Clinical Pharmacology of Incretin Therapies for Type 2 Diabetes Mellitus: Implications for Treatment

Background: Increased understanding of the role of incretin hormones in maintaining glucose homeostasis has enabled the development of pharmacotherapies that target deficient incretin activity in type 2 diabetes mellitus (T2DM). Incretin therapies are premised on 1 of 2 approaches: (1) augmenting the activity of the hormone glucagon-like peptide (GLP)-1 (GLP-1 receptor agonists) and (2) inhibiting the degradation of GLP-1 by dipeptidyl peptidase (DPP)-4 (DPP-4 inhibitors). Objective: This review discusses the pharmacokinetic properties and clinical profiles of the GLP-1 receptor agonists (exenatide twice daily, liraglutide once daily, exenatide once weekly, taspoglutide, and albiglutide) and the DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, and alogliptin) available for use or in late-stage development. Methods: A search of PubMed for literature published between 2000 and mid-2010 was conducted using the names of each agent as key words. Phase III and IV studies were included in the review of efficacy and tolerability. Supplemental searches of abstracts from major diabetes conferences provided additional information on pharmacokinetic properties. Searches of all reference lists were performed to identify additional references of interest. Results: The PubMed search identified multiple randomized, controlled clinical studies of the GLP-1 receptor agonists and the DPP-4 inhibitors administered as monotherapy or in combination regimens. Reductions from baseline in glycosylated hemoglobin ranged from 0.4% to 1.5% with exenatide 5 to 10 mu g/d (7 studies), 0.6% to 1.5% with liraglutide 0.6 to 1.8 mg/d (6 studies), 0.3% to 1.0% with sitagliptin 25 to 200 mg/d (9 studies), 0.5% to 0.9% with saxagliptin 2.5 to 10 mg/d (3 studies), 0.4% to 1.0% with vildagliptin 50 to 100 mg/d (6 studies), and 0.4% to 0.8% with alogliptin 12.5 to 25 mg/d (4 studies). Dosage adjustments and caution in prescribing incretin therapies are recommended in patients with renal disease, with those recommendations varying based on the agent and the degree of dysfunction. Incretin therapies have been associated with few interactions with commonly used antihyperglycemic and cardiovascular therapies. Conclusion: Based on the pharmacokinetic and therapeutic characteristics described in previously published Phase III and IV studies of incretin therapies, these agents may provide an option for the management of T2DM. (Clin Ther. 2011;33:528-576) (C) 2011 Elsevier HS Journals, Inc. All rights reserved.