Effects of Exenatide vs. Metformin on endothelial function in obese patients with pre-diabetes: a randomized trial

Aaron S Kelly,Alan J Bank,Harold Katz,J Gonzalez-Campoy,Richard M Bergenstal

doi:10.1186/1475-2840-11-64

Abstract

BackgroundGlucagon like peptide-1 (GLP-1) receptor agonist treatment may improve endothelial function via direct and indirect mechanisms. We compared the acute and chronic effects of the GLP-1 receptor agonist exenatide vs. metformin on endothelial function in patients with obesity and pre-diabetes.MethodsWe performed a randomized, open-label, clinical trial in 50 non-diabetic individuals (mean age 58.5 ± 10.0; 38 females) with abdominal obesity and either impaired fasting glucose, elevated HbA1c, or impaired glucose tolerance (IGT) who were randomized to receive 3-months of exenatide or metformin. Microvascular endothelial function, assessed by digital reactive hyperemia (reactive hyperemic index: RHI), C-reactive protein (CRP), circulating oxidized LDL (oxLDL), and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and 3-months. Seven subjects with IGT participated in a sub-study comparing the effects of pre-administration of exenatide and metformin on postprandial endothelial function.ResultsThere were no differences for the change in RHI (Δ exenatide: 0.01 ± 0.68 vs. Δ metformin: -0.17 ± 0.72, P = 0.348), CRP, oxLDL, or VCAM-1 between exenatide and metformin treatment. Triglycerides were reduced more with exenatide compared to metformin (Δ exenatide: -25.5 ± 45.7 mg/dL vs. Δ metformin: -2.9 ± 22.8 mg/dL, P = 0.032). In the sub-study, there was no difference in postprandial RHI between exenatide and metformin.ConclusionsThree months of exenatide therapy had similar effects on microvascular endothelial function, markers of inflammation, oxidative stress, and vascular activation, as metformin, in patients with obesity and pre-diabetes.Clinical trials registrationThis study is registered on http://www.clinicaltrials.gov/: NCT00546728

Highlights

Glucagon like peptide-1 (GLP-1) receptor agonist treatment may improve endothelial function via direct and indirect mechanisms
There were no Hispanic individuals in the exenatide group and two in the metformin group, which did not differ significantly (P = 0.490)
Triglycerides were reduced more with exenatide compared to metformin (Δ exenatide: -25.5 ± 45.7 mg/dL vs. Δ metformin: -2.9 ± 22.8 mg/dL, P = 0.032)

Summary

Introduction

Glucagon like peptide-1 (GLP-1) receptor agonist treatment may improve endothelial function via direct and indirect mechanisms. Medications that attenuate postprandial glucose spikes may be attractive since these glucose excursions are associated with endothelial dysfunction, inflammation, oxidative stress, and atherosclerosis in individuals with pre-diabetes [7,8,9,10,11,12] In this regard, the glucagon-like peptide-1 (GLP-1) receptor agonist class may be an ideal candidate due to its primary mechanisms of action: reduction of postprandial glucose via increasing insulin secretion, decreasing glucagon secretion, and slowing gastric emptying [13], which leads to improved chronic glycemic control even when used in combination with other diabetes medications [14,15]. Evidence suggests that GLP-1 may act directly on the endothelium to improve endothelial function and inhibit atherosclerosis [16,17,18,19,20,21] and may have additional beneficial cardiovascular effects [22,23]

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