DIABETICMedicine
DOI: 10.1111/j.1464-5491.2012.03745.x
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
No. of pages: 8 PE: Padma
Accepted 26 June 2012
Journal: DME CE: Blackwell
Grunberger 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
Author Received:
1
Dispatch: 21.7.12
G. Grunberger1, A. Chang2, G. Garcia Soria3, F. T. Botros4, R. Bsharat4 and Z. Milicevic5
Abstract
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, inhibition 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,
Correspondence to: Zvonko Milicevic MD PhD, Lilly Research Laboratories,
Vienna, Austria. E-mail: [email protected]
ª 2012 Eli Lilly and Company.
Diabetic Medicine ª 2012 Diabetes UK
1
XXXXX, XXXXX), a long-acting GLP-1 analogue, consists of 2
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 interaction with high-affinity Fc receptors, cytotoxicity and immunogenicity [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].
1
Journal Name
Conclusions The observed dulaglutide dose-dependent reduction in HbA1c and its acceptable safety profile support further
clinical development for treatment of Type 2 diabetes.
Manuscript No.
5
4
7
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.
Results
3
Methods This 12-week, double-blind, placebo-controlled, dose–response trial randomized 167 patients who were antihyperglycaemic 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).
B
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.
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Dulaglutide monotherapy and glycaemic control • G. Grunberger et al.
COLOR
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NH2
NH2
2
GLP-1 peptide
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4
Linker peptide
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9
IgG4-Fc domain
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HOOC
COOH
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FIGURE 1 Dulaglutide structure of the molecule.
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Dose-dependent reductions in fasting plasma glucose,
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postprandial glucose and HbA1c were previously reported in
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patients with Type 2 diabetes (n = 43) receiving once-weekly
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dulaglutide (doses ranging from 0.05 to 8 mg) for 5 weeks [9].
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The objective of this Phase 2 study was to assess the dose–
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response relationship with respect to HbA1c across a narrower
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range of doses and a longer 12-week treatment period.
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Research design and methods
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Study design
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This 12-week, double-blind, placebo-controlled, dose–response
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study assessed the safety and efficacy of dulaglutide in patients
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with Type 2 diabetes (n = 167). The study was conducted
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between November 2008 and January 2010 in 44 sites in seven
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countries. Eligible patients were anti-hyperglycaemic medica34
tion-naı̈ve or on metformin monotherapy. Inclusion criteria
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were: age ‡ 18 and £ 75 years; BMI ‡ 23 to £ 40 kg ⁄ m2 for
36
patients native to and residents of South and ⁄ or East Asia; ‡ 25
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to £ 40 kg ⁄ m2 for all other patients; stable weight for 3 months
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before screening; and HbA1c ‡ XX to £ XX mmol ⁄ mol (‡ 7.0
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to £ 9.5%) for anti-hyperglycaemic medication-naı̈ve patients
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and > XX to £ XX mmol ⁄ mol (> 6.5 to £ 9.0%) [> XX to
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£ XX mmol ⁄ mol (> 6.0 to £ 8.5% prior to a protocol
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43 3 amendment)] for patients who were taking metformin. Exclusion criteria included treatment with any oral anti-diabetes
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drug other than metformin within 3 months or other GLP-1
45
analogue within 6 months prior to screening, prior use of
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insulin for long-term glycaemic control, serious cardiovascular
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condition, liver disease, history of pancreatitis or serum creat48
inine ‡ 1.5 mg ⁄ dl (men) or ‡ 1.4 mg ⁄ dl (women).
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Study periods included: 2-week screening, 4- to 8-week lead50
in (8-week washout after discontinuing metformin was
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required prior to obtaining the qualifying HbA1c); 12-week
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treatment period; and 4-week safety follow-up. After lead-in,
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an HbA1c value ‡ XX to £ XX mmol ⁄ mol (‡ 6.5 to £ 9.5%)
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[‡ XX to £ XX mmol ⁄ mol (‡ 7.0 to £ 9.5%) prior to protocol
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2
amendment)] was required for randomization. Patients were 4
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 once weekly; as this was a placebo-controlled 5
study, the use of additional oral anti-diabetes drugs was permitted only when needed for rescue therapy (according to prespecified 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 institutional review board and was performed in accordance with
the principles of the Declaration of Helsinki. Prior to participation, 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-monitored 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 antibodies. Electrocardiograms were recorded in triplicate and
tracings were over-read by a cardiologist at a centralized vendor (Biomedical Systems Corporation, XXXXX, XXXXX,
XXX); this report was used for analysis. Referencing the 6
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 assistance of another person to actively administer therapy [10].
Patients with at least one pancreatic enzyme measurement ‡ 3
times the upper limit of normal underwent a standardized 7
diagnostic examination.
Plasma analytes and HbA1c were quantified by Quintiles
Laboratories (Smyrna, GA, USA). Electrochemiluminescence immunosorbent assay was used for detection of antidulaglutide antibodies (Millipore, XXXX, XXXX, XXX); 8
ª 2012 Eli Lilly and Company.
