• Class III drugs
• Hypoglycemic effect
• Linagliptin
• Microemulsion
• Nigella oil
• Oral absorption

• Linagliptin/pharmacokinetics
• Linagliptin/administration & dosage
• Linagliptin/chemistry
• Animals
• Emulsions
• Biological Availability
• Administration, Oral
• Water/chemistry
• Male
• Diabetes Mellitus, Experimental/drug therapy
• Rats, Wistar
• Plant Oils/chemistry
• Plant Oils/administration & dosage
• Plant Oils/pharmacokinetics
• Hypoglycemic Agents/pharmacokinetics
• Hypoglycemic Agents/administration & dosage
• Hypoglycemic Agents/chemistry
• Rats
• Drug Liberation
• Carum
• Nigella sativa

• Tanta University

• Humans
• Dose-Response Relationship, Drug
• Pharmaceutical Preparations/administration & dosage
• Pharmaceutical Preparations/metabolism
• Drug Discovery/methods
• Japan
• Pharmacokinetics
• Models, Biological
• Administration, Oral

• Startup Grant by ShanghaiTech University

• Animals
• Linagliptin/blood
• Linagliptin/chemistry
• Linagliptin/pharmacokinetics
• Pioglitazone/chemistry
• Pioglitazone/blood
• Pioglitazone/pharmacokinetics
• Tandem Mass Spectrometry
• Rats
• Drug Interactions
• Rats, Sprague-Dawley
• Male
• Chromatography, High Pressure Liquid
• Molecular Structure
• Hypoglycemic Agents/blood
• Hypoglycemic Agents/pharmacokinetics
• Hypoglycemic Agents/chemistry
• Liquid Chromatography-Mass Spectrometry

• Humans
• Dipeptidyl-Peptidase IV Inhibitors/pharmacology
• Kinetics
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases

• (GLP)-1
• DPP-4 enzyme
• DPP-4 inhibitors
• T2DM
• incretin effect
• insulin

Background: As a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, TQ-F3083 represents a promising new drug for type 2 diabetes mellitus (T2DM). This phase I, first-in-human study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of TQ-F3083 in healthy Chinese adults.

Methods: Sixty healthy participants total were enrolled in the single-ascending dose, multiple-dose, and food-effect studies. Safety endpoints included adverse events (AEs), vital signs, 12-lead electrocardiogram, abdominal ultrasound, chest X-ray, physical examination, and clinical laboratory tests. Blood, urine, and feces samples were collected for pharmacokinetic analyses. Pharmacodynamic parameters were evaluated based on DPP-4 activity and the active glucagon-like peptide-1 concentration.

Results: In total, 22 treatment-related AEs, mostly grade 1 or 2, were reported in 14 individuals. No deaths, serious AEs, or grade ≥4 AEs occurred, and no dose-dependent AEs were demonstrated. For pharmacokinetic characteristics, dose linearity was analyzed using power model. The slopes (90% CIs) were 1.08 (1.02–1.13) and 1.05 (0.99–1.11) for AUC_0-t and AUC_0-∞, suggesting liner pharmacokinetic characteristic after oral dose TQ-F3083 from 2 to 160 mg. The accumulation factor was 1.39 after multiple dose for 7 days. Decreased plasma exposure (84.87% decrease in C_max, 49.23% in AUC_0-t, and 47.77% in AUC_0-∞) was observed with administration after a high-fat and high-calorie standardized breakfast. The 0–72 h TQ-F3083 excretion recovery percentages were 7.84% in urine and 5.76% in feces. Over 80% DPP-4 inhibition for 24 h was observed in the 20–160 mg cohorts, and the model-estimated 50% effective concentration was 1.10 ng/ml. The concentration of active glucagon-like peptide-1 increased after TQ-F3083 administration, but no obvious dose dependency was observed.

Conclusion: TQ-F3083 was well tolerated in healthy Chinese adults, and the pharmacokinetic and pharmacodynamic characteristics support further evaluation of TQ-F3083 in a trial in T2DM patients.

