Transcript 20150604Luseogliflozin&StatinToBrain

Journal Club
Alpérovitch A, Kurth T, Bertrand M, Ancelin ML, Helmer C, Debette S, Tzourio C.
Primary prevention with lipid lowering drugs and long term risk of vascular events
in older people: population based cohort study.
BMJ. 2015 May 19;350:h2335. doi: 10.1136/bmj.h2335.
Uchida S, Mitani A, Gunji E, Takahashi T, Yamamoto K.
In vitro characterization of luseogliflozin, a potent and competitive sodium glucose
co-transporter 2 inhibitor: Inhibition kinetics and binding studies.
J Pharmacol Sci. 2015 Apr 9. pii: S1347-8613(15)00074-2. doi:
10.1016/j.jphs.2015.04.001.
2015年6月4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
From: Cost-Effectiveness and Population Impact of Statins for Primary Prevention in Adults Aged 75 Years or
Older in the United StatesStatins for Primary Prevention in U.S. Adults Aged 75 Years or Older
Ann Intern Med. 2015;162(8):533-541. doi:10.7326/M14-1430
米国の高齢者に対する一次予防目的でのス
タチン療法の費用対効果をマルコフモデルで
検証。75-94歳の全成人でのスタチン療法実
施により、障害調整生命年当たりの増分費用
は2万5200ドルで、約11万人の心筋梗塞発
症、約7万人の冠動脈心疾患死亡が回避され
るが、機能的制限/軽度認知障害のわずかな
相対リスク増加で効果は相殺されると推定さ
れた。
Figure Legend:
Sensitivity analysis of magnitude of statin-associated DALY reduction needed to offset cardiovascular benefit.
The value of the statin-associated DALY reduction at which the lines cross the x-axis is the magnitude needed to offset the
cardiovascular benefit and result in no net DALYs gained. DALY = disability-adjusted life-year; LDL-C = low-density lipoprotein
cholesterol.
Date of download: 5/6/2015
Copyright © American College of Physicians. All rights
reserved.
From: Evaluation and Treatment of Older Patients With Hypercholesterolemia: A Clinical Review
JAMA. 2014;312(11):1136-1144. doi:10.1001/jama.2014.10924
Figure Legend:
No randomized clinical trials (RCTs) of
statin or any other hypocholesterolemic
medication included persons older than
80 years at baseline.
Suggested Treatment Algorithm for Statin Treatment in Patients Older Than 80 Years With Hypercholesterolemia and Without a
Condition Seriously Limiting Life ExpectancyThis approach is used by the authors and is based on the best available evidence but
does not represent treatments validated in clinical trials, because the clinical features of the patients considered in this article have
not been studied in randomized clinical trials. ASCVD indicates atherosclerotic cardiovascular disease; LDL-C, low-density
lipoprotein cholesterol.
Copyright © 2015 American Medical Association.
Date of download: 6/3/2015
All rights reserved.
From: Evaluation and Treatment of Older Patients With Hypercholesterolemia: A Clinical Review
JAMA. 2014;312(11):1136-1144. doi:10.1001/jama.2014.10924
Table Title:
Observational Studies and Randomized Clinical Trials of Statins in Older People With or Without ASCVD
Date of download: 6/3/2015
Copyright © 2015 American Medical Association.
All rights reserved.
From: Evaluation and Treatment of Older Patients With Hypercholesterolemia: A Clinical Review
JAMA. 2014;312(11):1136-1144. doi:10.1001/jama.2014.10924
Ideally, treatment of hypercholesterolemia for patients at risk of ASCVD should
start before they turn 80 years old. No RCT evidence exists to guide statin
initiation after age 80 years. Decisions to use statins in older individuals are made
individually and are not supported by high-quality evidence.
Table Title:
Observational Studies of Statin Therapy and Functioning in Older People
Date of download: 6/3/2015
Copyright © 2015 American Medical Association.
All rights reserved.
