Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2014 年 6 月 5 日 8:30-8:55 ８階 医局 Seino Y, Sasaki T, Fukatsu A, Ubukata M, Sakai S, Samukawa Y. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study. Curr Med Res Opin Apr 29. Perkins BA1, Cherney DZ, Partridge H, Soleymanlou N, Tschirhart H, Zinman B, Fagan NM, Kaspers S, Woerle HJ, Broedl UC, Johansen OE. Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial. Diabetes Care May;37(5): doi: /dc

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食事の糖質を減量するのと SGLT-2 阻害薬使用は根本的に異なる 食後血糖低下は食事の糖質減量で可能であるが、 夜間～早朝空腹時の膵 β 細胞保護効果は SGLT-2 阻害薬にしかない。 58 歳 男性

Yutaka Seino a, Takashi Sasaki b, Atsushi Fukatsu c, Michito Ubukata d, Soichi Sakai d, Yoshishige Samukawa d a Kansai Electric Power Hospital, Osaka, Japan b Division of Translational and Molecular Medicine, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan c Yachiyo Hospital, Aichi, Japan d Taisho Pharmaceutical Co. Ltd, Tokyo, Japan doi: /

Objective: Luseogliflozin – a novel, orally bioavailable, 1- thio-d-glucitol derivative and a selective sodium glucose cotransporter 2 inhibitor – has shown efficacy and tolerability in previous phase 2 studies. This phase 3, randomized, double-blind, placebo-controlled, comparative study aimed to confirm the superiority of 24 week luseogliflozin 2.5 mg monotherapy over placebo in reducing hemoglobin A1c (HbA1c) levels in Japanese patients with type 2 diabetes mellitus (T2DM).

Methods: Patients with HbA1c levels of 6.9%–10.5% were randomized to receive luseogliflozin 2.5 mg or placebo once daily for 24 weeks (n = 79 in each group). The primary endpoint was change from baseline in HbA1c at end of treatment. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) following a meal tolerance test, body weight, and abdominal circumference. Safety assessments included adverse events (AEs), clinical laboratory tests, and vital signs.

Data are shown as mean (SD) unless otherwise indicated. Data are reported for the full analysis set for all variables, except SBP and DBP. Data from the safety analysis set have been reported for SBP and DBP. BMI, body mass index; HbA1c, hemoglobin A1c; FPG, fasting plasma glucose; PPG, postprandial plasma glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure; SD, standard deviation. aChi-square test. bTwo-sample t-test. A significance level of p<0.15 (two-sided) was taken to indicate heterogeneity between the study groups. cSubjects who received treatment for diabetes within 6 to 18 weeks before Week -6 (start of the observation period).

Results: At the end of treatment, HbA1c was significantly decreased from baseline in the luseogliflozin 2.5 mg group (−0.63%) versus the placebo group (0.13%), with a between-group difference of −0.75% (p < 0.001). Additionally, significant reductions in FPG, PPG, body weight, and abdominal circumference were noted with luseogliflozin compared with placebo (all p < 0.05). Luseogliflozin was well tolerated; there was no significant difference between groups in the incidence of AEs (luseogliflozin, 59.5%; placebo, 57.0%). No AEs led to study drug discontinuation. Most AEs were mild in severity, with no severe AE reported. Limitations of this study include its short study duration and small sample size.

Conclusion: Luseogliflozin monotherapy for 24 weeks was superior to placebo in reducing HbA1c levels. It also reduced FPG, PPG, body weight, and abdominal circumference and was well tolerated in Japanese patients with T2DM. Clinical trial registration:JapicCTI