• TQ-F3083
• pharmacodynamics
• pharmacokinetics
• phase I
• type 2 diabetes

• DPP-4 inhibitor
• crescent formation
• fibrosis
• non-diabetic renal disease

Drugs targeting type 4 dipeptidyl peptidase (DPP‐4) are beneficial for glycemic control, whereas fibroblast activation protein alpha (FAP‐α) is a potential target for cancer therapies. Unlike other gliptins, linagliptin displays FAP inhibition. We compared biophysical and structural characteristics of linagliptin binding to DPP‐4 and FAP to better understand what differentiates linagliptin from other gliptins. Linagliptin exhibited high binding affinity (K_D) and a slow off‐rate (k_off) when dissociating from DPP‐4 (K_D 6.6 pM; k_off 5.1×10⁻⁵ s⁻¹), and weaker inhibitory potency to FAP (K_D 301 nM; k_off>1 s⁻¹). Co‐structures of linagliptin with DPP‐4 or FAP were similar except for one second shell amino acid difference: Asp663 (DPP‐4) and Ala657 (FAP). pH dependence of enzymatic activities and binding of linagliptin for DPP‐4 and FAP are dependent on this single amino acid difference. While linagliptin may not display any anticancer activity at therapeutic doses, our findings may guide future studies for the development of optimized inhibitors.

• DPP-4
• FAP
• kinetics
• linagliptin
• pH dependence

• dipeptidyl peptidase inhibitor
• human scale-up
• linagliptin
• physiologically-based pharmacokinetic model
• target-mediated drug disposition

• Caco-2 permeability
• In situ single-pass perfusion
• Linagliptin
• Oral bioavailability
• P-glycoprotein inhibition
• Pharmacodynamics
• Pharmacokinetics

Dipeptidyl peptidase-4 inhibitors, including linagliptin, prevent inflammation. However, the in vitro effects of linagliptin are unclear. Moreover, although linagliptin inhibits lipopolysaccharide (LPS)-induced inflammation, the anti-inflammatory effects of linagliptin in this context are not concentration-dependent. In the absence of LPS-binding protein (LBP), the pro-inflammatory effects of LPS involve pathways other than the Toll-like receptor (TLR) 4 pathway. Here, we aimed to determine the anti-inflammatory mechanisms of linagliptin in an experimental model in which LBP was added to the medium.

Human U937 monocytes were cultured at 1 × 10⁶ cells/mL in Roswell Park Memorial Institute medium and differentiated into macrophages using phorbol myristate acetate. All processes were carried out in medium containing 10% fetal bovine serum (FBS). After 48 hrs of culture, we replaced the medium and pretreated the cells with 100, 250, 500, or 2500 nM linagliptin for 1 hr. We exchanged the medium again, and the cells were treated with 1 ng/mL LPS with or without 100, 250, 500, or 2500 nM linagliptin. Interleukin (IL)-6 and LBP in the supernatant, nuclear factor (NF)-κB/p65 in the nucleus, and reactive oxygen species (ROS) in the cells, as important markers of the mechanism of inflammation induction by LPS, were measured using enzyme-linked immunosorbent assay kits.

Linagliptin significantly prevented LPS-stimulated IL-6 production and intranuclear NF-κB/p65 levels in a concentration-dependent manner. LPS-induced intracellular ROS levels were significantly decreased by linagliptin at all concentrations. LBP levels were markedly higher in FBS-containing medium than in medium without FBS. However, LBP levels did not change following administration of linagliptin and/or LPS.

Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment in the context of LPS-induced pro-inflammatory responses. Thus, our findings suggested that linagliptin induced two different mechanisms to repress inflammation, i.e., TLR4-dependent and -independent mechanisms.

