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Journal Club
Buse JB, Drucker DJ, Taylor KL, Kim T, Walsh B, Hu H, Wilhelm K, Trautmann M, Shen LZ, Porter LE;
DURATION-1 Study Group.
DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks.
Diabetes Care. 2010 Jun;33(6):1255-61. Epub 2010 Mar 9.
Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, Wilhelm K, Malone J, Porter LE; for
the DURATION-2 Study Group.
Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin
for treatment of type 2 diabetes (DURATION-2): a randomised trial.
Lancet. 2010 Jun 25. [Epub ahead of print]
Diamant M, Van Gaal L, Stranks S, Northrup J, Cao D, Taylor K, Trautmann M.
Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes
(DURATION-3): an open-label randomised trial.
Lancet. 2010 Jun 26;375(9733):2234-43.
2010年７月29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
GLP-1
a nasal spray formulation of
recombinant human GLP-1
a stabilized GLP-1 analogue
Taspoglutide (R1583/BIM51077) is a human GLP-1 analog with a
pharmacokinetic profile suitable for weekly subcutaneous
administration, through two amino acid substitutions in positions 8 and
35 with aminoisobutyric acid and a sustained release formulation.
The compound has been licensed exclusively to Roche for development and marketing worldwide except Japan,
where it will be comarketed with Teijin, and France, where Ipsen retains the right to comarket the product.
Figure 2—Effects of taspoglutide and placebo on A1C. All taspoglutide doses
were statistically significant (P<0.0001) (A). Black, placebo; magenta, 5 mg once
weekly; green, 10 mg once weekly; yellow, 20 mg once weekly; purple, 10 mg once
every 2 weeks; orange, 20 mg once every 2 weeks.
Diabetes Care 32:1237–1243, 2009
Figure 2—Effects of taspoglutide and placebo on body weight (D). Black, placebo;
magenta, 5 mg once weekly; green, 10 mg once weekly; yellow, 20 mg once
weekly; purple, 10 mg once every 2 weeks; orange, 20 mg once every 2 weeks.
Diabetes Care 32:1237–1243, 2009
BYETTA(exenatide) のHbA1cに及ぼす効果
Time (wk)
0
10
20
30
40
50
60
70
80
0.5
Baseline A1C
A1C (%)
0.0
Placebo BID (N = 128)
BYETTA 5 mcg BID (N = 128)
BYETTA 10 mcg BID (N = 137)
-0.5
-1.0
-1.5
-2.0 Placebo-Controlled Trials
Open-Label Extension
8.3%
8.3%
8.3%
90
BYETTA(exenatide)の減量効果
Time (wk)
D Wieght (lbs)
2
0
10
0
-2
20
30
40
50
60
70
80
90
Baseline Weight
215 lbs=98kg
Placebo BID (N = 128)
BYETTA 5 mcg BID (N = 128) 220 lbs=100kg
BYETTA 10 mcg BID (N = 137) 220 lbs=100kg
-4
-6
-8
-10 (=4.53kg)
-12 Placebo-Controlled Trials Open-Label Extension
Background
In the DURATION-1 study, the safety and
efficacy of 30 weeks of treatment with the GLP1 receptor agonist exenatide once weekly
(exenatide QW; 2mg) was compared to
exenatide BID in 295 patients with type 2
diabetes. We now report the safety and efficacy
of exenatide QW in a) patients who continued
treatment for an additional 22 weeks (52 weeks
total), and b) patients who switched from
exenatide BID to exenatide QW after 30 weeks.
Methods
In this randomized, multicenter, comparatorcontrolled, openlabel trial, 258 patients entered
the 22-week open-ended assessment phase
(n=128 QW-only; n=130 BID→QW). A1C,
fasting plasma glucose (FPG), body weight,
blood pressure, fasting lipids, safety, and
tolerability were assessed.
Results
Patients continuing exenatide QW maintained A1C
improvements through 52 weeks (-2.0% [-2.1 to -1.8%];
LS mean [95% CI]). Patients switching from exenatide
BID to exenatide QW achieved further A1C
improvements; both groups exhibited the same A1C
reduction and mean A1C (6.6%) at week 52. At week
52, 71% and 54% of all patients achieved an A1C
<7.0% and ≤6.5%, respectively. In both treatment arms,
FPG was reduced by >40 mg/dL and body weight was
reduced by >4 kg after 52 weeks. Nausea occurred
less frequently in this assessment period and was
predominantly mild. No major hypoglycemia was
observed.
Conclusion
Exenatide QW elicited sustained
improvements in glycemic control
and body weight through 52 weeks
of treatment; patients switching to
exenatide QW experienced further
improvements in A1C and FPG,
with sustained weight loss.
