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      Pharmacokinetic and pharmacodynamic interactions between metformin and a novel dipeptidyl peptidase-4 inhibitor, evogliptin, in healthy subjects

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          Abstract

          Evogliptin is a newly developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which is expected to be combined with metformin for treating type 2 diabetes mellitus. We investigated the potential pharmacokinetic and pharmacodynamic interactions between evogliptin and metformin. A randomized, open-label, multiple-dose, six-sequence, three-period crossover study was conducted in 36 healthy male subjects. All subjects received three treatments, separated by 7-day washout intervals: evogliptin, 5 mg od for 7 days (EVO); metformin IR, 1,000 mg bid for 7 days (MET); and the combination of EVO and MET (EVO + MET). After the last dose in a period, serial blood samples were collected for 24 hours for pharmacokinetic assessments. During steady state, serial blood samples were collected for 2 hours after an oral glucose tolerance test, and DPP-4, active glucagon-like peptide-1, glucose, glucagon, insulin, and C-peptide were measured to assess pharmacodynamic properties. EVO + MET and EVO showed similar steady state maximum concentration and area under the concentration–time curve at steady state values for evogliptin; the geometric mean ratios (90% confidence interval) were 1.06 (1.01–1.12) and 1.02 (0.99–1.06), respectively. EVO + MET slightly reduced steady state maximum concentration and area under the concentration–time curve at steady state values for metformin compared to MET, with geometric mean ratios (90% confidence interval) of 0.84 (0.79–0.89) and 0.94 (0.89–0.98), respectively. EVO + MET and EVO had similar DPP-4 inhibition efficacy, but EVO + MET increased active glucagon-like peptide-1 and reduced glucose to larger extents than either EVO or MET alone. Our results suggested that EVO+MET could provide therapeutic benefits without clinically significant pharmacokinetic interactions. Thus, the EVO + MET combination is a promising option for treating type 2 diabetes mellitus.

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          Most cited references 19

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          Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes.

          The secretion of glucagon by pancreatic alpha-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby increasing blood glucose concentrations. During the last decade, knowledge of alpha-cell physiology has greatly improved, especially concerning molecular and cellular mechanisms. In this review, we have addressed recent findings on alpha-cell physiology and the regulation of ion channels, electrical activity, calcium signals and glucagon release. Our focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs. Additionally, we have described the glucagon actions on glycaemia and energy metabolism, and discussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetes therapy related to alpha-cell function are also discussed in this review. A better understanding of the alpha-cell physiology is necessary for an integral comprehension of the regulation of glucose homeostasis and the development of diabetes.
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            Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1.

            The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon-like peptide 1 (GLP-1) (9-36) and glucagon. In healthy subjects, a DPP-4 inhibitor elevated both active GLP-1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP-1 (but not GIP), and the combination resulted in additive increases in active GLP-1 plasma concentrations. Metformin did not inhibit plasma DPP-4 activity either in vitro or in vivo. The study results show that metformin is not a DPP-4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP-1 concentrations. DPP-4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP-1 in plasma.
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              Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with Type 2 diabetes in UK primary care.

              To describe initial achievement of glycaemic targets and subsequent hyperglycaemia in patients with Type 2 diabetes managed with oral agent monotherapy in UK primary care from 1998 to 2004. Electronic medical records of patients initiating metformin (n = 3362) or a sulphonylurea agent (n = 3070) in 290 UK primary care practices were retrieved from the General Practice Research Database (GPRD). Patients included had an HbA(1c) recorded 0-90 days before and 90-365 days after initiating monotherapy. The probability of achieving glycaemic thresholds in the first year, and for those achieving such targets, the probability of inadequate glycaemic control (HbA(1c) > 6.5%, > 7.0%, > 7.5%) over time is described. Low baseline HbA(1c) and drug initiation within 3 months of diabetes diagnosis were the strongest predictors of initial achievement of glycaemic targets. The proportion of patients with diabetes duration > or = 4 months who achieved HbA(1c) < 7% in the first year ranged from 24% to 88% for highest to lowest baseline HbA(1c) category in sulphonylurea initiators and from 19% to 86% in metformin initiators, with slightly higher proportions for newly diagnosed patients. Kaplan-Meier analyses suggested that 55% and 70% of patients who initially achieved glycaemic targets had HbA(1c) measurements above these targets at 2 and 3 years. Many patients fail to achieve glycaemic goals with initial monotherapy and, of those who achieve current goals, few consistently maintain these targets over 3 years. Research is needed to evaluate whether more aggressive treatment or alternative treatments can improve the long-term maintenance of glycaemic control in patients with Type 2 diabetes.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                10 August 2016
                : 10
                : 2525-2534
                Affiliations
                [1 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
                [2 ]Clinical Trials Center, Seoul National University Hospital, Seoul, Republic of Korea
                [3 ]Department of Clinical Development, Dong-A ST Co., Ltd., Seoul, Republic of Korea
                Author notes
                Correspondence: Kyung-Sang Yu, Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea, Tel +82 2 2072 1920, Fax +82 2 742 9252, Email ksyu@ 123456snu.ac.kr
                [*]

                These authors contributed equally to this work

                Article
                dddt-10-2525
                10.2147/DDDT.S110712
                4986685
                © 2016 Rhee 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.

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