The nonglycemic actions of dipeptidyl peptidase-4 inhibitors

Na-Hyung Kim, Taeyang Yu, Dae Ho Lee, Na-Hyung Kim, Taeyang Yu, Dae Ho Lee

Abstract

A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

Figures

Figure 1
Figure 1
Nonglycemic actions of DPP-4 inhibitor in relation with pathophysiology of CV disease. Despite its many salutary effects on the CV system, DPP-4 inhibitor therapy in patients with type 2 diabetes and CV disease did not show a secondary prevention effect. Some unfavorable actions of DPP-4 inhibitor need to be further characterized to improve DPP-4 inhibitor therapy in patients with type 2 diabetes. ACEi, ACE inhibitor.

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