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Article: Treatment
Monotherapy with the once-weekly GLP-1 analogue
dulaglutide for 12 weeks in patients with Type 2
diabetes: dose-dependent effects o glycaemic control
in a randomized, double-blind, placebo-controlled study
G. Grunberger1, A. Chang2, G. Garcia Soria3, F. T. Botros4, R. Bsharat4 and Z. Milicevic5
1Grunberger Diabetes Institute, Bloomfield Hills, MI, 2John Muir Physician Network Clinical Research Center, Concord, CA, USA, 3IMIC Research, Mexico City,
Mexico, 4Lilly Research Laboratories, Indianapolis, IN, USA and 5Lilly Research Laboratories, Vienna, Austria
Accepted 26 June 2012
Abstract
Aims Evaluate dose-dependent effects of once-weekly dulaglutide, a glucagon-like peptide-1 analogue, on glycaemic control
in patients with Type 2 diabetes treated with lifestyle measures with or without previous metformin.
Methods This 12-week, double-blind, placebo-controlled, dose–response trial randomized 167 patients who were anti-
hyperglycaemic medication-naı̈ve or had discontinued metformin monotherapy [mean baseline HbA1c 59 � 8 to
61 � 8 mmol ⁄mol (7.6 � 0.7 to 7.8 � 0.8%)] to once-weekly injections of placebo or dulaglutide (0.1, 0.5, 1.0 or 1.5 mg).
Results A significant dose-dependent reduction in HbA1c (least squares mean � se) was observed across doses (P < 0.001).
HbA1c reductions in the 0.5, 1.0 and 1.5 mg dulaglutide groups were greater than in the placebo group [)10 � 1, )11 � 1
and )11 � 1 vs. 0 � 1 mmol ⁄mol ()0.9 � 0.1, )1.0 � 0.1 and )1.0 � 0.1 vs. 0.0 � 0.1%), respectively, all P < 0.001].
Dose-dependent reductions in fasting plasma glucose were also observed [least squares mean difference (95% CI) ranging
from )0.43 ()1.06 to 0.19) mmol ⁄ l for dulaglutide 0.1 mg to )1.87 ()2.56 to )1.19) mmol ⁄ l for dulaglutide 1.5 mg,
P < 0.001]. Dose-dependent weight loss was demonstrated across doses (P = 0.009), but none of the groups were different
from placebo. The most common adverse events were nausea and diarrhoea.
Conclusions The observed dulaglutide dose-dependent reduction in HbA1c and its acceptable safety profile support further
clinical development for treatment of Type 2 diabetes.
Diabet. Med. 29, 1–8 (2012)
Keywords fasting blood glucose, GLP-1 receptor agonist, glucagon-like peptide-1, HbA1c, homeostasis model
assessment 2
Abbreviations DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HOMA2-%B, homeostasis model
assessment of b-cell function; HOMA2-%S, homeostasis model assessment of insulin sensitivity
Introduction
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that
causes increases in glucose-dependent insulin secretion, inhibi-
tion of glucagon secretion, slowing of gastric emptying, and
increased satiety [1]. Several GLP-1 analogues have been
developed or are in development for treatment of Type 2
diabetes [2–7]. Dulaglutide (Dula; LY2189265; XXXXX,
XXXXX, XXXXX 2), a long-acting GLP-1 analogue, consists of
two GLP-1 peptides covalently linked by a small peptide to a
human IgG4-Fc heavy chain (Fig. 1). The GLP-1 moieties
contain amino acid substitutions that protect from inactivation
by dipeptidyl peptidase-4 (DPP-4), while the linker peptide
maintains the potency of the GLP-1 peptide. The IgG4-Fc is
modified by substituting several amino acids to reduce inter-
action with high-affinity Fc receptors, cytotoxicity and immu-
nogenicity [8]. The large molecule size is expected to limit renal
clearance. The resulting half-life is approximately 4 days and
time to peak concentration is 12–72 h [9].
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Correspondence to: Zvonko Milicevic MD PhD, Lilly Research Laboratories,
Vienna, Austria 1. E-mail: milicevic_zvonko@lilly.com
DIABETICMedicine
DOI:10.1111/j.1464-5491.2012.03745.x
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Diabetic Medicine ª 2012 Diabetes UK 1
Dose-dependent reductions in fasting plasma glucose,
postprandial glucose and HbA1c were previously reported in
patients with Type 2 diabetes (n = 43) receiving once-weekly
dulaglutide (doses ranging from 0.05 to 8 mg) for 5 weeks [9].
The objective of this Phase 2 study was to assess the dose–
response relationship with respect to HbA1c across a narrower
range of doses and a longer 12-week treatment period.
Research design and methods
Study design
This 12-week, double-blind, placebo-controlled, dose–response
study assessed the safety and efficacy of dulaglutide in patients
with Type 2 diabetes (n = 167). The study was conducted
between November 2008 and January 2010 in 44 sites in seven
countries. Eligible patients were anti-hyperglycaemic medica-
tion-naı̈ve or on metformin monotherapy. Inclusion criteria
were: age ‡ 18 and £ 75 years; BMI ‡ 23 to £ 40 kg ⁄m2 for
patients native to and residents of South and ⁄or East Asia; ‡ 25
to £ 40 kg ⁄m2 for all other patients; stable weight for 3 months
before screening; and HbA1c ‡ XX to £ XX mmol ⁄mol (‡ 7.0
to £ 9.5%) for anti-hyperglycaemic medication-naı̈ve patients
and > XX to £ XX mmol ⁄mol (> 6.5 to £ 9.0%) [> XX to
£ XX mmol ⁄mol (> 6.0 to £ 8.5% prior to a protocol
amendment)]3 for patients who were taking metformin. Exclu-
sion criteria included treatment with any oral anti-diabetes
drug other than metformin within 3 months or other GLP-1
analogue within 6 months prior to screening, prior use of
insulin for long-term glycaemic control, serious cardiovascular
condition, liver disease, history of pancreatitis or serum creat-
inine ‡ 1.5 mg ⁄dl (men) or ‡ 1.4 mg ⁄dl (women).