• interleukin-6
• intranuclear subunit of nuclear factor-κB/p65
• linagliptin
• lipopolysaccharide-binding protein
• reactive oxygen species

• DPP-4 inhibitor
• cytotoxicity
• genotoxicity
• linagliptin
• oxidative stress

Atherosclerosis and inflammation are more common in patients with diabetes than in patients without diabetes, and atherosclerosis progression contributes to inflammation. Therefore, anti-inflammatory therapy is important for the prognosis of patients with diabetes. Linagliptin is the only bile-excreted, anti-diabetic oral dipeptidyl peptidase-4 (DPP-4) inhibitor. Although the anti-inflammatory effects of DPP-4 inhibitors in vivo and in vitro have been reported, few in vitro studies have examined the effects of linagliptin using monocytes, which play a central role in arteriosclerosis-related inflammation. Herein, we assessed the anti-inflammatory effects of linagliptin in human U937 monocytes.

U937 cells at densities of 1 × 10⁶ cells/mL were cultured in Roswell Park Memorial Institute medium supplied with 10% fetal bovine serum and treated with 100 nM phorbol myristate acetate for 48 h for differentiation into macrophages. The media were replaced, and the cells were pretreated with 1, 5, 10, 50, and 100 nM linagliptin for 1 h or were left untreated. The media were then replaced again, and the cells were treated with 1 μg/mL lipopolysaccharide (LPS) or 10 nM interleukin (IL)-1β only, in combination with 1, 5, 10, 50, and 100 nM linagliptin or were left untreated. The extracted media were used to measure IL-6 and tumor necrosis factor (TNF)-α levels using enzyme-linked immunosorbent assay kits.

LPS alone significantly increased IL-6 and TNF-α production compared with the control treatment. The treatment of cells with linagliptin at all concentrations significantly inhibited the LPS-stimulated IL-6 and TNF-α production. Meanwhile, IL-1β alone significantly increased IL-6 production compared with the control treatment. No significant difference in IL-6 production was noted between the cells treated with IL-1β and simultaneous treatment with IL-1β and linagliptin.

Linagliptin inhibited LPS-induced inflammation in human monocytic U937 cells.

• Anti-inflammatory effects
• Human U937 monocytes
• Interleukin 6
• Linagliptin
• Lipopolysaccharide

• DPP-4 inhibitor
• SGLT-2 inhibitor
• Type 2 diabetes
• combination therapy
• empagliflozin
• linagliptin

• chronic kidney disease
• dialysis
• dipeptidyl peptidase-4
• type 2 diabetes

• Adamantane/analogs & derivatives
• Adamantane/therapeutic use
• Blood Glucose/analysis
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/metabolism
• Diabetic Nephropathies/therapy
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Female
• Glycated Hemoglobin/analysis
• Humans
• Kidney Failure, Chronic/etiology
• Kidney Failure, Chronic/therapy
• Linagliptin/therapeutic use
• Lipids/blood
• Male
• Middle Aged
• Nitriles/therapeutic use
• Peritoneal Dialysis
• Pyrrolidines/therapeutic use
• Renal Dialysis
• Retrospective Studies
• Sitagliptin Phosphate/therapeutic use
• Treatment Outcome
• Vildagliptin

Our aims were to summarize the clinical pharmacokinetics and pharmacodynamics of the dipeptidyl‐peptidase‐4 inhibitor, linagliptin, and to consider how these characteristics influence its clinical utility. Differences between linagliptin and other dipeptidyl‐peptidase‐4 inhibitors were also considered, in addition to the influence of Asian race on the pharmacology of linagliptin. Linagliptin has a xanthine‐based structure, a difference that might account for some of the pharmacological differences observed with linagliptin versus other dipeptidyl‐peptidase‐4 inhibitors. The long terminal half‐life of linagliptin results from its strong binding to dipeptidyl‐peptidase‐4. Despite this, linagliptin shows a short accumulation half‐life, as a result of saturable, high‐affinity binding to dipeptidyl‐peptidase‐4. The pharmacokinetic characteristics of linagliptin make it suitable for once‐daily dosing in a broad range of patients with type 2 diabetes mellitus. Unlike most other dipeptidyl‐peptidase‐4 inhibitors, linagliptin has a largely non‐renal excretion route, and dose adjustment is not required in patients with renal impairment. Furthermore, linagliptin exposure is not substantially altered in patients with hepatic impairment, and dose adjustment is not necessary for these patients. The 5‐mg dose is also suitable for patients of Asian ethnicity. Linagliptin shows unique pharmacological features within the dipeptidyl‐peptidase‐4 inhibitor class. Although most clinical trials of linagliptin have involved largely Caucasian populations, data on the pharmacokinetic/pharmacodynamic properties of linagliptin show that these features are not substantially altered in Asian populations. The 5‐mg dose of linagliptin is suitable for patients with type 2 diabetes mellitus irrespective of their ethnicity or the presence of renal or hepatic impairment.

