Incretin-Based Therapies for Type 2 Diabetes Mellitus: Properties, Functions, and Clinical Implications

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Abstract

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide–1 (GLP-1), which are secreted by cells of the gastrointestinal tract in response to meal ingestion, exercise important glucoregulatory effects, including the glucose-dependent potentiation of insulin secretion by pancreatic β-cells. Research on the defective incretin action in type 2 diabetes mellitus suggests that the observed loss of insulinotropic activity may be due primarily to a decreased responsiveness of β-cells to GIP. GLP-1 does retain efficacy, albeit not at physiologic levels. Accordingly, augmentation of GLP-1 is a logical therapeutic strategy to ameliorate this deficiency, although the short metabolic half-life of the native hormone renders direct infusion impractical. GLP-1 receptor agonists that resist degradation by the enzyme dipeptidyl peptidase–4 (DPP-4) and have protracted-action kinetics have been developed, and DPP-4 inhibitors that slow the enzymatic cleavage of native GLP-1 provide alternative approaches to enhancing incretin-mediated glucose control. However, GLP-1 receptor agonists and DPP-4 inhibitors are premised on highly divergent mechanisms of action. DPP-4 is ubiquitously expressed in many tissues and is involved in a wide range of physiologic processes in addition to its physiologic influence on incretin hormone biological activity. GLP-1 receptor agonists provide a pharmacologic level of GLP-1 receptor stimulation, whereas DPP-4 inhibitors appear to increase levels of circulating GLP-1 to within the physiologic range. This article examines the physiology of the incretin system, mechanistic differences between GLP-1 receptor agonists and DPP-4 inhibitors used as glucose-lowering agents in the treatment of type 2 diabetes, and the implications of these differences for treatment. The results of recent head-to-head trials are reviewed, comparing the effects of incretin-based therapies on a range of clinical parameters, including glycemia, β-cell function, weight, and cardiovascular function.

Section snippets

Impairment of the Incretin Effect in Type 2 Diabetes Mellitus

The incretin effect is greatly reduced in patients with type 2 diabetes mellitus, and this “defect” plays an important contributory role in the insulin insufficiency and chronic hyperglycemia characteristic of this disorder.16, 22, 23 Initial investigations into the incretin defect focused on an hypothesized impairment in the secretion of GLP-1.24, 25, 26 Evidence concerning this proposed secretion defect has, however, been unconvincing. The preponderance of studies have reported similar GLP-1

Glucagonlike Peptide–1 in the Treatment of Type 2 Diabetes Mellitus

In patients with type 2 diabetes, infusion of endogenous GLP-1 has been shown to provide not only improved glycemic control but also beneficial effects on β-cell function, weight, and cardiovascular risk factors.1 Intravenous administration of GLP-1 normalizes or greatly improves glycemia.57 This effect is seen even in patients with longstanding disease who have not responded to other treatments. Infusion of GLP-1 normalizes β-cell responsiveness to glucose, and restores first- and second-phase

Dipeptidyl Peptidase–4

The plasma membrane glycoprotein DPP-4 (also known as T-cell antigen CD26) is widely expressed throughout the human body and is involved in a broad spectrum of physiologic processes. DPP-4 is found on endothelial and epithelial cells throughout the vascular bed, and in the kidneys, intestines, exocrine pancreas, gastrointestinal tract, biliary tract, thymus, lymph nodes, uterus, placenta, prostate, myocardium, and brain, as well as the adrenal, sweat, salivary, and mammary glands. In addition,

Incretin Therapies: Clinical Trial Results

Incretin-based treatments for type 2 diabetes come in 2 classes: those that inhibit the enzymatic action of DPP-4, and those that mimic the biological activities and receptor stimulation of the endogenous hormone but have reduced susceptibility to enzymatic inactivation.

Sitagliptin is a triazolopiperazine-based DPP-4 inhibitor that binds selectively and reversibly to the active site of DPP-4. It is approved in the European Union and the United States for the treatment of type 2 diabetes in

Summary

GLP-1 is 1 of a group of incretin hormones that play a vital role in the metabolic response to nutrient intake and glucose disposal. The glycemic and extraglycemic effects of GLP-1 are blunted in type 2 diabetes. DPP-4 is a ubiquitously expressed plasma membrane glycoprotein engaged in the regulation of a large number of peptides, including the incretin hormones GLP-1 and GIP. Despite the many physiologic processes in which DPP-4 plays a regulatory role, inhibition of the enzyme as part of a

Author Disclosures

The author of this article has disclosed the following industry relationships:

Michael A. Nauck, MD, PhD, serves on the advisory boards of Amylin Pharmaceuticals, Inc., ConjuChem, Inc., Eli Lilly and Company, GlaxoSmithKline, Hoffman-La Roche Inc., Novartis AG, Novo Nordisk A/S, Probiodrug AG, Restoragen Inc. (formerly BioNebraska, Inc.), and sanofi-aventis; has worked as a consultant to AstraZeneca, Bayer Vital Pharma, Berlin Chemie/Menarini, Biovitrum AB, ConjuChem, Inc., Eli Lilly and

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