Message グリメピリドで血糖コントロールが不十分（ HbA1c ： 6.9 ～ 10.5 ％）な 2 型糖尿病患者を、ルセオグリフロジン（ 2.5mg/ 日）併用群（ 150 例）またはプラセボ併用（＝グリメピリド単独 投与）群（ 71 例）に二重盲検法により割り付け、 24 週追跡し た。 空腹時血糖値のベースラインからの変化量も、 24 週後の評価で はプラセボ併用群が＋ 18.9mg/dL 、ルセオグリフロジン併用群 が－ 16.6mg/dL 、群間差は－ 34.2mg/dL となり、ルセオグリ フロジン併用により有意な低下を認めた（ P ＜ ）。 体重の変化量は、 24 週後ではプラセボ併用群が＋ 0.16kg 、ル セオグリフロジン併用群が－ 1.35kg 、群間差が－ 1.51kg とな り、ルセオグリフロジン併用によって有意な低下を認めた（ P ＜ ）。 ルセオグリフロジンと既存の経口血糖降下薬の併用により血糖 コントロールは改善し、安全性のプロファイルも良好だった。既 存の経口薬で血糖コントロール不良の日本人 2 型糖尿病患者に対 し、ルセオグリフロジンの併用は新しい治療の選択肢となる

Sodium-Glucose Cotransporter 2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-of-Concept Trial Featured Article: Bruce A. Perkins, David Z.I. Cherney, Helen Partridge, Nima Soleymanlou, Holly Tschirhart, Bernard Zinman, Nora M. Fagan, Stefan Kaspers, Hans- Juergen Woerle, Uli C. Broedl, and Odd-Erik Johansen Diabetes Care Volume 37: May, 2014

STUDY OBJECTIVE Adjunctive-to-insulin therapy with sodium-glucose cotransporter 2 (SGLT2) inhibition may improve glycemic control in type 1 diabetes (T1D) Perkins B. A. et al. Diabetes Care 2014;37:

STUDY DESIGN AND METHODS We evaluated glycemic efficacy and safety of 25 mg empagliflozin daily in 40 patients treated for 8 weeks in a single-arm open-label proof-of-concept trial Perkins B. A. et al. Diabetes Care 2014;37:

RESULTS Mean A1C decreased from 8.0 ± 0.9 to 7.6 ± 0.9%, fasting glucose from 9.0 ± 4.3 to 7.0 ± 3.2 mmol/L, symptomatic hypoglycemia from 0.12 to 0.04 events per patient per day, and daily insulin dose from 54.7 ± 20.4 to 45.8 ± 18.8 units/day Mean urinary excretion of glucose increased from 19 ± 19 to 134 ± 61 g/day Weight decreased from 72.6 ± 12.7 to 70.0 ± 12.3 kg Waist circumference decreased from 82.9 ± 8.7 to 79.1 ± 8.0 cm Perkins B. A. et al. Diabetes Care 2014;37:

CONCLUSIONS Proof-of-concept study strongly supports a randomized clinical trial of adjunctive-to-insulin empagliflozin in T1D patients Perkins B. A. et al. Diabetes Care 2014;37:

Message SGLT-2 阻害薬を１型糖尿病にも使っ たという報告だが、 HbA1c の変化はそ れほどでもない。有用性は？

1 Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada 2 Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada 3 Boehringer Ingelheim Canada Ltd./Ltée, Burlington, Canada 4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, New York, NY 5 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 6 Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

OBJECTIVE Adjunctive-to-insulin therapy with sodium-glucose cotransporter 2 (SGLT2) inhibition may improve glycemic control in type 1 diabetes (T1D).

RESEARCH DESIGN AND METHODS We evaluated the glycemic efficacy and safety of empagliflozin 25 mg daily in 40 patients treated for 8 weeks in a single-arm open-label proof-of-concept trial (NCT ).

RESULTS Mean A1C decreased from 8.0 ± 0.9% (64 ± 10 mmol/mol) to 7.6 ± 0.9% (60 ± 10 mmol/mol) (P < ), fasting glucose from 9.0 ± 4.3 to 7.0 ± 3.2 mmol/L (P = 0.008), symptomatic hypoglycemia (<3.0 mmol/L) from 0.12 to 0.04 events per patient per day (P = ), and daily insulin dose from 54.7 ± 20.4 to 45.8 ± 18.8 units/day (P < ). Mean urinary excretion of glucose increased from 19 ± 19 to 134 ± 61 g/day (P < ). Weight decreased from 72.6 ± 12.7 to 70.0 ± 12.3 kg (P < ), and waist circumference decreased from 82.9 ± 8.7 to 79.1 ± 8.0 cm (P < ).

CONCLUSIONS This proof-of-concept study strongly supports a randomized clinical trial of adjunctive-to-insulin empagliflozin in patients with T1D.