Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: A phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male japanese subjects

Sarashina, Akiko; Sesoko, Shogo; Nakashima, Mitsuyoshi; Hayashi, Naoyuki; Taniguchi, Atsuhiko; Horie, Yoshiharu; Graefe-Mody, Eva U.; Woerle, Hans-Juergen; Dugi, Klaus A.

doi:10.1016/j.clinthera.2010.06.004

Cited by 54 publications

(39 citation statements)

References 41 publications

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“…Furthermore, results from modeling and simulation support a stable antidiabetic effect of linagliptin over 24 h at steady state and further indicate a low risk for off-target side effects 70 . These PK characteristics obtained in Caucasian people were confirmed in other populations such as Japanese 71 or Chinese 72 healthy adult male volunteers, both after a single oral administration and short-term multiple dosing.…”

Section: Healthy Volunteerssupporting

confidence: 60%

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Scheen

2013

Expert Opinion on Drug Metabolism & Toxicology

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SUMMARYIntroduction : The first-choice drug therapy in the management of type 2 diabetes is metformin. However, most patients require a combined therapy to reach and/or maintain targets of glucose control. Dipeptidylpeptidase-4 (DPP-4) inhibitors, commonly referred to as gliptins, offer new options for combined therapy with metformin. Linagliptin is the most recent launched gliptin, with a unique pharmacokinetic profile characterized by negligible renal excretion, and is now also available as a fixed-dose combination (FDC) with metformin.Area covered: An extensive literature search was performed to analyze the potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between linagliptin and metformin. Linaglipin and metformin may be administered together, either separately or as FDC supported by bioequivalence studies. Linagliptin and metformin are not prone to PK drug-drug interactions. Their co-administration improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metforminrelated gastrointestinal side effects.Expert Opinion : The combination linaglitpin plus metformin, if not contraindicated (renal failure), may be used as first-line or second-line therapy in the management of type 2 diabetes.

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Section: Healthy Volunteerssupporting

confidence: 60%

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Scheen

2013

Expert Opinion on Drug Metabolism & Toxicology

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“…The peak plasma concentration of linagliptin after administration of single oral dose of 5 mg is reported to be about 10 nM [49]. So, the concentration of linagliptin having beneficial effects on HUVECs used in the present experiments (10 nM) may also be comparable to the therapeutic level which is achieved in the treatment for patients with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 69%

Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor

Ishibashi

Matsui

Maeda

et al. 2013

Cardiovasc Diabetol

148

129

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BackgroundAdvanced glycation end products (AGEs) and receptor RAGE interaction play a role in diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potential therapeutic target for type 2 diabetes. However, the role of DPP-4 in AGE-induced endothelial cell (EC) damage remains unclear.MethodsIn this study, we investigated the effects of DPP-4 on reactive oxygen species (ROS) generation and RAGE gene expression in ECs. We further examined whether an inhibitor of DPP-4, linagliptin inhibited AGE-induced soluble DPP-4 production, ROS generation, RAGE, intercellular adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) gene expression in ECs.ResultsDPP-4 dose-dependently increased ROS generation and RAGE gene expression in ECs, which were prevented by linagliptin. Mannose 6-phosphate (M6P) and antibodies (Ab) raised against M6P/insulin-like growth factor II receptor (M6P/IGF-IIR) completely blocked the ROS generation in DPP-4-exposed ECs, whereas surface plasmon resonance revealed that DPP-4 bound to M6P/IGF-IIR at the dissociation constant of 3.59 x 10-5 M. AGEs or hydrogen peroxide increased soluble DPP-4 production by ECs, which was prevented by N-acetylcysteine, RAGE-Ab or linagliptin. Linagliptin significantly inhibited the AGE-induced ROS generation, RAGE, ICAM-1 and PAI-1 gene expression in ECs.ConclusionsThe present study suggests that AGE-RAGE-induced ROS generation stimulates the release of DPP-4 from ECs, which could in turn act on ECs directly via the interaction with M6P/IGF-IIR, further potentiating the deleterious effects of AGEs. The blockade by linagliptin of positive feedback loop between AGE-RAGE axis and DPP-4 might be a novel therapeutic target for vascular injury in diabetes.

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“…52,53 Based on empirical observations, the pharmacokinetics and pharmacodynamics of linagliptin are not affected to a clinically meaningful degree by race or ethnicity; consequently, dose adjustment is not required for patients based on their race or ethnicity. 8,9 Specifically, the pharmacokinetic and pharmacodynamic profiles of linagliptin were similar in white, 22,53,54 Japanese, 55,56 Chinese, 57 and black patients, 58 as well as in those of Hispanic or non-Hispanic ethnicity. 8,9 Patients Using Polypharmacy Polypharmacy is common in patients with T2DM, especially among elderly patients and those with comorbid conditions, which may lead to drug-drug interactions.…”

Section: Dose Adjustment Requirements According To Patients' Race or mentioning

confidence: 95%

Clinical Utility of the Dipeptidyl Peptidase-4 Inhibitor Linagliptin

Grunberger

2013

Postgraduate Medicine

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Linagliptin is a xanthine-based, oral DPP-4 inhibitor that has been approved in the United States and Europe. It has been evaluated extensively in clinical trials, and results in improved glycemic control when used as monotherapy, initial combination therapy with metformin or pioglitazone, add-on therapy to metformin and/or a sulfonylurea, or add-on therapy to basal insulin (with or without oral antidiabetic drugs). Consistent with other members of its class, the benefits of linagliptin also include a low risk of hypoglycemia and weight gain. However, linagliptin is the first DPP-4 inhibitor to be approved as a once-daily, 5-mg dose and, due to its primarily non-renal route of excretion, no dosage adjustment is required for patients with renal or hepatic impairment. The pharmacokinetics and pharmacodynamics of linagliptin are not affected to a clinically meaningful degree by race or ethnicity and linagliptin has very low potential for drug-drug interactions.

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Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: A phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male japanese subjects

Cited by 54 publications

References 41 publications

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor

Clinical Utility of the Dipeptidyl Peptidase-4 Inhibitor Linagliptin

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