Evaluation of Drug Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors Based on Target Molecular Binding Occupancy

Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by foc...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2018/02/01, Vol.41(2), pp.153-157
Main Authors: Takayanagi, Risa, Uchida, Takumi, Kimura, Koji, Yamada, Yasuhiko
Format: Article
Language:eng ; jpn
Subjects:
Agonists
Diabetes mellitus
dipeptidyl peptidase-4 inhibitor
Dipeptidyl-peptidase IV
Drug dosages
Glucagon
Glucagon-like peptide 1
glucagon-like peptide-1 receptor agonist
Hemoglobin
Inhibitors
Nitric oxide
Peptidase
pharmacodynamics
pharmacokinetics
target molecular binding occupancy
Theoretical analysis
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Summary:Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1–10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83–1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A1c (HbA1c) reduction after administration of the GLP-1 receptor agonists was higher than that of DPP-4 inhibitors. We clarified the differences between the therapeutic effects associated with GLP-1 receptor agonists and DPP-4 inhibitors theoretically. Together, the present findings provide a useful methodology for proper usage of GLP-1 receptor agonists and DPP-4 inhibitors.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.b17-00237