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.

Keywords: DPP4 protein, mouse; cardiovascular diseases; diabetes mellitus; glucagon-like peptide-1; incretins.

© 2015 American Heart Association, Inc.

Figures

Figure 1. DPP4 functions and structure

DPP4 consists of a 6-amino-acid cytoplasmic tail, a 22-amino-acid transmembrane domain and a large extracellular domain. The extracellular domain is responsible for the dipeptidase activity and binding to its ligands such as adenosine deaminase (ADA) and fibronectin. AA, amino acid; ADA, adenosine deaminase. Some concepts of this figure were adapted from Zhong J et al. Atherosclerosis. 2013;226:305–314 with modifications.

Figure 2. Mechanisms by which DPP4 modulates immune response of relevance to cardiovascular disease

DPP4 regulates immune response via multiple mechanisms that involve both adaptive and innate immune function. These include: 1) Control of pericellular adenosine levels: adenosine triphosphate (ATP) or ADP is converted into AMP by membrane-bound CD39. AMP is further catalyzed by CD73 and produce adenosine. Adenosine is degraded by ADA bound to membrane-anchored DPP4. Accumulation of adenosine suppresses T cell activation and proliferation; 2) ADA-DPP4 interaction provides co-stimulatory signaling for T cell activation. By signaling through CD45, DPP4 enhances T cell receptor signals to promote T cell activation; 3) Inactivation of Glucagon-Like Peptide-1 (GLP-1). GLP-1 binds to GLP-1R and increases cAMP resulting in Protein Kinase A (PKA) mediated suppression of ERK, JNK, and NFκB; 4) Activation of APCs by interaction with caveolin-1. DPP4 binds to caveolin-1 and activates IRAK and NFκB, leading to the activation of APCs.

Figure 3. Cardiovascular Effect of DPP4/Incretin Axis

ADA, adenosine deaminase; ANP, atrial natriuretic peptide; CM, chylomicrons; DPP4, dipeptidyl peptidase 4; FFAs, free fatty acids; NO, nitric oxide; sDPP4, soluble DPP4