Message
１日２回Byetta®を打たなくても１週間に
一度長期作用性Exenatideを用いればOK
International Diabetes Center at Park Nicollet, Minneapolis, MN, USA (R M
Bergenstal MD); Rockwood Clinic, Spokane WA, USA (C Wysham MD);
Amylin Pharmaceuticals, San Diego, CA, USA (L MacConell PhD, J Malloy
PhD, B Walsh PhD, P Yan PhD, K Wilhelm MD, L E Porter MD); and Eli Lilly,
Indianapolis, IN, USA (J Malone MD)
www.thelancet.com Published online June 26, 2010 DOI:10.1016/S0140-6736(10)60590-9
Background
Most patients with type 2 diabetes begin
pharmacotherapy with metformin, but
eventually need additional treatment. We
assessed the safety and efficacy of once
weekly exenatide, a glucagon-like peptide 1
receptor agonist, versus maximum
approved doses of the dipeptidyl peptidase4 inhibitor, sitagliptin, or the
thiazolidinedione, pioglitazone, in patients
treated with metformin.
Methods
In this 26-week randomised, double-blind, double-dummy,
superiority trial, patients with type 2 diabetes who had been
treated with metformin, and at baseline had mean
glycosylated haemoglobin (HbA1c) of 8・5% (SD 1・1), fasting
plasma glucose of 9・1 mmol/L (164mg/dl) (2・6), and weight
of 88・0 kg (20・1), were enrolled and treated at 72 sites in the
USA, India, and Mexico. Patients were randomly assigned to
receive: 2 mg injected exenatide once weekly plus oral
placebo once daily; 100 mg oral sitagliptin once daily plus
injected placebo once weekly; or 45 mg oral pioglitazone
once daily plus injected placebo once weekly. Primary
endpoint was change in HbA1c between baseline and week
26. Analysis was by intention to treat, for all patients who
received at least one dose of study drug. This trial is
registered with ClinicalTrials.gov, number NCT00637273
Figure 1: Trial profi le *All protocol violations after randomisation were due to non-compliance with study visits or treatment, or both.
†One adverse event was not treatmentemergent. ‡Patients completed study procedures through week 22 in compliance with the
protocol and received adequate exposure to the study drug during the treatment period.
Figure 2: Change in glycaemic control and bodyweight between baseline and week 26 (A) Change in
glycosylated haemoglobin (HbA1c) over 26 weeks. (B) Proportion of patients achieving HbA1c target values at
week 26. (C) Change in fasting plasma glucose over 26 weeks. (D) Change in bodyweight over 26 weeks. In A, C,
and D data are least squares mean, and error bars are SEs. All p values are adjusted according to the Hochberg
method.15 *p<0・05 for exenatide versus pioglitazone. †p<0・0001 for exenatide versus pioglitazone. ‡p<0・05 for
exenatide versus sitagliptin. §p<0・0001 for exenatide versus sitagliptin. ¶p<0・001 for exenatide versus
pioglitazone. ||p<0・001 for exenatide versus sitagliptin.
Figure 2: Change in glycaemic control and bodyweight between baseline and week 26
(E) Scatterplot of change in HbA1c versus change in bodyweight at week 26
Results
170 patients were assigned to receive once weekly exenatide, 172 to
receive sitagliptin, and 172 to receive pioglitazone. 491 patients
received at least one dose of study drug and were included in the
intention-to-treat analysis (160 on exenatide, 166 on sitagliptin, and
165 on pioglitazone). Treatment with exenatide reduced HbA1c (least
square mean –1・5%, 95% CI –1・7 to –1・4) signifi cantly more than did
sitagliptin (–0・9%, –1・1 to –0・7) or pioglitazone (–1・2%, –1・4 to –1・0).
Treatment diff erences were –0・6% (95% CI –0・9 to –0・4, p<0・0001) for
exenatide versus sitagliptin, and –0・3% (–0・6 to –0・1, p=0・0165) for
exenatide versus pioglitazone. Weight loss with exenatide (–2・3 kg,
95% CI–2・9 to –1・7) was significantly greater than with sitagliptin (diff
erence –1・5 kg, 95% CI –2・4 to –0・7, p=0・0002) or pioglitazone (diff
erence –5・1 kg, –5・9 to –4・3, p<0・0001). No episodes of major
hypoglycaemia occurred. The most frequent adverse events with
exenatide and sitagliptin were nausea (n=38, 24%, and n=16, 10%,
respectively) and diarrhoea (n=29, 18%, and n=16, 10%, respectively);
upper-respiratory-tract infection (n=17, 10%) and peripheral oedema
(n=13, 8%) were the most frequent events with pioglitazone.
Conclusion
The goal of many clinicians who manage
diabetes is to achieve optimum glucose
control alongside weight loss and a
minimum number of hypoglycaemic
episodes. Addition of exenatide once weekly
to metformin achieved this goal more often
than did addition of maximum daily doses of
either sitagliptin or pioglitazone.
Funding Amylin Pharmaceuticals and Eli Lilly.
Editorial Comments
Individualised incretin-based treatment for type 2
diabetes
Michael A Nauck, Juris J Meier
Notably, the induction of nausea typically occurs at doses that
are not sufficient to reduce fasting glucose concentrations to
within the normal range in most patients. By contrast, proof-ofprinciple studies with intravenous infusion of the natural parent
compound of these drugs—the incretin hormone GLP-1— show
that normal fasting glucose concentrations,10,11 and near
normal postprandial control,12 can be reached with doses that
do not produce nausea, vomiting, and other so-called
gastrointestinal side-effects simultaneously.
