The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Improves Vascular Endothelial Function in Type 2 Diabetes

Abstract

The vascular endothelial function is impaired in the very early stage of atherosclerosis in diabetic patients. The goal of this study was to identify the mechanism underlying the improvement in vascular endothelial function by sitagliptin in type 2 diabetes mellitus patients. This study was an open-labeled prospective observational single arm trial. Forty patients were treated with 50 mg of sitagliptin once daily for 12-weeks. The flow-mediated dilation (FMD) and plasma adiponectin were measured at baseline and 12 weeks after initiating treatment. The %FMD was significantly increased after treatment (4.13 ± 1.59 vs 5.12 ± 1.55, P < 0.001), whereas the nitroglycerin-mediated dilation (NMD) did not change. The plasma adiponectin levels significantly increased (13.0 ± 11.3 vs 14.3 ± 12.8, P < 0.001). The changes in the FMD were significantly correlated with those of the plasma adiponectin (r = 0.322, P < 0.05). A multivariate linear regression analysis demonstrated that the improvement in the FMD is associated with the plasma adiponectin (P < 0.05). The treatment of type 2 diabetes mellitus patients with sitagliptin reverses vascular endothelial dysfunction, as evidenced by increase in the FMD, and improvement of the adiponectin levels (UMIN Clinical Trials Registry System as trial ID UMIN000004236).

The effect of liraglutide on endothelial function in patients with type 2 diabetes

“…One recent study reports that 6 weeks of sitagliptin or alogliptin treatment significantly attenuated endothelial function in patients with type 2 diabetes, 34 which is in support of the hypothesis that normal degradation products of native GLP-1 such as GLP-1(9-36) may be mediating vascular improvements through GLP-1 receptor-independent mechanisms. However, it has also been shown that both 12 weeks of sitagliptin treatment and 4 weeks of vildagliptin treatment resulted in significant improvement in endothelial function in patients with type 2 diabetes, 35,36 possibly due to an increase in circulating levels of GLP-1, which may increase GLP-1 receptor-dependent responses, not only on vascular endothelial cells but also on myocardial and smooth muscle cells, where the GLP-1 receptor is also expressed.…”

Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus

“…The discoveries of that study indicate that the DPP-4 inhibitors could impact serum concentrations of ADMA. In fact, several DPP-4 inhibitors might reduce ADMA levels in T2DM subjects [99,100] . Incretin-based drugs were found to decrease serum concentrations of ADMA in T2DM subjects.…”

Impact of incretin-related agents on endothelial cell function

“…For FMD, neither sitagliptin nor liraglutide affected endothelial cell function in this treatment periods, and neither did glimepiride and glargine ( Table 2). Some previous clinical trials suggested that GLP-1 analogues and DPP-4 inhibitors improved FMD, [18][19][20] but there is some controversy including the lack of a control group, the study duration, the subject populations, and FMD measurement accuracy. Assessment of FMD is so sensitive that the results were greatly affected by many internal and environmental factors, such as patients' background (sex, age, obesity, heart rate and smoking), 21 conditions (air temperature, mental/physical stress), [22][23][24] and the medications described above.…”