From: Statins and Physical Activity in Older Men: The Osteoporotic Fractures in Men Study
JAMA Intern Med. 2014;174(8):1263-1270. doi:10.1001/jamainternmed.2014.2266
Figure Legend:
Mean Physical Activity Scale in the Elderly (PASE) Scores According to Statin User GroupsPASE scores were estimated by mixedeffects linear regression adjusted for age, site, and baseline total cholesterol (fixed-in-time), myocardial infarction, stroke,
hypertension, diabetes, perceived health and body mass index (time-varying). The error bars represent 95% confidence intervals for
the estimated mean PASE at each visit (n = 3039).
Date of download: 6/3/2015
Copyright © 2015 American Medical Association.
All rights reserved.
•1INSERM, U897-Epidemiology and Biostatistics, Bordeaux, France
•2Université de Bordeaux, Bordeaux, France
•3INSERM, U1061, Montpellier, France
•4Université de Montpellier I, Montpellier, France
BMJ. 2015 May 19;350:h2335. doi: 10.1136/bmj.h2335.
Objective To determine the association
between use of lipid lowering drugs (statin
or fibrate) in older people with no known
history of vascular events and long term risk
of coronary heart disease and stroke
Design Ongoing prospective population based cohort study
recruited in 1999-2000, with five face-to-face examinations.
Setting Random sample of community dwelling population
aged 65 years and over, living in three French cities (Bordeaux,
Dijon, Montpellier).
Participants 7484 men and women (63%) with mean age 73.9
years and no known history of vascular events at entry. Mean
follow-up was 9.1 years.
Main outcome measures Adjusted hazard ratios of coronary
heart disease and stroke in baseline lipid lowering drug users
compared with non-users, calculated using multivariable Cox
proportional hazard models adjusted for numerous potential
confounding factors. Hazard ratios were estimated for use of
any lipid lowering drug and for statin and fibrate separately.
mg/dL
NO
T-Chol
231(39)
207
239
HDL-C
63(15)
54
68
LDL-C
146(35)
125
152
TG
101
83
178
YES
216(35)
63(15)
131(31)
97
注意：スタチンを使っていること自体がCHDを起こすリスクのある対象とも考えられるが
mg/dL
T-Chol
201
251
LDL-C
152
174
HDL-C
35
42
TG
124
177
Results Lipid lowering drug users were at
decreased risk of stroke compared with nonusers (hazard ratio 0.66, 95% confidence interval
0.49 to 0.90); hazard ratios for stroke were similar
for statin (0.68, 0.45 to1.01) and fibrate (0.66,
0.44 to 0.98). No association was found between
lipid lowering drug use and coronary heart
disease (hazard ratio 1.12, 0.90 to 1.40).
Analyses stratified by age, sex, body mass index,
hypertension, systolic blood pressure, triglyceride
concentrations, and propensity score did not
show any effect modification by these variables,
