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The effects of linagliptin on endothelial function and global arginine bioavailability ratio in coronary artery disease patients with early diabetes: study protocol for a randomized controlled trial.

ABSTRACT: Patients with type 2 diabetes (T2DM) are at increased risk for macrovascular events as well as for microvascular complications. There is evidence that in patients with coronary artery disease (CAD), about 35 % suffer from manifest T2DM. Early glucose-lowering intervention in subjects with T2DM has been demonstrated to be beneficial in terms of cardiovascular risk reduction. But thus far, no data are available regarding investigating the impact of linagliptin treatment in patients with early diabetes on cardiovascular endpoints or surrogate parameters. Therefore, the aim of this study is to investigate the effects of linagliptin in CAD patients with early T2DM on various cardiovascular surrogate measurements including mechanical and biochemical endothelial function assessments.Forty-two subjects with early diabetes and CAD are included in this investigator-driven, randomized, placebo-controlled, double-blind, phase IV, single-center study. Participants will be randomized to receive either linagliptin (5 mg) administered once daily per os or placebo for 12 weeks. Before and after the intervention, evaluation of endothelial function (flow-mediated dilatation and biochemical biomarkers) and a Meal Tolerance Test are performed.Cardiovascular surrogate parameters, such as endothelial function, are able to provide insights into the potential mechanisms of the cardiovascular effects of antihyperglycemic agents. Currently ongoing trials do not specifically focus on early diabetes as a target of intervention and we therefore believe that our study will contribute to a better understanding of the cardiovascular effects of dipeptidylpeptidase-4 (DPP-4) inhibitors in early diabetes.NCT02350478 . Registered 26 January 2015. Protocol date/version 24 October 2014/version 2.4 EudraCT number: 2013-000330-35.

SUBMITTER: Tripolt NJ

PROVIDER: S-EPMC5062940 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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The effects of linagliptin on endothelial function and global arginine bioavailability ratio in coronary artery disease patients with early diabetes: study protocol for a randomized controlled trial.

Tripolt Norbert J NJ Aberer Felix F Riedl Regina R Hutz Barbara B Url Jasmin J Dimsity Gudrun G Meinitzer Andreas A Stojakovic Tatjana T Hödl Ronald R Brodmann Marianne M Hafner Franz F Sourij Harald H

Trials 20161013 1

<h4>Background</h4>Patients with type 2 diabetes (T2DM) are at increased risk for macrovascular events as well as for microvascular complications. There is evidence that in patients with coronary artery disease (CAD), about 35 % suffer from manifest T2DM. Early glucose-lowering intervention in subjects with T2DM has been demonstrated to be beneficial in terms of cardiovascular risk reduction. But thus far, no data are available regarding investigating the impact of linagliptin treatment in patie ...[more]

PMID: 27733180

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Project description:BACKGROUND:Early glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements. METHODS:In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose?>?200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c?<?75 mmol/mol) and established CAD. Participants were randomized to receive either linagliptin (5 mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD). The secondary objective was to investigate the effect of linagliptin treatment on arginine bioavailability ratios [Global arginine bioavailability ratio (GABR) and arginine to ornithine ratio (AOR)]. Arginine, ornithine and citrulline were measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. GABR was calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The AOR was calculated by dividing L-arginine by L-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances. RESULTS:We investigated 43 patients (21% female) with a mean age of 63.3?±?8.2 years. FMD at baseline was 3.5?±?3.1% in the linagliptin group vs. 4.0?±?2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43?±?4.84% vs. -?0.45?±?3.01%; p?=?0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p?=?0.608 and AOR; p?=?0.549). CONCLUSION:Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 ( https://clinicaltrials.gov/ct2/show/NCT02350478 ).

Project description:We hypothesized that an integrated assessment of arginine with its catabolic products might better predict cardiovascular risks than arginine levels alone.Arginine is the sole nitrogen source for nitric oxide (NO) synthesis. The major catabolic products of arginine are ornithine and citrulline.Plasma levels of free arginine, ornithine, citrulline, and the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) were measured with liquid chromatography coupled with tandem mass spectrometry. We examined the relationship of global arginine bioavailability ratio (GABR) (defined as arginine/[ornithine + citrulline]) versus arginine and its catabolic metabolites to prevalence of significantly obstructive coronary artery disease (CAD) and incidence of major adverse cardiovascular events (MACE) (death, myocardial infarction, stroke) over a 3-year follow-up in 1,010 subjects undergoing elective cardiac catheterization.Patients with significantly obstructive CAD had significantly lower GABR (median [interquartile range]: 1.06 [0.75 to 1.31] vs. 1.27 [0.96 to 1.73], p < 0.001) and arginine levels [mean: 68 +/- 20 micromol/l vs. 74 +/- 24 micromol/l, p < 0.001) than those without significantly obstructive CAD. After adjusting for Framingham risk score, C-reactive protein, and renal function, lower GABR (but not arginine levels) and higher citrulline levels remained significantly associated with both the prevalence of significantly obstructive CAD (adjusted odds ratio: 3.93, p < 0.001, and 5.98, p < 0.001, respectively) and 3-year risk for the incidence of MACE (adjusted hazard ratio: 1.98, p = 0.025, and 2.40, p = 0.01, respectively) and remained significant after adjusting for ADMA.GABR might serve as a more comprehensive concept of reduced NO synthetic capacity compared with systemic arginine levels. Diminished GABR and high citrulline levels are associated with both development of significantly obstructive atherosclerotic CAD and heightened long-term risk for MACE.

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The effects of linagliptin on endothelial function and global arginine bioavailability ratio in coronary artery disease patients with early diabetes: study protocol for a randomized controlled trial.

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The effects of linagliptin on endothelial function and global arginine bioavailability ratio in coronary artery disease patients with early diabetes: study protocol for a randomized controlled trial.

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