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.