either for stroke or for coronary heart disease.
Conclusion In a population based cohort of older
people with no history of vascular events, use of
statins or fibrates was associated with a 30%
decrease in the incidence of stroke.
Message
血管イベントの既往のない65歳以上の男女7484
人を対象に、脂質降下薬（スタチンまたはフィ
ブラート系薬）の使用と冠動脈疾患・脳卒中の
長期リスクの関連を集団ベースのコホート研究
で検証。平均9.1年の追跡の結果、使用者は非使
用者に比べ脳卒中リスクが低かった（ハザード
比0.66）。脂質降下薬の使用と冠動脈疾患に関
連はなかった。
スタチン/フィブラートは心臓でなく脳に効い
た！？
Decline of FPG during SGLT-2 inhibitors
Data from Phase 2 clinical trials in Japan
SGLT2 inhibitor Luseogliflozin
Duration (weeks)
24
dose (mg)
placebo
2.5
n
79
79
HbA1c
before
8.17
8.14
(%)
delta
0.13 -0.63
after
8.30
7.51
FPG
before
161.9 160.8
(mg/dL) delta
-0.8 -28.3
after
161.1 132.5
FPG/HbA1c比
before
19.8
19.8
after
19.4
17.6
Ratio to Placebo
0.91
Ipragliflozin
12
5
placebo
50
54
69
72
7.86
8.36
8.33
-0.46
0.49
-0.79
7.40
8.85
7.54
100
72
8.25
-0.79
7.46
157.2
167.2
166.6
165.0
-21.0
136.2
9.8
177.0
-31.4
135.2
-45.9
119.1
20.0
20.0
20.0
20.0
18.4
0.95
20.0
17.9
0.90
16.0
0.80
Dapagliflozin
24
placebo
5
75
64
7.84
7.86
-0.23 -0.77
7.61
7.09
155.9 162.2
-4.1 -24.1
151.8 138.1
19.9
20.6
19.9
19.5
0.98
10
70
8.01
-0.89
7.12
166.6
-28.8
137.8
20.8
19.4
0.97
Tofogliflozin
Canagliflozin
24
24
placebo
20
placebo 100
56
58
93
90
8.41
8.34
8.04
7.98
-0.03 -1.02
0.29 -0.74
8.38
7.32
8.33
7.24
168.8 168.7
163.0 157.7
-8.6 -35.9
3.7 -31.6
160.2 132.8
166.7 126.1
20.1
20.2
20.3
19.8
19.1
18.1
20.0
17.4
0.95
0.87
DPP-4 inhibitor Sitagliptin
Vildagliptin
Alogliptin
Linagliptin
Teneligliptin
Anagliptin
Duration (weeks)
12
12
12
12
12
12
dose (mg)
Placebo
50
100
Placebo 25ｘ2
50ｘ2 Placebo
25
Placebo
5
Placebo
20
40
Placebo 50ｘ2
n
～70
～70
～70
72
76
72
228
224
80
159
80
79
81
63
68
HbA1c
before
7.6
7.6
7.6
7.8
7.8
7.8
7.8
7.8
8.4
8.5
8.0
7.8
7.7
8.0
8.0
(%)
delta
0.3
-0.7
-0.7
0.3
-0.7
-0.9
0.1
-0.8
0.4
-0.5
0.1
-0.8
-0.9
0.1
-0.8
after
7.9
6.9
6.9
8.1
7.1
6.9
7.9
7.0
8.8
8.0
8.1
7.0
6.8
8.1
7.3
FPG
before
144.0 144.3 142.6
156.0 156.0 156.0
156.0 156.0
161.7 163.3
150.0 143.0 141.9
160.0 160.0
(mg/dL) delta
6.5 -11.0 -14.9
2.4 -14.1 -24.7
5.6 -17.5
7.4 -12.3
2.8 -14.1 -17.2
-4.1 -16.0
after
150.5 133.3 127.7
158.4 141.9 131.3
161.6 138.5
169.1 151.0
152.8 128.9 124.7
155.9 144.0
FPG/HbA1c比
before
18.9
19.0
18.8
20.0
20.0
20.0
20.0
20.0
19.3
19.2
18.8
18.4
18.4
20.0
20.0
after
19.1
19.3
18.5
19.6
19.9
19.1
20.6
19.7
19.2
18.9
18.9
18.5
18.3
19.2
19.9
Ratio to Placebo
1.01
0.97
1.02
0.97
0.96
0.98
0.98
0.97
1.03
100ｘ2
69
8.0
-0.8
7.2
160.0
-19.5
140.5
Saxagliptin
12
Placebo
5
87
81
8.0
8.00
-0.1 -0.90
7.9
7.1
160.0 160.0
0.9 -16.6
160.9 143.4
20.0
20.0
20.0
19.6
1.02
20.3
20.2
0.99
FPG/HbA1c was decreased to below 20 after the administration of SGLT-2 inhibitors!
