• DPP-4 inhibition
• angiogenesis
• coronary artery disease
• linagliptin
• sex disparities

• Coronary artery disease
• Dendritic cell
• Dipeptidyl peptidase-4 inhibitor
• Inflammation
• Ischemia
• Linagliptin

• Linagliptin/pharmacology
• Linagliptin/therapeutic use
• Animals
• Dipeptidyl-Peptidase IV Inhibitors/pharmacology
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Coronary Artery Disease/drug therapy
• Coronary Artery Disease/immunology
• Disease Models, Animal
• Swine
• Inflammation/drug therapy
• Inflammation/immunology
• Male
• NF-kappa B/metabolism
• Chronic Disease
• Female

• Antioxidant agent
• Atherosclerotic diseases
• Diabetes
• Drug combination
• Hypoglycemic agent
• Hypolipidemic agent
• Metformin

• DPP-4
• Inflammation
• Linagliptin
• Sepsis
• Vascular permeability

• Animals
• Linagliptin/pharmacology
• Dipeptidyl-Peptidase IV Inhibitors/pharmacology
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Sepsis/drug therapy
• Sepsis/complications
• Male
• Inflammation/drug therapy
• Mice
• Edema/drug therapy
• Cytokines/metabolism
• Mice, Inbred C57BL
• Disease Models, Animal
• Dipeptidyl Peptidase 4/metabolism

• Cyclosporine
• Hesperidin
• NF-κB
• Nephrotoxicity
• Nrf2
• Sitagliptin

• Rats
• Animals
• Male
• Cyclosporine/pharmacology
• NF-kappa B/metabolism
• Catalase/metabolism
• Tumor Necrosis Factor-alpha/metabolism
• bcl-2-Associated X Protein/metabolism
• Hesperidin/pharmacology
• Hesperidin/therapeutic use
• NF-E2-Related Factor 2/metabolism
• Rats, Wistar
• Sitagliptin Phosphate/adverse effects
• Creatinine
• Kidney Diseases/chemically induced
• Kidney Diseases/drug therapy
• Kidney Diseases/metabolism
• Kidney/metabolism
• Oxidative Stress
• Renal Insufficiency/pathology
• Glutathione/metabolism
• Urea/metabolism
• Superoxide Dismutase/metabolism
• Glucose/metabolism

• Assiut University

Pharmaceutical excipients should not interact with active substances, however, in practice, they sometimes do it, affecting the efficacy, stability and safety of drugs. Thus, interactions between active substances and excipients are not desirable. For this reason, two component mixtures of oral antidiabetic drug linagliptin (LINA) with four excipients of different reactivity, i.e., lactose (LAC), mannitol (MAN), magnesium stearate (MGS) and polyvinylpyrrolidone (PVP), were prepared in a solid state. A high temperature and a high humidity of 60 °C and 70% RH, respectively, were applied as stressors in order to accelerate the potential interactions between LINA and excipients. Differential scanning calorimetry (DSC) as well as Fourier transform infrared (FT-IR) and near infrared (NIR) spectroscopy were used to estimate the changes due to potential interactions. In addition, chemometric computation of the data with principal component analysis (PCA) and hierarchical cluster analysis (HCA) was applied to adequately interpret the findings. Of the excipients used in the present experiment, all of them were not inert in relation to LINA. Some of the interactions were shown without any stressing, whereas others were observed under high-temperature/high-humidity conditions. Thus, it could be concluded that selection of appropriate excipients for LINA is very important question to minimize its degradation, especially when new types of formulations with LINA are being developed and manufactured.

