An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease

Atherosclerosis. 2013 Feb;226(2):305-14. doi: 10.1016/j.atherosclerosis.2012.09.012. Epub 2012 Sep 21.


The introduction of dipeptidyl peptidase 4 (DPP4) inhibitors for the treatment of Type 2 diabetes acknowledges the fundamental importance of incretin hormones in the regulation of glycemia. Small molecule inhibitors of DPP4 exert their effects via inhibition of enzymatic degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The widespread expression of DPP4 in tissues such as the vasculature and immune cells suggests that this protein may play a role in cardiovascular function. DPP4 is known to exert its effects via both enzymatic and non-enzymatic mechanisms. A soluble form of DPP4 lacking the cytoplasmic and transmembrane domain has also been recently recognized. Besides enzymatic inactivation of incretins, DPP4 also mediates degradation of many chemokines and neuropeptides. The non-enzymatic function of DPP4 plays a critical role in providing co-stimulatory signals to T cells via adenosine deaminase (ADA). DPP4 may also regulate inflammatory responses in innate immune cells such as monocytes and dendritic cells. The multiplicity of functions and targets suggests that DPP4 may play a distinct role aside from its effects on the incretin axis. Indeed recent studies in experimental models of atherosclerosis provide evidence for a robust effect for these drugs in attenuating inflammation and plaque development. Several prospective randomized controlled clinical trials in humans with established atherosclerosis are testing the effects of DPP4 inhibition on hard cardiovascular events.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / prevention & control
  • Cardiovascular System / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dipeptidyl Peptidase 4 / physiology*
  • Dipeptidyl Peptidase 4 / therapeutic use
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Gastric Inhibitory Polypeptide / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Incretins / metabolism
  • Inflammation / drug therapy
  • Mice


  • Dipeptidyl-Peptidase IV Inhibitors
  • Incretins
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4