Transcript PowerPoint - 埼玉医科大学総合医療センター 内分泌・糖尿病内科

Journal Club
Aschner P, Chan J, Owens DR, Picard S, Wang E, Dain MP, Pilorget V, Echtay A,
Fonseca V; EASIE investigators.
Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus
uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial.
Lancet. 2012 Jun 16;379(9833):2262-9. Epub 2012 Jun 9.
Gallwitz B, Guzman J, Dotta F, Guerci B, Simó R, Basson BR, Festa A, Kiljański J,
Sapin H, Trautmann M, Schernthaner G.
Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in
patients with type 2 diabetes with metformin failure (EUREXA): an open-label,
randomised controlled trial.
Lancet. 2012 Jun 16;379(9833):2270-8. Epub 2012 Jun 9.
2012年8月2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
Diabetologia 55:1577-96, 2012, Diabetes Care Apr. 19, 2012
Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogota, Colombia
(Prof P Aschner MD); The Chinese University of Hong Kong, Prince of Wales Hospital,
Shatin, Hong Kong Special Administrative Region, China (Prof J Chan FRCP); Centre
for Endocrine and Diabetes Science, Cardiff University, Cardiff , UK (Prof D R Owens
MD); Point Medical Rond Point de la Nation, Dijon, France (S Picard MD); Sanofi ,
Bridgewater, NJ, USA (E Wang PhD); Sanofi , Paris, France (M-P Dain MD, V Pilorget
MD); Rafi c Hariri University Hospital, Beirut, Lebanon (A Echtay MD); and Tulane
University Medical Center, New Orleans, LA, USA (Prof V Fonseca MD)
Lancet 2012; 379: 2262–69
Background
In people with type 2 diabetes, a
dipeptidyl peptidase-4 (DPP-4) inhibitor
is one choice as second-line treatment
after metformin, with basal insulin
recommended as an alternative. We
aimed to compare the efficacy,
tolerability, and safety of insulin
glargine and sitagliptin, a DPP-4
inhibitor, in patients whose disease was
uncontrolled with metformin.
Methods
In this comparative, parallel, randomised, open-label trial,
metformin-treated people aged 35–70 years with glycated
haemoglobin A1c (HbA1c) of 7–11%, diagnosis of type 2 diabetes
for at least 6 months, and body-mass index of 25–45 kg/m² were
recruited from 17 countries. Participants were randomly assigned
(1:1) to 24-week treatment with insulin glargine (titrated from an
initial subcutaneous dose of 0·2 units per kg bodyweight to attain
fasting plasma glucose of 4·0–5·5 mmol/L) or sitagliptin (oral dose
of 100 mg daily). Randomisation (via a central interactive voice
response system) was by random sequence generation and was
stratified by centre. Patients and investigators were not masked to
treatment assignment. The primary outcome was change in
HbA1c from baseline to study end. Efficacy analysis included all
randomly assigned participants who had received at least one
dose of study drug and had at least one on-treatment assessment
of any primary or secondary efficacy variable. This trial is
registered at ClinicalTrials.gov, NCT00751114.
4, 5.5, 7.7 mmol/L = 72, 99, 139 mg/dl
All participants received a glucose meter to record self-monitored glucose values. Individuals randomly assigned
to insulin glargine implemented insulin titration to attain self-monitored fasting plasma glucose concentrations
between 4・0 mmol/L and 5・5 mmol/L (inclusive). The initial subcutaneous dose was 0・2 units per kg of
bodyweight injected at dinner or bedtime using a prefilled SoloSTAR pen. The dose was either decreased by two
units if fasting plasma glucose concentration was less than 4・0 mmol/L with or without symptomatic
hypoglycaemia, increased by two units if the concentration was 5・6–7・7 mmol/L, and increased by four units if the
concentration was greater than 7・7 mmol/L. Participants monitored fasting plasma glucose daily and generally
used the middle of the past three values to undertake the titration twice a week. Selfmonitored glucose values and
insulin doses were reviewed by an international titration committee on an ongoing basis via a website and the
study investigators were contacted by email if titration was inadequate. Minor departures from the algorithm were
allowed, although the final decision rested with the investigator.