• Linagliptin
• Pharmacodynamics
• Pharmacokinetics

• gastric inhibitory polypeptide
• glucagon
• glucagon-like peptide-1
• pharmacology
• type-2 diabetes mellitus

• alogliptin
• anagliptin
• dipeptidyl peptidase-4 inhibitor
• gemigliptin
• linagliptin
• saxagliptin
• sitagliptin
• teneligliptin
• type 2 diabetes
• vildagliptin

The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post‐hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase‐4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials.

Study 1 (with a 12‐week placebo‐controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24‐week trial) enrolled Asian (non‐Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90).

Linagliptin trough concentrations were equivalent across study and race groups, and were higher than half‐maximal inhibitory concentration, resulting in dipeptidyl peptidase‐4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase‐4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non‐Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group.

Trough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non‐Japanese) and white patients, confirming that the recommended 5‐mg once‐daily dose of linagliptin is appropriate for use among different race groups.

• Exposure-response
• Linagliptin
• Race effect

Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in patients with T2DM.

Linagliptin plasma concentrations and DPP-4 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and creatinine clearance, as well as study-related factors such as metformin co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination.

The pharmacokinetic analysis included 6,907 measurements of plasma linagliptin concentrations from 462 patients; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma DPP-4 activity and linagliptin plasma concentrations from 607 patients. The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of linagliptin to its target, DPP-4. The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC₅₀) and the concentration leading to 80 % DPP-4 inhibition was <20 %.

These analyses show that the investigated factors do not alter the pharmacokinetics and DPP-4 inhibitory activity of linagliptin to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight.

The online version of this article (doi:10.1007/s40262-014-0232-4) contains supplementary material, which is available to authorized users.

First report of a quality linagliptin assay in human plasma using UHPLC-ESI-MS/MS.

• Dipeptidyl-peptidase IV inhibitors
• Kidney transplantation
• New-onset diabetes after transplantation

• Animals
• Blood Glucose/drug effects
• Blood Glucose/metabolism
• Diabetes Mellitus/diagnosis
• Diabetes Mellitus/drug therapy
• Diabetes Mellitus/enzymology
• Diabetes Mellitus/etiology
• Dipeptidyl Peptidase 4/metabolism
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Humans
• Organ Transplantation/adverse effects
• Risk Assessment
• Risk Factors
• Treatment Outcome

• Diabetic nephropathy
• ESRD
• Hemodialysis
• Teneligliptin
• Type 2 diabetes

• Administration, Oral
• Aged
• Blood Glucose/analysis
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Diabetic Nephropathies/therapy
• Dipeptidyl-Peptidase IV Inhibitors/administration & dosage
• Dipeptidyl-Peptidase IV Inhibitors/adverse effects
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Female
• Glycated Hemoglobin/analysis
• Glycation End Products, Advanced
• Humans
• Hyperglycemia/prevention & control
• Hypoglycemia/chemically induced
• Hypoglycemia/physiopathology
• Hypoglycemia/prevention & control
• Japan
• Kidney Failure, Chronic/complications
• Kidney Failure, Chronic/therapy
• Male
• Middle Aged
• Monitoring, Ambulatory
• Pyrazoles/administration & dosage
• Pyrazoles/adverse effects
• Pyrazoles/therapeutic use
• Renal Dialysis
• Serum Albumin/analysis
• Serum Albumin, Human
• Severity of Illness Index
• Thiazolidines/administration & dosage
• Thiazolidines/adverse effects
• Thiazolidines/therapeutic use
• Glycated Serum Albumin