Masafumi Matsuda: DITN 442:9 January, 2015
empagliflozin
HbA1c
(％)
FPG
(mg/dL)
FPG/HbA1c比
12Weeks Placebo 10mg
25mg
n
109
109
109
使用前
7.94
7.93
7.93
変化
0.03
-0.4 -0.65
使用後
7.97
7.53
7.28
使用前
156.3
156.8
156
変化
4.06 -25.28 -33.70
使用後
160.36 131.52 122.3
使用前
19.7
19.8
19.7
使用後
20.1
17.5
16.8
ビール330ml (アルコール6%)
低血糖
副作用報告
埼玉医科大学総合医療センター内分泌・糖尿病内科 松田昌文 自験
各種SGLT-2阻害薬の血中ブドウ糖濃度に及ぼす効果
FBG and mean BG (CGM 4 days)
mg/dl
FBG
140
Mean BG (CGM)
135
130
125
120
115
110
105
100
95
90
Luseogliflozin
2.5
5 mg
Ipragliflozin
Dapagliflozin
50
5
100 mg
10 mg
TofoCanagliflozin gliflozin
20mg
100mg
Empagliflozin
10
25 mg
埼玉医科大学総合医療センター内分泌・糖尿病内科 松田昌文 自験
SGLT-2阻害薬服薬停止後の空腹時尿糖
mg/gCr
24hr
48hr
72hr
96hr
18000
16000
14000
12000
10000
8000
6000
4000
2000
0
luseogliflozin
2.5mg
luseogliflozin
5mg
ipragliflozin
50mg
ipragliflozin
100mg
dapagliflozin
5mg
dapagliflozin
10mg
tofogliflozin
20mg
canagliflozin
100mg
empagliflozin
10mg
empagliflozin
25mg
SGLT-2阻害薬は止めても、
空腹時に２~４日間は尿糖はかなり出る！
埼玉医科大学総合医療センター内分泌・糖尿病内科 松田昌文 自験
SGLT-2蛋白に対する結合及び解離
Uchida S, Mitani A, Gunji E, Takahashi T, Yamamoto K.: In vitro characterization of luseogliflozin, a potent
and competitive sodium glucose co-transporter 2 inhibitor: Inhibition kinetics and binding studies. J
Pharmacol Sci. 2015 Apr 9. pii: S1347-8613(15)00074-2. doi: 10.1016/j.jphs.2015.04.001.
［LSF00069EP0001］
J Pharmacol Sci. 2015 Apr 9. pii: S1347-8613(15)00074-2. doi: 10.1016/j.jphs.2015.04.001.
Abstract
In this study, we evaluated an inhibition model of
luseogliflozin on sodium glucose co-transporter 2
(SGLT2). We also analyzed the binding kinetics of the
drug to SGLT2 protein using [3H]-luseogliflozin.
Luseogliflozin competitively inhibited human SGLT2
(hSGLT2)-mediated glucose uptake with a Ki value of
1.10 nM. In the absence of glucose, [3H]-luseogliflozin
exhibited a high affinity for hSGLT2 with a Kd value of
1.3 nM. The dissociation half-time was 7 h, suggesting
that luseogliflozin dissociates rather slowly from hSGLT2.
These profiles of luseogliflozin might contribute to the
long duration of action of this drug.
Methods to prepare cells stably expressing hSGLT2 and glucose uptake study were
described in a previous study (5). The cells were incubated in 75 μL of sodium buffer
(140 mM NaCl, 2 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 5 mM Tris, pH
7.2–7.4) containing 1, 2, 4, 8 or 16 mM of the methyl-α-d-glucopyranoside (α-MG)
mixture ([14C]-α-MG: PerkinElmer, Tokyo and unlabeled α-MG: Sigma–Aldrich, St. Louis,
MO, USA) and 1, 2 or 4 nM of luseogliflozin (Taisho Pharmaceutical Co., Ltd., Saitama)
or dimethyl sulfoxide vehicle at 37 °C for 60 min; each of the incubations was
performed in triplicate.
Binding assays were performed using a modification of the method of Grempler (7). For
the saturation binding experiments, cell membranes (60 μg/well) were incubated with
1.3–368.8 nM [3H]-luseogliflozin (Quotient Bioresearch Ltd., Cardiff, UK) in assay buffer
[10 mM HEPES (pH 7.4), 137 mM NaCl] in the absence and presence of glucose
(20 mM, Wako Pure Chemical Industries Ltd., Osaka), respectively, for 6 h at 25 °C in
96-well plates. For the association experiments, membranes were incubated with 5.2
and 19 nM of [3H]-luseogliflozin in the absence and presence of glucose (20 mM),
respectively, for 0.25, 1, 3, 6, 9 and 12 h at 25 °C. For the dissociation experiments,
12 h after association, 760 and 1970 nM of unlabeled luseogliflozin, approximately 100
times the amount of [3H]-luseogliflozin, in the absence and presence of glucose,
respectively, were added, followed by incubation for 2, 4, 7.67, 18.5 and 30 h at 25 °C.
