Recent Advances in Dipeptidyl-Peptidase-4 Inhibition Therapy: Lessons from the Bench and Clinical Trials

Abstract

DPP4 inhibitors (DPP4i) are a class of newly developed antidiabetic drugs which preserve incretin hormones and promote postprandial insulin secretion. Although the cardiovascular effect of DPP4 inhibition has been substantially studied, the exact role of DPP4 in cardiovascular disease especially in humans remains elusive. Previous small studies and meta-analyses have suggested a benefit in both surrogate outcomes and cardiovascular events for these agents. However, there was growing evidence in recent years questioning the cardioprotective effect of DPP4i. Further, a signal of heart failure hospitalization in a recent large scale clinical trial SAVOR-TIMI 53 has called into question the safety of these agents and their utility in the treatment of cardiovascular disease. In this review, we will revisit the physiologic function of DPP4 and discuss its role in cardiometabolic disease based on recent experimental and clinical studies.

Cardiovascular Safety of Oral Antidiabetic Drugs.

“…In the large, well designed, placebo-controlled EXAMINE study, alogliptin did not increase the risk of major adverse cardiovascular events (MACE) in DMT2 patients with recent acute coronary syndrome (<90 days of randomization). A decreasing trend of cardiovascular mortality is described, however, without reaching statistical significance [49][50][51] . Results of the EXAMINE, SAVOR-TIMI 53 and TECOS studies confirm cardiovascular safety of DPP-4 inhibitors, which neither reduced nor increased the prevalence of MACE in these three studies 49 .…”

“…DPP-4 inhibitors act favorably on appetite, have neutral effect on body weight, and do not cause hypoglycemia. The first drug from the group of DPP-4 inhibitors is sitagliptin, and the others are vildagliptin, linagliptin, omarigliptin and alogliptin, some of these still in the phase of development or research 49 . Cardiovascular effects of DPP-4 inhibitors in high-risk DMT2 patients have been investigated in three large randomized studies (alogliptin in EXAMINE, saxagliptin in SAVOR-TIMI 53, and sitagliptin in TECOS), while a number of similar studies are just being under way (linagliptin in CAROLINA and CARMELINA, and omarigliptin in MK-3102-015 AMI and MK-3102-018) (Figure 2) 49-52 .…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…The two main human incretins are glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) whose secretions are impaired in diabetes. GLP-1-mediated effects may be sustained and improved with two strategies currently available: longer-acting GLP-1 receptor agonists resistant to degradation of the dipeptidyl peptidase 4 (DPP4) enzyme, that can provide supraphysiological stimulation of GLP-1 receptor [141]; and inhibitors of DPP4 enzyme, that extends the half-life of endogenous GLP-1 [142].…”

Cost-Minimization Analysis of Linagliptin Compared to Sitagliptin in the Treatment of Type 2 Diabetes Mellitus from a Turkish Healthcare Perspective

“…DPP-4 is responsible for the degradation of many bioactive peptides in the body, such as GLP-1 and gastric inhibitor peptide (GIP). In order to regulate glucose levels, inhibitors of DPP-4 (DPP-4i), however, inhibit DPP-4 that inactivate incretin hormones released from the small intestines, and cause increased GLP-1 and GIP levels, and thereby, reduce levels of glucose and consequently HbA1c [9][10][11]. The (oral antidiabetic OAD) agents in the DPP-4i group, sitagliptin and linagliptin were included in the reimbursement list in Turkey, by the years 2008 and 2015, respectively.…”