Asia has a growing diabetic population. Linagliptin, a member of dipeptidyl peptidase-4 inhibitor class, is unique in its nonlinear pharmacokinetics with the characteristics of rapid attainment of steady state, little accumulation, predominantly nonrenal route of elimination, prolonged terminal half-life, and sustained inhibition of dipeptidyl peptidase-4 enzyme. No clinically relevant difference in pharmacokinetics was observed between Asians and non-Asians. The management of type 2 diabetes is increasingly challenging with the progression of disease, especially with the requirements of minimal hypoglycemia, weight gain, fluid retention, and other adverse effects. Linagliptin was efficacious and well-tolerated in Asian type 2 diabetes patients with or without renal or hepatic dysfunctions, comparable to that in Caucasians. This review will focus on the usage of linagliptin in clinical studies in Asians.

• Asians
• linagliptin
• type 2 diabetes

The inhibition of dipeptidyl peptidase-4 (DPP4) via specific inhibitors is known to result in improved glucose tolerance and insulin sensitivity and decreased accumulation of hepatic fat in type II diabetic human patients. The metabolic situation of dairy cows can easily be compared to the status of human diabetes and non-alcoholic fatty liver. For both, insulin sensitivity is reduced, while hepatic fat accumulation increases, characterized by high levels of non-esterified fatty acids (NEFA) and ketone bodies.Therefore, in the present study, a DPP4 inhibitor was employed (BI 14332) for the first time in cows. In a first investigation BI 14332 treatment (intravenous injection at dosages of up to 3 mg/kg body weight) was well tolerated in healthy lactating pluriparous cows (n = 6) with a significant inhibition of DPP4 in plasma and liver. Further testing included primi- and pluriparous lactating cows suffering from subclinical ketosis (β-hydroxybutyrate concentrations in serum > 1.2 mM; n = 12). The intension was to offer effects of DPP4 inhibition during comprehensive lipomobilisation and hepatosteatosis. The cows of subclinical ketosis were evenly allocated to either the treatment group (daily injections, 0.3 mg BI 14332/kg body weight, 7 days) or the control group. Under condition of subclinical ketosis, the impact of DPP4 inhibition via BI 14332 was less, as in particular β-hydroxybutyrate and the hepatic lipid content remained unaffected, but NEFA and triglyceride concentrations were decreased after treatment. Owing to lower NEFA, the revised quantitative insulin sensitivity check index (surrogate marker for insulin sensitivity) increased. Therefore, a positive influence on energy metabolism might be quite possible. Minor impacts on immune-modulating variables were limited to the lymphocyte CD4⁺/CD8⁺ ratio for which a trend to decreased values in treated versus control animals was noted. In sum, the DPP4 inhibition in cows did not affect glycaemic control like it is shown in humans, but was able to impact hyperlipemia, as NEFA and TG decreased.

• Anti-inflammatory effects
• Blood glucose-related factors
• Diabetes mellitus
• Dipeptidase-4 inhibitors
• Hemodialysis

• Blood Glucose/metabolism
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/metabolism
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Humans
• Hyperglycemia/drug therapy
• Hyperglycemia/metabolism
• Insulin-Secreting Cells/metabolism

Dipeptidyl-peptidase-IV (DPP-4) inhibitors are oral antidiabetic agents that can be administered as monotherapy in patients with contraindications to metformin or metformin intolerance, and in combination with other oral compounds and/or insulin. DPP-4 inhibitors act in a glucose-dependent manner and only increase insulin secretion and inhibit glucagon secretion under hyperglycemic conditions. Renal impairment is frequent in type 2 diabetes as a result of microvascular complications and diabetes treatment, and options in these patients are limited. Linagliptin is a DPP-4 inhibitor with a hepatobiliary route of elimination. In comparative studies, it was noninferior to metformin and sulfonylureas in lowering glycated hemoglobin (HbA_1c) and improving glycemic parameters. It can be used throughout all stages of renal impairment without dose adjustments. This review gives an overview of linagliptin in various stages of chronic kidney disease and has a focus on efficacy and safety parameters from clinical studies in patients with impaired renal function. These data are interpreted in the context of type 2 diabetes therapy in general.

