DPP4 Activity, Hyperinsulinemia, and Atherosclerosis

J Clin Endocrinol Metab. 2021 May 13;106(6):1553-1565. doi: 10.1210/clinem/dgab078.


Context: Obesity and type 2 diabetes are associated with chronic hyperinsulinemia, elevated plasma levels of dipeptidyl peptidase-4 (DPP4), and a pro-atherosclerotic milieu.

Evidence acquisition: PubMed search of the term "insulin and atherosclerosis," "hyperinsulinemia," "atherosclerosis," or "cardiovascular outcomes" cross-referenced with "DPP4." Relevant research and review articles were reviewed.

Evidence synthesis: Hyperinsulinemia in the setting of insulin resistance promotes vascular inflammation, vascular smooth muscle cell growth, pathological cholesterol profile, hypertension, and recruitment of immune cells to the endothelium, all contributing to atherosclerosis. DPP4 has pleiotropic functions and its activity is elevated in obese humans. DPP4 mirrors hyperinsulinemia's atherogenic actions in the insulin resistant state, and genetic deletion of DPP4 protects rodents from developing insulin resistance and improves cardiovascular outcomes. DPP4 inhibition in pro-atherosclerotic preclinical models results in reduced inflammation and oxidative stress, improved endothelial function, and decreased atherosclerosis. Increased incretin levels may have contributed to but do not completely account for these benefits. Small clinical studies with DPP4 inhibitors demonstrate reduced carotid intimal thickening, improved endothelial function, and reduced arterial stiffness. To date, this has not been translated to cardiovascular risk reduction for individuals with type 2 diabetes with prior or exaggerated risk of cardiovascular disease.

Conclusion: DPP4 may represent a key link between central obesity, insulin resistance, and atherosclerosis. The gaps in knowledge in DPP4 function and discrepancy in cardiovascular outcomes observed in preclinical and large-scale randomized controlled studies with DPP4 inhibitors warrant additional research.

Keywords: DPP4; atherosclerosis; diabetes; hyperinsulinemia; insulin resistance; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / metabolism
  • Cardiovascular Diseases / pathology
  • Dipeptidyl Peptidase 4 / physiology*
  • Humans
  • Hyperinsulinism / genetics*
  • Hyperinsulinism / metabolism
  • Insulin Resistance / genetics
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology


  • DPP4 protein, human
  • Dipeptidyl Peptidase 4