linagliptin and Hypertension

To evaluate the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on aortic pulse wave velocity (PWV) as a surrogate marker of arterial stiffness and early atherosclerosis in people with early type 2 diabetes.. A total of 45 people with type 2 diabetes (median [interquartile range] age 63 [54-66] years, 61% men, mean ± standard deviation glycated haemoglobin [HbA1c] 6.3% ± 0.4% [45 ± 4.6 mmol/mol]), without cardiovascular disease and naïve to antidiabetic treatment, were randomized (1:1) to treatment with linagliptin 5 mg once daily or placebo for 26 weeks in a double-blind fashion. PWV was assessed at baseline, 4 and 26 weeks of treatment, and again at 30, 4 weeks after treatment. The primary endpoint was between-group difference in PWV (corrected for systolic blood pressure [SBP]) at week 26. Secondary endpoints included differences in central SBP and augmentation index (AIx).. Compared with placebo, 26 weeks of linagliptin decreased PWV by an average of 0.91 m/s (95% confidence interval -1.76 to -0.06; P = .035). PWV returned to baseline after 4 weeks washout. Differences in central SBP and AIx were not different between linagliptin and placebo. Linagliptin decreased HbA1c (-0.4%; P < .001), fasting plasma glucose (-0.7 mmol/L; P = .002) and triglycerides (-0.49 mmol/L; P = .019) as compared with placebo. The changes in body weight, cholesterol and high-sensitivity C-reactive protein did not differ between groups.. Linagliptin decreased aortic PWV in people with early-stage type 2 diabetes as compared with placebo after 26 weeks of treatment. These results suggest that linagliptin has a favourable effect on arterial stiffness.

Topics: Aorta; Atherosclerosis; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertension; Hypertriglyceridemia; Hypoglycemia; Linagliptin; Male; Middle Aged; Pulse Wave Analysis; Severity of Illness Index; Vascular Stiffness

Recent studies suggest vascular benefits of dipeptidylpeptidase IV (DPP-IV) inhibition in patients with diabetes mellitus. Only little is known about potential vascular effects of DPP-IV inhibitors in nondiabetic individuals. The aim of this study was to investigate the effect of DPP-IV inhibition in a nondiabetic hypertensive population.. This was a double-blinded, randomized, placebo-controlled, mechanistic study, comparing microvascular effects of the DPP-IV inhibitor linagliptin with placebo in nondiabetic individuals with a history of arterial hypertension. Twenty-one patients received 5 mg linagliptin (5 women; age 67.6 ± 6.0 years; mean ± SD), whereas 22 patients were randomized to placebo (5 women; age 64.8 ± 7.1 years).. At baseline, after 6 and 12 weeks, retinal microcirculation and arterial blood pressure profiles were assessed. Moreover, blood samples were taken for the measurement of HbA1c, asymmetric dimethylarginine, C-reactive peptide, cyclic guanosinmonophosphate, transforming growth factor beta (TGF-ß1) and cystatin C. Retinal capillary perfusion increased by 23.7 ± 10.3% (mean ± SEM; P < 0.05), retinal arterial flow by 7.6 ± 0.6 (P < 0.05) and the retinal hyperemic response by 290 ± 263% (P < 0.05) during treatment with linagliptin. No change in retinal blood flow was found in the placebo group. Although blood pressure declined in both groups, a significant decline in TGF-ß1 by 9.3 ± 4.5% (P < 0.05) could only be observed in the linagliptin group. No significant change in other laboratory parameters could be observed in both groups.. Our study suggests microvascular and antifibrotic effects of linagliptin in a nondiabetic, hypertensive population.

Topics: Aged; Arginine; Arterial Pressure; C-Reactive Protein; Cyclic GMP; Cystatin C; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypertension; Linagliptin; Male; Microvessels; Middle Aged; Regional Blood Flow; Retinal Vessels; Transforming Growth Factor beta1