• DPP-4 inhibitors
• incretin based therapies
• linagliptin
• oral antidiabetic drugs
• renal impairment
• type 2 diabetes

• Animals
• Dipeptidyl Peptidase 4/chemistry
• Dipeptidyl Peptidase 4/metabolism
• Dipeptidyl-Peptidase IV Inhibitors/chemistry
• Dipeptidyl-Peptidase IV Inhibitors/pharmacology
• Drug Design
• Glucose/metabolism
• Homeostasis/drug effects
• Mice
• Time Factors
• Xanthine/chemistry
• Xanthine/pharmacology

• DPP-4 inhibitors
• Dipeptidyl peptidase 4
• GLP-1 receptor agonists
• Glucagon-like peptide 1
• Incretin effect
• Incretin mimetics
• Pharmacotherapy

• Administration, Oral
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/metabolism
• Dipeptidyl-Peptidase IV Inhibitors/pharmacology
• Drug Monitoring
• Glucagon-Like Peptide-1 Receptor
• Humans
• Hypoglycemia/chemically induced
• Hypoglycemia/prevention & control
• Hypoglycemic Agents/pharmacology
• Incretins/pharmacology
• Insulin/metabolism
• Insulin Secretion
• Receptors, Glucagon/agonists
• Treatment Outcome
• Weight Loss/drug effects

• sdf-1α
• linagliptin
• nadph oxidase
• dpp4 activity
• obesity

• Animals
• Dipeptidyl-Peptidase IV Inhibitors/pharmacology
• Glomerular Filtration Barrier/drug effects
• Glomerular Filtration Barrier/injuries
• Glucagon-Like Peptide 1/metabolism
• Hypoglycemic Agents/pharmacology
• Kidney Diseases/metabolism
• Kidney Glomerulus/drug effects
• Male
• Obesity/metabolism
• Obesity/pathology
• Oxidative Stress/drug effects
• Podocytes/drug effects
• Podocytes/metabolism
• Rats
• Rats, Zucker

• R01 HL073101 NHLBI NIH HHS
• HL73101 NHLBI NIH HHS
• HL1079100 NHLBI NIH HHS
• R01 HL107910 NHLBI NIH HHS
• R03 AG040638 NIA NIH HHS
• AG040638 NIA NIH HHS

• dipeptidyl peptidase-4 inhibitors
• pharmacokinetics
• renal impairment
• safety

• Adamantane/analogs & derivatives
• Adamantane/pharmacokinetics
• Adamantane/therapeutic use
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Diabetic Nephropathies/blood
• Diabetic Nephropathies/drug therapy
• Dipeptides/pharmacokinetics
• Dipeptides/therapeutic use
• Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Dose-Response Relationship, Drug
• Glycated Hemoglobin/drug effects
• Humans
• Piperidines/pharmacokinetics
• Piperidines/therapeutic use
• Renal Insufficiency/drug therapy
• Risk Factors
• Treatment Outcome
• Uracil/analogs & derivatives
• Uracil/pharmacokinetics
• Uracil/therapeutic use

• Diabetic nephropathy
• glomerular filtration rate
• incretin
• renal impairment
• type 2 diabetes

• Albuminuria/etiology
• Albuminuria/prevention & control
• Animals
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/diagnosis
• Diabetes Mellitus, Type 2/drug therapy
• Diabetic Nephropathies/blood
• Diabetic Nephropathies/diagnosis
• Diabetic Nephropathies/etiology
• Diabetic Nephropathies/prevention & control
• Dipeptidyl Peptidase 4/metabolism
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Glucagon-Like Peptide 1/analogs & derivatives
• Glucagon-Like Peptide 1/therapeutic use
• Humans
• Kidney/drug effects
• Kidney/enzymology
• Risk Factors
• Sodium-Glucose Transporter 2/metabolism
• Sodium-Glucose Transporter 2 Inhibitors
• Treatment Outcome

• DPP4-inhibitor
• hypoglycemia
• linagliptin
• safety
• type 2 diabetes mellitus

