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Gerstein HC, Miller ME, Ismail-Beigi F, Largay J, McDonald C, Lochnan HA, Booth GL; for
the ACCORD Study Group.
Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the
randomised, controlled ACCORD trial.
Lancet. 2014 Jul 31. pii: S0140-6736(14)60611-5. doi: 10.1016/S0140-6736(14)60611-5. [Epub
ahead of print]
Zambrowicz B, Ogbaa I, Frazier K, Banks P, Turnage A, Freiman J, Boehm KA, Ruff D, Powell
D, Sands A.
Effects of LX4211, a dual sodium-dependent glucose cotransporters 1 and 2 inhibitor, on
postprandial glucose, insulin, glucagon-like peptide 1, and peptide tyrosine tyrosine in a dosetiming study in healthy subjects.
Clin Ther. 2013 Aug;35(8):1162-1173.e8. doi: 10.1016/j.clinthera.2013.06.011. Epub 2013 Jul 31.
2014年8月14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
Median Glycated Hemoglobin Levels at Each Study Visit
The Action to Control Cardiovascular Risk in Diabetes
Study Group. N Engl J Med 2008;358:2545-2559
Kaplan-Meier Curves for
the Primary Outcome and
Death from Any Cause
The prespecified primary
outcome of ACCORD was the
first occurrence of non-fatal
myocardial infarction, non-fatal
stroke, or cardiovascular death,
defined as death that was
unexpected or presumed to be
due to cardiovascular disease,
congestive heart failure,
myocardial infarction, stroke,
other cardiovascular disease, a
study procedure, or arrhythmia.
NS (P=0.16)
P=0.04
Hazard Ratios for the
Primary Outcome and
Death from Any
Cause in Prespecified
Subgroups
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
2008;358:2545-2559
N Engl J Med 2011;364:818-28
非致死性心筋梗塞
脳卒中
虚血性心疾患
死亡
Lancet 2009; 373: 1765–72
1.
2.
3.
4.
5.
6.
7.
Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health
Sciences, Hamilton, ON, Canada
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine,
Winston-Salem, NC, USA
Case Western Reserve University and Cleveland VA Medical Center, Cleveland, OH, USA
Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
St Joseph's Health Care London, Schulich School of Medicine, Western University, London, ON, Canada
Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
www.thelancet.com Published online August 1, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60611-5
Background
Hyperglycaemia could substantially
increase the risk of ischaemic heart disease
in patients with type 2 diabetes. We
investigated whether intensive lowering of
glucose concentrations affects risk.
The reduced rate of ischaemic heart disease in
ACCORD was not explored. Here we report the
effects of the ACCORD glucose-lowering
interventions on indices of ischaemic heart disease,
including fatal and non-fatal myocardial infarction
and unstable and new-onset angina, and the degree
to which change in HbA1c concentration accounts for
any of these effects.
Lancet 2009年のメタ解析ありますが？？？
Methods
We assessed 10 251 adults aged 40–79 years with
established type 2 diabetes, mean glycated
haemoglobin A1c (HbA1c) concentration of 67 mmol/mol
(8·3%), and risk factors for ischaemic heart disease
enrolled in the ACCORD trial. Participants were
assigned to intensive or standard therapy (target HbA1c
less than 42 or 53–63 mmol/mol [less than 6·0% or 7·0–
7·9%], respectively). We assessed fatal or non-fatal
myocardial infarction, coronary revascularisation,
unstable angina, and new angina during active treatment
(mean 3·7 years) plus a further mean 1·2 years. This
trial is registered with ClinicalTrials.gov, number
NCT00000620.
Table. Ischaemic heart disease risk
factors and event rates
Data are mean (SD) or number (%)
unless otherwise stated.
HbA1c=glycated haemoglobin A1c.
ACE=angiotensin-converting enzyme.
ARB=angiotensin-receptor blocker.
SBP=systolic blood pressure.
DBP=diastolic blood pressure.
*Time from randomisation to occurrence of
primary outcome, censoring date, or last day
before treatment transition.
