Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm

Abstract

Background: Dipeptidyl-peptidase 4 (DPP4) inhibitors improve glycemic control in patients with diabetes mellitus by preventing the degradation of glucagon-like peptide-1 (GLP-1). GLP-1 causes vasodilation in animal models but also increases sympathetic activity; the effect of GLP-1 in the human vasculature and how it is altered by DPP4 inhibition is not known. DPP4 also degrades the vasodilator brain natriuretic peptide (BNP) to a less potent metabolite. This study tested the hypothesis that DPP4 inhibition potentiates the vasodilator responses to GLP-1 and BNP in the human forearm.

Method and results: Seventeen healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received DPP4 inhibitor (sitagliptin 200 mg by mouth) or placebo. Sitagliptin increased forearm blood flow and decreased forearm vascular resistance without affecting mean arterial pressure and pulse. GLP-1 and BNP were infused in incremental doses via brachial artery. Venous GLP-1 concentrations were significantly higher during sitagliptin use, yet there was no effect of GLP-1 on forearm blood flow in the presence or absence of sitagliptin. BNP caused dose-dependent vasodilation; however, sitagliptin did not affect this response. GLP-1 and BNP had no effect on net norepinephrine release.

Conclusions: These data suggest that GLP-1 does not act as a direct vasodilator in humans and does not contribute to sympathetic activation. Sitagliptin does not regulate vascular function in healthy humans by affecting the degradation of GLP-1 and BNP.

Clinical trial registration url: www.clinicaltrials.gov/ Unique identifier: NCT01413542.

Keywords: diabetes mellitus; dipeptidyl‐peptidase 4; glucagon‐like peptide‐1; natriuretic peptide; vasodilation.

© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1.

Study protocol. Intra‐arterial GLP‐1 was first infused in 3 graded doses, lasting 5 minutes each, followed by BNP. A 30‐minute washout separated the 2 peptide infusions. Forearm blood flow measurement, followed by arterial and venous sampling, was performed at baseline and at completion of each dose of peptide. A minimum of 7 days separated each study day. BNP indicates brain natriuretic peptide; GLP‐1, glucagon‐like peptide‐1.

Figure 2.

Effect of DPP4 inhibition on venous GLP‐1 levels at baseline and during the maximum dose of GLP‐1. Data presented as mean±SEM (14 subjects). P values obtained from Wilcoxon signed rank. *P<0.05 vs baseline during same treatment. †P<0.05 vs placebo at same peptide dose. Dotted lines indicate references for fasting and postprandial GLP‐1 levels in healthy subjects. DPP4 indicates dipeptidyl‐peptidase 4; GLP‐1, glucagon‐like peptide‐1.

Figure 3.

Effect of DPP4 inhibition on forearm blood flow response to intra‐arterial GLP‐1 (14 subjects) and to BNP (17 subjects). As noted in the methods, the first 3 subjects received lower doses of GLP‐1. Data presented as mean±SEM. P values from mixed‐effect models are presented in the text. BNP indicates brain natriuretic peptide; DPP4, dipeptidyl‐peptidase 4; GLP‐1, glucagon‐like peptide‐1.