• molecular medicine
• molecular biology

• Atherosclerosis/complications
• Atherosclerosis/drug therapy
• Atherosclerosis/genetics
• Genome-Wide Association Study
• Humans
• Inflammasomes/metabolism
• Inflammasomes/therapeutic use
• Inflammation/complications
• Inflammation/genetics
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Signal Transduction/genetics

• National Natural Science Foundation of China (National Science Foundation of China)
• This work was supported by the National Natural Science Foundation of China (91849102, 91739301); the Key Natural Science Foundation Projects of Hebei Province (H2019206028);
• Natural Science Foundation of Hebei Province (Hebei Provincial Natural Science Foundation)
• Natural Science Youth Fund of Hebei Province Education Department (QN2020167)

• Acquired
• Children
• Diabetes mellitus
• Genetic
• Insulin resistance
• Obesity

• cardiology
• endocrinology

• Adult
• Aged
• Body Mass Index
• Cardiotoxicity/etiology
• Cardiovascular Diseases/epidemiology
• Cardiovascular Diseases/etiology
• Comorbidity
• Diabetes Mellitus, Type 2/drug therapy
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Dipeptidyl-Peptidase IV Inhibitors/toxicity
• Female
• Humans
• Hypoglycemic Agents/administration & dosage
• Hypoglycemic Agents/therapeutic use
• Hypoglycemic Agents/toxicity
• Male
• Metformin/administration & dosage
• Metformin/therapeutic use
• Middle Aged
• Smoking/epidemiology
• Sulfonylurea Compounds/administration & dosage
• Sulfonylurea Compounds/therapeutic use
• Sulfonylurea Compounds/toxicity

• MC_UU_12023/29 Medical Research Council
• MC_UU_00004/07 Medical Research Council
• MC_UU_00004/09 Medical Research Council
• NIHR School for Primary Care Research
• UK Medical Research Council

• Acute kidney injury
• Cardiorenal diseases
• Diabetes
• Klotho
• SGLT2 inhibitors

• Heart failure
• cardiac fibrosis
• pharmacotherapy

• Bioactive peptides
• Combienzymes
• Enzyme selectivity
• Enzyme specificity
• Protease immobilization
• Protein hydrolysis

Atherosclerosis is one of the major causes of cardiovascular diseases. Lipid uptake and accumulation in macrophages play a major role in atherosclerotic plaque formation from its initiation to advanced atheroma formation. The dipeptidyl peptidase-4 (DPP-4) inhibitor Linagliptin is commonly used to lower blood glucose in type 2 diabetes patients. Recent studies report that Linagliptin has cardiovascular protective and anti-inflammatory effects.

THP-1 macrophage cells were treated with 100 nM PMA for 72 hour to induce foam cell formation. The differentiated cells were exposed to 100 μg/mL ox-LDL in the presence or absence of the DPP-4 inhibitor Linagliptin. The expression levels of DPP-4 and inflammatory cytokines were detected by RT-PCR, ELISA, and Western blot experiments. The cellular ROS level was measured by staining the cells with the fluorescent probe DCFH-DA. The separation of lipoprotein fractions was achieved by high-performance liquid chromatography (HPLC). The cells were labeled with fluorescent-labeled cholesterol to measure cholesterol efflux, and lipid droplets were revealed by Nile red staining.

The presence of Linagliptin significantly reduced ox-LDL-induced cytokine production (IL-1β and IL-6) and ROS production. Linagliptin ameliorated ox-LDL-induced lipid accumulation and impaired cholesterol efflux in macrophages. Mechanistically, this study showed that Linagliptin mitigated ox-LDL-induced expression of the scavenger receptors CD36 and LOX-1, but not SRA. Furthermore, Linagliptin increased the expression of the cholesterol transporter ABCG1, but not ABCA1.

Linagliptin possesses a potent inhibitory effect on THP-1 macrophage-derived foam cell formation in response to ox-LDL. This effect could be mediated through a decrease in the expression of CD36 and LOX-1 on macrophages and an increase in the expression of the cholesterol transporter ABCG1. This study indicates that the DPP-4 inhibitor Linagliptin plays a critical role in preventing foam cell formation in vitro. However, future research using an atherosclerotic animal model is necessary to determine its effectiveness and to prove its potential implication in the prevention and treatment of atherosclerosis.