Study periods included: 2-week screening, 4- to 8-week lead-
in (8-week washout after discontinuing metformin was
required prior to obtaining the qualifying HbA1c); 12-week
treatment period; and 4-week safety follow-up. After lead-in,
an HbA1c value ‡ XX to £ XX mmol ⁄mol (‡ 6.5 to £ 9.5%)
[‡ XX to £ XX mmol ⁄mol (‡ 7.0 to £ 9.5%) prior to protocol
amendment)] 4was required for randomization. Patients were
randomized (block sizes of 5) to one of five treatment arms:
placebo, 0.1 mg, 0.5 mg, 1.0 mg or 1.5 mg dulaglutide
(Dula 0.1, Dula 0.5, Dula 1.0 and Dula 1.5) in a 1:1:1:1:1
ratio via an interactive voice-response system. In the original
design, patients were randomized to placebo, 0.1 mg, 0.5 mg,
1.0 mg or 3.0 mg dulaglutide. Based on recommendations
from the data monitoring committee of another dulaglutide
study, the Dula 3.0 arm was discontinued in May 2009 and the
protocol was amended to replace the Dula 3.0 arm with the
Dula 1.5 arm. A total of 17 patients had been randomized
prior to protocol amendment; the three patients on the
Dula 3.0 dose were discontinued and the other 14 patients
continued on randomized treatment.
Patients were stratified for randomization by country, BMI
and pre-study therapy (metformin use or not). Study drug was
administered 5once weekly; as this was a placebo-controlled
study, the use of additional oral anti-diabetes drugs was per-
mitted only when needed for rescue therapy (according to pre-
specified criteria). If rescued, patients continued to administer
the study drug until the last on-treatment visit. Other GLP-1
agonists and DPP-4 inhibitors were not allowed at any time.
A common protocol was approved at each site by an insti-
tutional review board and was performed in accordance with
the principles of the Declaration of Helsinki. Prior to partici-
pation, all patients provided written informed consent.
Study endpoints
The primary efficacy measure was change from baseline in
HbA1c at 12 weeks. Additional measures included changes in
fasting plasma glucose (central laboratory), 7-point self-moni-
tored plasma glucose, b-cell function and insulin sensitivity
using the homeostasis model assessment 2 (HOMA2-%B and
HOMA2-%S, respectively), body weight and proportion of
patients achieving HbA1c < XX or £ XX mmol ⁄mol (< 7 or
£ 6.5%). Safety assessments included cardiovascular (pulse
rate, blood pressure, electrocardiogram) and laboratory
parameters, reported adverse events and anti-dulaglutide anti-
bodies. Electrocardiograms were recorded in triplicate and
tracings were over-read by a cardiologist at a centralized ven-
dor (Biomedical Systems Corporation, XXXXX, XXXXX,
XXX 6); this report was used for analysis. Referencing the
American Diabetes Association definition, hypoglycaemia was
defined as plasma glucose £ 3.9 mmol ⁄ l (£ 70 mg ⁄dl) and ⁄or
symptoms and ⁄or signs attributable to hypoglycaemia. Severe
hypoglycaemia was defined as an episode requiring the assis-
tance of another person to actively administer therapy [10].
Patients with at least one pancreatic enzyme measurement ‡ 3
times the upper limit of normal 7underwent a standardized
diagnostic examination.
Plasma analytes and HbA1c were quantified by Quintiles
Laboratories (Smyrna, GA, USA). Electrochemilumines-
cence immunosorbent assay was used for detection of anti-
dulaglutide antibodies (Millipore, XXXX, XXXX, XXX) 8;
GLP-1 peptide
NH2
Linker peptide
IgG4-Fc domain
NH2
COOHHOOC
FIGURE 1 Dulaglutide structure of the molecule.
COLOR
DIABETICMedicine Dulaglutide monotherapy and glycaemic control • G. Grunberger et al.
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2 Diabetic Medicine ª 2012 Diabetes UK
positive samples were titrated for titres. Fasting plasma
glucose and insulin concentrations were used for HOMA2
calculations [11].
Statistical analysis
The target sample size of 36 patients per group was calculated
to provide 90% power for detecting a linear dose–response,
excluding the placebo group, with a 0.60 slope in change from
baseline HbA1c for each 1-mg change in dose. Assumptions
included residual standard deviation (sd) of 1.2%, 0.61 mg sd
of the doses, 2-sided 0.05 significance level and 20% dropout
rate. With this sample size, a 0.9% difference in change from
baseline in HbA1c could be detected between any dulaglutide
group and the placebo group with 80% power.
The primary and secondary analyses were performed on the
intention-to-treat population (n = 167), defined as all
randomized patients who received study therapy, including
patients from the discontinued Dula 3.0 mg arm (n = 3).
Changes from baseline were reported as least-squares mean and
standard error (least-squares mean � se), although summary
statistics were not provided for the discontinued Dula 3.0 arm
because of the small number.
A mixed-effects model for repeated measures (MMRM) was
used for analyses of continuous variables. To evaluate the dose–
response relationship on the change in HbA1c at 12 weeks, the
model included: country, dose, pre-study therapy (metformin
yes ⁄no), visit and dose-by-visit interaction as the fixed effects;
baseline BMI and ⁄or baseline HbA1c as a covariate; and patient
as a random effect. If baseline BMI and baseline HbA1c were
significantly correlated at the 0.10 alpha level, the model
included the one that had a higher correlation with the change
in HbA1c at 12 weeks. Orthogonal contrasts considering the
unequal spacing between doses were used to examine the linear
and log linear dose–response without placebo at 12 weeks. The
contrast with the smaller se, representing the better fit, was
reported. Dunnett’s test was used to control the type I error
when comparing placebo to the individual doses.