In the future, the choice of incretin-based antidiabetic treatment
will be determined by individual characteristics of patients and
personal preferences, perhaps with the assistance of
pharmacogenomic profiles.
Message
週に一度のExenatideはsitagliptinや
pioglitazoneに比較しても有用と考え
られる。
用量やコストの問題は今後の課題だが。
Diabetes Centre, VU University Medical Centre, Amsterdam, Netherlands (Prof M
Diamant MD); Department of Diabetology, Metabolism and Clinical Nutrition,
Antwerp University Hospital, Antwerp, Belgium (Prof L Van Gaal MD); Southern
Adelaide Diabetes and Endocrine Services, Adelaide, SA, Australia (S Stranks
MD); Eli Lilly and Company, Indianapolis, IN, USA (J Northrup MPT, D Cao PhD, M
Trautmann MD); and Amylin Pharmaceuticals Inc, San Diego, CA, USA (K Taylor
PhD)
www.thelancet.com Vol 375 June 26, 2010
Background
Diabetes treatments are needed that are
convenient, provide effective glycaemic
control, and do not cause weight gain. We
aimed to test the hypothesis that
improvement in haemoglobin A1c (HbA1c)
achieved with once weekly exenatide was
superior to that achieved with insulin
glargine titrated to glucose targets.
Methods
In this 26-week, open-label, randomised, parallel study, we
compared exenatide with insulin glargine in adults with type 2
diabetes who had suboptimum glycaemic control despite use of
maximum tolerated doses of blood-glucoselowering drugs for 3
months or longer. Patients were randomly assigned to add
exenatide (2 mg, once-a-week injection) or insulin glargine (oncedaily injection, starting dose 10 IU, target glucose range 4・0–5・5
mmol/L) to their blood glucose-lowering regimens.
Randomisation was with a one-to-one allocation and block size
four, stratified according to country and concomitant treatment
(70% metformin only; 30% metformin plus sulphonylurea).
Participants and clinical investigators were not masked to
assignment, but investigators analysing data were. The primary
endpoint was change in HbA1c from baseline, and analysis of
this outcome was by modifi ed intention to treat for all patients
who received at least one dose of study drug. This trial is
registered at ClinicalTrials.gov, number NCT00641056.
Mean doses of insulin glargine
increased from a baseline 10 IU per day
to 31 IU per day at endpoint (last
measurement brought forward). Mean
doses of metformin were roughly 2000
mg throughout the study; nearly one in
four patients had a reduction in
sulphonylurea dose.
Figure 2: Mean changes in HbA1c concentration from baseline in patients
receiving exenatide once weekly or insulin glargine titrated to target (A)
Haemoglobin A1c (HbA1c) changes with time. Baseline values were 8・3% (SE 0・07)
for both treatment groups. Curves diverge slightly between weeks 14 and 26; these diff
erences were not significant. (B) HbA1c changes in patients with baseline HbA1c <8%
and ≥8%. Sample sizes were: exenatide, n=102 for baseline <8%, and n=126 for ≥8%;
insulin glargine, n=97 for <8%, n=123 for ≥8%. Error bars show standard error.
*Between-group diff erence was signifi cant (p<0・05).
Figure 3: Mean changes in bodyweight in patients receiving exenatide once
weekly or insulin glargine titrated to target
(A)Mean changes in bodyweight with time. Baseline bodyweights were 91・2 kg (SE 1・
2) for patients taking exenatide and 90・6 kg (1・2) for those taking insulin glargine.
(B)Mean changes in bodyweight for all patients versus patients receiving study drug
plus metformin only. Error bars show standard error. *Between-group difference was
significant (p<0・05).
Results
456 patients were randomly allocated to treatment and were
included in the modified intention-to-treat analysis (233
exenatide, 223 insulin glargine). Participants who received at
least one dose of study drug and for whom baseline and at
least one postbaseline measurement of HbA1c were available
were included in the primary efficacy analysis. Change in
HbA1c at 26 weeks was greater in patients taking exenatide
(n=228; –1・5%, SE 0・05) than in those taking insulin glargine
(n=220; –1・3%, 0・06; treatment difference –0・16%, 0・07, 95%
CI –0・29 to –0・03). 12 (5%) of 233 patients allocated to
exenatide and two (1%) of 223 taking insulin glargine
discontinued participation because of adverse events (p=0・
012). A planned extension period (up to 2・5 years’ duration)
is in progress.
Conclusion
Once weekly exenatide is an
important therapeutic option for
patients for whom risk of
hypoglycaemia, weight loss, and
convenience are particular
concerns.
Funding Amylin Pharmaceuticals; Eli Lilly
and Company.
Message
1日一度のグラルギンよりも１
週間に一度のExenatideの方が
血糖管理もよく体重も増加せず、
何と言っても低血糖が少ない！