• ABCG-1
• ATP binding cassette transporter G1
• CD36
• LOX-1
• Linagliptin
• atherosclerosis
• foam cells

• Biomarkers
• HbA1c
• Sodium-glucose co-transporter 2 inhibitor
• Steglatro

• Anti-diabetic drugs
• Clinical trials
• Comorbidities
• Diabetes mellitus
• Drug repurposing

• CD34+
• Diabetic kidney disease
• EPC
• Endothelium
• Linagliptin
• Type 2 diabetes

• Adult
• Aged
• Antigens, CD34/blood
• Biomarkers/blood
• Cells, Cultured
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/diagnosis
• Diabetes Mellitus, Type 2/drug therapy
• Diabetic Nephropathies/blood
• Diabetic Nephropathies/diagnosis
• Diabetic Nephropathies/drug therapy
• Dipeptidyl-Peptidase IV Inhibitors/adverse effects
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• District of Columbia
• Double-Blind Method
• Drug Therapy, Combination
• Endothelial Progenitor Cells/drug effects
• Endothelial Progenitor Cells/metabolism
• Endothelial Progenitor Cells/pathology
• Female
• Humans
• Hypoglycemic Agents/adverse effects
• Hypoglycemic Agents/therapeutic use
• Insulin/adverse effects
• Insulin/therapeutic use
• Linagliptin/adverse effects
• Linagliptin/therapeutic use
• Male
• Metformin/adverse effects
• Metformin/therapeutic use
• Middle Aged
• Pilot Projects
• Receptors, CXCR4/blood
• Renal Insufficiency, Chronic/blood
• Renal Insufficiency, Chronic/diagnosis
• Renal Insufficiency, Chronic/drug therapy
• Time Factors
• Treatment Outcome

• Boehringer Ingelheim

• Anacamptis pyramidalis
• antioxidant
• docking study
• enzyme inhibition
• network pharmacology
• phytochemical fingerprint

• Alzheimer Disease/drug therapy
• Antioxidants/chemistry
• Antioxidants/pharmacology
• Computer Simulation
• Diabetes Mellitus, Type 2/drug therapy
• Glycoside Hydrolase Inhibitors/chemistry
• Glycoside Hydrolase Inhibitors/pharmacology
• Horticulture/methods
• Humans
• Hyperpigmentation/drug therapy
• Methanol/chemistry
• Molecular Docking Simulation
• Monophenol Monooxygenase/antagonists & inhibitors
• Monophenol Monooxygenase/chemistry
• Orchidaceae/chemistry
• Phytochemicals/chemistry
• Phytochemicals/pharmacology
• Plant Extracts/chemistry
• Plant Extracts/pharmacology
• Skin Diseases/drug therapy
• alpha-Amylases/antagonists & inhibitors
• alpha-Amylases/chemistry
• alpha-Glucosidases/chemistry
• alpha-Glucosidases/drug effects

• Cluster of differentiation 26
• Dipeptidyl peptidase 4
• Immunotherapy
• Type 2 diabetes mellitus

• Animals
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/immunology
• Dipeptidyl Peptidase 4/immunology
• Dipeptidyl-Peptidase IV Inhibitors/administration & dosage
• Dipeptidyl-Peptidase IV Inhibitors/immunology
• Humans
• Immunologic Factors/administration & dosage
• Immunologic Factors/immunology
• Immunotherapy/methods
• Immunotherapy/trends
• T-Lymphocytes/drug effects
• T-Lymphocytes/immunology

The current study aimed to compare the effects of dapagliflozin and sitagliptin on insulin resistant and body fat distribution in newly diagnosed type 2 diabetic patients.

This study was an open-label, parallel controlled study. Patients were included if they were newly diagnosed with type 2 diabetes (<6 months) and had been receiving dapagliflozin or sitagliptin for 12 weeks in combination with a stable dose of metformin in the last month. At baseline and 12 weeks, insulin resistant (homeostatic model assessment of insulin resistance [HOMA-IR]), body fat distribution (waist/hip ratio), fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), lipid profiles, and C-reactive protein (CRP) level were compared.