Participants in the sitagliptin group received a fixed oral dose of 100 mg once daily taken in the morning either
with or without food and no changes in dose were allowed during the trial.
T-chol <200mg/dl 0.0259 <5.18mmol/ HDL-C 35mg/dl=0.91 mmol/L, LDL-C 3mmol/L = 116mg/dl
Triglyceride <250 mg/dl 0.0113 <2.8mmol/L, 150 mg/dl =1.69mmol/L
Figure 3:
HbA1c (A),
HbA1c less than 7% or
6·5% (B),
in a 24-week study
comparing glargine
versus sitagliptin in
patients with type 2
diabetes who did not
respond to metformin
monotherapy
HbA1c=glycated
haemoglobin A1c.
SMFPG=self-monitored
fasting plasma glucose.
*p<0・0001. †p=0・0012.
‡p=0・0008 versus
sitagliptin (endpoint).
Figure 3:
self-monitored fasting
plasma glucose (C)
and seven-point selfmonitored blood
glucose profiles during
a 24-h period (D)
in a 24-week study
comparing glargine
versus sitagliptin in
patients with type 2
diabetes who did not
respond to metformin
monotherapy
HbA1c=glycated
haemoglobin A1c.
SMFPG=self-monitored
fasting plasma glucose.
*p<0・0001. †p=0・0012.
‡p=0・0008 versus
sitagliptin (endpoint).
4, 5.5, 7.7 mmol/L = 72, 99, 139 mg/dl
Findings
732 people were screened and 515 were randomly
assigned to insulin glargine (n=250) or sitagliptin
(n=265). At study end, adjusted mean reduction in
HbA1c was greater for patients on insulin glargine
(n=227; –1・72%, SE 0・06) than for those on sitagliptin
(n=253; –1・13%, SE 0・06) with a mean difference of –
0・59% (95% CI –0・77 to –0・42, p<0・0001). The
estimated rate of all symptomatic hypoglycaemic
episodes was greater with insulin glargine than with
sitagliptin (4・21 [SE 0・54] vs 0・50 [SE 0・09] events per
patient-year; p<0・0001). Severe hypoglycaemia
occurred in only three (1%) patients on insulin glargine
and one (<1%) on sitagliptin. 15 (6%) of patients on
insulin glargine versus eight (3%) on sitagliptin had at
least one serious treatment-emergent adverse event.
Interpretation
Our results support the option of
addition of basal insulin in patients
with type 2 diabetes inadequately
controlled by metformin. Long-term
benefits might be expected from the
achievement of optimum glycaemic
control early in the course of the
disease.
Funding Sanofi .
To date, however, there is insufficient evidence to guide
clinicians in choice of the second agent after metformin.
Arguments of benefit that go beyond glucose control
need to be provided. Therefore, the use of composite
endpoints, additionally encompassing favourable effects
on bodyweight, hypoglycaemia risk, blood pressure, and
lipids, all of which might improve patients’
cardiovascular risk, has been advocated to enable
evaluation of an agent’s true benefit.
At present, it is unclear whether initiation of basal
insulin in the early stage of type 2 diabetes translates
into longer term outcome benefits or whether its early
use is ultimately off set by progressive weight gain and
more hypoglycaemic events, both of which could result
in increased cardiovascular risk, higher cost, and poor
quality of life.
