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.