There were 59 patients receiving dapagliflozin and 67 patients receiving sitagliptin. There was no significant between-group difference in baseline characteristics. After 12 weeks of treatment, compared to the sitagliptin group, the FBG (6.4±0.5 versus 6.7±0.7 mmol/L), HbA1c (7.0±0.4 versus 7.2±0.5%), HOMA-IR (1.6±0.5 versus 1.8±0.6), triglyceride (1.6±0.4 versus 1.8±0.3 mmol/L), and CRP (3.1±0.7 versus 3.3±0.5 mg/L) were slightly lower in the dapagliflozin group. Within each group, compared to baseline, FBG (dapagliflozin [6.4±0.5 versus 7.8±0.7 mmol/L]; sitagliptin [6.7±0.7 versus 7.7±0.6 mmol/L]), HbA1c (dapagliflozin [7.0±0.4 versus 8.0±0.5%]; sitagliptin [7.2±0.5 versus 8.1%±0.6%]), HOMA-IR (dapagliflozin [1.6±0.5 versus 2.4±0.4]; sitagliptin [1.8±0.6 versus 2.5±0.4]), triglyceride (dapagliflozin [1.6±0.4 versus 2.2±0.5 mmol/L]; sitagliptin [1.8±0.3 versus 2.1±0.5 mmol/L]), and CRP (dapagliflozin [3.1±0.7 versus 6.2±1.1 mg/L]; sitagliptin [3.3±0.5 versus 6.1±1.0 mg/L]) were significantly decreased.

Dapagliflozin and sitagliptin had comparable effects on improving insulin resistant and blood glucose control, and these benefits may be associated with improvement of systemic inflammation.

• Bioactive peptide
• Boarfish
• Dipeptidyl peptidase-IV
• Insulinotropic
• Type 2 diabetes

• atherosclerosis
• endothelial dysfunction
• magnesium
• metal ions
• microparticles
• platelets
• thrombosis
• zinc

• Blood Coagulation
• Blood Coagulation Disorders/blood
• Blood Coagulation Disorders/complications
• Blood Coagulation Disorders/therapy
• Diabetes Mellitus, Type 1/blood
• Diabetes Mellitus, Type 1/complications
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/complications
• Humans
• Lipid Metabolism
• Risk Factors

• FS/15/42/31556 British Heart Foundation
• PG/15/9/31270 British Heart Foundation

In Japan, the choice of anti-diabetic medication is officially recommended according to the patient’s glycemic condition and disease phenotype, unlike most other regions where metformin is recommended as the first-line medication. There has been an increase in the number of available glucose-lowering agents, making it necessary to select these agents based on ever-improving evidence obtained from clinical trials. For the dipeptidyl peptidase-4 inhibitor class of drugs, nine drugs are currently available on the market in Japan. Although previous cardiovascular outcome trials (CVOTs) demonstrated non-inferiority for both major adverse cardiovascular events (MACEs) and safety for some drugs of the class, the design and results of the CARMELINA trial seemed to be slightly different from earlier trials in that it showed the drugs were safe and partially effective even in patients with renal impairment. Thus, recent CVOTs on newer glucose-lowering agents have mainly focused on the major impacts of individual classes and drugs on clinical outcomes behind their glucose-lowering action. The diverse features of the classes and individual drugs may have also highlighted not only the class-effects, but also the drug-effects of glucose-lowering agents. This will lead to clinical-based evidence and assist with optimum selection of the class and/or drug for tailored medication in patients with type 2 diabetes.

• Cardiovascular outcome trial
• Dipeptidyl peptidase-4 inhibitor
• Glucose-lowering agent
• Tailored medication
• Type 2 diabetes

Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db).

Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg⁻¹ day⁻¹, and fed for 5 weeks, initiated at 11 weeks of age.

Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of “reversion inducing cysteine rich protein with Kazal motifs” (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells.

Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.

• Pulsatility index
• RECK
• Renal resistivity
• SGLT2
• Vascular stiffness

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.

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.

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).

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)

The online version of this article (10.1186/s12933-018-0716-x) contains supplementary material, which is available to authorized users.

• Coronary artery disease
• DPP-4 inhibitor
• Endothelial function
• Flow mediated dilatation
• Linagliptin
• RCT
• Type 2 diabetes