GLP-1 RA story: A closer look
Prof Yehia Ghanem
Head of Internal Medicine, Diabetes Unit
Alexandria University

Agenda
• The Incretin effect
• GLP-1 RA position in guidelines
• What’s Liraglutide
• Difference between Incretin-based therapies

Pathophysiology of type 2 diabetes
Cernea S & Raz I. Diabetes Care 2011;34(suppl 2):S264–S271
CNS, central nervous system; GI, gastrointestinal; T2DM, type 2 diabetes mellitus
Adipocyte
CNS
Incretin
deficiency
GI tract
Altered fat
metabolism
INSULIN
RESISTANCE
INADEQUATE
INSULIN
SECRETION
↑ HEPATIC
GLUCOSE
PRODUCTION
↑ BLOOD GLUCOSE
Hyperglucagonaemia
↑ hepatic sensitivity
to glucagon
 cells
α cells
Skeletal
Muscle
Pancreas
Muscle
Kidney
Enhanced glucose
reabsorption

Role of incretin effect in healthy insulin
response
• Insulin response is greater following oral glucose than IV glucose,
despite similar plasma glucose concentration
1. Nauck M et al. Diabetologia 1986;29:46–52; 2. Wick A & Newlin K. J Am Acad Nurse Pract 2009;21(suppl 1):623–360
Oral glucose load (50 g) IV glucose infusion
PlasmaGlucose(mmol/L)
–10 –5 60 120 180
10
Time (min)
5
0
15
Plasma Glucose1
Insulin Response2
Insulin(mU/L)
80
60
40
20
–10 –5 60 120 180
0
Time (min)
Incretin
effect

The incretin hormones
1. Glucagon-like Peptide-1 (GLP-1)
• secreted by cells in the distal ileum and colon, in
response to food intake – nerve and hormonal stimulation
• more potent than GIP in stimulating insulin secretion
2. Glucose-dependent insulinotropic Peptide (GIP)
• secreted by cells in duodenum when food enters the area
• circulating levels up to 10x higher than GLP-1

Insulin(pmol/L)
Continuous IV infusion during
hyperglycaemic clamp (15 mmol/L)
Time (min)
GLP-1 (1 pmol)
GIP (16 pmol)
0
500
1000
1500
2000
2500
–20 30 80 120
3000
0
GLP-1 (but not GIP) increases both early- and
late-stage insulin secretion
Vilsbøll T et al. Diabetologia 2002;45:1111–1119
Mean±SEM
GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; IV, intravenous; SEM, standard error of the mean

Effect of GLP-1 is glucose-dependent
• Effects of 4-hour GLP-1 infusion (1.2 pmol/kg/min) in 10 patients with type 2 diabetes
GLP-1, glucagon-like peptide-1; SE, standard error
Nauck M et al. Diabetologia 1993;36:741–744
Mean (SE); n=10
*p<0.05
Placebo Native human GLP-1
300
200
100
0
Insulin (pmol/L)
Time (min)
-30 0 60 120 180 240
*** *
*
* *
*
Glucagon (pmol/L)
-30 0 60 120 180 240
20
10
0
Time (min)
**
*
*
Glucose (mmol/L)
15
10
5
0
-30 0 60 120 180 240
Time (min)
*
*
*
*
* *
*

Liraglutide
GLP-1R
Insulin exocytosis
ATP
Glut2Potassium Channel
Calcium Channel
Glucose
K+
TCA
Amplifying
Pyruvate
Epac
Triggering
AC
GsαGsα
ATPcAMP
Ca2+
Ca2+
GLP-1 Receptor agonist Liraglutide mode of
action in the β cell
Hinke SA et al. J Physiol 2004;558:369–380; Henquin JC. Diabetes 2000;49:1751–1760;
Henquin JC. Diabetes 2004;53:S48–S58; Drucker D. Cell Metab 2006;3:153–165

The incretin effect is diminished in patients with
type 2 diabetes
*p<0.05, healthy volunteers (n=8)
Nauck M et al. Diabetologia 1986;29:46–52
Type 2 Diabetes
Insulin(mU/L)
80
60
40
20
0 30 60 120 180
0
Time (min)
15090
*
*
*
Insulin(mU/L)
0 30 60 120 180
40
Time (min)
20
0
80
Healthy Controls
60
90 150
**
*
***
*
Incretin
effect
Oral glucose IV glucose

Diminished insulin response to physiological
levels of GLP-1impaired in T2DM
Physiological levels of GLP-11
(15 mM hyperglycaemic clamp)
GLP-1, glucagon-like peptide 1, T2DM, type 2 diabetes mellitus
1. Højberg PV et al. Diabetologia 2009;52:199–207; 2. Vilsbøll T et al. Diabetologia 2002;45:1111–1119
0
0 30 60 90 120
Time (min)
1000
2000
3000
4000
5000
6000
Insulin(pmol/L)
GLP-1 infusion period
(0.5 pmol/kg/min)
Plasma GLP-1:
46 pmol/L
Healthy
Plasma GLP-1:
41 pmol/L
T2DM
Pharmacological levels of GLP-12
(15 mM hyperglycaemic clamp)
0
1000
2000
3000
4000
0 45 90 135 180
Time (min)
Insulin(pmol/L)
5000
6000
GLP-1 infusion period
(1.0 pmol/kg/min)
Plasma GLP-1:
126 pmol/L
T2DM

n=8
GLP-1, glucagon-like peptide-1
Larsen J et al. Diabetes Care 2001;24:1416–1421
24-hour GLP-1 presence required for 24-hour
glucose control
Time (h)
Before native human GLP-1 treatmentBlood glucose profiles:
After 7 days’ native human GLP-1 treatment
24-h GLP-1 infusion
12 00 0408 16 2004
5
10
20
15
25
PlasmaGlucose(mmol/L)
5
10
20
25
15
04 12 00 0408 16 20
16-h GLP-1 infusion

13

Agenda
• The Incretin effect
• GLP-1 RA position in guidelines
• What’s Liraglutide
• Difference between Incretin-based therapies

ADAEASD position statement 2015-2016
Early combination therapy is recommended
Healthy eating, weight control, increased physical activity,
and diabetes education
Metformin
Mono-
therapy
Dual
therapy
Triple
therapy
Combination
injectable
therapy
Metformin +
Sulphonylurea +
TZD
DPP-4i
GLP-1 RA
Insulin
or
or
or
Metformin +
Thiazolidinedione +
SU
DPP-4i
GLP-1 RA
Insulin
or
or
or
Metformin +
DPP-4 inhibitor +
SU
TZD
Insulin
or
or
Metformin +
GLP-1 RA +
SU
TZD
Insulin
or
or
Metformin +
Insulin (basal) +
TZD
DPP-4i
GLP-1 RA
or
or
+
Sulphonylurea
+
Thiazolidinedione
+
DPP-4 inhibitor
+
GLP-1 receptor
agonist
+
Insulin
(basal)
Metformin +
SGLT2 inhibitor +
SU
TZD
Insulin
or
or
SGLT2i SGLT2i
SGLT2i DPP-4i SGLT2i
Metformin +
Mealtime insulinBasal insulin +
or or or
or or
+
SGLT2 inhibitor
or GLP-1 RA
SU, sulphonylurea; TZD, thiazolidinedione; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT2-i, sodium-glucose cotransporter-2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor
agonist
Inzucchi SE et al. Diabetes Care 2015;38:140–149

ADAEASD position statement 2015:
Choice of therapy after metformin.
DPP-4i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist;
HbA1c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione; ↑, weight gain; ↓, weight loss; ↔, weight neutral
SU TZD DPP-4i SGLT-2i GLP-1RA
Insulin
(basal)
Efficacy
(↓HbA1c)
High High Intermediate Intermediate High Highest
Hypoglycaemia
risk
Moderate Low Low Low Low High
Weight effect ↑ ↑ ↔ ↓ ↓ ↑
Major side
effects
Hypo-
glycaemia
Oedema
Heart failure
Bone fractures
Rare
Genitourinary
Dehydration
GI
Hypo-
glycaemia
Inzucchi SE et al. Diabetes Care 2015;38:140–149

Strictly Confidential. Proprietary

Agenda
• The Incretin effect
• GLP-1 RA position in guidelines
• What’s Liraglutide
• Difference between Incretin-based therapies

Liraglutide is a once-daily, human GLP-1
analogue
glutamoyl spacer
34
26
Knudsen et al. J Med Chem 2000;43:1664–9; Degn et al. Diabetes 2004;53:1187–94

Liraglutide: Mechanisms of protraction
• Self-association to form heptamers: slow absorption.
• Reversible albumin binding: protection against cleavage.
• Higher enzymatic stability to DPP-4: Longer half life.
• Half life is 13 hours and suitable for once daily injection.
Knudsen et al. J Med Chem 2000;43:1664–9; Degn et al. Diabetes 2004;53:1187–94

Percentage of patients
with increase in
antibodies
Liraglutide1
0
20
40
60
80
100
Exenatide +
metformin2
43%
8.6%
Liraglutide: greater homology to native human GLP-1, less
antibody formation
97% amino
acid homology
to human GLP-1
53% amino acid
homology to
human GLP-1 • There was no blunting
of efficacy by liraglutide
antibodies
Study duration: Liraglutide 26 weeks; exenatide 30 weeks.
1LEAD1,2,3,4,5 meta-analysis of antibody formation; Data on file; 2DeFronzo et al. Diabetes Care 2005;28:1092
Native human GLP-1
Liraglutide
Exenatide

H2H incretins
Liraglutide clinical trial program covers different
treatment modalities
BID, twice daily; Met, metformin; OAD, oral antidiabetes drug; SU, sulphonylurea; TZD, thiazolidinedione
Source: ClinicalTrials.gov
Drug naive Special populations
LIRA-RENAL™ (n=279)
vs placebo
Add-on to SOC
≥1 OAD Insulin users
LIRA-DETEMIR (n=323)
vs liraglutide plus IDet
Add-on to met
LIRA-ADD2BASAL™ (n=446)
vs placebo
Add-on to basal insulin ± met
ellipse™ (paediatric; n=172)
vs placebo
Add-on to met
To be finished in 2020
LIRA-LIXI™ (n=400)
vs lixisenatide
Add-on to met
LIRA-SWITCH™ (n=396)
vs sitagliptin
Add-on to met, switch from
sitagliptin
To be published in ADA-16
LIRA-Ramadan™ (n=320)
vs SU
Add-on to met, switch from SU
LEAD-3 (n=746)
vs SU
LEAD-4 (n=533)
vs placebo
Add-on to met + TZD
LEAD-2 (n=1091)
vs SU or placebo
Add-on to met
LEAD-1 (n=1041)
vs TZD or placebo
Add-on to SU
LEAD-5 (n=581)
vs insulin glargine or placebo
Add-on to met + SU
LEAD-6 (n=564)
vs exenatide BID
Add-on to met ± SU
LIRA-DPP-4 (n=665)
vs sitagliptin
Add-on to met
Completed
Ongoing
LEADER® (cardiovascular outcomes trial) SOC plus liraglutide 0.6 mg–1.8 mg vs SOC plus placebo (n=9,340)
Drug-naïve or add-on to ≥1 OAD or add-on to basal or premix insulin (alone or in combination with OADs)
To be published in ADA-16

