linagliptin and Diabetic-Retinopathy

To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes.. Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial.. Males and females aged 45-74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey.. Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function.. One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%.. ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes.. - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39.

Topics: Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Europe; Female; Galvanic Skin Response; Humans; Hyperglycemia; International Cooperation; Life Style; Linagliptin; Male; Metformin; Microcirculation; Middle Aged; Patient Selection; Research Design; Risk Factors

People with diabetes are at high risk of developing diabetes-related eye disease, termed as diabetic retinopathy, due damage being caused to the blood vessels in the retina. An efficient medical treatment to reduce diabetic retinopathy can improve the quality of life for diabetes patients. In our study, we show that linagliptin, a commercially available DPP-4 inhibitor, plays a protective role in retinal vascular endothelial cells. The presence of linagliptin protects retinal endothelial cells against TNF-α-induced cytotoxicity and enhances their viability. Linagliptin treatment suppresses TNF-α-induced production of reactive oxygen species and improves mitochondrial membrane potential. Moreover, linagliptin suppresses TNF-α-induced production of pro-inflammatory and pro-adhesive vascular cytokines including IL-6, IL-8, ICAM-1, and VCAM-1. The presence of linagliptin in cell media can reduce the number of THP-1 cells that adhere to retina endothelial cells. Mechanistically, linagliptin potently suppresses TNF-α-induced accumulation of NF-κB nuclear protein p65 and activation of NF-κB promoter. Our data indicate that linagliptin is an anti-inflammatory diabetic agent, with the potential to be applied as a treatment for diabetic retinopathy.

Topics: Cytokines; Diabetic Retinopathy; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Humans; Hypoglycemic Agents; Inflammation; Intercellular Adhesion Molecule-1; Linagliptin; NF-kappa B; Reactive Oxygen Species; Retina; Signal Transduction; THP-1 Cells; Vascular Cell Adhesion Molecule-1

Linagliptin has protective effects on the retinal neurovascular unit but, in proliferative retinopathy, dipeptidyl peptidase 4 (DPP-4) inhibition could be detrimental. The aim of this study was to assess the effect of linagliptin on ischaemia-induced neovascularisation of the retina.. Systemic treatment with linagliptin demonstrated GLP-1R-independent anti-angiogenic effects mediated by an inhibition of VEGF receptor downstream signalling. The specific effects of linagliptin on diabetic retinopathy are of potential benefit for individuals with diabetes, independent of metabolic effects.

Topics: Animals; Diabetic Retinopathy; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Linagliptin; Male; Mice; Mice, Inbred C57BL; Oxygen; Retina; Retinal Neovascularization; Signal Transduction; Vascular Endothelial Growth Factor A

Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in type 2 diabetes, however, their influence on the retinal neurovascular unit remains unclear.. Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats (diabetes duration of 24 weeks), DPP4 activity (fluorometric assay), GLP-1 (ELISA), methylglyoxal (LC-MS/MS), acellular capillaries and pericytes (quantitative retinal morphometry), SDF-1a and heme oxygenase-1 (ELISA), HMGB-1, Iba1 and Thy1.1 (immunohistochemistry), nuclei in the ganglion cell layer, GFAP (western blot), and IL-1beta, Icam1, Cxcr4, catalase and beta-actin (quantitative RT-PCR) were determined. In C. elegans, neuronal function was determined using worm tracking software.. Linagliptin decreased DPP4 activity by 77% and resulted in an 11.5-fold increase in active GLP-1. Blood glucose and HbA1c were reduced by 13% and 14% and retinal methylglyoxal by 66%. The increase in acellular capillaries was diminished by 70% and linagliptin prevented the loss of pericytes and retinal ganglion cells. The rise in Iba-1 positive microglia was reduced by 73% with linagliptin. In addition, the increase in retinal Il1b expression was decreased by 65%. As a functional correlate, impairment of motility (body bending frequency) was significantly prevented in C. elegans.. Our data suggest that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative effects of linagliptin on the neurovascular unit.

Topics: Animals; Blood Glucose; Caenorhabditis elegans; Diabetic Retinopathy; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Hypoglycemic Agents; Linagliptin; Male; Pericytes; Pyruvaldehyde; Rats; Rats, Wistar; Retinal Ganglion Cells