A Cochran–Armitage trend test was used to assess categori-
cal data, and a one-way ANOVA on the ranks with treatment
as a fixed effect was conducted for laboratory data. All
statistical analyses were performed using the SAS System�
version 8.2 or higher (SAS Institute, Cary, NC, 9USA).
Results
Patients
In total, 460 patients were screened; most frequent reasons for
screen failure were not fulfilling inclusion ⁄ exclusion criteria
(n = 244), patient decision (n = 36) and physician decision
(n = 12). The three patients randomized to Dula 3.0 were
discontinued at 1, 64 and 72 days post-randomization; 164
patients were randomized to the other five treatment arms and
153 completed the 12-week treatment (Fig. 2). Twelve patients
discontinued before the last safety follow-up visit (Table 1 and
Fig. 2). Three patients received rescue therapy (two in the
placebo group and one in the Dula 1.0 group). Patient
characteristics at entry were well balanced with no significant
differences between groups (Table 1).
167 patients enrolled/randomized
Dulaglutide 3.0 mg3 patients
293 patients failed screening or discontinued prior to randomization
460 patients entered trial
3 patients discontinued
Dose discontinued from study
Sponsor decision (3)
Dulaglutide 1.0 mg34 patients
Dulaglutide 0.5 mg34 patients
Dulaglutide 0.1 mg35 patients
Placebo32 patients
Dulaglutide 1.5 mg29 patients
2 patients
discontinued
treatment period
Protocol violation (2)
0 patients
discontinued
treatment period
4 patients
discontinued
treatment period
Adverse event (2)
Protocol violation (1)
Patient decision (1)
2 patients
discontinued
treatment period
Adverse event (1)
Patient decision (1)
3 patients
discontinued
treatment period
Adverse event (1)
Protocol violation (1)
Lost to follow-up (1)
153 patients completed treatment period
31 patients completed treatment
34 patients completed treatment
25 patients completed treatment
30 patients completed treatment
33 patients completed treatment
0 patients completed
1 patient in the placebo group discontinued (lost to follow-up) after treatment but before
completing the safety period
152 patients completed safety period
FIGURE 2 Patient disposition from entry to completing safety period throughout the study.
DIABETICMedicineOriginal article
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Diabetic Medicine ª 2012 Diabetes UK 3
Primary endpoint
At randomization, baseline HbA1c (mean � sd) was com-
parable among groups [60 � 9, 60 � 8, 59 � 8, 61 � 8
and 60 � 7 mmol ⁄mol (7.7 � 0.8, 7.6 � 0.7, 7.6 � 0.7,
7.8 � 0.8 and 7.6 � 0.7%)] for placebo, Dula 0.1, Dula 0.5,
Dula 1.0 and Dula 1.5, respectively (Fig. 3a). Dose-dependent
reductions in HbA1c were observed across the dulaglutide
groups (P < 0.001) at endpoint. Reductions in HbA1c were
greater than placebo for each of the dulaglutide doses
(P < 0.001) except the Dula 0.1 group (P = 0.069); least-
squares mean difference (95% CI): Dula 0.1, )4 ()8 to )1)
mmol ⁄mol [)0.37 ()0.69 to )0.06) %]; Dula 0.5, )10 ()13 to
)6) mmol ⁄mol [)0.89 ()1.21 to )0.57) %]; Dula 1.0, )11
()15 to )8) mmol ⁄mol [)1.04 ()1.36 to )0.72) %]; and
Dula 1.5, )11 ()15 to )8) mmol ⁄mol [)1.04 ()1.39 to )0.70)
%] (Fig. 3b); change in the placebo group was least-squares
mean � se: 0 � 1 mmol ⁄mol (0.01 � 0.13%). HbA1c reduc-
tions in Dula 0.5, Dula 1.0 and Dula 1.5 were greater than
Dula 0.1 (P £ 0.001). There was no difference among the other
dulaglutide dose groups.
Secondary endpoints
At endpoint, dose-dependent reductions in mean daily plasma
glucose and fasting plasma glucose were observed across all
doses (P < 0.001) (Fig. 3c and d). Changes in fasting plasma
glucose were greater than placebo for each of the doses
(P < 0.001), except for the Dula 0.1 group (P = 0.456); least-
squares mean difference (95% CI): Dula 0.1, )0.43 ()1.06 to
0.19) mmol ⁄ l; Dula 0.5, )1.47 ()2.12 to )0.83) mmol ⁄ l;
Dula 1.0, )1.66 ()2.31 to )1.02) mmol ⁄ l; and Dula 1.5, )1.87
()2.56 to )1.19) mmol ⁄ l (Fig. 3d); change in the placebo group
was least-squares mean � se: )0.21 � 0.25 mmol ⁄ l. Dose-
dependent reductions in mean pre-meal and postprandial plas-
ma glucose from 7-point self-monitored plasma glucose were
observed at endpoint in response to treatment with dulaglutide
(P £ 0.003, data not shown). Additionally, decreases in mean
pre-meal and postprandial plasma glucose in Dula 0.5,
Dula 1.0 and Dula 1.5 groups were significantly greater than
placebo (data not shown).