Diabetic Medicine ª 2012 Diabetes UK
Original article
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DIABETICMedicine
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 categorical 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, USA).
9
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).
460 patients entered trial
293 patients failed screening or discontinued
prior to randomization
167 patients enrolled/randomized
Dulaglutide 3.0 mg
3 patients
Dulaglutide 0.1 mg
35 patients
Dulaglutide 0.5 mg
34 patients
Dulaglutide 1.0 mg
34 patients
Dulaglutide 1.5 mg
29 patients
Placebo
32 patients
3 patients
discontinued
2 patients
discontinued
treatment period
3 patients
discontinued
treatment period
0 patients
discontinued
treatment period
4 patients
discontinued
treatment period
2 patients
discontinued
treatment period
Protocol violation (2)
Adverse event (1)
Protocol violation (1)
Lost to follow-up (1)
Adverse event (2)
Protocol violation (1)
Patient decision (1)
Adverse event (1)
Patient decision (1)
33 patients completed
treatment
31 patients completed
treatment
25 patients completed
treatment
30 patients completed
treatment
Dose discontinued
from study
Sponsor decision (3)
0 patients completed
34 patients completed
treatment
153 patients completed treatment period
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.
ª 2012 Eli Lilly and Company.
Diabetic Medicine ª 2012 Diabetes UK
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DIABETICMedicine
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Dulaglutide monotherapy and glycaemic control • G. Grunberger et al.
Table 1 Patient characteristics at entry (screening) for intent-to-treat population and reasons for discontinuation
Intent-to-treat
population
(mean sd)
Age (years)
Sex
Female, n (%)
Male, n (%)
Race, Caucasian
⁄ Asian ⁄ Black
or African
American ⁄ Others (%)
Body weight (kg)
BMI (kg ⁄ m2)
HbA1c (mmol ⁄ mol)
HbA1c (%)
Duration of
diabetes (years)
History of
metformin, n (%)
No
Yes
Systolic blood
pressure (mmHg)
Diastolic blood
pressure (mmHg)
Reason for
discontinuation, n (%)
Adverse events
Lost to follow-up
Protocol violation
Subject decision
Completers, n (%)
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*
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
14 (43.8)
18 (56.3)
78 ⁄ 16 ⁄ 3 ⁄ 3
24 (68.6)
11 (31.4)
83 ⁄ 11 ⁄ 3 ⁄ 3
18 (52.9)
16 (47.1)
82 ⁄ 15 ⁄ 3 ⁄ 0
18 (52.9)
16 (47.1)
77 ⁄ 15 ⁄ 0 ⁄ 9
16 (55.2)
13 (44.8)
83 ⁄ 14 ⁄ 3 ⁄ 0
90 (54.9)
74 (45.1)
81 ⁄ 14 ⁄ 2 ⁄ 3
0.360
90.9 18.9
32.1 5.2
57 7
7.4 0.6
3.9 4.7
87.1 17.3
32.9 4.8
54 6
7.1 0.6
3.9 3.2
90.2 21.3
32.3 5.4
55 7
7.2 0.6
3.7 3.8
86.9 17.0
32.2 4.5
56 7
7.3 0.7
3.3 2.5
85.8 18.6
31.0 4.3
56 5
7.3 0.4
4.6 4.1
88.2 18.6
32.1 4.8
56 6
7.2 0.6
3.9 3.7
0.770
0.657
0.547
6 (18.8)
26 (81.3)
128.5 12.3
7 (20.0)
28 (80.0)
130.7 15.9
6 (17.6)
28 (82.4)
129.6 16.1
8 (23.5)
26 (76.5)
125.6 15.1
4 (13.8)
25 (86.2)
127.3 14.4
31 (18.9)
133 (81.1)
128.4 14.8
0.912
0.662
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
1 (3.1)
1 (3.1)
0 (0.0)
1 (3.1)
29 (90.6)
0 (0.0)
0 (0.0)
2 (5.7)
0 (0.0)
33 (94.3)
1 (2.9)
1 (2.9)
1 (2.9)
0 (0.0)
31 (91.2)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
34 (100)
2 (6.9)
0 (0.0)
1 (3.4)
1 (3.4)
25 (86.2)
4 (2.4)
2 (1.2)
4 (2.4)
2 (1.2)
152 (92.7)
0.254
0.652
0.562
0.265
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.
0.980
0.722
15
Primary endpoint
Secondary endpoints
At randomization, baseline HbA1c (mean sd) was comparable 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); leastsquares 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 reductions 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.
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); leastsquares 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. Dosedependent reductions in mean pre-meal and postprandial plasma 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
4
ª 2012 Eli Lilly and Company.
