Evaluating Second-Line Treatment Options for Type 2 Diabetes: Focus on Secondary Effects of GLP-1 Agonists and DPP-4 Inhibitors

OBJECTIVE: To discuss the controversy surrounding selection of second-line type 2 diabetes mellitus (T2DM) therapy by reviewing available data regarding secondary effects of glucagon-like peptide-1 receptor (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, which include low hypoglycemia risk, weight loss, and cardiovascular (CV) and beta-cell function benefits. DATA SOURCES: A MEDLINE search (1966-March 2013) was conducted using the following key terms: beta-cell protection, blood pressure, DPP-4 inhibitors, exenatide, exenatide extended-release, GLP-1 agonists, hypoglycemia, linagliptin, lipid, liraglutide, pancreatitis, saxagliptin, sitagliptin, and type 2 diabetes. STUDY SELECTION AND DATA EXTRACTION: Identified articles published in English were evaluated for inclusion, with priority given to randomized controlled trials in humans receiving incretin monotherapy or incretin combination therapy with met formin. References identified in these articles were reviewed for additional trials. DATA SYNTHESIS: Most patients with T2DM use combination therapy; however, determination of the second-line agent that is most appropriate is debatable. Prior to the use of incretin therapies, traditional second-line agents included sulfonylureas, thiazolidinediones, and basal insulin, all of which demonstrate undesirable adverse effects. In addition to improving glycemic control, incretin therapies have demonstrated benefits concerning hypoglycemic risk and weight loss in addition to potential improvements in CV risk factors and beta-cell function. While there are risks associated with using incretins, most patients with T2DM are good candidates for incretins and could benefit from their potential secondary effects. Cost remains a barrier to initiating these agents. CONCLUSIONS: Demonstrated secondary benefits in addition to efficacy may make GLP-1 agonists and DPP-4 inhibitors a more favorable option than other second-line T2DM therapies.