzyme that degrades both GIP and GLP-1.