262 | MAY 2009 | VOLUME 5 www.nature.com/nrendo REVIEWS Department of Medicine, Samuel Lunenfeld Research Institute, Mt Sinai Hospital, University of Toronto, Toronto, Canada (JA Lovshin, DJ Drucker). Correspondence: DJ Drucker, Mt Sinai Hospital, Samuel Lunenfeld Research Institute, 60 Murray Street, Mail Box 39, Toronto, ON M5T 3L9, Canada d.drucker@utoronto.ca Incretin-based therapies for type 2 diabetes mellitus Julie A. Lovshin and Daniel J. Drucker Abstract | Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This Review highlights our current understanding of the mechanisms of action of incretin-based drugs, with an emphasis on the emerging clinical profile of new agents. Lovshin, J. A. & Drucker, D. J. Nat. Rev. Endocrinol. 5, 262–269 (2009); doi:10.1038/nrendo.2009.48 Introduction The observation that the incretin hormone glucagon-like peptide 1 (GLP-1) stimulates insulin release in response to an enteric glucose load in humans 1 was followed by major advances in our understanding of how GLP-1 regu- lates glucose metabolism. 2,3 In addition, GLP-1—unlike the other incretin hormone, glucose-dependent insulino- tropic polypeptide (GIP)—retains its glucose-regulatory actions in patients with diabetes mellitus. These findings led to the discovery and generation of structurally dis- tinct GLP-1 receptor (GLP-1R) agonists, which mimic the actions of GLP-1 in vivo in humans. 2–4 Furthermore, characterization of the essential role of dipeptidyl pep- tidase 4 (DPP-4) in the inactivation of bioactive GLP-1 and GIP 5,6 promoted the development of orally available DPP-4 inhibitors, administration of which stabilizes both incretin hormones at physiologically active levels. Herein, we review the data from clinical trials that have assessed GLP-1R agonists and DPP-4 inhibitors (Table 1) and highlight emerging incretin-based therapies that are in the late stages of clinical testing. Incretin action and incretin mimetics Biologically active GLP-1 7–36 amide is derived from proglucagon through post-translational processing. Pro- glucagon is generated throughout the small and large intestines in specialized intestinal L-cells, the majority of which are located in the distal part of the small intestine and in the colon. GLP-1 is secreted at low basal rates in the fasting state, and its secretion is increased following nutri- ent ingestion. GLP-1 exerts its actions through binding to GLP-1R, a heptahelical transmembrane surface receptor that is expressed on pancreatic β cells. GLP-1R signaling increases the β cells’ sensitivity to glucose, directly pro- tects rodent and human pancreatic β cells from apoptotic cell death, and triggers proliferative pathways that lead to expansion of the β-cell mass in animal experiments. GLP-1 also suppresses glucagon secretion from pancre- atic α cells, which reduces hepatic glucose production and delays transit of nutrients from the stomach to the duodenum via inhibition of gastric emptying. 7 Additional, extrapancreatic functions of GLP-1 include its actions on the hypothalamus to promote satiety, which results in body weight loss during chronic GLP-1 administration. Although GIP also exerts potent incretin-like effects on β cells in healthy individuals, the actions of GIP are impaired in patients with dia- betes mellitus, which limits the possibilities of its clinical use. 8 Moreover, sustained GIP administration promotes expansion of the adipocyte mass and insulin resistance in diabetic rodents, whereas the effect of GIP on human adipocyte biology is uncertain. New evidence suggests that the insulinotropic actions of GIP may be partially restored in patients with diabetes mellitus in whom hyperglycemia has been corrected as a result of insulin administration. 9 Hence, the therapeutic role, if any, of GIP in the treatment of patients with diabetes mellitus requires further clarification. Continuous, subcutaneous administration of native GLP-1 to patients with type 2 diabetes mellitus (T2DM) lowers fasting and postprandial levels of glucose and HbA 1c effectively, and also results in weight loss. 10 Competing interests D. J. Drucker has declared associations with the following companies: Amylin Pharmaceuticals, Arena Pharmaceuticals, Arisaph Pharmaceuticals, Conjuchem, Eli Lilly, Emisphere Technologies, GlaxoSmithKline, Glenmark Pharmaceuticals, Hoffman LaRoche, Isis Pharmaceuticals, Mannkind, Merck Research Laboratories, Metabolex, Novartis Pharmaceuticals, Novo Nordisk, Phenomix, Takeda and Transition Pharmaceuticals. See the article online for full details of the relationships. J. A. Lovshin declared no competing interests. © 2009 Macmillan Publishers Limited. All rights reserved