There was an increasing trend across groups in the per cent
of patients achieving HbA1c < 53 mmol ⁄mol (< 7.0%) at
Table 1 Patient characteristics at entry (screening) for intent-to-treat population and reasons for discontinuation
Intent-to-treat
population
(mean � sd)
Placebo
(n = 32)
Dula 0.1�
(n = 35)
Dula 0.5�
(n = 34)
Dula 1.0�
(n = 34)
Dula 1.5�
(n = 29)
Total
(n = 164) P-value*
Age (years) 55.0 � 9.3 56.3 � 9.2 56.9 � 9.1 57.2 � 8.8 57.5 � 7.9 56.6 � 8.8 0.830
Sex
Female, n (%) 14 (43.8) 24 (68.6) 18 (52.9) 18 (52.9) 16 (55.2) 90 (54.9) 0.360
Male, n (%) 18 (56.3) 11 (31.4) 16 (47.1) 16 (47.1) 13 (44.8) 74 (45.1)
Race, Caucasian
⁄Asian ⁄ Black
or African
American ⁄Others (%)
78 ⁄ 16 ⁄ 3 ⁄ 3 83 ⁄ 11 ⁄ 3 ⁄ 3 82 ⁄ 15 ⁄ 3 ⁄ 0 77 ⁄ 15 ⁄ 0 ⁄ 9 83 ⁄ 14 ⁄ 3 ⁄ 0 81 ⁄ 14 ⁄ 2 ⁄ 3 0.980
Body weight (kg) 90.9 � 18.9 87.1 � 17.3 90.2 � 21.3 86.9 � 17.0 85.8 � 18.6 88.2 � 18.6 0.770
BMI (kg ⁄m2) 32.1 � 5.2 32.9 � 4.8 32.3 � 5.4 32.2 � 4.5 31.0 � 4.3 32.1 � 4.8 0.657
HbA1c (mmol ⁄mol) 57 � 7 54 � 6 55 � 7 56 � 7 56 � 5 56 � 6 0.547
HbA1c (%) 7.4 � 0.6 7.1 � 0.6 7.2 � 0.6 7.3 � 0.7 7.3 � 0.4 7.2 � 0.6
Duration of
diabetes (years)
3.9 � 4.7 3.9 � 3.2 3.7 � 3.8 3.3 � 2.5 4.6 � 4.1 3.9 � 3.7 0.722
History of
metformin, n (%)
No 6 (18.8) 7 (20.0) 6 (17.6) 8 (23.5) 4 (13.8) 31 (18.9) 0.912
Yes 26 (81.3) 28 (80.0) 28 (82.4) 26 (76.5) 25 (86.2) 133 (81.1)
Systolic blood
pressure (mmHg)
128.5 � 12.3 130.7 � 15.9 129.6 � 16.1 125.6 � 15.1 127.3 � 14.4 128.4 � 14.8 0.662
Diastolic blood
pressure (mmHg)
77.9 � 10.5 77.1 � 9.9 75.7 � 8.9 77.3 � 9.2 76.8 � 9.2 77.0 � 9.5 0.922
Reason for
discontinuation, n (%)
Adverse events 1 (3.1) 0 (0.0) 1 (2.9) 0 (0.0) 2 (6.9) 4 (2.4) 0.254
Lost to follow-up 1 (3.1) 0 (0.0) 1 (2.9) 0 (0.0) 0 (0.0) 2 (1.2) 0.652
Protocol violation 0 (0.0) 2 (5.7) 1 (2.9) 0 (0.0) 1 (3.4) 4 (2.4) 0.562
Subject decision 1 (3.1) 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.4) 2 (1.2) 0.265
Completers, n (%) 29 (90.6) 33 (94.3) 31 (91.2) 34 (100) 25 (86.2) 152 (92.7) 0.236
*P-values from analysis of variance or Fisher‘s exact test.
�0.1 mg, 0.5 mg, 1.0 mg or 1.5 mg dulaglutide 15.
DIABETICMedicine Dulaglutide monotherapy and glycaemic control • G. Grunberger et al.
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4 Diabetic Medicine ª 2012 Diabetes UK
endpoint (P < 0.001): placebo (21%), Dula 0.1 (47%),
Dula 0.5 (73%), Dula 1.0 (75%) and Dula 1.5 (71%). There
was also an increasing trend in the per cent of patients
achieving HbA1c £ 48 mmol ⁄mol (£ 6.5%) (P < 0.001): pla-
cebo (7%), Dula 0.1 (15%), Dula 0.5 (53%), Dula 1.0 (50%)
and Dula 1.5 (52%) (Fig. 3e).
At week 12, dose-dependent increases in the homeostasis
model assessment of b-cell function (HOMA2-%B) were
observed across the dulaglutide groups (P = 0.036). Increases
were larger in each of the dulaglutide dose groups (P £ 0.013)
except the Dula 0.1 group (P = 0.325) compared with placebo;
least-squares mean difference (95% CI): Dula 0.1, 15.2 ()3.8
to 34.3) %; Dula 0.5, 33.7 (14.2 to 53.2) %; Dula 1.0, 41.1
(20.6 to 61.6) %; and Dula 1.5, 31.4 (10.4 to 52.3) %; change
in the placebo group (least-squares mean � se) was
)2.1 � 7.4%; (Fig. 3f). No significant changes were observed
in any dulaglutide group for HOMA2-%S.
Changes in body weight at week 12 (least-squares mean -
se) were )1.4 � 0.5 kg for placebo, )0.2 � 0.4 kg for
Dula 0.1, )0.3 � 0.4 kg for Dula 0.5, )1.1 � 0.4 kg for
Dula 1.0 and )1.5 � 0.5 kg for Dula 1.5. Dose-dependent
reductions in body weight were observed across the dulaglutide
groups at week 12 (P = 0.009), but were not significant when
compared with placebo. This outcome may be partially related
to two patients in the placebo group who experienced weight
loss of 11.2 and 11.3 kg as a result of haemorrhagic pancrea-
titis and participation in a weight-loss programme, respectively.
