title: DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition.
abstract: The discovery of incretin-based medications represents a major therapeutic advance in the pharmacological management of type 2 diabetes mellitus (T2DM), as these agents avoid hypoglycemia, weight gain, and simplify the management of T2DM. Dipeptidyl peptidase-4 (CD26, DPP4) inhibitors are the most widely used incretin-based therapy for the treatment of T2DM globally. DPP4 inhibitors are modestly effective in reducing HbA1c (glycated hemoglobin) (≈0.5%) and while these agents were synthesized with the understanding of the role that DPP4 plays in prolonging the half-life of incretins such as glucagon-like peptide-1 and gastric inhibitory peptide, it is now recognized that incretins are only one of many targets of DPP4. The widespread expression of DPP4 on blood vessels, myocardium, and myeloid cells and the nonenzymatic function of CD26 as a signaling and binding protein, across a wide range of species, suggest a teleological role in cardiovascular regulation and inflammation. Indeed, DPP4 is upregulated in proinflammatory states including obesity, T2DM, and atherosclerosis. Consistent with this maladaptive role, the effects of DPP4 inhibition seem to exert a protective role in cardiovascular disease at least in preclinical animal models. Although 2 large clinical trials suggest a neutral effect on cardiovascular end points, current limitations of performing trials in T2DM over a limited time horizon on top of maximal medical therapy must be acknowledged before rendering judgment on the cardiovascular efficacy of these agents. This review will critically review the science of DPP4 and the effects of DPP4 inhibitors on the cardiovascular system.
authors: From the Divisions of Cardiovascular Medicine and Endocrinology, University of Maryland, Baltimore.
authors: Jixin
authors: J
authors: Zhong
authors: From the Divisions of Cardiovascular Medicine and Endocrinology, University of Maryland, Baltimore.
authors: Andrei
authors: A
authors: Maiseyeu
authors: From the Divisions of Cardiovascular Medicine and Endocrinology, University of Maryland, Baltimore.
authors: Stephen N
authors: SN
authors: Davis
authors: From the Divisions of Cardiovascular Medicine and Endocrinology, University of Maryland, Baltimore. srajagopalan@medicine.umaryland.edu.
authors: Sanjay
authors: S
authors: Rajagopalan
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: DPP4 protein, mouse; cardiovascular diseases; diabetes mellitus; glucagon-like peptide-1; incretins