Effects of linagliptin on endothelial function and postprandial lipids in coronary artery disease patients with early diabetes: a randomized, placebo-controlled, double-blind trial

Abstract

BackgroundEarly 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.MethodsIn 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.ResultsWe 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).ConclusionLinagliptin 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)Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0716-x) contains supplementary material, which is available to authorized users.

Acute and Long-term Effects of Saxagliptin on a Set of Cardiovascular Targets Measured at Fasting and Post-prandially in Obese Patients With Impaired Glucose Tolerance: a Randomized, Placebo-controlled, Double-blind Study

“…Both at fasting and post-prandially we studied endothelial function by two different methods, at microvascular level using Ach-induced vasodilatation and at small artery level by measuring reactive hyperhemia, and we measured VCAM-1 and E-selectin as endothelial markers. Endothelial function was shown to impair after glucose or fat load in relation with oxidative stress both in healthy individuals and in patients with type 2 diabetes (49). Such changes did not occur in our patients as we previously reported in patients with type 2 diabetes (22).…”

DPP‐4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic/high‐glucose conditions, potentially through the SIRT1/HIF‐1/VEGF pathway

“…Given observed counteracting effects against stroke‐mimic high‐glucose and hypoxic conditions by DPP‐4 inhibitor, for example, increased expression of NOS and VEGF, as well as the essential role of NOS and VEGF in cerebrovascular endothelial health, it could be suggested that DPP‐4 inhibitor may have impact on the vascular endothelial function. Interestingly, previous studies have reported controversial results about the effects of DPP‐4 inhibitor on endothelial function . On this basis, further investigations are in demand which constitute our future work.…”

Effects of Antidiabetic Drugs on Endothelial Function in Patients With Type 2 Diabetes Mellitus: A Bayesian Network Meta-Analysis

“…The CVD group consisted of five studies ( 31 , 32 , 37 , 42 , 45 ) in which participants were all diagnosed with CVD (hypertension, coronary atherosclerosis, or carotid atherosclerotic disease). The non-CVD group consisted of 25 studies ( 27 – 30 , 33 – 36 , 38 – 41 , 43 , 44 , 46 – 49 ), none of whom were diagnosed with CVD. The participant characteristics and interventions in the studies are summarized in Table 1 .…”