†Time from randomisation until initial
occurrence of primary outcome, censoring date,
or exit visit.
Results
Myocardial infarction was less frequent in the intensive
than in the standard therapy group during active
treatment (hazard ratio [HR] 0·80, 95% CI 0·67–0·96;
p=0·015) and overall (0·84, 0·72–0·97; p=0·02).
Findings were similar for combined myocardial infarction,
coronary revascularisation, and unstable angina (active
treatment HR 0·89, 95% CI 0·79–0·99, overall 0·87
0·79–0·96) and for coronary revascularisation alone
(0·84, 0·75–0·94) and unstable angina alone (0·81,
0·67–0·97) during full follow-up. With lowest achieved
HbA1c concentrations included as a time-dependent
covariate, all hazards became non-significant.
Interpretation
Raised glucose concentration is a modifiable risk
factor for ischaemic heart disease in middle-aged
people with type 2 diabetes and other
cardiovascular risk factors.
Funding
National Heart, Lung, and Blood Institute,
National Institute of Diabetes and Digestive and
Kidney Diseases, National Institute on Aging,
National Eye Intitute, and Centers for Disease
Control and Prevention.
The findings together suggest that early intensive glucose lowering (target HbA1C
concentration lower than 53 mmol/mol [7·0%]) in patients with diabetes combined
with intensive treatment of other risk factors is likely to result in long-term
reductions in cardiovascular disease.
Further assessment of the risks and benefits is required. In the meantime, it is
probably wise to aim for a target HbA1C concentration of less than 64 mmol/mol
(8·0%) in patients older than 65 years with comorbidities.
Message
ACCORD研究はおそらく低血糖のせい（試験では
低血糖が原因としないように）で死亡が増えたと
いうことで有名であるが、
血糖を管理した群で虚血性心疾患は２割減！
（虚血性心疾患のデータは発表されていなかっ
たらしい？？？）
JDOIT-3の結果が期待される。
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5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
SGLT-2阻害薬の効果
8.0
FPG(mg/dL)
160
HbA1c(%)
7.5
150
7.0
140
6.5
130
6.0
120
5.5
110
5.0
100
205.5 308.3 205.5 411.0 205.5 308.3 205.5 205.5 円/日
添付文書データを標準化補正 (HbA1c8%､FPG200mg/dLを)
FPG and MEAN BG (CGM)
FBG
135
Mean PG (CGM)
130
125
120
115
110
105
100
Luseogliflozin
2.5mg
Luseogliflozin
5mg
ipragliflozin
50mg
ipragliflozin
100mg
dapagliflozin
5mg
dapagliflozin
10mg
tofogliflozin
20mg(2nd)
canagliflozin
100mg
205.5 308.3 205.5 411.0 205.5 308.3 205.5 205.5 円/日
SGLT-2阻害薬服薬停止後の空腹時尿糖
last dose
mg/gCr
off 1st
18000
off 2nd
16000
off 3rd
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
Diamant M, Morsink LM.: SGLT2 inhibitors for diabetes: turning symptoms into therapy.
Lancet. 2013 Jul 11. doi:pii: S0140-6736(13)60902-2. 10.1016/S0140-6736(13)60902-2.
[Epub ahead of print]
Background
LX4211 is a first-in-class dual inhibitor of sodiumdependent glucose cotransporters 1 and 2
(SGLT1 and SGLT2). SGLT1 is the primary
transporter for glucose absorption from the
gastrointestinal tract, and SGLT2 is the primary
transporter for glucose reabsorption in the kidney.
SGLT1 inhibition reduces postprandial glucose
(PPG) levels and increases the release of
gastrointestinal peptides such as glucagon-like
peptide 1 (GLP-1) and peptide tyrosine tyrosine
(PYY), whereas SGLT2 inhibition results in
increased urinary glucose excretion (UGE).
Purpose
This study evaluated how timing of dose relative to
meals changes the pharmacodynamic (PD) effects of
LX4211 treatment, including effects on UGE, fasting
plasma glucose, PPG, insulin, total and active GLP-1,
and PYY. The safety and tolerability of LX4211 in healthy
subjects were also assessed.