The approximate Kd values calculated from the saturation binding experiments were
used as the concentrations for [3H]-luseogliflozin in the presence or absence of glucose.
Nonspecific binding was determined with 50 μM of phlorizin (Sigma–Aldrich). The data
were analyzed using GraphPad Prism 5.04 (GraphPad Software, Inc., La Jolla, CA,
USA).
Fig. 1. Kinetic analysis of the inhibition of hSGLT2 by luseogliflozin. Cells stably expressing hSGLT2
were incubated in sodium buffer containing various concentrations of an α-MG mixture ([14C]-α-MG
and unlabeled α-MG) and luseogliflozin at 37 °C for 60 min. Sodium-dependent α-MG uptake was
calculated by subtracting radioactivity (cpm) in the absence of sodium from radioactivity in the
presence of sodium. The inhibition pattern was analyzed by Lineweaver–Burk plots. The data points
represent the mean of three wells from a single representative experiment.
Fig. 2. Analysis of the binding kinetics of [3H]-luseogliflozin to hSGLT2 protein. A and B) Saturation curve and Scatchard plot of [ 3H]luseogliflozin binding to hSGLT2. Membranes of hSGLT2 cells were incubated with [ 3H]-luseogliflozin in an assay buffer in the
absence and presence of glucose (20 mM) for 6 h at 25 °C. The data points represent the mean of two wells from a single
representative experiment. C and D) Association and dissociation curves of [ 3H]-luseogliflozin binding to hSGLT2 in the absence and
presence of glucose. For the association time-course experiments, membranes were incubated with [3H]-luseogliflozin [5.2 nM (C)
and 19 nM (D)] for 0.25–12 h at 25 °C. For the dissociation time-course experiments, after 12 h incubation with [3H]-luseogliflozin,
unlabeled luseogliflozin was added in excess [760 nM (C) or 1970 nM (D)] and incubated for 2–30 h at 25 °C. Data represent the
mean ± SEM of three experiments.
Recently, empagliflozin, a novel Cglucoside, was shown as a slowdissociating SGLT2 inhibitor with a half-time of empagliflozinehSGLT2 binding
of approximately 60 min
Figure 1. Potency of empagliflozin for sodium glucose cotransporter (SGLT)-2 and selectivity over
SGLT-1, 4, 5 and 6. Inset shows the chemical structure of empagliflozin. Results show inhibition of
monosaccharide uptake by hSGLT-2, 1, 4, 5 and 6, respectively, at different concentrations of
empagliflozin. [14C]-AMG was used as substrate for hSGLT-1, 2 and 4, mannose was used as
substrate for hSGLT-5 and myo-inositol for hSGLT-6. Data are shown from representative
experiments and are expressed as mean % of respective control ± standard error of the mean,
where the control value was measured at 10−11 M empagliflozin of each individual assay.
Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P.:
Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with
other SGLT-2 inhibitors. Diabetes Obes Metab. 2012 Jan;14(1):83-90. doi: 10.1111/j.1463-1326.2011.01517.x.
Table 1. Overview of potency on SGLT-2 and selectivity over SGLT-1, 4, 5 and 6 of structurally known SGLT-2 inhibitors.
Luseogliflozin, a structurally novel C-5-thioglucoside, is a potent
inhibitor of SGLT2 with an IC50 value of 2.26 nM, and exhibits a
1765-fold selectivity for hSGLT2 as compared to hSGLT1
Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P.:
Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with
other SGLT-2 inhibitors. Diabetes Obes Metab. 2012 Jan;14(1):83-90. doi: 10.1111/j.1463-1326.2011.01517.x.
Conclusions:
In conclusion, luseogliflozin is a highly potent and
competitive inhibitor of SGLT2, and specifically
binds to SGLT2. Furthermore, the results of the
present study indicated that the dissociation of
luseogliflozin from SGLT2 occurs very slowly. The
results suggest that the binding kinetics of
luseogliflozin to SGLT2 localized in the S1 and S2
segments of the renal proximal tubules may
contribute to the sustained pharmacological effect
of this drug.
Message
Luseogliflozin はEmpagliflozin の7倍くっつ
いているらしい。