Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy

Abstract

Cell culture and animal work indicate that dipeptidyl peptidase-4 (DPP-4) inhibition may exert cardiovascular benefits through favorable effects on the vascular endothelium. Prior human studies evaluating DPP-4 inhibition have shown conflicting results that may in part be related to heterogeneity of background anti-diabetes therapies. No study has evaluated the acute response of the vasculature to DPP-4 inhibition in humans. We recruited 38 patients with type 2 diabetes on stable background metformin therapy for a randomized, double-blind, placebo-controlled crossover trial of DPP-4 inhibition with sitagliptin (100 mg/day). Each treatment period was 8 weeks long separated by 4 weeks of washout. Endothelial function and plasma markers of endothelial activation (intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)) were measured prior to and 2 hours following acute dosing of sitagliptin or placebo, as well as following 8 weeks of intervention with each pill. Thirty subjects completed the study and were included in analyses. Neither acute nor chronic sitagliptin therapy resulted in significant changes in vascular endothelial function. While post-acute sitagliptin ICAM-1 levels were lower than that post-chronic sitagliptin, the ICAM-1 concentration was not significantly different than pre-acute sitagliptin levels or levels measured in relationship to placebo. There were no significant changes in plasma VCAM-1 levels at any time point. Acute and chronic sitagliptin therapies have neutral effects on the vascular endothelium in the setting of metformin background therapy. In conclusion, our findings suggest DPP-4 inhibition has a neutral effect on cardiovascular risk in patients without a history of heart failure or renal insufficiency.

Trial registration: NCT01859793.

Keywords: DPP-4 inhibition; endothelium; inflammation; nitric oxide; sitagliptin; vascular.

Figures

Figure 1

Figure

Impact of DPP-4 inhibition and placebo on acute and chronic endothelial function. Eight weeks of intervention with sitagliptin 100 mg/day and placebo had no significant effect on brachial artery flow-mediated dilation (FMD%: 5.6±2.3, 6.3±2.4, 5.8±2.3, 5.2±1.8, 5.6±2.1, 6.0±2.9 for pre-sitagliptin, post-acute sitagliptin, post-chronic sitagliptin, pre-placebo, post-acute placebo, and post-chronic placebo, respectively; P=0.31 by repeated measures ANOVA). Data presented as mean±SE.