Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study

Seino, Yutaka; Sasaki, Takashi; Fukatsu, Atsushi; Ubukata, Michito; Sakai, Soichi; Samukawa, Yoshishige

doi:10.1185/03007995.2014.909390

Cited by 52 publications

(56 citation statements)

References 29 publications

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“…*P< 0.001 (compared to baseline using the one-sample t-test). CI, confidence interval; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; SD, standard deviation ies [6,7,11]. It was also comparable to that observed in a 52-week study of sitagliptin (1.7%), a DPP-4 inhibitor known for its low incidence of hypoglycemia when administered as monotherapy [12].…”

Section: (Compared With Baseline By One-sample T-test)supporting

confidence: 73%

“…In addition, no patients experienced ketoacidosis. Further, previous studies of luseogliflozin showed a post-meal rapid decrease in fasting ketone bodies [6,7]. Given that luseogliflozin will be administered to patients comprising various metabolic types in clinical practice, further investigation is needed.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous dose-finding 12-week study [6], monotherapy with luseogliflozin, a selective SGLT2 inhibitor, provided clinically meaningful glycemic control at doses of 2.5 mg or more (for some parameters such as body weight, maximum effect was seen at a dose of 5 mg) and had good tolerability up to a dose of 10 mg. In addition, efficacy and safety of the drug given as monotherapy for up to 24 weeks compared to placebo was confirmed [7].…”

Section: Patientsmentioning

confidence: 94%

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Fifty-two-week long-term clinical study of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise

et al. 2015

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Section: (Compared With Baseline By One-sample T-test)supporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 94%

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Fifty-two-week long-term clinical study of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise

et al. 2015

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“…These studies are registered at the Japan Pharmaceutical Information Center (identifier: JapicCTI‐090908, JapicCTI‐101191 and JapicCTI‐111661)2, 3, 4. The major inclusion criteria were as follows: Japanese patients with type 2 diabetes mellitus receiving diet and exercise therapy alone, age ≥20 years and with glycated hemoglobin levels ≥6.9% to ≤10.5%.…”

mentioning

confidence: 99%

Changes in heart rate in patients with type 2 diabetes mellitus after treatment with luseogliflozin: Subanalysis of placebo‐controlled, double‐blind clinical trials

Sano

Chen

Imazeki

et al. 2018

J of Diabetes Invest

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“…Studies in Japanese patients with T2DM have confirmed that treatment with luseogliflozin increases urinary glucose excretion (UGE) and reduces plasma glucose levels. [7][8][9][10][11][12] In a clinical pharmacology study conducted in Japanese patients with T2DM, reported by Sasaki et al, intensive sampling of UGE (nine sampling intervals a day) was performed and UGE change from pre-dose was analyzed; a significant increase in UGE was observed with once-daily luseogliflozin administration. The UGE was dose-dependent and the relationship of change in daily UGE and area under the curve (AUC) 0-24h of plasma luseogliflozin could be expressed by means of the E max model.…”

Section: -4)mentioning

confidence: 99%

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

Samukawa

Mutoh

Chen

et al. 2017

Biological & Pharmaceutical Bulletin

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Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by promoting urinary glucose excretion (UGE). A clinical pharmacology study conducted in Japanese patients with T2DM confirmed dose-dependency of UGE with once-daily administration of luseogliflozin; however, the reason for sustained UGE after plasma luseogliflozin decreased was unclear. To elucidate the effect of inhibition rate constants, K on and K off , and to explain the sustained UGE, a pharmacokinetic-pharmacodynamic (PK-PD) model was built based on the mechanisms of glucose filtration in the glomerulus and reabsorption in the renal proximal tubule of kidney as well as the kinetics of competitive inhibition of SGLT1/2 and inhibition rate constants of SGLT2, by using UGE and plasma glucose levels and luseogliflozin concentrations. This acquired population PK-PD model adequately described the sustained UGE and the estimated population means of the inhibition constant for SGLT2 (K i2 ) and inhibition-rate constants for SGLT2 (K on and K off ) were 0.31-and 3.6-fold lower or higher than the in vitro values. Because the dissociation half-time of luseogliflozin from SGLT2 calculated from K off , 6.81 h, was consistent with the value in vitro, we considered that the sustained UGE could be explained by the long dissociation half-time. Moreover, by calculating the SGLT2 inhibition ratio using the model, we discuss other properties of the UGE time course after luseogliflozin administration.Key words luseogliflozin; urinary glucose excretion; pharmacokinetic-pharmacodynamic model; sodium glucose co-transporter 2; type 2 diabetes mellitus In the human kidney, plasma glucose entering the glomeruli is filtered into the nephron fluid, and the filtered glucose is reabsorbed almost completely by two isoforms of sodium glucose co-transporter (SGLT), SGLT2 and SGLT1. SGLT2 is a high-capacity, low-affinity glucose transporter located in the early convoluted segment (S1 segment) of the proximal tubule that mediates 90% of renal glucose reabsorption. SGLT1 is a high-affinity, low-capacity glucose transporter located in the straight section of the proximal tubule (S3 segment) that is responsible for 10% of renal glucose reabsorption. 1) Inhibition of SGLT2 causes glucose excretion in urine and a reduction in plasma glucose. Several SGLT2 inhibitors have been developed for treatment of type 2 diabetes mellitus (T2DM). 2-4)Luseogliflozin is a novel selective SGLT2 inhibitor 5,6) currently marketed for the treatment of T2DM. The recommended dose is 2.5 mg (or 5 mg depending on the symptoms) once daily before or after breakfast. Studies in Japanese patients with T2DM have confirmed that treatment with luseogliflozin increases urinary glucose excretion (UGE) and reduces plasma glucose levels. [7][8][9][10][11][12] In a clinical pharmacology study conducted in Japanese patients with T2DM, reported by Sasaki et al., intensive sampling of UGE (nine sampling intervals a day) was performed and UGE ...

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Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study

Cited by 52 publications

References 29 publications

Fifty-two-week long-term clinical study of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise

Fifty-two-week long-term clinical study of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise

Changes in heart rate in patients with type 2 diabetes mellitus after treatment with luseogliflozin: Subanalysis of placebo‐controlled, double‐blind clinical trials

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

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