Diabetic Medicine ª 2012 Diabetes UK
Original article
(a)
9.0
HbA1c (mmol/mol)
Change from baseline
66
8.0
60
7.5
7.0
54
6.5
48
6.0
5.0
0.0
Baseline
42
31
0
4
8
0.0
0
–0.2
–0.8
–9
*†
–1.0
–1.2
0
12
0
*
–1
–2
*†
–18
–36
Fasting plasma
glucose (mmol/l)
Change from baseline
0
1
0
0
*
–1
–18
*†
–2
0
12
–36
–54
–3
–54
–3
18
4
8
12
∆ Fasting plasma glucose(mg/dl)
18
∆ 7-point self monitored
plasma glucose (mg/dl)
7-point self monitored plasma
glucose (mmol/l)
Change from baseline
8
(d)
Time (weeks)
Time (weeks)
(e)
(f)
60
100
Placebo
Dula 0.1
Dula 0.5
Dula 1.0
Dula 1.5
75
50
25
HOMA2-%B (%)
Change from baseline
Per cent of patients achieving
HbA1c target (%)
4
Time (weeks)
1
8
–12
–15
–1.4
12
Time (weeks)
4
–6
–0.6
(c)
0
–3
*
–0.4
∆ HbA1c (%)
HbA1c (mmol/mol)
(b)
0.2
72
8.5
HbA1c (%)
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0
50
40
*†
30
20
10
0
–10
–20
< 53 mmol/mol
(< 7.0%)
≤ 48 mmol/mol
(≤ 6.5%)
0
Placebo
Dula 0.1
4
8
12
Time (weeks)
HbA1c target
Dula 0.5
Dula 1.0
Dula 1.5
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) leastsquares 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%) at week 12. Statistically significant dose effect is observed for both targets, P < 0.001 by Cochran–Armitage trend exact 14
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.
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): placebo (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.
ª 2012 Eli Lilly and Company.
Diabetic Medicine ª 2012 Diabetes UK
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 pancreatitis and participation in a weight-loss programme, respectively.
Safety and tolerability
Overall, 51.8% (n = 85) of patients reported ‡ 1 treatmentemergent adverse event during the treatment period, with no
significant trend across groups (see also Supporting Information, Table S1). The most frequent treatment-emergent adverse
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Dulaglutide monotherapy and glycaemic control • G. Grunberger et al.
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 (placebo) 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 baseline 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) demonstrated 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 antibody was 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 treatmentemergent 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 secretory 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%)
6
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 significant 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 glucose were 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]. Treatment 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 agonistmediated increase in insulin secretion and may not translate into
long-term improvement in b-cell function. These observations
are consistent with the previous 16-week, Phase-2, placebocontrolled trial showing that treatment with dulaglutide caused
significant decreases in HbA1c and blood glucose, and improvement 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 on body weight has been studied as a secondary 10
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 placebo 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 incidence 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, measurements 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
ª 2012 Eli Lilly and Company.
Diabetic Medicine ª 2012 Diabetes UK
Original article
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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 patients) demonstrated increased pancreatic enzyme levels before randomization. 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 dulaglutide 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 significant changes in systolic and diastolic blood pressures were
observed. There were no significant changes observed in lipid
values associated with dulaglutide treatment (see also Supporting Information, Table S3).
In conclusion, once-weekly administration of dulaglutide for
12 weeks in patients with Type 2 diabetes (who were antihyperglycemic 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 effects 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, SanofiAventis, AZ, BMS 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
ª 2012 Eli Lilly and Company.
Diabetic Medicine ª 2012 Diabetes UK
DIABETICMedicine
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)
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2 Moretto TJ, Milton DR, Ridge TD, Macconell LA, Okerson T,
Wolka AM et al. Efficacy and tolerability of exenatide
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3 Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Courreges JP et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy, significantly improves
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Fineman M et al. Effects of once-weekly dosing of a long-acting
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6 Matthews JE, Stewart MW, De Boever EH, Dobbins RL, Hodge RJ,
Walker SE et al. Pharmacodynamics, pharmacokinetics, safety, and
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7 Rosenstock J, Reusch J, Bush M, Yang F, Stewart M. Potential
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et al. A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1
analog, in patients with type 2 diabetes. Diabetes Obes Metab
2011; 13: 426–433.
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modeling. Diabetes Care 2004; 27: 1487–1495.
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glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week,
double-blind, randomized, controlled trial. Diabetes Care 2004; 27:
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Zhuang D et al. Exenatide once weekly versus twice daily for
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non-inferiority study. Lancet 2008; 372: 1240–1250.
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16 Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez9
Pattzi H, Olvera-Alvarez I et al. Liraglutide versus glimepiride
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monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised,
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17 Bastyr EJ, Barkin J, Botros FT, Shu J. High incidence of elevated
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18 Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH
et al. Efficacy and safety comparison of liraglutide, glimepiride, and
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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.
ª 2012 Eli Lilly and Company.
Diabetic Medicine ª 2012 Diabetes UK
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
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Query
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Query
Q1
AUTHOR: is this postal address OK as it is or is there, for example, a
postcode to be included?
Q2
AUTHOR: please give the name of the manufacturer and address
details of the company for this product; i.e. town or city and
state ⁄ country
Q3
AUTHOR: in accordance with journal style of dual reporting, please
give 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 – was
it by sub-cutaneous injection?
Q6
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Q7
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Q9
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correct
Q10
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Q11
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