Methods:
This was a randomized, double-blind, placebo-controlled,
multiple-dose study to determine the PD effects of
LX4211 dose timing relative to meals in 12 healthy
subjects. Blood and urine were collected for the analysis
of PD variables.
Figure 2.
Least-squares mean 24-hour urinary glucose excretion (UGE). (A) Dosing 1 hour before breakfast. (B) Dosing 0.5
hour before breakfast. (C) Dosing immediately before breakfast. (D) Dosing immediately before lunch. (E) Dosing
a split dose 1 hour before breakfast and dinner. Error bars represent SEM. UGE was significantly elevated for all
doses relative to baseline (day −1) and for the pooled LX4211 doses relative to placebo (P < 0.001 for all
comparisons).
Figure 3. Pharmacodynamic effects of LX4211 dosing schedules on gastrointestinal peptides relative to placebo. (A) Before
breakfast dosing relative to placebo for total glucagon-like peptide 1 (GLP-1). (B) Before breakfast dosing relative to placebo
for active GLP-1. (C) Before breakfast dosing relative to placebo for peptide tyrosine tyrosine (PYY). (D) Immediately before
breakfast versus immediately before lunch dosing relative to placebo for total GLP-1. (E) Immediately before breakfast
versus immediately before lunch dosing relative to placebo for active GLP-1. (F) Immediately before breakfast versus
immediately before lunch dosing relative to placebo for PYY. (G) Immediately before breakfast versus split dosing relative to
placebo for total GLP-1. (H) Immediately before breakfast versus split dosing relative to placebo for active GLP-1. (I)
Immediately before breakfast versus split dosing relative to placebo for PYY. SGLT-1 = sodium-dependent glucose
cotransporter 1. Error bars represent SEM.
Figure 4.
Pharmacodynamic effects of
LX4211 dosing schedules on
glucose and insulin relative to
placebo. (A) Before breakfast
dosing relative to placebo for
glucose. (B) Before breakfast
dosing relative to placebo for
insulin. (C) Immediately before
breakfast versus immediately
before lunch dosing relative to
placebo for glucose. (D)
Immediately before breakfast
versus immediately before lunch
dosing relative to placebo for
insulin, (E) Immediately before
breakfast versus split dosing
relative to placebo for glucose.
(F) Immediately before breakfast
versus split dosing relative to
placebo for insulin. Error bars
represent SEM.
Results
Twelve healthy subjects 30 to 51 years of age were enrolled
and treated. Treatment with LX4211 resulted in significant
elevation of total and active GLP-1, and PYY while
significantly decreasing PPG levels relative to placebo, likely
by reducing SGLT1-mediated intestinal glucose absorption.
Comparisons performed among the dosing schedules
indicated that dosing immediately before breakfast
maximized the PD effects of LX4211 on both SGLT1 and
SGLT2 inhibition. The comparative results suggested distinct
SGLT1 effects on GLP-1, PYY, glucose, and insulin, which
were separate from SGLT2-mediated effects, indicating that
SGLT1 inhibition with LX4211 may be clinically meaningful.
All treatments were well tolerated with no evidence of
diarrhea with LX4211 treatment.
Conclusions
This clinical study indicates that dosing of LX4211
immediately before breakfast maximized the PD effects
of both SGLT1 and SGLT 2 inhibition and provided a
convenient dosing schedule for future trials. LX4211 was
safe and well tolerated and, due to its SGLT1 inhibition,
produced strong PPG reductions and low UGE relative
to selective SGLT2 inhibitors. LX4211 may provide a
promising new therapy for patients with type 2 diabetes
mellitus. The potential long-term clinical benefits and
safety of LX4211 treatment will need to be confirmed in
large clinical trials.
ClinicalTrials.gov identifier: NCT01334242.
Message
SGLT-2阻害薬にSGLT-1阻害特性のあるLX4211も
加わりそうである。
GLP-1増加はSGLT-2阻害薬にもあるので機序は今
後の課題。

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