• dipeptidyl peptidase-4 inhibitor
• linagliptin
• type 2 diabetes

• Animals
• Diabetes Mellitus, Type 2/drug therapy
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Glycated Hemoglobin/analysis
• Humans
• Hypoglycemic Agents/therapeutic use
• Linagliptin
• Purines/adverse effects
• Purines/pharmacokinetics
• Purines/pharmacology
• Purines/therapeutic use
• Quinazolines/adverse effects
• Quinazolines/pharmacokinetics
• Quinazolines/pharmacology
• Quinazolines/therapeutic use
• Wound Healing/drug effects

• adverse effects
• dipeptidyl-peptidase inhibitors
• drug interactions
• elimination
• excretion
• gliptins
• metabolism
• pharmacokinetics
• safety
• tolerability

• dipeptidyl peptidase-4 inhibitor
• linagliptin
• oral antidiabetic agents
• pharmacodynamic
• pharmacokinetic
• type 2 diabetes mellitus

• Black or African American
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/ethnology
• Diabetes Mellitus, Type 2/urine
• Dipeptidyl Peptidase 4/metabolism
• Dipeptidyl-Peptidase IV Inhibitors/adverse effects
• Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics
• Dipeptidyl-Peptidase IV Inhibitors/pharmacology
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Dose-Response Relationship, Drug
• Female
• Humans
• Hypoglycemic Agents/adverse effects
• Hypoglycemic Agents/pharmacokinetics
• Hypoglycemic Agents/pharmacology
• Hypoglycemic Agents/therapeutic use
• Linagliptin
• Male
• Purines/pharmacokinetics
• Purines/pharmacology
• Purines/therapeutic use
• Quinazolines/pharmacokinetics
• Quinazolines/pharmacology
• Quinazolines/therapeutic use

• DPP-4 inhibitor
• clinical trial
• diabetes mellitus
• glycaemic control
• phase III study
• type 2 diabetes

• Asian People/statistics & numerical data
• Biguanides/administration & dosage
• Blood Glucose/metabolism
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/epidemiology
• Drug Therapy, Combination
• Female
• Glycated Hemoglobin/metabolism
• Humans
• Hypoglycemic Agents/administration & dosage
• Japan/epidemiology
• Linagliptin
• Male
• Metformin/administration & dosage
• Middle Aged
• Purines/administration & dosage
• Quinazolines/administration & dosage
• Sulfonylurea Compounds/administration & dosage
• Thiazolidinediones/administration & dosage
• Time Factors
• Treatment Outcome

• Administration, Oral
• Adult
• Analysis of Variance
• Area Under Curve
• Benzhydryl Compounds/administration & dosage
• Benzhydryl Compounds/adverse effects
• Benzhydryl Compounds/blood
• Benzhydryl Compounds/pharmacokinetics
• Cross-Over Studies
• Dipeptidyl Peptidase 4/blood
• Dipeptidyl-Peptidase IV Inhibitors/administration & dosage
• Dipeptidyl-Peptidase IV Inhibitors/adverse effects
• Dipeptidyl-Peptidase IV Inhibitors/blood
• Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics
• Drug Administration Schedule
• Drug Interactions
• Drug Therapy, Combination
• Germany
• Glucose/metabolism
• Glucosides/administration & dosage
• Glucosides/adverse effects
• Glucosides/blood
• Glucosides/pharmacokinetics
• Half-Life
• Humans
• Hypoglycemic Agents/administration & dosage
• Hypoglycemic Agents/adverse effects
• Hypoglycemic Agents/blood
• Hypoglycemic Agents/pharmacokinetics
• Kidney/drug effects
• Kidney/metabolism
• Linagliptin
• Male
• Metabolic Clearance Rate
• Middle Aged
• Models, Biological
• Purines/administration & dosage
• Purines/adverse effects
• Purines/blood
• Purines/pharmacokinetics
• Quinazolines/administration & dosage
• Quinazolines/adverse effects
• Quinazolines/blood
• Quinazolines/pharmacokinetics
• Sodium-Glucose Transporter 2/metabolism
• Sodium-Glucose Transporter 2 Inhibitors
• Young Adult