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      Pharmacokinetic/Pharmacodynamic Interactions Between Evogliptin and Glimepiride in Healthy Male Subjects

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          Abstract

          Purpose

          Evogliptin, a dipeptidyl peptidase-4 inhibitor, and glimepiride, a sulfonylurea, are used to treat type 2 diabetes mellitus. In this study, we aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between evogliptin and glimepiride.

          Materials and Methods

          A randomized, open-label, 3-period, 3-treatment, 2-sequence crossover study was conducted in healthy male subjects. During each period, subjects received multiple doses of evogliptin 5 mg alone (EVO), glimepiride 4 mg alone (GLI), or a combination of the two (EVO+GLI). Serial blood and urine samples were collected 168 and 24 h post dosing, respectively, for PK and PD analyses.

          Results

          Thirty-four subjects completed the study. The co-administration of evogliptin and glimepiride did not alter their plasma and urine PK profiles. For evogliptin, the geometric mean ratio (GMR) (90% confidence intervals) for the maximum plasma concentrations at steady-state (C max,ss) and the area under the curve during dosing interval at steady-state (AUC τ,ss) of EVO+GLI to E were 1.02 (0.98–1.06) and 0.97 (0.95–1.00), respectively. For glimepiride, the corresponding values of EVO+GLI to GLI were 1.08 (1.01–1.17) and 1.08 (1.02–1.14), respectively. All values were within the regulatory bioequivalence criteria of 0.8–1.25. Glucose excursion decreased with the co-administration of evogliptin and glimepiride compared with that observed with the evogliptin or glimepiride monotherapy.

          Conclusion

          Evogliptin and glimepiride had no PK interactions when co-administered, while the combination therapy showed an additive glucose-lowering effect compared to those of evogliptin or glimepiride monotherapy.

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          Most cited references 28

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          WITHDRAWN: Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition

          To provide global estimates of diabetes prevalence for 2019 and projections for 2030 and 2045.
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            Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

            In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.
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              Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.

              The available evidence suggests that about two-thirds of the insulin response to an oral glucose load is due to the potentiating effect of gut-derived incretin hormones. The strongest candidates for the incretin effect are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). In patients with type 2 diabetes, however, the incretin effect is lost or greatly impaired. It is hypothesized that this loss explains an important part of the impaired insulin secretion in patients. Further analysis of the incretin effects in patients has revealed that the secretion of GIP is near normal, whereas the secretion of GLP-1 is decreased. On the other hand, the insulintropic effect of GLP-1 is preserved, whereas the effect of GIP is greatly reduced, mainly because of a complete loss of the normal GIP-induced potentiation of second-phase insulin secretion. These two features, therefore, explain the incretin defect of type 2 diabetes. Strong support for the hypothesis that the defect plays an important role in the insulin deficiency of patients is provided by the finding that administration of excess GLP-1 to patients may completely restore the glucose-induced insulin secretion as well as the beta-cells' sensitivity to glucose. Because of this, analogs of GLP-1 or GLP-1 receptor activations are currently being developed for diabetes treatment, so far with very promising results.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                24 November 2020
                2020
                : 14
                : 5179-5187
                Affiliations
                [1 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , Seoul, Republic of Korea
                Author notes
                Correspondence: SeungHwan LeeDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital , 101 Daehak-ro, Jongno-gu, Seoul03080, Republic of KoreaTel +82-2-2072-2343Fax +82-2-742-9252 Email leejh413@snu.ac.kr
                Article
                275343
                10.2147/DDDT.S275343
                7699451
                © 2020 Yoo et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, Tables: 11, References: 28, Pages: 9
                Categories
                Original Research

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