Journal ArticleDOI
Pharmacokinetics of dipeptidylpeptidase-4 inhibitors.
Reads0
Chats0
TLDR
Besides their pharmacodynamic properties leading to effective glucose‐lowering effect without inducing hypoglycaemia or weight gain, DPP‐4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice.Abstract:
Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase-4 (DPP-4) inhibitors are new oral glucose-lowering agents, so-called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed-dose combined formulations with metformin. Other DPP-4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP-4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle-aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half-life and sustained DPP-4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice-daily administration is recommended because of a shorter half-life. DPP-4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP-4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP-4 inhibitors suggest that these compounds are not exposed to a high risk of drug-drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose-lowering effect without inducing hypoglycaemia or weight gain, DPP-4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice.read more
Citations
More filters
Journal ArticleDOI
Incretin therapies: highlighting common features and differences in the modes of action of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors
TL;DR: This review endeavours to outline the commonalities and differences among incretin‐based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.
Journal ArticleDOI
Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen
Keizo Kanasaki,Sen Shi,Megumi Kanasaki,Jianhua He,Takako Nagai,Yuka Nakamura,Yasuhito Ishigaki,Munehiro Kitada,Swayam Prakash Srivastava,Daisuke Koya +9 more
TL;DR: It is found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s.
Journal ArticleDOI
A review of the efficacy and safety of oral antidiabetic drugs
TL;DR: Of the recently introduced oral hypoglycemic/antihyperglycemic agents, the DPP-4 inhibitors are moderately efficacious compared with mainstay treatment with metformin with a low side-effect profile and have good efficacy in combination with other oral agents and insulin.
Journal ArticleDOI
Efficacy and safety of linagliptin in persons with Type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24‐week randomized study1
TL;DR: In this paper, the authors examined the efficacy and safety of linagliptin in persons with Type 2 diabetes mellitus inadequately controlled [HbA1c 53-86 mmol/mol (7.0-10.0%) by metformin and sulphonylurea combination treatment.
Journal ArticleDOI
Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences.
Roberta Baetta,Alberto Corsini +1 more
TL;DR: A comprehensive and updated comparison of the pharmacodynamic and pharmacokinetic properties of DPP-4 inhibitors is provided, and pharmacological differences of potential interest for their use in therapy are pinpointed.
References
More filters
Journal ArticleDOI
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes
TL;DR: Clinical trials with the incretin mimetic exenatide and liraglutide show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) associated with weight loss, but long-term clinical studies are needed to determine the benefits of targeting the inc retin axis for the treatment of type 2 diabetes.
Journal ArticleDOI
Type 2 diabetes - principles of pathogenesis and therapy
TL;DR: Type 2 diabetes mellitus has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6.2, peroxisome proliferator-activated receptor gamma, insulin receptor substrate-1, and others.
Journal ArticleDOI
The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes.
TL;DR: Greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 1 diabetes.
Journal ArticleDOI
Oral antidiabetic agents: current role in type 2 diabetes mellitus.
TL;DR: Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS, and the insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome.
Journal ArticleDOI
Effect of Single Oral Doses of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Incretin and Plasma Glucose Levels after an Oral Glucose Tolerance Test in Patients with Type 2 Diabetes
Gary A. Herman,Arthur J. Bergman,Catherine Stevens,Paul Kotey,Bingming Yi,Peng Zhao,Bruno Dietrich,George Golor,Andreas Schrodter,Bart Keymeulen,Kenneth C. Lasseter,Mark Kipnes,Karen Snyder,Deborah Hilliard,Michael Tanen,Caroline Cilissen,Marina De Smet,Inge De Lepeleire,Kristien Van Dyck,Amy Qiu Wang,Wei Zeng,Michael J. Davies,Wesley Tanaka,Jens J. Holst,Carolyn F. Deacon,Keith Gottesdiener,John A. Wagner +26 more
TL;DR: In patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitgliptin concentration of 100 nm or greater and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.
Related Papers (5)
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes
Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus
Benjamin M. Scirica,Deepak L. Bhatt,Deepak L. Bhatt,Eugene Braunwald,P. Gabriel Steg,Jaime A. Davidson,Boaz Hirshberg,Peter Öhman,Robert Frederich,Stephen D. Wiviott,Elaine B. Hoffman,Matthew A. Cavender,Jacob A. Udell,Nihar R. Desai,Ofri Mosenzon,Darren K. McGuire,Kausik K. Ray,Lawrence A. Leiter,Itamar Raz +18 more