Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide is non-inferior to once-daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: A 26-week randomized phase III study

Abstract

We examined the efficacy and safety of once weekly dulaglutide monotherapy (0.75 mg) (dulaglutide) compared to placebo and once daily liraglutide (0.9 mg) (liraglutide) in Japanese patients with type 2 diabetes.
This was a phase 3, 52-week (26-week primary endpoint), randomised, double-blind, placebo-controlled, open-label comparator (liraglutide) trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, 281; liraglutide, 141; and placebo, 70) who were 20 years or older. Participants and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the superiority of dulaglutide vs placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the Full Analysis Set.
At 26 weeks, once weekly dulaglutide was superior to placebo and non-inferior to once daily liraglutide for HbA1c change from baseline (LSM difference: dulaglutide vs placebo -1.57% [95% CI (-1.79 to -1.35)]; dulaglutide vs liraglutide -0.10% [95% CI (-0.27 to 0.07)]). The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension, and decreased appetite; only decreased appetite was different between dulaglutide and liraglutide (dulaglutide, 2 [0.7%]; liraglutide, 8 [5.8%]; p = 0.003). Nine (1.8%) patients experienced hypoglycaemia (dulaglutide, 6 [2.1%]; liraglutide, 2 [1.5%]; placebo, 1 [1.4%]), with no event being severe.
In Japanese patients with type 2 diabetes, once weekly dulaglutide (0.75 mg) was superior to placebo and non-inferior to once daily liraglutide (0.9 mg) for reduction in HbA1c at 26 weeks. Dulaglutide was safe and well tolerated.
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ORIGINAL
ARTICLE
Diabetes, Obesity and Metabolism 17: 974–983, 2015.
© 2015 e Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
original article
Once-weekly glucagon-like peptide-1 receptor agonist
dulaglutide is non-inferior to once-daily liraglutide and superior
to placebo in Japanese patients with type 2 diabetes: a 26-week
randomized phase III study
J. Miyagawa1,M.Odawara
2, T. Takamura3,N.Iwamoto
4,Y.Takita
4& T. Imaoka4
1Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
2Division of Diabetes, Endocrinology and Metabolism, Department of Diabetes, Endocrinology, Metabolism and Rheumatology,Tokyo Medical University, Tokyo, Japan
3Department of Comprehensive Metabology,Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
4Eli Lilly Japan K.K, Kobe, Japan
Aims: To examine the efcacy and safety of once-weekly dulaglutide monotherapy (0.75 mg) compared with placebo and once-daily liraglutide (0.9 mg)
in Japanese patients with type 2 diabetes.
Methods: This was a phase III, 52-week (26-week primary endpoint), randomized, double-blind, placebo-controlled, open-label comparator (liraglutide)
trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, n =281; liraglutide, n =141; and placebo, n=70) who were aged ≥20 years.
Patients and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the
superiority of dulaglutide versus placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the full
analysis set.
Results: At 26 weeks, once-weekly dulaglutide was superior to placebo and non-inferior to once-daily liraglutide for HbA1c change from baseline [least
squares mean difference: dulaglutide vs placebo −1.57% (95% condence interval −1.79 to −1.35); dulaglutide vs liraglutide −0.10% (95% condence
interval −0.27 to 0.07)]. The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension and
decreased appetite; only decreased appetite was different between the dulaglutide and liraglutide groups [dulaglutide, n =2 (0.7%); liraglutide, n =8
(5.8%); p =0.003]. Nine (1.8%) patients experienced hypoglycaemia [dulaglutide, n =6 (2.1%); liraglutide, n =2 (1.5%); placebo, n =1 (1.4%)], with no
event being severe.
Conclusions: In Japanese patients with type 2 diabetes, once-weekly dulaglutide (0.75 mg) was superior to placebo and non-inferior to once-daily
liraglutide (0.9 mg) for reduction in HbA1c at 26weeks. Dulaglutide was safe and well tolerated.
Keywords: dulaglutide, GLP-1 receptor agonist, liraglutide, placebo, type 2 diabetes
Date submitted 6 April 2015; date of rst decision 28 April 2015; date of nal acceptance 2 July 2015
Introduction
Glucagon-like peptide-1 (GLP-1) is a member of an endoge-
nous class of incretin hormones synthesized in intestinal
epithelial L-cells as a response to gastrointestinal nutrients [1].
GLP-1 enhances glucose-dependent secretion of insulin [2,3],
inhibits glucagon secretion [4], slows gastric emptying [5] and
reduces food intake [6,7].
Dulaglutide(EliLillyandCo.,Indianapolis,IN,USA),a
long-acting GLP-1 receptor agonist [8], mimics some endoge-
nous GLP-1 eects. Dulaglutide has been approved in the USA
and European Union at once-weekly doses of 0.75 and 1.5 mg
as a subcutaneous injection to improve glycaemic control in
patients with type 2 diabetes [9,10], and has been approved in
Correspondence to: Dr Noriyuki Iwamoto, Eli Lilly Japan K.K., 7-1-5, Isogamidori, Chuoku, Kobe
6510086, Japan.
E-mail: Iwamoto_noriyuki@lilly.com
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited and is not used for commercial
purposes.
Japan at a once-weekly dose of 0.75 mg to improve glycaemic
control in patients with type 2 diabetes.
Dulaglutide has been modied to stabilize against dipeptidyl
peptidase-4 inactivation, increase the solubility of the peptide,
reduce immunogenic potential and increase its activity dura-
tion. e pharmacokinetic half-life of dulaglutide in Japanese
patients is approximately 5days, supporting once-weekly
dosing.
In global clinical trials completed to date, dulaglutide
(1.5 mg) has been shown to be superior to metformin,
sitagliptin and exenatide twice daily and non-inferiority
to liraglutide (1.8 mg) for glycated haemoglobin (HbA1c)
changes, and has been associated with reductions in body
weight in patients with type 2 diabetes [11–14].
In the present study, we compared once-weekly dulaglutide
(0.75 mg) with placebo and once-daily liraglutide (0.9mg, the
highest available dose in Japan), with regard to multiple ecacy
and safety markers. e results from the present study were
used to evaluate dulaglutide as a treatment for Type 2 diabetes
inJapanesepatients,andthisstudywastherstcomparisonofa

DIABETES, OBESITY AND METABOLISM
original article
once-weekly GLP-1 receptor agonist with once-daily liraglutide
in Japanese patients.
Materials and Methods
Study Design and Participants
is study was a 52-week, multicentre, randomized,
placebo-controlled, double-blind (dulaglutide and placebo)
and open-label liraglutide comparator trial examining the
ecacy and safety of once-weekly dulaglutide monotherapy in
Japanese patients with type 2 diabetes who were discontinued
from their oral antidiabetic medication (OAM) monotherapy
or were OAM-naïve. ese analyses present the data from
this study through the 26-week primary endpoint. ese data
were collected at 33 Japanese sites between April 2012 and
October 2013. e study was registered with ClinicalTrials.gov
(NCT01558271).
During the 2-week screening period, patients were screened
for eligibility and then entered a 2-week lead-in period for
OAM-naïve patients or an 8-week wash-out period for patients
receiving OAM monotherapy.
Eligible Japanese subjects were male or female, aged
≥20 years, were OAM-naïve (diet and exercise only) or
had discontinued OAM monotherapy (excluding thiazolidine-
dione). Eligible patients had a body mass index (BMI) in the
range of 18.5–35.0 kg/m2and a conrmed HbA1c value at the
randomization visit of 7.0–10.0%.e key exclusion criteria
for patients screened were: type 1 diabetes, previous GLP-1
receptor agonist treatment, treatment with more than half of
the sulphonylurea maximum dose at screening, current insulin
or thiazolidinedione use, chronic systemic glucocorticoid
use, or gastric emptying abnormality. Eligible patients were
randomized and treated during the 26-week primary evalua-
tionperiod.At26weeks,patientsintheplacebogroupwere
switched to once-weekly dulaglutide for the remainder of the
52-week controlled study. At the completion of participation or
early discontinuation, all patients were required to participate
in a 30-day safety follow-up period.
A common protocol was approved at each site by the relevant
institutional review board, and the study was performed in
accordance with the principles of the Declaration of Helsinki
and Good Clinical Practice [15]. Each patient provided written
informed consent before participation.
Procedures
Eligiblepatientswererandomizedtotreatmentata4:2:1ratio
(dulaglutide: liraglutide: placebo). Randomization was strati-
ed by pre-study OAM status (yes/no), BMI group (<25 and
≥25 kg/m2), and HbA1c (≤8.5 or >8.5%). e randomization
was carried out according to a computer-generated random
sequence with an interactive voice response system. Patients
and investigators were masked to dulaglutide and placebo treat-
ment assignments but were not masked to liraglutide treatment
assignment.
Dulaglutide and placebo were provided as non-identiable
solutions in prelled syringes. Liraglutide was supplied as an
open-label pen. Subcutaneous blinded dulaglutide (or placebo)
injections were initiated at the full dose. Subcutaneous liraglu-
tide injections were uptitrated from 0.3 mg/day during week 1
to 0.6 mg/day during week 2 and 0.9 mg/day starting at week
3, according to the Japanese label. Patients not tolerating study
treatment were discontinued from the study drug but remained
in the study to collect safety data.
Hypoglycaemia was dened as a blood glucose concen-
tration ≤3.9 mmol/l. Severe hypoglycaemia was dened as
an episode that required the assistance of another person to
actively administer carbohydrate, glucagon or other resuscita-
tive actions. Patients were allowed to initiate rescue therapy
for severe, persistent hyperglycaemia according to predened
thresholds on fasting blood glucose for at least 2 weeks with no
readily identiable cause.
Deaths, cardiovascular adverse events and pancreatitis were
adjudicated by separate independent, external committees,
using prespecied criteria, study evidence and clinical knowl-
edge and experience. All patients were tested for the develop-
ment of dulaglutide antidrug antibodies.
Outcomes and Statistical Analyses
eprimaryobjectivewastoshowthesuperiorityofdulaglu-
tide vs placebo as measured by HbA1c change from baseline at
26 weeks. Key secondary objectives at 26 weeks were to show
that dulaglutide was non-inferior or superior to liraglutide on
HbA1c change from baseline values using a serial gatekeeping
strategy [16]. Secondary objectives at 26 weeks evaluated the
proportions of patients who achieved HbA1c targets (<7.0 or
≤6.5%), change in fasting serum glucose from baseline, change
in seven-point self-monitored blood glucose (SMBG) proles
from baseline, and change in body weight from baseline. SMBG
proles were collected on two separate, non-consecutive days
within 2 weeks before baseline and weeks 14 and 26. Safety
assessments included adverse events, vital signs (pulse rate and
blood pressure), ECGs, laboratory variables and dulaglutide
antidrug antibodies.
e sample size of at least 490 randomized patients was
selected to provide >99% power to demonstrate superiority of
dulaglutide to placebo. is assumed a true mean dierence in
HbA1c change from baseline between dulaglutide and placebo
of 0.8%, a common standard deviation of 1.1%, a one-sided
signicance level of 0.025, and a 9% drop-out rate between
randomization and week 26. Moreover, assuming no dierence
between dulaglutide and liraglutide, the given sample size pro-
vided at least 90% power to conrm non-inferiority of dulaglu-
tide to liraglutide with a margin of 0.4%.
Ecacy analyses used the full analysis set, dened as all
randomized patients who took at least one dose of study
drug. Safety analyses were conducted on the as-treated pop-
ulation according to the patients’ actual treatments (safety
analysis set).
e primary ecacy analysis model was a mixed model
for repeated measures for change from baseline to week 26
for HbA1c. e model included treatment, prestudy therapy
(OAM: yes/no), baseline BMI (<25/≥25 kg/m2), visit, treat-
ment by visit interaction as xed eects, baseline HbA1c as
a covariate, and patient as a random eect. An unstructured
covariance structure was used to model the within-patient
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original article
DIABETES, OBESITY AND METABOLISM
Figure 1. Trial prole. Patients were randomized to treatment at a 4 : 2 : 1 ratio (dulaglutide: liraglutide: placebo). N =number of patients.
errors. e 95% condence interval (CI) for the treatment dif-
ference (dulaglutide −placebo) in the least-squares (LS) mean
atweek26basedonthismodelwasusedtoassesstheprimary
objective. If the primary objective was met, the key secondary
hypotheses for non-inferiority and superiority of dulaglutide
compared with liraglutide were to be tested using a serial gate-
keeping strategy to control the family-wise type I error rate.
Statistical analyses comparing liraglutide and placebo were not
conducted.
For other continuous measurements, mixed model for
repeated measures was performed with the same model as the
primary ecacy analysis, with the relevant baseline value as a
covariate. Seven-point SMBG was analysed using an analysis of
covariance model with terms for treatment, prestudy therapy
and baseline BMI as xed eects, and baseline value as a
covariate.
For categorical measurements, the Cochran–Mantel–
Haenszel test stratied by prestudy therapy and baseline BMI
or Fisher’s exact test was performed.
Results
Patients
Overall, 587 patients entered the study, 492 were randomized,
487 were treated with study drug, and 462 completed 26 weeks
of treatment (Figure 1). irty patients discontinued the
study [dulaglutide, n =10 (3.6%); liraglutide, n =13 (9.2%);
and placebo, n =7 (10.0%); p =0.020], with ‘withdrawal by
subject’ being the most common reason [dulaglutide, n =6
(2.1%); liraglutide, n =11 (7.8%); and placebo, n =5 (7.1%);
p=0.011]. Patient demographics and baseline characteristics
were similar between the groups (Table 1).
Efcacy
At 26 weeks, once-weekly dulaglutide was superior to placebo
for HbA1c change from baseline (p <0.001; Figures 2A,
3A). Dulaglutide was also non-inferior, but not superior, to
once-daily liraglutide (pnon-inferiority <0.001). e LS mean
(standard error) changes in HbA1c from baseline to 26 weeks
were −1.43% (0.05) for dulaglutide, −1.33% (0.07) for liraglu-
tide, and 0.14% (0.10) for placebo. e LS mean dierence
between dulaglutide and placebo was −1.57% (95% CI
−1.79, −1.35) and between dulaglutide and liraglutide was
−0.10% (95% CI −0.27, 0.07). For each timepoint from base-
line to primary endpoint, dulaglutide signicantly reduced
HbA1c compared with placebo (p <0.001 all timepoints;
Figure 2A).
At 26 weeks (LOCF), a signicantly greater proportion
of patients on dulaglutide achieved HbA1c <7.0% com-
pared with placebo [dulaglutide, 200/280 (71.4%); placebo,
4/68 (5.9%); p <0.001; Figure 3B]. A signicantly greater
proportion of patients on dulaglutide [140/280 (50.0%)]
achieved HbA1c ≤6.5% compared with placebo [1/68 (1.5%)]
at 26 weeks (LOCF; p <0.001; Figure 3B). Proportions of
patients who achieved HbA1c <7.0 and ≤6.5% were simi-
lar between dulaglutide and liraglutide at 26 weeks [LOCF,
976 Miyagawa et al. Volume 17 No. 10 October 2015

DIABETES, OBESITY AND METABOLISM
original article
Table 1. Baseline demographics and characteristics.
Var iable
Dulaglutide 0.75 mg
(N =280)
Liraglutide 0.9 mg
(N =137) Placebo (N =70) Total (N =487)
Sex, n (%)
Men 228 (81) 113 (83) 55 (79) 396 (81)
Women 52 (19) 24 (18) 15 (21) 91 (19)
Mean (s.d.) age, years 57.2 (9.6) 57.9 (10.4) 57.7 (8.3) 57.4 (9.6)
Age ≥65 years, n (%) 68 (24) 39 (29) 13 (19) 120 (25)
Mean (s.d.) weight, kg 71.3 (12.5) 70.2 (12.5) 69.3 (11.6) 70.7 (12.4)
Mean (s.d.) BMI, kg/m225.6 (3.6) 25.5 (3.5) 25.2 (3.2) 25.5 (3.5)
Mean (s.d.) diabetes duration, years 6.8 (5.6) 6.3 (6.0) 6.3 (5.1) 6.6 (5.6)
Mean (s.d.) HbA1c, % 8.15 (0.77) 8.08 (0.89) 8.20 (0.83) 8.14 (0.81)
HbA1c >8.5%, n (%) 89 (32) 42 (31) 26 (37) 157 (32)
Mean (s.d.) fasting serum glucose, mmol/l 9.4 (1.9) 9.0 (1.9) 9.6 (2.2) 9.3 (1.9)
Pre-study OAM therapy, n (%) 94 (34) 48 (35) 22 (31) 164 (34)
OAM-naïve, n (%) 186 (66) 89 (65) 48 (69) 323 (66)
Mean (s.d.) HOMA2-%𝛽(fasting insulin) 34.5 (19.4) 36.9 (20.3) 33.0 (23.5) 34.9 (20.3)
Mean (s.d.) HOMA2-%S (fasting insulin) 99.3 (53.8) 100.7 (52.8) 109.1 (57.8) 101.1 (54.1)
All patients were from Japan. BMI, body mass index; HbA1c, glycated haemoglobin; HOMA2-%𝛽, updated homeostasis model assessment of 𝛽-cell func-
tion; HOMA2-%S, updated homeostasis model assessment of insulin sensitivity; N, number of patients in full analysis set; OAM, oral antihyperglycaemic
medication; s.d., standard deviation.
200/280 (71.4%) vs 94/136 (69.1%) and 140/280 (50.0%) vs
67/136 (49.3%), respectively].
e LS mean changes in fasting serum glucose from base-
line at week 26 were −2.18, −2.21 and 0.06 mmol/l for dulaglu-
tide, liraglutide and placebo, respectively (Figures 2B, 3C);
dulaglutide signicantly reduced fasting serum glucose com-
pared with placebo at week 26 (p <0.001). Dulaglutide sig-
nicantly reduced SMBG values from baseline compared with
placebo for all measures (seven-point prole values, mean
SMBG values, 2-h excursion values for each meal, and circa-
dian variation; all p <0.05), except for the 2-h excursion for
the evening meal (Figure 3D and Table S1). Dulaglutide treat-
ment resulted in similar LS mean decreases from baseline in all
SMBG values compared with liraglutide.
Treatmentdidnotresultinsignicantchangesinbody
weight from baseline at week 26 (LS mean changes: dulaglu-
tide, −0.02 kg; liraglutide, −0.36 kg; and placebo, −0.63 kg),
and there were no signicant dierences between groups
(Figure 2C).
Dulaglutide signicantly increased the updated homoeosta-
sis model assessment of 𝛽-cell function from baseline compared
with placebo (p <0.001) at week 26 (LOCF); the dierence
between dulaglutide and liraglutide was not signicant. No sig-
nicant dierences were observed between dulaglutide and the
other treatment groups for the updated homoeostasis model
assessment of insulin sensitivity (Figure S1).
Safety
No deaths were reported during the treatment period
(Table 2). e incidence rates of serious adverse events
and treatment-emergent adverseeventsweresimilarbetween
the groups up to 26weeks (Tables 2 and S2). e most fre-
quently reported treatment-emergent adverse events (≥5%
of patients in any group) are shown in Table 2; of these, only
decreased appetite was dierent between dulaglutide and
liraglutide [dulaglutide, n =2 (0.7%); liraglutide, n =8 (5.8%);
p=0.003].
One patient, in the dulaglutide group, reported severe
constipation; all other treatment-emergent gastrointestinal
adverse events up to week 26 were considered to be of mild
or moderate intensity. e numbers of patients in each group
who discontinued the study because of an adverse event were
dulaglutide, n =3 (1.1%), liraglutide, n =1 (0.7%) and placebo,
n=0 (Table 2). Six patients discontinued the study drug within
the rst 26 weeks of treatment because of treatment-emergent
gastrointestinal adverse events: dulaglutide, n =1(gastroen-
teritis) and liraglutide, n =5 (abdominal discomfort, n =2;
constipation, decreased appetite and nausea, n=1foreach).
Up to 26 weeks, 9 patients (1.8%) experienced any hypo-
glycaemia [dulaglutide, n =6 (2.1%); liraglutide, n =2 (1.5%);
placebo, n =1 (1.4%)]; no episodes of severe hypoglycaemia
were reported. Two patients (0.7%; both dulaglutide) experi-
enced nocturnal hypoglycaemia up to 26weeks.
Inapairwisecomparisonat26weeks,dulaglutidesignif-
icantly increased total amylase and lipase levels compared
with placebo (p <0.001; Table 2). No dierence was observed
between dulaglutide and liraglutide in changes in total amy-
lase level. Liraglutide signicantly increased lipase levels com-
pared with dulaglutide (median increases were 11.0 and 7.0 U/l,
respectively; p <0.001; Table 2). No patients in the dulaglu-
tide or liraglutide groups had amylase levels >3×upper limit
of normal (ULN; Table 2). Four (1.5%) patients in the dulaglu-
tide group and 2 (1.5%) in the liraglutide group had lipase levels
>3×ULN; the elevated values decreased below 3 ×ULN while
the patients continued on study medication. None of these
patients discontinued study treatment because of pancreatic
adverse events. ere were no adjudicated events of conrmed
pancreatitis.
One patient, a 67-year-old female who was treated with
liraglutide for approximately 15 weeks, was diagnosed with
pancreatic carcinoma.
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DIABETES, OBESITY AND METABOLISM
6.0
6.5
7.0
7.5
8.0
8.5
9.0
048 14 20 26
Hba1c (LSM [s.e.], %)
Treatment Duration (Weeks)
Dulaglutide 0.75 mg Liraglutide 0.9 mg Placebo
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
0 2 4 6 8 101214161820222426
FSG (LSM [s.e.], mmol/L)
Treatment Duration (Weeks)
Dulaglutide 0.75 mg Liraglutide 0.9 mg Placebo
B
A
-1.5
-1
-0.5
0
0.5
1
1.5
024 8 14 20 26
Body Weight, Change from
baseline (LSM [s.e.], kg)
Treatment Duration (Weeks)
Dulaglutide 0.75 mg Liraglutide 0.9 mg Placebo
§
§§ §
§
§
C
*
*
***
**
Figure 2. Glycated haemoglobin (HbA1c), fasting serum glucose and body weight baseline values up to 26 weeks. (A) HbA1c values from baseline to
26 weeks (%). (B) Fasting serum glucose values from baseline to 26 weeks (mmol/l). (C) Body weight change from baseline to 26 weeks. FSG, fasting serum
glucose; LSM, least-squares mean; s.e., standard error. *p <0.001 dulaglutide vs placebo. §All dulaglutide comparisons vs placebo and liraglutide p>0.05.
Seated vital signs and ECG PR interval are summarized
in Table 2. ere were no dierences in systolic or dias-
tolic blood pressure change from baseline between dulaglu-
tide and placebo; liraglutide resulted in a signicantly greater
decrease from baseline in seated systolic blood pressure com-
pared with dulaglutide (p =0.013). Seated pulse rates were
increased in all groups, with no signicant dierences between
the groups. ECG PR interval was prolonged from baseline
in dulaglutide compared with placebo (p =0.052); the ECG
PR interval increase with liraglutide was similar to dulaglu-
tide. No conrmed adjudicated cardiovascular events were
observed.
From baseline up to 26weeks, all patients had serum cal-
citonin values within normal limits. e patient with pancre-
atic carcinoma described previously also had a thyroid neo-
plasm treatment-emergent adverse event, which was consid-
eredtobeofmildseverityandnotrelatedtostudydrugbythe
investigator.
Dulaglutide signicantly reduced urine albumin : creatinine
ratio (p <0.001) from baseline to 26 weeks compared with
placebo (Table S3). Dulaglutide treatment resulted in signi-
cant percent reductions in triglycerides (−8.0%; p =0.020) and
total cholesterol (−2.9%; p =0.009) from baseline compared
with placebo (Table S4).
978 Miyagawa et al. Volume 17 No. 10 October 2015

DIABETES, OBESITY AND METABOLISM
original article
-1.43 -1.33
0.14
-1.5
-1
-0.5
0
0.5
HbA1c, Change from
Baseline (LSM [s.e.],%)
Dulaglutide 0.75 mg Liraglutide 0.9 mg Placebo
*
A
71.4
50.0
69.1
49.3
5.9 1.5
0
20
40
60
80
HbA1c <7% HbA1c ≤6.5%
Patients (%)
Achieving HbA1c Target
Dulaglutide 0.75 mg Liraglutide 0.9 mg Placebo
*
*
B
-2.18 -2.21
0.06
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
FSG, Change from
Baseline (LSM [s.e.],
mmol/l)
Dulaglutide 0.75 mg Liraglutide 0.9 mg Placebo
C
*
0
4
8
12
16
20
BB AB BL AL BD AD BT BB AB BL AL BD AD BT BB AB BL AL BD AD BT
SMBG
(LSM [s.e.], mmol/l)
SMBG Timepoints (Seven-Point)
Endpoint Baseline
D
Liraglutide 0.9 mg Placebo
Dulaglutide 0.75 mg
Figure 3. Glycated haemoglobin (HbA1c) change from baseline, HbA1c target, fasting serum glucose, and self-monitored blood glucose. (A) Change in
HbA1c from baseline at week 26 (%). (B) Proportions of patients achieving predened HbA1c targets at week 26 (LOCF). (C) Change in fasting serum
glucose from baseline at week 26 (mmol/l). (D) Seven-point SMBG measurements at baseline and endpoint (week 26; LOCF) (mmol/l). AB, aer breakfast;
AD, aer dinner; AL, aer lunch; BB, before breakfast; BD, before dinner; BL, before lunch; BT, bedtime; FSG, fasting serum glucose; HbA1c, glycated
haemoglobin; LOCF, last observation carried forward; LSM, least-squares mean; s.e., standard error; SMBG, self-monitored blood glucose. *p <0.001
dulaglutide vs placebo.
ree patients in the dulaglutide group had treatment-
emergent dulaglutide antidrug antibodies (Table 2).
Discussion
eaimofthepresentstudywastoexaminetheecacy
and safety of once-weekly dulaglutide (0.75mg) in Japanese
patients with type 2 diabetes. Overall, in the rst head-to-head
GLP-1 receptor agonist study in Japanese patients with type 2
diabetes, once-weekly dulaglutide (0.75 mg) was non-inferior
to once-daily liraglutide (0.9mg) and superior to placebo in
change from baseline HbA1c.
is is the rst study to demonstrate the ecacy and safety
of dulaglutide monotherapy in Japanese patients with type 2
Volume 17 No. 10 October 2015 doi :10.1111 /d o m. 12534 979

original article
DIABETES, OBESITY AND METABOLISM
Table 2. Safety assessments and vital signs up to 26 weeks of treatment.
pvalue
Dulaglutide
0.75 mg
(N =280)
Liraglutide
0.9 mg
(N =137)
Placebo
(N =70)
Dulaglutide
0.75 mg vs
liraglutide 0.9 mg
Dulaglutide
0.75 mg vs
placebo
Deaths 0 0 0 N/A N/A
Serious adverse events* 3 (1.1) 2 (1.5) 2 (2.9) 0.665 0.262
Patients with at least one treatment-emergent adverse event 157 (56.1) 76 (55.5) 39 (55.7) 0.917 >0.999
Treatment-emergent adverse events (≥5% in any group)
Nasopharyngitis 37 (13.2) 16 (11.7) 4 (5.7) 0.755 0.097
Decreased appetite 2 (0.7) 8 (5.8) 0 0.003 >0.999
Gastrointestinal disorders 61 (21.8) 42 (30.7) 11 (15.7) 0.054 0.322
Constipation 19 (6.8) 8 (5.8) 3 (4.3) 0.834 0.587
Diarrhoea 16 (5.7) 5 (3.6) 1 (1.4) 0.477 0.212
Nausea 15 (5.4) 11 (8.0) 1 (1.4) 0.289 0.211
Abdominal distension 6 (2.1) 7 (5.1) 0 0.133 0.604
Patients who discontinued study due to an adverse event 3 (1.1) 1 (0.7) 0 >0.999 >0.999
Vital signs, mean change from baseline (s.e.)†
Seated systolic blood pressure, mmHg 0.62 (0.62) −2.10 (0.89) 0.53 (1.25) 0.013 0.944
Seated diastolic blood pressure, mmHg 1.09 (0.39) 0.43 (0.56) 0.29 (0.78) 0.336 0.360
Seated pulse rate, bpm 3.35 (0.45) 4.77 (0.64) 1.49 (0.90) 0.070 0.064
ECG PR interval mean change from baseline (s.e.)†, ms 2.20 (0.60) 2.07 (0.88) −0.45 (1.22) 0.899 0.052
Pancreatic enzymes, median change (IQR)
Tot al amy las e, U /l ‡7.0 (2.0–15.0) 7.0 (1.0–15.0) 0.0 (−6.0–6.0) 0.605 <0.001
Lipase, U/l‡7.0 (1.0–13.0) 11.0 (5.0–21.0) 1.0 (−6.0–5.0) <0.001 <0.001
Patients with treatment-emergent abnormal changes in pancreatic enzymes (>ULN)
Total amylase§ 11/261 (4.2) 8/124 (6.5) 4/62 (6.5) 0.450 0.500
Lipase§ 47/254 (18.5) 36/121 (29.8) 3/61 (4.9) 0.017 0.006
Patients with pancreatic enzyme concentration >3×ULN
Total amylase 0 0 1 (1.5) N/A 0.191
Lipase 4 (1.5) 2 (1.5) 0 1.000 1.000
Treatment-emergent dulaglutide antidrug antibodies¶
Dulaglutide antidrug antibodies 3 (1.1) 0 0 N/A N/A
Dulaglutide neutralising antidrug antibodies 0 0 0 N/A N/A
nsGLP-1 cross-reactive antibodies 2 (0.7) 0 0 N/A N/A
nsGLP-1 neutralizing antibodies 0 0 0 N/A N/A
Both nsGLP-1 neutralizing and cross-reactive antibodies 0 0 0 N/A N/A
Data are n (%) unless otherwise specied. Treatment-emergent adverse events coded using MedDRA Version 16.1. IQR, interquartile range; MedDRA,
Medical Dictionary for Regulatory Activities; N, number of patients in safety analysis set; N/A, not applicable; nsGLP-1, native-sequence glucagon-like
peptide-1;s.e.,standarderror;ULN,upperlimitofnormal.
*Reported serious adverse events are listed in Table S2.
†Data are least-squares mean change (s.e.).
‡Data are LOCF, median change (IQR).
§Data represent the number of patients with treatment-emergent abnormal change in pancreatic enzymes at week 26 over the number of patients with
normal results at baseline.
¶ese values include all postbaseline observations including the safety follow-up.
diabetes, and these ndings may help inform treatment deci-
sions for those patients. is is also the rst study in Japanese
patients to show non-inferiority of once-weekly dulaglutide
(0.75 mg) to once-daily liraglutide (0.9 mg), the maximum
doses evaluated in Japanese phase III registration programmes
for these compounds. In other once-weekly GLP-1 recep-
tor agonist studies DURATION-6 [26 weeks: exenatide once
weekly (AstraZeneca, London, UK)] and HARMONY-7
[32 weeks: albiglutide (GlaxoSmithKline, Wilmington, DE,
USA)], neither exenatide once weekly nor albiglutide demon-
strated non-inferiority to liraglutide (1.8 mg) on HbA1c change
from baseline values [LS mean dierences 0.21% (95% CI 0.08,
0.33), non-inferiority margin of 0.25%; and 0.21% (95% CI
0.08, 0.34), non-inferiority margin of 0.3%, respectively]
[17,18]. AWARD-6 (26 weeks: dulaglutide 1.5 mg) has been
theonlyphaseIIIstudytodatetodemonstratenon-inferiority
to liraglutide (1.8 mg) on HbA1c change from baseline mea-
surements, in mainly Caucasian patients with type 2 diabetes
[LS mean dierence −0.06% (95% CI −0.19, 0.07), with a
non-inferiority margin of 0.4%] [12].
e HbA1c reduction observed at 26weeks in the present
study in Japanese patients with type 2 diabetes is consis-
tent with the upper range of reductions seen in the global
AWARD studies for dulaglutide (0.75 or 1.5mg) [11–14]. It
has been previously reported that GLP-1 receptor agonists
exert greater HbA1c-lowering eects in Asian compared with
980 Miyagawa et al. Volume 17 No. 10 October 2015

DIABETES, OBESITY AND METABOLISM
original article
non-Asian people, and it has been suggested that dierences
in BMI between the ethnicities may be a contributing factor
in the observed dierential eects [19]. In the present study,
once-weekly dulaglutide (0.75 mg) resulted in approximately
70 and 50% of patients achieving HbA1c targets of <7.0 or
≤6.5% at week 26 (LOCF), respectively. ese results were also
consistentwithaphaseIIstudyofdulaglutideinJapanese
patients [20].
IthasbeenreportedthatJapanesepatientswithtype2
diabetes tend to have a pathophysiology of insulin secretion
impairment rather than insulin resistance and are inclined to
be less obese compared with Western populations [21]. Because
GLP-1 receptor agonists have a potential for improving 𝛽-cell
function and increasing insulin secretion, this class may be
particularly eective in lean East-Asian patients with type 2
diabetes. In the present study, both dulaglutide and liraglu-
tide resulted in improvement in 𝛽-cell function, consistent with
previous reports for liraglutide 0.9mg in a study of Japanese
patients with type 2 diabetes [22].
Notably, there was no clinically relevant reduction in weight
in any group over the 26-week period. is was not unex-
pected and is consistent with observations in studies of liraglu-
tide (0.9 mg) in Japanese patients [23,24]. e reason for this is
unclear. One could speculate that it might be related to con-
comitant background medications or to lower baseline body
weights in the Japanese population, or that it might be an eect
of improvement in 𝛽-cell function, as described below. e
mean baseline body weight was approximately 70 kg (mean
BMI 25.6 kg/m2), which is typical of Japanese patients with
type 2 diabetes and lower than in Caucasian patients. In such
patients, dulaglutide improved HbA1c regardless of weight
change during treatment, possibly through improvement in
𝛽-cell function rather than insulin resistance.
Overall, once-weekly dulaglutide (0.75 mg) was generally
well tolerated, with a low number of overall discontinuations
in each group. e safety prole of dulaglutide in this study
(Table 2) was similar to that seen in previous GLP-1 receptor
agonist studies [11–14,17,18]. e most-frequently reported
adverse event was nasopharyngitis, reported by 12–13% of
patients in the active treatment groups. e incidence of
nasopharyngitis in this study was not considered clinically
relevant, and the dierence between the treatment groups was
not statistically signicant. e incidence of gastrointestinal
symptoms was also similar between dulaglutide and liraglutide.
Nausea was transient and occurred most oen during the rst
2 weeks of treatment. Notably, decreased appetite occurred
signicantly more oen with liraglutide than with dulaglu-
tide. e incidence of hypoglycaemia was similar between
the groups and very low as a whole, with no events of severe
hypoglycaemia observed. ese results are similar to those seen
in the class [11–14,17–19,23], indicating that GLP-1 receptor
agonists, including dulaglutide, when used as monotherapy,
show a low propensity to cause hypoglycaemia.
Vital signs at week 26 showed mean increases in seated pulse
rate in the dulaglutide and liraglutide groups, and these changes
appear to be a GLP-1 receptor agonist class eect [25].
Compared with placebo, dulaglutide resulted in statistically
signicant increases in amylase and lipase levels at week 26.
Liraglutideresultedinastatisticallysignicantincreasein
lipase level compared with dulaglutide. ese ndings are
also consistent with a recent meta-analysis of GLP-1 receptor
agonist clinical trials [26]. ese types of elevations were
not predictive of pancreatitis during the dulaglutide global
development programme [11–14]; however, the long-term
clinical signicance of these elevations remains unclear. Acute
pancreatitiswasnotobservedinthepresentstudy.
e urine albumin : creatinine ratio and triglyceride levels
were both decreased with dulaglutide and liraglutide. ese
pleiotropic eects might be a class eect of GLP-1 receptor ago-
nists. A recent report showed that liraglutide protected against
albuminuria in streptozotocin-induced diabetic rats in a pro-
tein kinase A-mediated manner, which was not related to low-
ered glucose levels [27]. Meier et al. [28] and Xiao et al. [29]
have reported that GLP-1 improves postprandial lipidaemia
because of delayed gastric emptying and insulin-mediated inhi-
bition of lipolysis and intestinal lipoprotein production. e
combined eects of lowered urine albumin : creatinine ratio,
triglycerides and cholesterol levels with dulaglutide treatment
may provide protection against cardiovascular disease. GLP-1
receptor agonists also exhibit numerous overlapping and dis-
tinct actions in the cardiovascular system [30,31]. Several
studies of cardiovascular event outcomes aer treatment with
GLP-1 receptor agonists are currently ongoing; the results will
provide more information on the clinical relevance of GLP-1
receptor agonist treatment with regard to the cardiovascular
system.
ree (1.1%) patients in the dulaglutide group and
no patients in the liraglutide or placebo groups had
treatment-emergent dulaglutide antidrug antibodies detected.
e incidence of antibodies in the present study was lower
than in other GLP-1 compounds with an exendin-4 backbone
(exenatide twice daily, 44–60% [32]; exenatide once weekly,
61–68% [33,34]; and lixisenatide, approximately 70% [35]); the
lower incidence in the present study is probably attributable to
the design of the dulaglutide molecule [36].
e present study has several limitations. An open-label for-
mat for liraglutide was used because placebo pens mimick-
ing liraglutide were not commercially available. e length of
the study was relatively short in clinical practice with type
2 diabetes; however, the 26-week primary endpoint was long
enough to reach steady-state in order to evaluate the dulaglu-
tide treatment eect for the primary and secondary objectives
on HbA1c. is randomized, controlled study continued for
another 26-week period, during which all patients on placebo
were switched to dulaglutide to gather further safety data; these
resultswillbereportedatalaterdate.
In conclusion, monotherapy with once-weekly dulaglutide
(0.75 mg) was safe and eective in Japanese patients with type
2 diabetes and resulted in similar safety and ecacy proles
compared with once-daily liraglutide (0.9 mg).
Acknowledgements
etrialwassponsoredbyEliLillyandCompany.Wewould
like to thank the study investigators, sta, and participants
for their needed contributions. We would also like to thank
Volume 17 No. 10 October 2015 d oi : 10 .1111 /do m.12534 981

original article
DIABETES, OBESITY AND METABOLISM
Miwa Sakaridani for clinical trial management of the study. e
authors would like to thank David Meats (inVentiv Health Clin-
ical) for his medical writing contributions for the submission of
this manuscript.
Conict of Interest
All authors participated in reviewing and interpreting the data
and providing comments and revisions to the manuscript. All
authors approved the nal version of the manuscript and take
full responsibility for the content. J. M. was a trial investigator,
participated in data collection, and has received: grants from
Boehringer Ingelheim and Eli Lilly; and research support from
Astra Zeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly,
Kowa Pharmaceutical, Novartis Pharma, Ono Pharmaceutical
and Sanwa Kagaku Kenkyusho. M. O. was a trial investigator,
participated in data collection, and has received: grants from
Eli Lilly, Novo Nordisk and Sano; advisory panel fees from
Eli Lilly, Novo Nordisk and Sano; research support from Eli
Lilly, Novo Nordisk and Sano; and speaker’s bureau fees from
EliLilly,NovoNordiskandSano.T.T.wasatrialinvestigator,
participatedindatacollection,andhasreceivedagrantfromEli
Lilly and speaker’s bureau fees from Eli Lilly and Novo Nordisk.
N. I. prepared the rst dra of the manuscript, was responsible
for trial design and medical oversight during the trial, and is an
employee of Eli Lilly Japan K.K. Y. T. prepared the rst dra of
the manuscript, was responsible for the statistical consideration
in the analysis and trial design, and is an employee of Eli Lilly
Japan K.K. T. I. prepared the rst dra of the manuscript,
was responsible for trial design and medical oversight during
thetrial,craedthediscussionandresearchcontext,isan
employee of Eli Lilly Japan K.K. and has the company stock
option.
Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Figure S1. Updated homeostasis model assessment changes
from baseline at 26 weeks (LOCF).
Table S1. Summary of least squares (±standard error)
mean changes from baseline in self-monitored blood glucose
(mmol/l) values (LOCF at week 26).
Table S2. Summary of serious adverse events by preferred
term and treatment for the treatment period from baseline to
26 weeks.
Table S3. Summary and analysis of renal analytes: median
baselinevaluesandmedianchangesfrombaselineto26weeks
(LOCF).
Table S4. Summary and analysis of lipid proles: median
baseline values and median absolute and percent changes from
baseline to 26 weeks (LOCF).
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Volume 17 No. 10 October 2015 doi :10.1111 /d o m. 12534 983