Diamant M.: Choosing a blood-glucose-lowering agent after metformin Lancet. 379(9833):2221-2, 2012
Message
Metforminの次の選択で注射薬と経口薬を比較し
ている。
グラルギンインスリン
vs
DPP-4阻害薬
そもそもA1Cが8.5%などという集団でインスリン
やSU薬でないと血糖管理できないと感じるので、
「インスリンも選択肢となりうる」という結論
であるが、現実的にはとても疑問。（SU薬が本
来の適用と思われる集団）
ちなみにORIGIN研究では、あまり差がなさそう。
Diabetologia 55:1577-96, 2012, Diabetes Care Apr. 19, 2012
Department of Medicine IV, Eberhard-Karls-University Tubingen, Tubingen, Germany, (Prof B Gallwitz MD);
Celaya Centre for Specialist Medicine, Guanajuato, Mexico (J Guzman MD); Department of Internal
Medicine, Endocrine and Metabolic Sciences, Policlinico Le Scotte, Sienna, Italy (F Dotta MD); Hospital
Brabois and Centres d’Investigation Clinique Inserm, CHU de Nancy, Vandoeuvre-Les-Nancy, France (B
Guerci MD); Vall d’Hebron Research Institute and Centro de Investigacion Biomedica en Red de Diabetes
y Enfermedades Metabolicas Asociadas, Carlos III Health Institute, Barcelona, Spain (R Simo MD); Eli Lilly
and Company, St Cyr au Mont D’Or, France (B R Basson MSc); Eli Lilly and Company, Vienna, Austria (A
Festa MD); Eli Lilly Polska, Warsaw, Poland (J Kiljański MD); Eli Lilly and Company, Suresnes, France (H
Sapin MSc); Lilly Deutschland, Hamburg, Germany (M Trautmann MD); and Department of Medicine I,
Rudolfstiftung Hospital, Vienna, Austria (Prof G Schernthaner MD)
Lancet 2012; 379: 2270–78
Background
Glycaemic control deteriorates
progressively over time in patients with
type 2 diabetes. Options for treatment
escalation remain controversial after
failure of first-line treatment with
metformin. We compared add-on
exenatide with glimepiride for durability
of glycaemic control in patients with
type 2 diabetes inadequately controlled
by metformin alone.
Methods
We did an open-label, randomised controlled trial at 128
centres in 14 countries between Sept 5, 2006, and March 29,
2011. Patients aged 18–85 years with type 2 diabetes
inadequately treated by metformin were randomly assigned
via a computer-generated randomisation sequence to
receive exenatide twice daily or glimepiride once daily as
add-on to metformin. Randomisation was stratified by
predetermined categories of glycated haemoglobin (HbA1C)
concentration. The primary outcome was time to inadequate
glycaemic control and need for alternative treatment, defined
as an HbA1c concentration of more than 9% after the first 3
months of treatment, or more than 7% at two consecutive
visits after the first 6 months. Analysis was by intention to
treat.
This trial is registered with EudraCT, number 2005-00544821, and ClinicalTrials.gov, number NCT00359762.
Eligible participants had type 2 diabetes; were
overweight to obese (body-mass index [BMI] ≥25 kg/m2
to <40 kg/m2); aged 18–85 years; had been on stable,
maximum tolerated doses of metformin; and had
developed suboptimum glycaemic control, defined by a
glycated haemoglobin (HbA1c) concentration of 6・5%
and more or 9・0% and less.
Randomisation and masking
We used a computer-generated randomisation
sequence to randomly assign patients, in a 1:1 ratio, to
receive either exenatide or glimepiride. Randomisation
was stratified by HbA1c categories of 7・3% and less,
more than 7・3% to 8・2% and less, and more than 8・2%.
Before database lock the study team were masked to
group assignment and statistical anlyses were planned
with no knowledge of groups.
Procedures
Exenatide was injected subcutaneously within 60 min before
breakfast and evening meals, starting at 5 μg twice daily for 4
weeks, followed by 10 μg twice daily for the remaining study
period. If patients had daily episodes of nausea for more than 1
week, the 10 μg dose was reduced to 5 μg twice daily and could
be increased again after nausea subsided.
The recommended starting dose for patients in the glimepiride
group was 1 mg per day, given once daily immediately before
breakfast. Attending physicians established the glimepiride dose
as per their usual practice, and investigators were instructed to
adjust the dose every 4 weeks, according to tolerability, up to the
maximum tolerated dose in accordance with the country specific
summary of product characteristics.
Concomitant metformin was continued throughout the study for all
patients, in the same form and at the same dose as used at study
entry
Study outcomes
The primary outcome was time to inadequate glycaemic control,
defined as an HbA1c concentration of more than 9% after the
first 3 months of treatment, or more than 7% at two consecutive
visits 3 months apart after the first 6 months. We defined
treatment failure in line with recommendations of diabetes
associations and the known timecourse of changes in HbA1c
concentration, and allowed quick identification of patients with
poor glycaemic control who needed alternative treatment.