This study aims to investigate whether stabilization of glucagon-like peptide-1 (GLP-1) level reduces angiotensin II (Ang II)-induced cardiac fibrosis and -elevated blood pressure accompanying with inhibition of NADPH oxidase (NOX) expression and preservation of mitochondrial integrity. The study was performed in Sprague-Dawley rat model of Ang II infusion (500 ng/kg/min) using osmotic minipumps for 4 weeks. GLP-1 receptor agonist liraglutide (0.3 mg/kg, injected subcutaneously twice daily) and dipeptidyl peptides-4 inhibitor, linagliptin (8 mg/kg, administered via oral gavage) were selected to preserve GLP-1 level. Blood pressure was measured noninvasively. Heart and aorta were saved for histological analysis. Relative to the animals with Ang II infusion, in the heart, liraglutide and linagliptin comparatively reduced the protein levels of NOX4 and TGFβ1 and expression of monocyte chemoattractant protein 1, and attenuated the proliferation of myofibroblasts (15 ± 4 and 13 ± 3 vs. 42 ± 22/HPF in Ang II group). The number of distorted mitochondria in both groups was significantly reduced (8 ± 4 and 10 ± 6 vs. 27 ± 13/HPF in Ang II group), in company with a significant reduction in cardiac fibrosis. In the aorta, treatment with liraglutide and linagliptin significantly downregulated the expression of NOX4 and intercellular adhesion molecule 1, and enhanced endothelial NOS expression. Aortic wall thickness was reduced comparatively (267 ± 22 and 286 ± 25 vs. 339 ± 40 μm in Ang II group). The area of fibrotic aorta was also reduced (13 ± 6 and 14 ± 5 vs. 38 ± 24 mm

Topics: Angiotensin II; Animals; Cardiomyopathies; Fibrosis; Glucagon-Like Peptide 1; Hypertension; Linagliptin; Liraglutide; Mitochondria; NADPH Oxidase 4; Rats; Rats, Sprague-Dawley

Angiotensin-1 converting enzyme inhibitors (ACEIs) improve insulin sensitivity. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are anti-diabetic drugs with several cardio-renal effects. Both ACE and DPP-4 share common features. Thus, we tested if they could be inhibited by one inhibitor. First, in silico screening was used to investigate the ability of different DPP-4 inhibitors or ACEIs to interact with DPP-4 and ACE. The results of screening were then extrapolated into animal study. Fifty Sprague Dawley rats were randomly assigned into 5 groups treated with vehicle, captopril, enalapril, linagliptin or sitagliptin. Both low and high doses of each drug were tested. Baseline blood samples and samples at days 1, 8, 10, 14 were used to measure plasma DPP-4 and ACE activities and angiotensin II levels. Active glucagon-like peptide-1 (GLP-1) levels were measured after oral glucose challenge. All tested DPP-4 inhibitors could interact with ACE at a relatively reasonable binding energy while most of the ACEIs only interacted with DPP-4 at a predicted high inhibition constant. In rats, high dose of sitagliptin was able to inhibit ACE activity and reduce angiotensin II levels while linagliptin had only a mild effect. ACEIs did not significantly affect DPP-4 activity or prevent GLP-1 degradation. It seems that some DPP-4 inhibitors could inhibit ACE and this could partially explain the cardio-renal effects of these drugs. Further studies are required to determine if such inhibition could take place in clinical settings.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enalapril; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Linagliptin; Peptidyl-Dipeptidase A; Protein Binding; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate

It remains to be elucidated whether dipeptidylpeptidase-4 (DPP-4) inhibitor can ameliorate cardiovascular injury in salt-sensitive hypertension. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration initiated after onset of hypertension and cardiac hypertrophy can ameliorate cardiovascular injury in Dahl salt-sensitive hypertensive rats (DS rats).. High-salt loaded DS rats with established hypertension and cardiac hypertrophy were divided into two groups, and were orally given (1) vehicle or (2) linagliptin (3 mg/kg/day) once a day for 4 weeks, and cardiovascular protective effects of linagliptin in DS rats were evaluated.. Linagliptin did not significantly affect blood pressure and blood glucose levels in DS rats. Linagliptin significantly lessened cardiac hypertrophy in DS rats, as estimated by cardiac weight and echocardiographic parameters. Linagliptin significantly ameliorated cardiac fibrosis, cardiac macrophage infiltration, and coronary arterial remodeling in DS rats. Furthermore, linagliptin significantly mitigated the impairment of vascular function in DS rats, as shown by the improvement of acetylcholine-induced or sodium nitroprusside-induced vascular relaxation by linagliptin. These cardiovascular protective effects of linagliptin were associated with the attenuation of oxidative stress, NADPH oxidase subunits, p67phox and p22 phox, and angiotensin-converting enzyme (ACE).. Our results provided the experimental evidence that linagliptin treatment initiated after the appearance of hypertension and cardiac hypertrophy protected against cardiovascular injury induced by salt-sensitive hypertension, independently of blood pressure and blood glucose. These beneficial effects of linagliptin seem to be attributed to the reduction of oxidative stress and ACE.

Topics: Animals; Blood Glucose; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Heart; Hypertension; Linagliptin; Male; Purines; Quinazolines; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary