GLP-1 receptor agonists

Esteban Jódar Gimeno

Dept. of Endocrinology & Clinical Nutrition. University Hospitals Quirón Salud Madrid.
Professor of Endocrinology. Health Sciences School.
Universidad Europea de Madrid.
Madrid, Spain
Contents

• Pharmacokinetics
• Size
• Structure
• Clinical ‘head-to-head’ comparisons
 Anti-diabetic treatment options for T2DM

Human Thiazolidinediones DPP-4

Metformin
insulin inhibitors

1950s 1960s 1970s 1980s 1990s 2000s 2010s

Sulphonylureas GLP-1 receptor SGLT-2

agonists inhibitors

DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium glucose co-transporter-2; T2DM, type 2 diabetes
mellitus
 GLP-1 as a therapeutic target
Albiglutide

Exenatide Dulaglutide
Exenatide BID Liraglutide OW Lixisenatide

2005 2006 2007 2008 2009 2010 2011 2012 2013 2016

Exenatide Liraglutide Exenatide Dulaglutide

BID OW

Lixisenatide
& Albiglutide
 GLP-1 receptor agonist class overview 5

GLP-1 RAs have multifactorial effects

Pancreas Brain
 Beta-cell function1  Body weight5
 Beta-cell apoptosis1  Food intake6
 Insulin biosynthesis1  Satiety7,8
 Glucose-dependent
insulin secretion1
 Glucose-dependent
Stomach
glucagon secretion1
 Gastric emptying9

 Endogenous glucose
 Cardiovascular risk2 production10
 Fatty acid metabolism3  Hepatic insulin sensitivity10
 Cardiac function3  De novo lipogenesis10
 Systolic blood pressure3  Lipotoxicity10
 Inflammation4  Steatosis11
Heart Liver

GLP-1 RA, glucagon-like peptide-1 receptor agonist.

Adapted from Campbell JE, Drucker DJ. Cell Metab 2013;17:819–37 and Pratley RE, Gilbert M. Rev Diabet Stud 2008;5:73–94. A full reference list for this slide can be found in the
slide notes.
GLP-1RAs

• Exenatide (BID and QW)

• Lixisenatide
• Liraglutide
• Albiglutide
• Dulaglutide
• Semaglutide*

*Semaglutide is under development and not approved

BID, twice daily; GLP-1RA, glucagon-like peptide-1 receptor agonist; QW, once weekly
GLPRAs therapies: Are all the same?
 Structure of GLP-1RAs
GLP-1 analogues

Liraglutide Semaglutide*
His Ala Glu Gly Thr Phe Thr Ser Asp
97% His Aib Glu Gly Thr Phe Thr Ser Asp
C-16
fatty acid
Valamino acid C-18 fatty Val 94%
homology di-acid
Glu Ser
Spacer amino acid
Ser

Lys Ala Ala Gln Gly Glu Leu Tyr Ser to human GLP-1 Lys Ala Ala Gln Gly Glu Leu Tyr Ser homology
Glu Native human GLP-1 Glu
to human GLP-1
Phe Phe
His Ala Glu Gly Thr Phe Thr Ser Asp
Ile Ala Trp Leu Val Arg Gly Arg Gly Ile Ala Trp Leu Val Arg Gly Arg Gly
Val

Ser
Albiglutide Dulaglutide
His Gly Glu Gly Thr Phe Thr Ser Asp
97% Glu
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
His Gly Glu Gly Thr Phe Thr Ser Asp Val
Val amino acid Ser
Phe Lys Ala Ala Gln Glu Glu Leu Tyr Ser
Ser
homology Glu
Lys Ala Ala Gln Gly Glu Leu Tyr Ser Ile Ala Trp Leu Val Lys Gly Arg Gly Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
Glu to human GLP-1 FC domain
Phe Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
Glu
Ile Ala Trp Leu Val Lys Gly Arg His Gly Glu Gly Thr Phe Thr Ser Asp
Lys Ala Ala Gln Glu Glu Leu Tyr Ser
Val

Ser His Gly Glu Gly Thr Phe Thr Ser Asp Val
Ser 90%
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
amino acid
Glu
homology
Phe
to human GLP-1
Ile Ala Trp Leu Val Lys Gly Arg rH-albumin

*Semaglutide is under development and not approved; FC, IgG variable domain; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor
agonist; rH, recombinant human. Victoza SmPC, July 2016; Bush et al. Diabetes Obes Metab 2009;11:498–505; Kapitza et al. J Clin Pharmacol 2015;55:497–
504; Kuritzky et al. Postgrad Med 2014;126:60–72
Structure of GLP-1RAs
Exendin-4 based peptides

Exenatide BID ~50% Lixisenatide ~50%

His Gly Glu Gly Thr Phe Thr Ser Asp amino acid His Gly Glu Gly Thr Phe Thr Ser Asp amino acid
Leu
homology Leu
homology
Ser
to human GLP-1 Ser
to human GLP-1
Arg Val Ala Glu Glu Glu Met Gln Lys Native human GLP-1 Arg Val Ala Glu Glu Glu Met Gln Lys
Leu Leu

Phe His Ala Glu Gly Thr Phe Thr Ser Asp
Phe
Val
Ile Glu Trp Leu Lys Asp Gly Gly Pro Ile Glu Trp Leu Lys Asp Gly Gly Pro
Ser Ser
Ser
Ser Ser
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Gly Gly
Glu
Ser Pro Pro Ala Gly Lys Ser Pro Pro Ala Gly
Phe Lys

Exenatide QW Ile Ala Trp Leu Val Lys Gly Arg Gly Lys

Lys
Lys Lys

Exenatide molecules in a
biodegradable
polylactide-co-glycolide
polymer matrix

BID, twice daily; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; QW, once weekly
De Young et al. Diab Technol Ther 2011;13:1145–54; Fineman et al. Clin Pharmacokinet 2011;50:65–74; Christensen et al. IDrugs 2009;12:503–13;
Brown et al. Drug Des Devel Ther. 2014;8:25–38
Pharmacokinetics of GLP-1RAs

GLP-1RA, glucagon-like peptide-1 receptor agonist

 01:57 11

Protaction and protection from DPPiv and renal clearance:

Liraglutide as an example

Human GLP-1 Liraglutide

C-16 Fatty
Acid
(palmitoyl)

Half Life ≈ 1.8 minutes Half Life ≈ 13 hours

• Linked to a fatty acid, auto association in s.c. tissue

and binding to albumin (Liraglutide, Semaglutide)

• Linked to aldumin (Albiglutide) FC portion of IgG

(Dulaglutide)

• Included into a biodegradable (polylactide-co-glycolide)

polymer matrix
Knudsen et al. J Med Chem 2000;43:1664-1669, Degn et al. Diabetes 2004;53:1187–94;
Bush et al. Diabetes Obes Metab 2009;11:498–505; Kapitza et al. J Clin Pharmacol
2015;55:497–504; Kuritzky et al. Postgrad Med 2014;126:60–72; De Young et al. Diab
Technol Ther 2011;13:1145–54; Fineman et al. Clin Pharmacokinet 2011;50:65–74;
Continuous-acting and short-acting GLP-1RAs

concentration
Plasma

Liraglutide1
Exenatide QW2
Albiglutide3 1 2 3 4 5 6 8
Dulaglutide4 Time (days)
concentration
Plasma

Exenatide BID5
Lixisenatide6
BID, twice daily; GLP-1RA, glucagon-like peptide-1 receptor agonist; QW, once weekly
1. Elbrønd et al. Diabetes Care 2002;25:1398–404; 2. Fineman et al. Clin Pharmacokinet 2011;50:65–74; 3. Bush et al. Diabetes Obes Metab 2009;11:498–
505; 4. Kuritzky et al. Postgrad Med 2014;126:60–72; 5. Reddy et al. AAPS J 2005;7:M1285; 6. Christensen et al. IDrugs 2009;12:503–13
Is the pharmacokinetic profile important for efficacy?
24-hour GLP-1 presence required for 24-hour glucose
control Blood glucose profiles (n=8):
Before native human GLP-1 treatment
After 7 days’ native human GLP-1 treatment

25 25

20 20
Plasma glucose (mmol/l)

15 15

10 10

5 5
16h GLP-1 infusion 24h GLP-1 infusion

04 08 12 16 20 00 04 04 08 12 16 20 00 04
Time (h) Time (h)

GLP-1, glucagon-like peptide-1; h, hours

Larsen et al. Diabetes Care 2001;24:1416–21
Lixisenatide vs. liraglutide
24-hour plasma glucose profiles

Short-acting vs. long-acting GLP-1RAs

• Lixisenatide reduced PPG
15 Liraglutide (baseline) significantly more than liraglutide
n=77
14 Liraglutide (day 28)
• Liraglutide resulted in
13 Lixisenatide (baseline)
Plasma glucose (mM)

n=71 significantly greater

12 Lixisenatide (day 28)
reductions in:
11 • FPG (−1.3 vs. −0.34 mM)
10 • HbA1c (−0.51 vs. −0.32%)
9 • Body weight (−2.4 vs. −1.6 kg)
8
• Comparable safety and
7
tolerability profiles
6
5
0.5 2.5 4.5 6.5 8.5 10.5 12.5 14.5 24
Time after study drug administration (h)
Subjects had type 2 diabetes, were treated with metformin alone and had an HbA 1c between 6.5–9.0% at inclusion
FPG, fasting plasma glucose; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin; PPG, postprandial plasma
glucose Kapitza et al Diabetes Obes Metab 2013;15:642–9
Does size matter?
The differing molecular masses of the GLP-1RA class

Molecular mass (kDa)

0 10 20 30 40 50 60 70 80 90 100

His Ala Glu Gly Thr PheThr Ser Asp His Gly Glu Gly Thr PheThr Ser AspVal

Liraglutide C-16
Dulaglutide2
Ser
1
Val
Lys Ala Ala Gln Glu Glu Leu Tyr Ser
Glu Ser Glu
Lys Ala Ala Gln Gly Glu Leu Tyr Ser PheIle Ala Trp Leu Val Lys Gly Gly Gly
Glu

(3.8 kDa) Phe

Ile Ala Trp Leu Val Arg Gly Arg Gly
Glu
PheIle Ala Trp Leu Val Lys Gly Gly Gly

Lys Ala Ala Gln Glu Glu Leu Tyr Ser

Ser
(59.7 kDa)
His Gly Glu Gly Thr PheThr Ser AspVal
HisGlyGluGly ThrPheThrSerAsp
Leu

Exenatide2
Ser
Arg Val Ala GluGluGluMetGlnLys
Leu
Phe

(4.2 kDa) Ile GluTrpLeuLysAspGlyGly ProSer

Ser
His Gly GluGly ThrPheThrSerAsp

Albiglutide2
Gly
Val
SerPro Pro Ala Gly
Ser
HisGlyGluGly ThrPheThrSerAsp Lys Ala Ala Gln Gly GluLeu Tyr Ser
Glu

(73.0 kDa)
Leu
Ser Phe

Lixisenatide
Ile Ala TrpLeuVal Lys GlyArgHis Gly GluGly ThrPheThrSerAsp
2 Arg Val Ala GluGluGluMetGlnLys
Leu Val
Phe Ser
Ile GluTrpLeuLysAspGlyGlyProSer Lys Ala Ala Gln Gly GluLeu Tyr Ser

(4.9 kDa)
Glu
Ser
Gly Phe
Lys Lys Pro Pro Ala Gly Ile Ala TrpLeuVal Lys GlyArg rH-albumin
Lys
Lys
Lys Lys Lys

C-18 His Aib GluGly Thr PheThr Ser Asp

Semaglutide * 2 Val
fatty
Spacer Ser
di-acid Lys Ala Ala Gln Gly Glu LeuTyr Ser

(4.1 kDa)
Glu

Phe
Ile Ala Trp LeuVal Arg Gly Arg Gly

*Semaglutide is under development and not approved

C-16, 16-carbon fatty acid; GLP-1RA, glucagon-like peptide-1 receptor agonist; rH, recombinant human
1. Malm-Erjefält et al. Drug Metab Dispos 2010;38:1944–53; 2. Dhruv et al. JCD 2016;2:18–25
How does GLP-1 mediate its CNS effects?
Tissue sections of rat brain Access of peripherally injected 125I-
125
I-GLP-1 binding sites1 GLP-1 to area postrema (rat)2

CNS, central nervous system; GLP-1, glucagon-like peptide-1

1. Göke et al. Eur J Neurosci 1995;7:2294–300; 2. Unpublished microphotograph from the study reported by Ørskov et al. Diabetes 1996;45:832–5
Intraportal infusions of exenatide and albiglutide increase
c-Fos expression in the CNS of rat differently
The area postrema and nucleus of the solitary tract

IP PBS did not increase IP exenatide

c-Fos expression increased c-Fos expression

IP HSA did not increase IP albiglutide increased

c-Fos expression c-Fos expression

AP, area postrema; CNS, central nervous system; HSA, human serum albumin; IP, intraperitoneal; NTS, nucleus of the solitary tract; PBS, phosphate
buffered saline Baggio et al. Diabetes 2004;53:2492–500
Is structure (exendin-4 vs. human analogue) important?
 Immunogenicity of the available GLP-1RAs
EMA specifications

100 • EMA SmPC VICTOZA1

Exendin-4 based • Antibody formation has not been associated with change in HbA 1c
GLP-1 analogue
peptide
Proportion of patients with

• EMA SmPC TRULICITY2

80 70 • Antibody formation has not been associated with change in HbA 1c
antibodies (%)

• EMA SmPC EPERZAN3

60 57
• Antibody formation has not been associated with change in HbA 1c
44 • Patients who develop antibodies tend to have more injection-site reactions
40 • EMA SmPC LYXUMIA4
• Antibody status is not predictive of HbA 1c reduction
• Patients who develop antibodies tend to have more injection-site reactions
20
• EMA SmPC BYETTA5
9
1.6 4 • In most patients antibody titres diminish over time and remain low
0 • Patients who develop antibodies tend to have more injection-site reactions
BID

QW
Exenatide

Exenatide
Liraglutide

Dulaglutide

Albiglutide

Lixisenatide

• No cross-reactivity with GLP-1 or glucagon

• EMA SmPC BYDUREON6
• HbA1c was comparable to that observed in patients without antibody titres
• Patients who develop antibodies tend to have more injection-site reactions
• No cross-reactivity with GLP-1 or glucagon

BID, twice daily; EMA, European Medicines Agency; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated
haemoglobin; QW, once weekly; SmPC, summary of product characteristics 1. Victoza SmPC, July 2016; 2. Trulicity SmPC, March 2016; 3. Eperzan SmPC,
April 2016; 4. Lyxumia SmPC, May 2016; 5. Byetta SmPC, January 2016; 6. Bydureon SmPC, March 2016
Clinical GLP-1RA head-to-head comparisons
Pharmacodynamics, efficacy and/or safety

DURATION-1 DURATION-6 HARMONY-7

Exenatide QW vs. exenatide BID1 Exenatide QW vs. liraglutide2 Albiglutide vs. liraglutide3

LEAD-6 Nauck et al. AWARD-1

Liraglutide vs. exenatide BID4 Semaglutide* vs. liraglutide5 Dulaglutide vs. exenatide BID6

Rosenstock et al. GetGoal-X AWARD-6

Albiglutide vs. exenatide BID 7
Lixisenatide vs. exenatide BID 8
Dulaglutide vs. liraglutide9

DURATION-5 Kapitza et al. Lira–Lixi

Exenatide QW vs. exenatide BID10 Lixisenatide vs. liraglutide11 Liraglutide vs. lixisenatide12

SUSTAIN-3
Semaglutide* vs. exenatide QW13
*Semaglutide is under development and not approved; BID, twice daily; GLP-1RA, glucagon-like peptide-1 receptor agonist; QW, once weekly
1. Drucker et al. Lancet 2008;372:1240–50; 2. Buse et al. Lancet 2013;381:117–24; 3. Pratley et al. Lancet Diabetes Endocrinol 2014;2:289–97; 4. Buse et al.
Lancet 2009;374:39–47; 5. Nauck et al. Diabetes Care 2016;39:231–41; 6. Wysham et al. Diabetes Care 2014;37:2159–67; 7. Rosenstock et al. Diabetes Care
2009;32:1880–6; 8. Rosenstock et al. Diabetes Care 2013;36:2945–51; 9. Dungan et al. Lancet 2014;384:1349–57; 10. Blevins et al. J Clin Endocrinol Metab
2011;96:1301–10; 11. Kapitza et al. Diabetes Obes Metab 2013;15:642–9; 12. Nauck et al. Diabetes Care 2016;39:1501–9; 13.
https://clinicaltrials.gov/ct2/show/NCT01885208
Clinical ‘head-to-head’ comparisons of different GLP-1RAs
(efficacy and safety)

Short-acting / Long-acting Short-acting / Long-acting

Exendin-4-based / GLP-1-based Exendin-4-based
GLP-1RA X vs. GLP-1RA Y / GLP-1-based
Small / Large Small / Large

GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist

LEAD-6
Liraglutide vs. Exenatide BID

Long-acting Short-acting Type 2 diabetes (failure on metformin and/or SU)

GLP-1-based vs. Exendin-4-based Liraglutide 1.8 mg QD (n=233)
Small GLP-1RA Small GLP-1RA
Exenatide 10 μg BID (n=231)
HbA1c FPG Body weight
(%) (mM) (kg)
Baseline 8.2 8.1 9.8 9.5 93.0 93.0
70 ‡

treatment-specific antibodies (%)

61

with
60

patients
50
Mean change
from baseline

patients
Minor hypoglycaemia less frequent with liraglutide
(1.9 vs. 2.6 events per patient per year, p=0.01)
* 40

of of
* 30

Percentage
Percentage
20
†
10
2.6
0
During breakfast and dinner PPG were reduced more by
79 weeks 26 weeks
exenatide BID (vs. liraglutide); ETD: 1.3 mM and 1.0 mM
*p<0.0001 vs exenatide. †n=154. ‡n=185
BID, twice daily; ETD, estimated treatment difference; FPG, fasting plasma glucose; GLP-1RA, glucagon-like peptide-1 receptor
agonist;
HbA1c, glycosylated haemoglobin; PPG, postprandial plasma glucose; QD, once daily; SU, sulphonylurea
Buse et al. Lancet 2009;374:39–47; Buse et al. J Clin Endocrinol Metab 2011;96:1695–702
 GLP-1 receptor agonist class overview 25

Exenatide ER phase 3 programme overview

DURATION-8 (n=695) Completed trials
exenatide ER + dapagliflozin
vs exenatide ER or dapagliflozin Completed but not yet
Add-on to MET reported trials
CVOT trial:
DURATION-2 (EU, n=514) NCT00753896 (n=134) completed but not yet
exenatide ER vs sitagliptin/TZD Safety of exenatide ER reported
Add-on to MET Add-on to TZD±MET

NCT01003184 (n=216)
exenatide ER vs insulin detemir
Add-on to MET±SU

DURATION-6 (n=912)
exenatide ER vs liraglitide 1.8 mg
Add-on to MET, SU, MET+SU or MET+TZD

DURATION-4 (n=820) DURATION-3 (EU, n=456)

exenatide ER vs exenatide ER vs IGlar
sitagliptin/MET/TZD Add-on to MET±SU

DURATION-1 (n=303) and DURATION-5 (US+EU, n=254) DURATION-7 (n=440)

exenatide ER vs exenatide BID exenatide ER vs PBO
Add-on to diet and exercise or OADs Add-on to IGlar±MET

EXSCEL (US+EU, n=14,000; completion date: May, 2017) exenatide ER vs PBO

Add-on to 0–3 OADs or insulin±1–2 OADs

Drug-naïve Single OAD Multiple OADs Insulin users

BID, twice daily; exenatide ER, exenatide extended release; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly; IGlar, insulin glargine; MET, metformin; OAD, oral
antidiabetic drug; PBO, placebo; SU, sulphonylurea; TZD, thiazolidinedione.
1. Buse JB, et al. Diabetes Care 2010; 33(6): 1255–61; 2. Wysham C et al. Diabet Med 2011;28(6):705–14; 3. Diamant M et al. Lancet Diabetes Endocrinol 2014; 2(6):464–73; 4. Russell-Jones D et al. Diabetes Care 2012; 35(2):252–8; 5. Blevins T, et al. J Clin
Endocrinol Metab 2011; 96(5):1301–10; 6. Buse JB et al. Lancet 2013; 381(9861):117–2; 7. Frias JP et al. Lancet Diab Endocrinol 2016; 4(12):1004–16;
8. Davies M, et al. Diabetes Care 2013; 36(5):1368–76; 9. Norwood P et al. Clin Ther 2012; 34(10):2082–90; 10. Holman et al. Am Heart J 2016; 174:103–10.
 GLP-1 receptor agonist class overview 26

Change in HbA1c with exenatide ER

CHANGE FROM BASELINE AT END OF TREATMENT (%)
DURATION-11 DURATION-22 DURATION-33 DURATION-44 DURATION-55 DURATION-66 DURATION-87
Comparator: Exenatide BID Sitagliptin/TZD IGlar Sitagliptin/TZD/MET Exenatide BID Liraglutide Dapagliflozin
Background: N/A MET MET ± SU N/A MET/SU/TZD MET/SU/TZD MET ± Dapa
Trial duration: 52 weeks 52 weeks 156 weeks 26 weeks 24 weeks 26 weeks 28 weeks
Baseline: 8.2–8.3% 8.4–8.6% 8.2–8.3% 8.5% 8.4–8.5% 8.4–8.5% 9.3%

* *
*

*
*
*p<0.05 vs comparator(s). Dapa, dapagliflozin; BID, twice daily; exenatide ER, exenatide extended release; IGlar, insulin glargine; MET, metformin; PBO placebo; SU, sulphonylurea; TZD,
thiazolidinedione.
1. Buse JB et al. Diabetes Care 2010; 33(6):1255–61; 2. Wysham C et al. Diabet Med 2011; 28(6):705–14; 3. Diamant M et al. Lancet Diabetes Endocrinol 2014; 2(6):464–73;
4. Russell-Jones D et al. Diabetes Care 2012;35(2):252–8; 5. Blevins T et al. J Clin Endocrinol Metab 2011; 96(5):1301–10; 6. Buse JB et al. Lancet 2013; 381(9861):117–2; 7. Frias JP, et al.
Lancet Diab Endocrinol 2016; 4(12):1004–16.
 GLP-1 receptor agonist class overview 27

Change in body weight with exenatide ER

CHANGE FROM BASELINE AT END OF TREATMENT (kg)
DURATION-11 DURATION-22 DURATION-33 DURATION-44 DURATION-55 DURATION-66 DURATION-87
Comparator: Exenatide BID Sitagliptin/TZD IGlar Sitagliptin/TZD/MET Exenatide BID Liraglutide Dapagliflozin
Background: N/A MET MET ± SU N/A MET/SU/TZD MET/SU/TZD MET ± Dapa
Trial duration: 52 weeks 52 weeks 156 weeks 26 weeks 24 weeks 26 weeks 28 weeks
89.61–91.94
Baseline: 102–103 kg 86–90 kg 89.3–90.5 kg 87 kg 94.3–97.0 kg 90.9–91.1 kg
kg

*
*

*
*

*p<0.05 vs comparator(s). BID, twice daily; Dapa, dapagliflozin; exenatide ER, exenatide extended release; IGlar, insulin glargine; MET, metformin; PBO placebo; SU, sulphonylurea; TZD,
thiazolidinedione.
1. Buse JB et al. Diabetes Care 2010; 33(6):1255–61; 2. Wysham C et al. Diabet Med 2011; 28(6):705–14; 3. Diamant M et al. Lancet Diabetes Endocrinol 2014; 2(6):464-73;
4. Russell-Jones D et al. Diabetes Care 2012;35(2):252–8; 5. Blevins T et al. J Clin Endocrinol Metab 2011; 96(5):1301–10; 6. Buse JB et al. Lancet 2013; 381(9861):117–2; 7. Frias JP, et
al. Lancet Diab Endocrinol 2016; 4(12):1004–16.
DURATION-6
Liraglutide vs. Exenatide QW

Long-acting Long-acting Type 2 diabetes (failure on OAD)

GLP-1-based vs. Exendin-4-based Liraglutide 1.8 mg QD (n=450)
Small GLP-1RA Small GLP-1RA Exenatide 2mg QW (n=461)
HbA1c FSG Body weight
(%) (mM) (kg) 25
Baseline
0 8.5 8.4 9.6 9.8 90.9 91.1 21.0
20

Percentage of patients
-1
Mean change
from baseline

15
-1.3
-1.5 10.0
-2 -1.8 10 9.0
‡ 8.0
-2.1 6.0
†
5
-3 -2.7
1.0
0
Nausea Diarrhea Injection site nodule
-4 *-3.6

The criteria for non-inferiority of Exenatide vs liraglutide for HbA 1c were not met; ‡p=0.0018 vs Exenatide; *p=0.0005 vs Exenatide; † p<0.001 vs Exenatide
FSG, fasting serum glucose; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated haemoglobin; QD, once daily; QW, once weekly;
Buse. J. B. et al, Lancet 2013; 381: 117–24
 GLP-1 receptor agonist class overview 29

Albiglutide phase 3 programme overview

NCT02683746 (n=300) Completed trials
Liquid susp. albiglutide in auto-
injector vs old formulation; Completed but not
add-on to MET yet reported trials
Ongoing trials
HARMONY 8 (n=507) albiglutide vs sitagliptin; add-on to D/E±MET/TZD/SU
in patients with mild, moderate or severe renal impairment Ongoing CVOT trial

HARMONY 7 (n=841)
albiglutide vs liraglutide; add-on to MET/TZD/SU

HARMONY 4 (n=779)
albiglutide vs IGlar; add-on to MET±SU
NCT02229227
(n=794)
HARMONY 1 (n=310)
albiglutide vs insulin lispro,
albiglutide vs PBO; add-on to TZD±MET
add-on IGlar±MET
HARMONY 3 HARMONY 5 HARMONY 6
HARMONY 2
(n=1,049) (n=685) (n=586)
(n=309)
albiglutide vs sitagliptin/SU/PBO albiglutide vs TZD/PBO albiglutide vs insulin lispro add-
albiglutide vs PBO
add-on to MET add-on to MET+SU on to IGlar±OADs

HARMONY Outcomes trial (estimated completion date: February, 2018), albiglutide vs PBO (n=9,400)
T2D with CV disease in addition to standard of care. Event-driven trial targeting 611 MACE events in 3–5 years

Drug-naïve Single OAD Multiple OADs Insulin users

D/E, diet and exercise; CV, cardiovascular; CVOT, cardiovascular outcomes trial; MACE, major adverse cardiovascular event; MET, metformin; IGlar, insulin glargine; OAD, oral antidiabetic drug; PBO, placebo;
SU, sulphonylurea; TZD, thiazolidinedione. 1. Reusch J et al. Diabetes Obes Metab 2014; 16(12):1257–64; 2. Nauck MA et al. Diabetologia 2016; 59(2):266–74; 3. Ahrén B et al. Diabetes Care 2014; 37(8):2141–8; 4. Weissman PN et al. Diabetologia 2014;
57(12):2475–84; 5. Home PD et al. Diabetes Obes Metab 2015; 17(2):179–87; 6. Rosenstock J et al. Diabetes Care 2014; 37(8):2317–25; 7. Pratley RE et al. Lancet Diabetes Endocrinol 2014; 2(4):289–97; 8. Leiter LE et al. Diabetes Care 2014;
37(10):2723–30.
 GLP-1 receptor agonist class overview 30

Change in HbA1c with albiglutide

CHANGE FROM BASELINE AT END OF TREATMENT (%)
HARMONY 11 HARMONY 22 HARMONY 33 HARMONY 44 HARMONY 55 HARMONY 66 HARMONY 77 HARMONY 88
Comparator: PBO PBO Sitagliptin/SU/PBO Iglar TZD/PBO Insulin lispro Liraglutide Sitagliptin
Background: TZD/MET N/A MET MET±SU MET+SU IGlar±OADs MET/TZD/SU MET/TZD/SU
Trial duration: 52 weeks 52 weeks 104 weeks 52 weeks 156 weeks ¤
52 weeks† 32 weeks 52 weeks‡
Baseline: 8.1% 8.02–8.21% 8.1% 8.31% 8.24% 8.4–8.5% 8.15–8.18% 8.2%
*

*
*
* *
*

*p<0.05 vs comparator(s). ¤Week 52 endpoint data reported for HARMONY 5. †Week 26 endpoint data reported for HARMONY 6. ‡Week 26 endpoint data reported for HARMONY 8.
IGlar, insulin glargine; MET, metformin; OAD, oral antidiabetic drug; PBO, placebo; SU, sulphonylurea; TZD, thiazolidinedione.
1. Reusch J et al. Diabetes Obes Metab 2014; 16(12):1257–64; 2. Nauck MA et al. Diabetologia 2016; 59(2):266–74; 3. Ahrén B et al. Diabetes Care 2014; 37(8):2141–8; 4. Weissman PN et
al. Diabetologia 2014; 57(12):2475–84; 5. Home PD et al. Diabetes Obes Metab 2015; 17(2):179–87; 6. Rosenstock J et al. Diabetes Care 2014; 37(8):2317–25; 7. Pratley RE et al. Lancet
Diabetes Endocrinol 2014; 2(4):289–97;
8. Leiter LE et al. Diabetes Care 2014; 37(10):2723–30.
 GLP-1 receptor agonist class overview 31

Change in body weight with albiglutide

CHANGE FROM BASELINE AT END OF TREATMENT (kg)
HARMONY 11 HARMONY 22 HARMONY 33 HARMONY 44 HARMONY 55 HARMONY 66 HARMONY 77 HARMONY 88
Comparator: PBO PBO Sitagliptin/SU/PBO IGlar TZD/PBO Insulin lispro Liraglutide Sitagliptin
Background: TZD/MET N/A MET MET±SU MET+SU IGlar±OADs MET/TZD/SU MET/TZD/SU
Trial duration: 52 weeks 52 weeks 104 weeks 52 weeks 156 weeks ¤
52 weeks† 32 weeks 52 weeks‡
Baseline: 98.9 kg 95.4–97.1 kg 89.6–91.8 kg 94.9 kg 90.8 kg 91.6–92.5 kg 91.7–92.8 kg 83.04 kg

* *

*p<0.05 vs comparator(s). ¤Week 52 endpoint data reported for HARMONY 5. †Week 26 endpoint data reported for HARMONY 6. ‡Week 26 endpoint data reported for HARMONY 8.
CV, cardiovascular; IGlar, insulin glargine; MET, metformin; NR, not reported; OAD, oral antidiabetic drug; PBO, placebo; SU, sulphonylurea; TZD, thiazolidinedione.
1. Reusch J et al. Diabetes Obes Metab 2014; 16(12):1257–64; 2. Nauck MA et al. Diabetologia 2016; 59(2):266–74; 3. Ahrén B et al. Diabetes Care 2014; 37(8):2141–8; 4. Weissman PN et al.
Diabetologia 2014; 57(12):2475–84; 5. Home PD et al. Diabetes Obes Metab 2015; 17(2):179–87; 6. Rosenstock J et al. Diabetes Care 2014; 37(8):2317–25; 7. Pratley RE et al. Lancet
Diabetes Endocrinol 2014; 2(4):289–97;
8. Leiter LE et al. Diabetes Care 2014; 37(10):2723–30.
HARMONY-7
Liraglutide vs. Albiglutide
Long-acting Long-acting Type 2 diabetes (failure on metformin, SU and/or TZD)
GLP-1-based vs. GLP-1-based
Liraglutide 1.8 mg QD (n=408)
Small GLP-1RA Large GLP-1RA
Albiglutide 50 mg QW (n=404)
HbA1c FPG Body weight
(%) (mM) (kg)
Baseline 0 8.2
-1.0 8.2
-0.8 -1.7 -1.2
N/A 92.8 -0.6
91.7 35
N/A

30 29.2†

Percentage of patients
25
-1
Mean change
from baseline

20
§

15 12.9
‡
-2 * 9.9 9.3
10
-2.2 5.0 5.4
† 5

-3 0
Nausea Vomiting Injection-site_x000d_reactions

The criteria for non-inferiority of albiglutide vs liraglutide for HbA 1c were not met; *p=0.0048 vs albiglutide; †p<0.0001 vs albiglutide; ‡p=0·0154 vs albiglutide; §p=0.0002 vs
liraglutide FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated haemoglobin; QD, once
daily; QW, once weekly;
SU, sulphonylurea; TZD, thiazolidinedionePratley et al. Lancet Diabetes Endocrinol 2014;2:289–97
Lira-Lixi
Liraglutide vs. Lixisenatide

Long-acting Short-acting Type 2 diabetes (failure on metformin)

GLP-1-based vs. Exendin-4-based Liraglutide 1.8 mg QD (n=202)
Small GLP-1RA Small GLP-1RA Lixisenatide 20 µg QD (n=202)
HbA1c FPG PPG† Body weight
(%) (mM) (mM) (kg)
Baseline 8.4 8.4 10.5 10.3 N/A N/A 101.9 100.6 80 75.4
70

Patients with treatment-specific

64.2
60
Mean change
from baseline

antibodies (%)
50
40
*
30
20
*
10 0.0 1.0 0.0 1.1
0
0 weeks 12 weeks 27 weeks

*p<0.0001; †Post-breakfast increment for lixi-morning injection (n=135) vs. post-breakfast increment for liraglutide
FPG, fasting plasma glucose; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated haemoglobin; PPG, postprandial plasma glucose; QD,
once daily
Nauck et al. Diabetes Care 2016;39:1501–9
 GLP-1 receptor agonist class overview 34

Dulaglutide phase 3 programme overview

AWARD-PEDS
Completed trials (n=150)
dulaglutide vs PBO
Ongoing trials Add-on to MET±basal insulin
AWARD-10
(n=300)
Ongoing CVOT trial AWARD-7
dulaglutide vs PBO
(n=577)
Add-on to SGLT2is
dulaglutide+insulin lispro (TID)
AWARD-8 vs insulin glargine+ insulin lispro
(n=300) (TID)±OAD
dulaglutide vs PBO
Add-on to SU AWARD-9
AWARD-2
(n=300)
(n=810)
AWARD-6 dulaglutide vs PBO
dulaglutide vs insulin glargine
(n=599) Add-on to IGlar±MET
Add-on to MET+SU
dulaglutide vs liraglutide 1.8 mg
Add-on to MET AWARD-4
AWARD-1 (n=884)
AWARD-5 (Phase 2/3) (n=978)
AWARD-3 dulaglutide+insulin lispro vs
(n=1,098) dulaglutide vs exenatide BID/PBO
(n=807) insulin glargine+insulin lispro
dulaglutide vs sitagliptin Add-on to MET+TZD
dulaglutide vs MET/PBO ±OADs
Add-on to MET

REWIND CVOT (estimated completion date: July, 2018) dulaglutide 1.5 mg vs PBO (n=9,622)
Drug-naïve or add-on to ≤2 antihyperglycaemic agents

Drug-naïve Single OAD Multiple OADs Insulin users

AWARD, Assessment of Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes; BID, twice daily; CVOT, cardiovascular outcomes trial; IGlar, insulin glargine; MET, metformin; OAD, oral antidiabetic drug; PBO, placebo; SLGT2i, sodium-glucose cotransporter-2 inhibitor; SU, sulphonylurea;
TID, three times a day; TZD, thiazolidinedione.
1. Wysham C et al. Diabetes Care 2015; 38:1393–1394; 2. Giorgino F et al. Diabetes Care 2015; 38:2241–2249; 3. Umpierrez G et al. Diabetes Care 2014; 37:2168‑2176; 4. Blonde L et al. Lancet 2015; 385:2057–2066;
5. Nauck M et al. Diabetes Care 2014; 37:2149–2158; 6. Dungan KM et al. Lancet 2014; 384:1349–1357; 7. Dungan KM et al. Diabetes Obes Metab 2016; 18:475–482; 8. Pozzilli P et al. Diabetes 2016; 65(Suppl 1):A62.
 GLP-1 receptor agonist class overview 35

Change in HbA1c with dulaglutide

CHANGE FROM BASELINE AT WEEK 26 (%)
AWARD-11 AWARD-22 AWARD-33 AWARD-44 AWARD-55 AWARD-66 AWARD-87 AWARD-98
Comparator: Exenatide BID/PBO IGlar MET/PBO IGlar Sitagliptin Liraglutide PBO PBO
Background: MET+TZD MET+SU N/A Insulin lispro±OADs MET MET SU IGlar±MET
Trial duration: 52 weeks 78 weeks 52 weeks 52 weeks 52 weeks 26 weeks 24 weeks 28 weeks
Endpoint: 26 weeks 52 weeks 26 weeks 26 weeks 52 weeks 26 weeks 24 weeks 28 weeks
Baseline: 8.1% 8.1% 7.6% 8.40–8.53% 8.1% 8.1% 8.4% 8.4%

*
* *

* *
* *
*
* *

* *

*p<0.05 vs comparator(s). Week 52 data reported for AWARD-2, Week 24 data reported for AWARD-8 and Week 28 data reported for AWARD-9; Week 26 data reported for all other trials (not primary endpoint for all
trials).
BID, twice daily; IGlar, insulin glargine; MET, metformin; N/A, not applicable; OAD, oral antidiabetic drug; PBO placebo; SU, sulphonylurea; TZD, thiazolidinedione.
1. Wysham C et al. Diabetes Care 2015; 38:1393–1394; 2. Giorgino F et al. Diabetes Care 2015; 38:2241–2249; 3. Umpierrez G et al. Diabetes Care 2014; 37:2168‑2176; 4. Blonde L et al. Lancet 2015; 385:2057–2066;
5. Nauck M et al. Diabetes Care 2014; 37:2149–2158; 6. Dungan KM et al. Lancet 2014; 384:1349–1357; 7. Dungan KM et al. Diabetes Obes Metab 2016; 18:475–482;
8. Pozzilli P et al. Diabetes 2016; 65(Supplement 1):A62.
 GLP-1 receptor agonist class overview 36

Change in body weight with dulaglutide

CHANGE FROM BASELINE AT WEEK 26 (kg)
AWARD-11 AWARD-22 AWARD-33 AWARD-44 AWARD-55 AWARD-66 AWARD-87 AWARD-98
Comparator: Exenatide BID/PBO IGlar MET/PBO IGlar Sitagliptin Liraglutide PBO PBO
Background: MET+TZD MET+SU N/A Insulin lispro±OADs MET MET SU IGlar±MET
Trial duration: 52 weeks 78 weeks 52 weeks 52 weeks 52 weeks 26 weeks 24 weeks 28 weeks
Endpoint: 26 weeks 52 weeks 26 weeks 26 weeks 52 weeks 26 weeks 24 weeks 28 weeks
Baseline: 94–97 kg 85–88 kg 92–93 kg 90.8–91.7 kg 86.4 kg 93.8–94.4 kg 87.0 kg NR
*

*
*
*
* *
* NS
*
* *

* *

*p<0.05 vs comparator(s). Week 52 data reported for AWARD-2, Week 24 data reported for AWARD-8; Week 28 data reported for AWARD-9. Week 26 data reported for all other trials (not primary endpoint for all trials).
BID, twice daily; MET, metformin; N/A, not applicable; PBO placebo; NR, not reported; NS, not significant.
1. Wysham C et al. Diabetes Care 2015; 38:1393–1394; 2. Giorgino F et al. Diabetes Care 2015; 38:2241–2249; 3. Umpierrez G et al. Diabetes Care 2014; 37:2168‑2176; 4. Blonde L et al. Lancet 2015; 385:2057–2066;

5. Nauck M et al. Diabetes Care 2014; 37:2149–2158; 6. Dungan KM et al. Lancet 2014; 384:1349–1357; 7. Dungan KM et al. Diabetes Obes Metab 2016; 18:475–482;
8. Pozzilli P et al. Diabetes 2016; 65(Supplement 1):A62.
AWARD-6
Liraglutide vs. Dulaglutide QW

Long-acting Long-acting Type 2 diabetes (failure on metformin)

GLP-1-based vs. GLP-1-based Liraglutide 1.8 mg QD (n=300)
Small GLP-1RA Large GLP-1RA Dulaglutide 1.5mg QW (n=299)
HbA1c FPG Body weight
(%) 8.1 (mM) (kg) 69 68.3
Baseline 8.1 9.3 9.2 94.4 67.9
0 93.8 68 †

67
66
-1

Percentage of patients
Mean change
from baseline

65
-1.4 -1.4
64
‡
-2 -1.9 -1.9 63 62.7
62.5
62
-3 61
-2.9
60
* -3.6 59
-4 A1C<7% A1C<7% & no
persistent nausea
or vomiting
The criteria for non-inferiority of dulaglutide vs liraglutide for HbA1c; *p=0.011 vs dulaglutide; ‡p<0.0001 vs Liraglutide
FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin; QD, once daily; QW, once weekly;
Dungan KM et al. Lancet 2014; doi: 10.1016/S0140-6736(14)60976-4. [Epub ahead of print]
 GLP-1 receptor agonist class overview 38

Semaglutide phase 3 programme overview

SUSTAIN 10 (N=576; 30 w)
semaglutide vs liraglutide Completed trials
Add-on to 1–3 OADs Completed but not
(MET ± SU ± SGLT-2i) yet reported trials

SUSTAIN 9 (N=300; 30 w) Ongoing trials

SUSTAIN China (N=1050; 30 w)
semaglutide vs placebo CVOT trial
semaglutide vs sitagliptin
Add-on to SGLT2i ± MET ± SU
Add-on to MET

SUSTAIN 8 (N=784; 52 w) SUSTAIN 4 (N=1,089; 30 w)

semaglutide vs canagliflozin semaglutide vs IGlar
Add-on to MET Add-on to MET ± SU

SUSTAIN 7 (N=1,196; 40 w) SUSTAIN 3 (N=813; 56 w)

SUSTAIN JP monotherapy semaglutide vs dulaglutide semaglutide vs exenatide ER
(N=306; 30 w) Add-on to MET Add-on to 1–2 OADs
semaglutide vs sitagliptin (MET/SU/TZD)
SUSTAIN JP OAD combination
SUSTAIN 1 (N=388; 30 w) (N=595; 56 w) SUSTAIN 2 (N=1,231; 56 w) SUSTAIN 5 (N=397; 30 w)
semaglutide vs placebo semaglutide vs pre-trial OAD + semaglutide vs sitagliptin semaglutide vs placebo
Monotherapy additional OAD Add-on to MET ± TZD Add-on to basal insulin ± MET

SUSTAIN 6 (Completed, March 2016; n=3,297; 104 w)

0–2 OADs ± basal or pre-mix insulin

Drug-naïve Single OAD Multiple OADs Insulin users

Exenatide ER, exenatide extended release; IGlar, insulin glargine; MET, metformin; OAD, oral antidiabetic drug; SLGT2i, sodium-glucose cotransporter-2 inhibitor; SU, sulphonylurea; SUSTAIN, Semaglutide
Unabated Sustainability in Treatment of Type 2 Diabetes; TZD, thiazolidinedione; w, week.
 GLP-1 receptor agonist class overview 39

Change in HbA1c with semaglutide

CHANGE FROM BASELINE AT END OF TREATMENT (%)
SUSTAIN 11 SUSTAIN 22 SUSTAIN 33 SUSTAIN 44 SUSTAIN 55 SUSTAIN 66
Comparator: PBO Sitagliptin Exenatide ER IGlar PBO PBO†
0–2 OADs ± basal or
Background: N/A MET±TZD 1–2 OADs MET±SU Basal insulin±MET
pre-mix insulin
Trial duration: 30 weeks 56 weeks 56 weeks 30 weeks 30 weeks 104 weeks
Baseline: 8.05% 8.1% 8.3% 8.2% 8.4% 8.7%

*
* *
* * *
* *
* * *
* *

*p<0.0001 vs comparator. †Placebo 0.5 mg and 1.0 mg shown. Exenatide ER, exenatide extended release; IGlar, insulin glargine.
1. Sorli C et al. Lancet Diabetes Endocrinol 2017; 5(4):251–60; 2. Ahrén B et al. Lancet Diabetes Endocrinol 2017; 5(5):341–54; 3. Ahmann AJ et al. Diabetes 2016;65(Suppl 1):A49; 4. Aroda V et al. Lancet
Diabetes Endocrinol 2017; 5(5):355–66; 5. Rodbard H et al. Diabetologia 2016; Suppl 1(59): S364–5; 6. Marso SP et al. N Engl J Med 2016; 375(19): 1834–44.
 GLP-1 receptor agonist class overview 40

Change in body weight with semaglutide

CHANGE FROM BASELINE AT END OF TREATMENT (kg)
SUSTAIN 11 SUSTAIN 22 SUSTAIN 33 SUSTAIN 44 SUSTAIN 55 SUSTAIN 66
Comparator: PBO Sitagliptin Exenatide ER IGlar PBO PBO†
0–2 OADs ± basal or
Background: N/A MET±TZD 1–2 OADs MET±SU Basal insulin±MET
pre-mix insulin
Trial duration: 30 weeks 56 weeks 56 weeks 30 weeks 30 weeks 104 weeks
Baseline: 91.93 kg 89.5 kg 95.8 kg 93.5 kg 91.7 kg 92.1 kg

*
*
*
* * *
* *
*
*
*
*
*

*p<0.0001 vs comparator. †Placebo 0.5 mg and 1.0 mg shown. Exenatide ER, exenatide extended release; IGlar, insulin glargine; PBO, placebo.
1. Sorli C et al. Lancet Diabetes Endocrinol 2017; 5(4):251–60; 2. Ahrén B et al. Lancet Diabetes Endocrinol 2017; 5(5):341–54; 3. Ahmann AJ et al. Diabetes 2016;65(Suppl 1):A49; 4. Aroda V et al. Lancet
Diabetes Endocrinol 2017; 5(5):355–66; 5. Rodbard H et al. Diabetologia 2016; Suppl 1(59): S364–5; 6. Marso SP et al. N Engl J Med 2016; 375(19): 1834–44.
 GLP-1 receptor agonist class overview 41

Sustain 7

https://www.novonordisk.com/bin/getPDF.2127298.pdf
Summary
GLP-1 receptor agonists are not alike…
Pharmacokinetics Structure Size

Exendin-4-
Short-acting Long-acting GLP-1-based Small Large
based

Exenatide BID Exenatide QW Exenatide BID Liraglutide Exenatide BID Albiglutide

Lixisenatide Liraglutide Exenatide QW Albiglutide Exenatide QW Dulaglutide

Albiglutide Lixisenatide Semaglutide Liraglutide

Semaglutide Dulaglutide Lixisenatide

Dulaglutide Semaglutide
Short-acting GLP-1RAs retain effect on Exendin-based GLP-1RAs seem to The large GLP-1RAs may not be able
gastric emptying (and PPG), while give rise to the formation of antibodies to penetrate into the brain to the same
long-acting GLP-1RAs seem to have to a higher degree than the GLP-1- extent as the smaller types; possibly
more pronounced effects on FPG and based ones; clinical implication affecting appetite signalling differently
HbA1c uncertain
*Semaglutide is under development and not approved; BID, twice daily; FPG, fasting plasma glucose; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c,
glycosylated haemoglobin;
PPG, postprandial plasma glucose; QW, once weekly