article: treatment monotherapy with the once-weekly...

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: [email protected]

DIABETICMedicine

DOI:10.1111/j.1464-5491.2012.03745.x

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ª 2012 Eli Lilly and Company.

Diabetic Medicine ª 2012 Diabetes UK 1

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Eli Lilly & Co., Indianapolis, IN, U.S.A.

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

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53.00 to 80.33

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47.54 to 74.86

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42.08 to 69.40

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47.54 to 80.33

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53.00 to 80.33

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by subcutaneous injection

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53.00 or 47.54

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fine to use

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)




Placebo32 patients


2 patients

discontinued

treatment period

Protocol violation (2)

0 patients

discontinued

treatment period

4 patients

discontinued

treatment period

Adverse event (2)


Patient decision (1)

2 patients

discontinued

treatment period

Adverse event (1)

Patient decision (1)

3 patients

discontinued

treatment period

Adverse event (1)


Lost to follow-up (1)

153 patients completed treatment period

31 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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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.


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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

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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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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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fine

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.

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AZ= Astra Zeneca, BMS= Bristol Myers Squibb

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Bastyr EJ 3rd. The effects of LY2189265, a long-acting glucagon-

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Zhuang D et al. Exenatide once weekly versus twice daily for

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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

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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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13: 418-425.

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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that illegible mark-ups may delay publication.

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

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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 .

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