Safety and tolerability
Overall, 51.8% (n = 85) of patients reported ‡ 1 treatment-
emergent adverse event during the treatment period, with no
significant trend across groups (see also Supporting Informa-
tion, Table S1). The most frequent treatment-emergent adverse
Baseline 4 8 12
0.0
5.06.0
6.5
7.0
7.5
8.0
8.5
9.0
0
3142
48
54
60
66
72
Time (weeks)H
bA
1c (
mm
ol/m
ol)
Hb
A1
c (
mm
ol/m
ol)
Hb
A1
c (%)
0 4 8 12–1.4
–1.2
–1.0
–0.8
–0.6
–0.4
–0.2
0.0
0.2
–15
–12
–9
–6
–3
0
Time (weeks)
Ch
an
ge
fro
m b
ase
line
∆ H
bA
1c (%
)
†*
*
0 4 8 12
–3
–2
–1
0
1
–54
–36
18
–18
0
Time (weeks)
7-p
oin
t se
lf m
on
ito
red
pla
sm
a
g
luco
se
(m
mo
l/l)
Ch
an
ge
fro
m b
ase
line
∆ 7
-po
int s
elf m
on
itore
d
pla
sm
a g
luco
se
(mg
/dl)
†*
*
0 4 8 12–3
–2
–1
0
1
–54
–36
18
–18
0
Time (weeks)
Fa
stin
g p
lasm
a
glu
co
se
(m
mo
l/l)
Ch
an
ge
fro
m b
ase
line
∆ F
astin
g p
lasm
a g
luco
se
(mg
/dl)
†*
*
< 53 mmol/mol ≤ 48 mmol/mol0
25
50
75
100 Placebo
Dula 0.1Dula 0.5Dula 1.0
Dula 1.5
(< 7.0%) (≤ 6.5%)
HbA1c target
Pe
r ce
nt o
f p
atie
nts
ach
ievin
gH
bA
1c ta
rge
t (%
)
*†
0 4 8 12–20
–10
0
10
20
30
40
50
60
Time (weeks)
HO
MA
2-%
B (
%)
Ch
an
ge
fro
m b
ase
line
Placebo Dula 0.1 Dula 0.5 Dula 1.0 Dula 1.5
(a) (b)
(c) (d)
(e) (f)
FIGURE 3 Glycaemic control in patients with Type 2 diabetes (intent-to-treat population, n = 164) in response to treatment with placebo (n = 32), Dula
0.1 (n = 35), Dula 0.5 (n = 34), Dula 1.0 (n = 34) or Dula 1.5 mg (n = 29): (a) HbA1c by study visit (mean � sd); (b) least-squares mean change from
baseline in HbA1c by study visit (least-squares mean � se); (c) least-squares mean change in mean 7-point self-monitored plasma glucose by visit; (d) least-
squares mean change from baseline in fasting plasma glucose by study visit; (e) percentage of patients achieving HbA1c targets of < 53 mmol ⁄mol (< 7.0%)
and £ 48 mmol ⁄mol (£ 6.5%) 14at week 12. Statistically significant dose effect is observed for both targets, P < 0.001 by Cochran–Armitage trend exact
test; and (F) least-squares mean change in HOMA2-%B by visit. Glucose values in mg ⁄ dl were converted to mmol ⁄ l by dividing by 18. *P < 0.05 vs.
baseline; �P < 0.05 vs. placebo.
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Diabetic Medicine ª 2012 Diabetes UK 5
events were nausea, diarrhoea, and nasopharyngitis, with
overall incidences of 7.9% (n = 13), 6.1% (n = 10) and 5.5%
(n = 9), respectively; there was no significant trend across
groups (Table S1). Four patients (2.4%) discontinued because
of adverse events (Table 1).
Investigators reported four cases of serious adverse events
(2.4%). Two were considered possibly related to study drug:
haemorrhagic pancreatitis associated with cholelithiasis (pla-
cebo) and abdominal pain ⁄distension (Dula 1.5). The other
two cases were breast cancer (Dula 0.5), diagnosed based on a
mammogram completed 6 months prior to study enrolment,
and atrial flutter (Dula 1.0). No deaths occurred during the
study.
There were no severe hypoglycaemic events reported. The
overall incidence of hypoglycaemia was not different among
groups (P = 0.822): placebo, 3.1% (n = 1 ⁄32); Dula 0.1, 5.7%
(n = 2 ⁄35); Dula 0.5, 8.8% (n = 3 ⁄34); Dula 1.0, 5.9%
(n = 2 ⁄34); and Dula 1.5, 10.3% (n = 3 ⁄29).
Systolic and diastolic blood pressures were not different
between dulaglutide groups and placebo. Changes from base-
line in electrocardiogram-derived heart rate were not different
between dulaglutide groups and placebo (see also Supporting
Information, Table S2).
There were no significant differences between the groups in
levels of pancreatic enzymes (lipase, pancreatic amylase and
total amylase) at endpoint. Two patients (Dula 1.5 mg) dem-
onstrated increases > 3 times the upper limit of normal on
consecutive testing during the study; both underwent computed
tomography (CT) scans and results were within normal range.
Administration of study drug was not interrupted and both
patients showed improvement or normalization of laboratory
findings during the trial.
A treatment-emergent anti-dulaglutide antibodywas reported
in one patient in the Dula 1.0 group (4-fold or greater increase
in antibody titre from baseline); antibody titre 1:64 at week 4
and 1:8 at week 12. One patient (Dula 0.1) reported treatment-
emergent skin rash and skin exfoliation (anti-dulaglutide
antibody negative).
Discussion
This dose–response study assessed the effect of a range of doses
of dulaglutide, a once-weekly administered GLP-1 analogue, on
HbA1c over a 12-week treatment period. The results of the
study demonstrate a significant dose–response effect on change
in HbA1c from baseline to 12-week endpoint.