Significant HbA1c reduction up to 1.6% from 8.6%
baseline
Significant *vs. comparator; #change in HbA1c from baseline for overall population (LEAD-4) add-on to diet and exercise failure (LEAD-3); or add-on to previous
OAD monotherapy (LEAD-2,-1)
Marre M et al. Diabet Med 2009;26:268–278 (LEAD-1); Nauck M et al. Diabetes Care 2009;32:84–90 (LEAD-2); Garber A et al. Lancet 2009;373:473–481
(LEAD-3); Zinman B et al. Diabetes Care 2009;32:1224–1230 (LEAD-4); Russell-Jones D et al. Diabetologia 2009;52:2046–2055 (LEAD-5);
n= 702
Duration= 52 w
Previous : Diet
(272)
n= 1026
Duration= 26 w
Previous: 1 OAD
(385)
n= 1026
Duration= 26 w
Previous: 1 or more
OAD
n= 492
Duration= 26 w
Previous: 1 or more
OAD
n= 570
Duration= 26 w
Previous: 94% on
OAD combination

Liraglutide is effective early and late in the
treatment but early is better than late
Early use defined as liraglutide add-on to ≤1 OAD; late use defined as add-on to 2 oral OADs
Analysis includes data from the liraglutide vs. sitagliptin study
HbA1c, glycosylated haemoglobin; OAD, oral antidiabetic drug; T2DM, type 2 diabetes mellitus
Garber et al. Diabetes 2011;60(Suppl. 1):967-P`

A quartile of patients have an average weight
loss of 7.7 Kg.
(Metformin + liraglutide 1.8 mg/day) Mean±2SE
Nauck MA, et al. Diabetes Care 2009; 32; 84–90 (LEAD-2)
More than 80% of patients lost weight

Agenda
• The Incretin effect
• GLP-1 RA position in guidelines
• What’s Liraglutide
• Difference between Incretin-based therapies

Family of Incretin-based therapies

Summary of mode of action of GLP-1 receptor agonists
and DPP-4 inhibitors
1. Degn et al. Diabetes 2004;53:1187–94; 2. Mari et al. J Clin Endocrinol Metab 2005;90:4888–94
Subcutaneous injection
Resist degradation by DPP-4
Active GLP-1 level
~80 pmol/L1
High pharmacological level
of GLP-1 receptor activity
Oral ingestion
Inhibit DPP-4 enzyme
Active GLP-1 level
~20 pmol/L2
Increased physiological
activity of GLP-1 receptor
(mainly after meals)
GLP-1 receptor agonists DPP-4 inhibitors

Concentration of active liraglutide is higher than
GLP-1 concentration with a DPP-4 inhibitor
*GLP-1 levels for liraglutide calculated as 1.5% free liraglutide
GLP-1, glucagon-like peptide-1; OD, once daily; OGTT, oral glucose tolerance test
1. Adapted from Degn KB et al. Diabetes 2004;53:1187–1194; 2. Herman GA et al. J Clin Endocrinol Metab. 2006;91(11):4612–4619.
OGTT
2 h (n=55)
Active GLP-12
Hours Postdose
GLP-1,(pmol/L)
GLP-1 levels after 7 days’ liraglutide
6 µg/kg OD* (n=13)1
120
90
60
30
0
0 2 4 6 24 26 288 12 16 20 24
GLP-1receptoragonist
(pmol/L)
Time (h)
Liraglutide dose
Placebo Sitagliptin 200 mg
OGTT
24 h (n=19)90
60
30
120
0

 Gastric
emptying
Additional physiological benefits are observed at
pharmacological levels of GLP-1
Adapted from Holst et al.1
1. Holst JJ et al. Trends Mol Med 2008;14:161–168; 2. Flint A et al. Adv Ther 2011;28:213–226
Physiological
GLP-1 levels
Pharmacological GLP-1
levels
GLP-1 effects
IncreasingPlasmaGLP-1Concentrations
GLP-1RAs
DPP-4is
DPP-4is, dipeptidyl peptidase-4 inhibitors; GLP-1, glucagon-like peptide 1; GLP-1RAs, glucagon-like peptide 1 receptor agonists
Insulin
 Glucagon
=  Plasma glucose2
 Appetite
 Food intake
= Weight loss2

Sustained better HbA1c reduction vs. Sitagliptin
– 52 weeks
Estimated treatment difference (ANCOVA): liraglutide 1.2 mg vs. sitagliptin 0.40; liraglutide 1.8 mg vs. sitagliptin 0.63
(both p<0.0001). