Abstract 10813: Dipeptidyl Peptidase-4 Inhibitors Attenuate Endothelial Function as Evaluated by Flow-mediated Vasodilatation in Type 2 Diabetic Patients

Abstract

Endothelial dysfunction is an independent predictor for cardiovascular events in patients with type 2 diabetes (T2DM). Glucagon like peptide-1 (GLP-1) reportedly exerts vasodilatory actions and inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme degrading GLP-1, are widely used to treat T2DM. We therefore hypothesized that DPP-4 inhibitors (DPP-4I) improve endothelial function in T2DM patients and performed a prospective, randomized crossover trials where 24 males with T2DM (46±5 y/o) were randomized to the DPP-4I sitagliptin or an α-glucosidase inhibitor, voglibose, for 6 weeks. To our surprise, sitagliptin significantly reduced flow-mediated vasodilatation (FMD, 4.4 to 2.1% p<0.05) of the brachial artery despite an improved diabetic status, whereas voglibose did not affect FMD. To confirm this result and determine whether it is a class effect, we conducted another crossover trial where sitagliptin and alogliptin were compared in 42 T2DM patients (66±8 y/o) for 6 weeks. As shown in Figure A, both DPP-4Is improved glycemic control but significantly attenuated FMD (7.2/4.3%, p<0.001, before/after sitagliptin; 7.0/4.8%, p<0.001, before/after alogliptin, respectively). Although changes in most biochemical parameters, including DPP-4 activity and GLP-1 levels, were not correlated with those in FMD, it was of note that changes in ADMA were negatively correlated with FMD changes (Figure B). Our 2 independent trials demonstrated that DPP-4 inhibition attenuated endothelial function as evaluated by FMD in T2DM patients. This unexpected, unfavorable effect may be a class-effect of DPP-4Is and due to, at least in part, increased ADMA levels.