Journal Club 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. 2014 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. 2014 May;37(5):1480-3. doi: 10.2337/dc13-2338. 2014年6月5日 8:30-8:55 8階 医局 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 選択的SGLT2阻害剤 フロリジン 国内で承認済又は開発中の主なSGLT2阻害剤(2014年6月現在) トホグリフロジン HO HO Et O O OH カナグリフロジン Me HO OH HO O OH S OH F エンパグリフロジン Me HO HO O OH OH O O ダパグリフロジン CI HO HO OEt イプラグリフロジン O OH OH ルセオグリフロジン MeO F O HO S OH HO OH HO Me OEt S OH HO OH Liu JJ et al.:Diabetes 61(9):2199,2012より改変 New Current 24(15):2,2013より改変 FBG (mg/dL) 130 125 120 115 110 105 100 Luseogliflozin 5mg ipragliflozin 50mg ipragliflozin 100mg dapagliflozin 10mg tofogliflozin 20mg Mean PG & MAGE 250 308.3 205.5 411.0 308.3 205.5 円/日 200 150 100 50 0 Luseogliflozin 5mg ipragliflozin 50mg ipragliflozin 100mg dapagliflozin 10mg tofogliflozin 20mg mg/gCr SGLT-2阻害薬服薬停止後の尿糖 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 Luseogliflozin 5mg ipragliflozin 50mg last dose off 1st ipragliflozin 100mg dapagliflozin 10mg off 2nd off 3rd 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 SGLT-2阻害薬服用時のインスリン・グルカゴン値 140 40 35 130 30 FBG(mg/dL) 90 インスリン(μU/mL) 膵グルカゴン(pg/mL) 80 25 120 20 70 15 110 10 60 5 100 50 0 58歳 男性 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。 Yutaka Seino a, Takashi Sasaki b, Atsushi Fukatsu c, Michito Ubukata d, Soichi Sakai d, so-sakai@so.taisho.co.jp Yoshishige Samukawa d aKansai Electric Power Hospital, Osaka, Japan bDivision of Translational and Molecular Medicine, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan cYachiyo Hospital, Aichi, Japan dTaisho Pharmaceutical Co. Ltd, Tokyo, Japan doi:10.1185/03007995.2014.912983 Objective: Luseogliflozin – a novel, orally bioavailable, 1thio-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-111661. 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<0.001)。 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< 0.001)。 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 Featured Article: Sodium-Glucose Cotransporter 2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-of-Concept Trial Bruce A. Perkins, David Z.I. Cherney, Helen Partridge, Nima Soleymanlou, Holly Tschirhart, Bernard Zinman, Nora M. Fagan, Stefan Kaspers, HansJuergen Woerle, Uli C. Broedl, and Odd-Erik Johansen Diabetes Care Volume 37: 1480-1483 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;37:1480-1483 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;37:1480-1483 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;37:1480-1483 Perkins B. A. et al. Diabetes Care 2014;37:1480-1483 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;37:1480-1483 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? 1Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada 2Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada 3Boehringer Ingelheim Canada Ltd./Ltée, Burlington, Canada 4Samuel Lunenfeld Research Institute, Mount Sinai Hospital, New York, NY 5Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 6Boehringer 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 (NCT01392560). RESULTS Mean A1C decreased from 8.0 ± 0.9% (64 ± 10 mmol/mol) to 7.6 ± 0.9% (60 ± 10 mmol/mol) (P < 0.0001), 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 = 0.0004), and daily insulin dose from 54.7 ± 20.4 to 45.8 ± 18.8 units/day (P < 0.0001). Mean urinary excretion of glucose increased from 19 ± 19 to 134 ± 61 g/day (P < 0.0001). Weight decreased from 72.6 ± 12.7 to 70.0 ± 12.3 kg (P < 0.0001), and waist circumference decreased from 82.9 ± 8.7 to 79.1 ± 8.0 cm (P < 0.0001). CONCLUSIONS This proof-of-concept study strongly supports a randomized clinical trial of adjunctive-to-insulin empagliflozin in patients with T1D.