The trial involved patients earlier in the course of disease,
supported by the relatively short mean duration of diabetes and
the relatively modest increase in mean HbA1c level at the end of
the lead-in period after discontinuation of metformin. This
population was selected because a less advanced b-cell secre-
tory deficit and modest hyperglycaemia were characteristics
suitable for a monotherapy, placebo-comparator study. The
HbA1c-lowering effect of the higher dulaglutide doses was
clinically relevant [up to )11 � 1 mmol ⁄mol ()1.0 � 0.1%)
in the Dula 1.5 group]. The magnitude of this effect, when
compared with that reported for other GLP-1 analogues in
similar patient populations, suggests that this compound is
effective in reducing elevated glucose levels [2,7,12]. No signifi-
cant difference in glucose lowering between the three higher dose
groups (0.5, 1.0 and 1.5 mg) was observed, but relatively lower
baseline HbA1c levels and near-normal levels at endpoint in all
three groups may have decreased the ability to fully differentiate
the effect of increasing doses. As maximal reductions in average
and fasting plasma glucosewere not observed until 2–4 weeks of
completed treatment (Fig. 3c and d), it is also possible that a
longer treatment period (> 12 weeks) is needed for the full effect
on haemoglobin glycosylation to be demonstrated [13]. Treat-
ment with dulaglutide increased b-cell function as measured by
the increase in HOMA2-%B. Caution must be taken in the
interpretation of this observation because this is a short study.
The increase in HOMA2-%B may just reflect GLP-1 agonist-
mediated increase in insulin secretion andmay not translate into
long-term improvement in b-cell function. These observations
are consistent with the previous 16-week, Phase-2, placebo-
controlled trial showing that treatment with dulaglutide caused
significant decreases in HbA1c and blood glucose, and improve-
ment in b-cell function in patients with Type 2 diabetes treated
with two other oral anti-diabetes drugs [14].
The effect of exenatide, liraglutide, albiglutide and exenatide
once weekly 10on body weight has been studied as a secondary
objective in several large clinical trials. When compared with
placebo or other glucose-lowering agents, these medications
are, on average, associated with no weight gain or with weight
loss [2,3,5,7,12]. In this study, dulaglutide was associated with
dose-dependent reductions in body weight similar to other
GLP-1 analogues; however, no difference was observed in
comparison with placebo. One possible reason for this outcome
is the large change in body weight in two patients in the pla-
cebo group. An exploratory, post-hoc analysis that excluded
outliers from all treatment groups (� 3 sd) indicated that these
two patients could explain, to a significant extent, the body
weight reductions observed in the placebo group and the lack
of difference between the placebo arm and each dulaglutide
dose. More comprehensive assessments will be conducted in
larger, ongoing, Phase 3 studies.
The most commonly reported treatment-emergent adverse
events were nausea and diarrhoea, consistent with the adverse
event profile of other agents in this class [2,15,16]. The inci-
dence of these events in dulaglutide-treated patients was not
different from that in placebo-treated patients and the severity
infrequently resulted in discontinuation (one patient from
Dula 0.5; two patients from Dula 1.5), indicating acceptable
gastrointestinal tolerability.
Because of previously reported cases of acute pancreatitis in
conjunction with the use of marketed GLP-1 analogues, mea-
surements of serial pancreatic enzymes were included to assess
the predictive value for pancreatic adverse events. As mild
increases in these laboratory parameters, without any known
clinical association, frequently occur in patients with Type 2
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6 Diabetic Medicine ª 2012 Diabetes UK
diabetes [17], patients with greater changes (‡ 3 times the
upper limit of normal) were of special interest. The six patients
who were noted to have enzyme elevations above this threshold
were in the Dula 1.0 and Dula 1.5 groups, but none presented
with clinical symptoms. In only two patients was an increase in
pancreatic enzymes hyperenzymemia confirmed on subsequent
testing (both had a normal CT scan of the pancreas). These
laboratory findings did not require change in the treatment
regimen. Importantly, the majority (four patients11 ) demon-
strated increased pancreatic enzyme levels before randomiza-
tion. Of note, the patient who presented with acute
haemorrhagic pancreatitis shortly after randomization to the
placebo-treated group had normal pancreatic enzymes at
baseline. Therefore, the observed changes in pancreatic
enzymes do not appear to be predictive of clinical outcomes
and their relevance in this setting remains to be determined.
Changes in heart rate have been reported with the use of
marketed GLP-1 analogues [16,18]. Administration of dula-
glutide did not result in any significant difference in heart rate
in comparison with non-exposed individuals. Similar to the
assessment of the effects of dulaglutide on heart rate, no sig-
nificant changes in systolic and diastolic blood pressures were
observed. There were no significant changes observed in lipid
values associated with dulaglutide treatment (see also Sup-
porting Information, Table S3).
In conclusion, once-weekly administration of dulaglutide for
12 weeks in patients with Type 2 diabetes (who were anti-
hyperglycemic medication-naı̈ve or had previously been treated
with metformin monotherapy) resulted in dose-dependent
improvement in glycaemic control, with a significant increase in
b-cell function. Dose-dependent decrease in body weight was
observed; however, the decrease in body weight in the placebo
group attenuated the significance of this analysis. In this study,
dulaglutide displayed an acceptable safety and tolerability
profile. Further studies are needed to fully characterize the ef-
fects of dulaglutide on safety and efficacy parameters, and
clinical investigation is ongoing in the large Phase 3 Assessment
of Weekly AdministRation of LY2189265 in Diabetes
(AWARD) programme.
Competing interests
GG has commonality of interest with Eli Lilly and Company,
Amylin, Merck, Novo Nordisk, GSK, Takeda, Merck, Sanofi-
Aventis, AZ, BMS12 by the nature of research grants and ⁄or
speaking engagements. GGS has commonality of interest with
Eli Lilly and Company, Amylin, Xoma, Takeda and Roche by
the nature of research grants. FTB, RB and ZM are employees
and shareholders of Eli Lilly and Company. AC has nothing to
declare.
Acknowledgements
This study was supported by Eli Lilly and Company. The
authors would like to thank the patients and investigators who
participated in the study. The authors would also like to
thank Sherry A. Martin MD for her critical review of the
manuscript.
References
1 Verspohl EJ. Novel therapeutics for type 2 diabetes: incretin
hormone mimetics (glucagon-like peptide-1 receptor agonists)
and dipeptidyl peptidase-4 inhibitors. Pharmacol Ther 2009; 124:
113–138.