Because the primary outcome was a time-to-event measure,
we regarded a study period of 2–3 years as appropriate.
Patients who had treatment failure were discontinued, but could
enrol in an extension study to examine further treatment
options; findings from this study will be described elsewhere.
Secondary outcomes were markers of β-cell function,
bodyweight, hypoglycaemia, and surrogate markers of
cardiovascular risk (blood pressure and heart rate).
Figure 1: Trial profile
The intention-to-treat population consisted
of 490 patients randomised to exenatide
(five did not receive the study drug and 20
did not have at least one baseline or postbaseline HbA1c measurement) and 487
randomised to glimepiride (six did not
receive the study drug and 21 did not have
at least one baseline or post-baseline
HbA1c measurement). *p=0・001 for
difference between groups.
Table 1: Baseline demographic and clinical characteristics
time to inadequate glycaemic control, defined as an HbA1c
concentration of more than 9% after the first 3 months of
treatment, or more than 7% at two consecutive visits 3 months
apart after the first 6 months.
Consistent with inclusion criteria, patients were taking
metformin at close to the recommended maximum dose, with
a median dose of 2000 mg per day (IQR 1700–2550).
Average treatment time was about 2 years (exenatide group,
mean 101・9 weeks [SD 73・8]; glimepiride group, 113・1
weeks [70・9]). Mean exenatide dose was 17・35 (4・07) μg per
day and mean glimepiride dose was 2・01 (1・02) mg per day.
Figure 2: Time-to-event curves for patients meeting criteria for treatment failure (A) and for those
meeting treatment failure criteria according to baseline HbA1c categories (B) Event rates in figure
2A are Kaplan-Meier estimates. The sharp drop at 9 months corresponds to when patients could
first meet the criterion of HbA1c concentration >7・0% at two consecutive visits after the first 6
months of treatment. HbA1c=glycated haemaglobin A1c.
Bodyweight fell from baseline to endpoint in
the exenatide group (–3・32 kg [SD 5・45]) and
rose in the glimepiride group (1・15 kg [4・18]);
difference in change from baseline between
groups was significant after 4 weeks and at
each time thereafter (p<0・0001).
Findings
We randomly assigned 515 patients to the exenatide group and 514 to
the glimepiride group, of whom 490 versus 487 were the intention-totreat population. 203 (41%) patients had treatment failure in the
exenatide group compared with 262 (54%) in the glimepiride group (risk
difference 12・4 [95% CI 6・2–18・6], hazard ratio 0・748 [0・623–0・899];
p=0・002). 218 (44%) of 490 patients in the exenatide group, and 150
(31%) of 487 in the glimepiride group achieved an HbA1c concentration
of less than 7% (p<0・0001), and 140 (29%) versus 87 (18%) achieved
concentrations of 6・5% and less (p=0・0001). We noted a significantly
greater decrease in bodyweight in patients given exenatide than in
those given glimepiride (p<0・0001). Five patients in each treatment
group died from causes unrelated to treatment. Significantly fewer
patients in the exenatide group than in the glimepiride group reported
documented symptomatic (p<0・0001), nocturnal (p=0・007), and nonnocturnal (p<0・0001) hypoglycaemia. Discontinuation because of
adverse events (mainly gastrointestinal) was significantly higher (p=0・
0005) in the exenatide group than in the glimepiride group in the first 6
months of treatment, but not thereafter.
Interpretation
These findings provide evidence for
the benefits of exenatide versus
glimepiride for control of glycaemic
deterioration in patients with type-2
diabetes inadequately controlled by
metformin alone.
Funding
Eli Lilly and Company; Amylin Pharmaceuticals.
Madsbad S.: Type 2 diabetes: which drug as add-on to metformin? Lancet. 379(9833):2222-3, 2012
Message
Metforminの次の選択で注射薬と経口薬を比較し
ている。
GLP-1受容体作動薬
vs
SU薬
プロインスリンの値が低すぎるがSU薬よりも
GLP-1受容体作動薬の注射も選択肢となりうる。
というのはまぁ妥当かもしれない。