2 Moretto TJ, Milton DR, Ridge TD, Macconell LA, Okerson T,
Wolka AM et al. Efficacy and tolerability of exenatide
monotherapy over 24 weeks in antidiabetic drug-naive
patients with type 2 diabetes: a randomized, double-blind,
placebo-controlled, parallel-group study. Clin Ther 2008; 30:
1448–1460.
3 Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Cour-
reges JP et al. Liraglutide, a long-acting human glucagon-like pep-
tide-1 analog, given as monotherapy, significantly improves
glycemic control and lowers body weight without risk of hypogly-
cemia in patients with type 2 diabetes. Diabetes Care 2007; 30:
1608–1610.
4 Aschner P, Katzeff HL, Guo H, Sunga S, Williams-Herman D,
Kaufman KD et al. Efficacy and safety of monotherapy of sitagliptin
compared with metformin in patients with type 2 diabetes. Diabe-
tes Obes Metab 2010; 12: 252–261.
5 Kim D, MacConell L, Zhuang D, Kothare PA, Trautmann M,
Fineman M et al. Effects of once-weekly dosing of a long-acting
release formulation of exenatide on glucose control and body
weight in subjects with type 2 diabetes. Diabetes Care 2007; 30:
1487–1493.
6 Matthews JE, Stewart MW, De Boever EH, Dobbins RL, Hodge RJ,
Walker SE et al. Pharmacodynamics, pharmacokinetics, safety, and
tolerability of albiglutide, a long-acting glucagon-like peptide-1
mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab
2008; 93: 4810–4817.
7 Rosenstock J, Reusch J, Bush M, Yang F, Stewart M. Potential
of albiglutide, a long-acting GLP-1 receptor agonist, in type 2
diabetes: a randomized controlled trial exploring weekly,
biweekly, and monthly dosing. Diabetes Care 2009; 32: 1880–
1886.
8 Glaesner W, Vick AM, Millican R, Ellis B, Tschang SH, Tian Y
et al. Engineering and characterization of the long-acting glucagon-
like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes
Metab Res Rev 2010; 26: 287–296.
9 Barrington P, Chien JY, Showalter HD, Schneck K, Cui S, Tibaldi F
et al. A 5-week study of the pharmacokinetics and pharmacody-
namics of LY2189265, a novel, long-acting glucagon-like peptide-1
analog, in patients with type 2 diabetes. Diabetes Obes Metab
2011; 13: 426–433.
10 ADA. Defining and reporting hypoglycemia in diabetes: a report
from the American Diabetes Association Workgroup on Hypogly-
cemia. Diabetes Care 2005; 28: 1245–1249.
11 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA
modeling. Diabetes Care 2004; 27: 1487–1495.
12 Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR.
Improved glycemic control with no weight increase in patients with
type 2 diabetes after once-daily treatment with the long-acting
glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week,
double-blind, randomized, controlled trial. Diabetes Care 2004; 27:
1335–1342.
13 Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan DM,
Peterson CM. Tests of glycemia in diabetes. Diabetes Care 2004;
27: S91–S93.
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Diabetic Medicine ª 2012 Diabetes UK 7
14 Umpierrez GE, Blevins T, Rosenstock J, Cheng C, Anderson JH,
Bastyr EJ 3rd. The effects of LY2189265, a long-acting glucagon-
like peptide-1 analog, in a randomized, placebo-controlled, double-
blind study of overweight ⁄ obese patients with type 2 diabetes: the
EGO study. Diabetes Obes Metab 2011; ???: ???–???.13
15 Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M,
Zhuang D et al. Exenatide once weekly versus twice daily for
the treatment of type 2 diabetes: a randomised, open-label,
non-inferiority study. Lancet 2008; 372: 1240–1250.
16 Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-
Pattzi H, Olvera-Alvarez I et al. Liraglutide versus glimepiride
monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised,
52-week, phase III, double-blind, parallel-treatment trial. Lancet
2009; 373: 473–481.
17 Bastyr EJ, Barkin J, Botros FT, Shu J. High incidence of elevated
lipase and amylase in Type 2 diabetes patients (T2DM). Pancreas
2009; 38: 980–1067.
18 Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH
et al. Efficacy and safety comparison of liraglutide, glimepiride, and
placebo, all in combination with metformin, in type 2 diabetes: the
LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes
Care 2009; 32: 84–90.
Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Table S1. Treatment-emergent adverse events observed in
‡ 3% of patients until the end of treatment period.
Table S2. Baseline values and changes from baseline to
week 12 in heart rate, systolic and diastolic blood pressures
after treatment with placebo or dulaglutide.
Table S3. Baseline values and changes from baseline to
week 12 in triglycerides, cholesterol, HDL and LDL after
treatment with placebo or dulaglutide.
Please note: Wiley-Blackwell are not responsible for the content
or functionality of any supporting materials supplied by the
authors. Any queries (other than for missing material) should
be directed to the corresponding author for the article.
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Author Query Form
Journal: DME
Article: 3745
Dear Author,
During the copy-editing of your paper, the following queries arose. Please respond to these by marking up
your proofs with the necessary changes/additions. Please write your answers on the query sheet if there is
insufficient space on the page proofs. Please write clearly and follow the conventions shown on the attached
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Many thanks for your assistance.
Queryreference
Query Remarks
Q1 AUTHOR: is this postal address OK as it is or is there, for example, apostcode to be included?
Q2 AUTHOR: please give the name of the manufacturer and addressdetails of the company for this product; i.e. town or city andstate ⁄ country
Q3 AUTHOR: in accordance with journal style of dual reporting, pleasegive the HbA1c units in mmol ⁄mol where indicated in addition to the% already given.
Q4 AUTHOR: see note above re dual reporting of HbA1c measurements
Q5 AUTHOR: Please describe how the study drug was administered – wasit by sub-cutaneous injection?
Q6 AUTHOR: please give address details for this company; i.e. town orcity and state ⁄ country
Q7 AUTHOR: ULN has been written in full throughout as ‘upper limit ofnormal’. Please check
Q8 AUTHOR: please give address details for this company; i.e. town orcity and state ⁄ country
Q9 AUTHOR: address details have been inserted here. Please amend if notcorrect
Q10 AUTHOR: QW has been changed to once weekly – OK?
Q11 AUTHOR: patients has been added here – OK?
Q12 AUTHOR: AZ, BMS – please clarify this – are these the names ofother companies
Q13 AUTHOR: please update with page range and volume number
Q14 AUTHOR: the mmol ⁄mol units have been added. Please check
Q15 AUTHOR: this footnote has been added. Please amend if desired
O n c e y o u h a v e A c r o b a t R e a d e r o p e n o n y o u r c o m p u t e r , c l i c k o n t h e C o m m e n t t a b a t t h e r i g h t o f t h e t o o l b a r :
S t r i k e s a l i n e t h r o u g h t e x t a n d o p e n s u p a t e x tb o x w h e r e r e p l a c e m e n t t e x t c a n b e e n t e r e d .‚ H i g h l i g h t a w o r d o r s e n t e n c e .‚ C l i c k o n t h e R e p l a c e ( I n s ) i c o n i n t h e A n n o t a t i o n ss e c t i o n .‚ T y p e t h e r e p l a c e m e n t t e x t i n t o t h e b l u e b o x t h a ta p p e a r s .
T h i s w i l l o p e n u p a p a n e l d o w n t h e r i g h t s i d e o f t h e d o c u m e n t . T h e m a j o r i t y o ft o o l s y o u w i l l u s e f o r a n n o t a t i n g y o u r p r o o f w i l l b e i n t h e A n n o t a t i o n s s e c t i o n ,p i c t u r e d o p p o s i t e . W e ’ v e p i c k e d o u t s o m e o f t h e s e t o o l s b e l o w :S t r i k e s a r e d l i n e t h r o u g h t e x t t h a t i s t o b ed e l e t e d .
‚ H i g h l i g h t a w o r d o r s e n t e n c e .‚ C l i c k o n t h e S t r i k e t h r o u g h ( D e l ) i c o n i n t h eA n n o t a t i o n s s e c t i o n .
H i g h l i g h t s t e x t i n y e l l o w a n d o p e n s u p a t e x tb o x w h e r e c o m m e n t s c a n b e e n t e r e d .‚ H i g h l i g h t t h e r e l e v a n t s e c t i o n o f t e x t .‚ C l i c k o n t h e A d d n o t e t o t e x t i c o n i n t h eA n n o t a t i o n s s e c t i o n .‚ T y p e i n s t r u c t i o n o n w h a t s h o u l d b e c h a n g e dr e g a r d i n g t h e t e x t i n t o t h e y e l l o w b o x t h a ta p p e a r s .
M a r k s a p o i n t i n t h e p r o o f w h e r e a c o m m e n tn e e d s t o b e h i g h l i g h t e d .‚ C l i c k o n t h e A d d s t i c k y n o t e i c o n i n t h eA n n o t a t i o n s s e c t i o n .‚ C l i c k a t t h e p o i n t i n t h e p r o o f w h e r e t h e c o m m e n ts h o u l d b e i n s e r t e d .‚ T y p e t h e c o m m e n t i n t o t h e y e l l o w b o x t h a ta p p e a r s .
I n s e r t s a n i c o n l i n k i n g t o t h e a t t a c h e d f i l e i n t h ea p p r o p r i a t e p a c e i n t h e t e x t .‚ C l i c k o n t h e A t t a c h F i l e i c o n i n t h e A n n o t a t i o n ss e c t i o n .‚ C l i c k o n t h e p r o o f t o w h e r e y o u ’ d l i k e t h e a t t a c h e df i l e t o b e l i n k e d .‚ S e l e c t t h e f i l e t o b e a t t a c h e d f r o m y o u r c o m p u t e ro r n e t w o r k .‚ S e l e c t t h e c o l o u r a n d t y p e o f i c o n t h a t w i l l a p p e a ri n t h e p r o o f . C l i c k O K .
I n s e r t s a s e l e c t e d s t a m p o n t o a n a p p r o p r i a t ep l a c e i n t h e p r o o f .‚ C l i c k o n t h e A d d s t a m p i c o n i n t h e A n n o t a t i o n ss e c t i o n .‚ S e l e c t t h e s t a m p y o u w a n t t o u s e . ( T h e A p p r o v e ds t a m p i s u s u a l l y a v a i l a b l e d i r e c t l y i n t h e m e n u t h a ta p p e a r s ) .‚ C l i c k o n t h e p r o o f w h e r e y o u ’ d l i k e t h e s t a m p t oa p p e a r . ( W h e r e a p r o o f i s t o b e a p p r o v e d a s i t i s ,t h i s w o u l d n o r m a l l y b e o n t h e f i r s t p a g e ) .
A l l o w s s h a p e s , l i n e s a n d f r e e f o r m a n n o t a t i o n s t o b e d r a w n o n p r o o f s a n d f o rc o m m e n t t o b e m a d e o n t h e s e m a r k s . .‚ C l i c k o n o n e o f t h e s h a p e s i n t h e D r a w i n gM a r k u p s s e c t i o n .‚ C l i c k o n t h e p r o o f a t t h e r e l e v a n t p o i n t a n dd r a w t h e s e l e c t e d s h a p e w i t h t h e c u r s o r .‚
T o a d d a c o m m e n t t o t h e d r a w n s h a p e ,m o v e t h e c u r s o r o v e r t h e s h a p e u n t i l a na r r o w h e a d a p p e a r s .‚
D o u b l e c l i c k o n t h e s h a p e a n d t y p e a n yt e x t i n t h e r e d b o x t h a t a p p e a r s .
Recommended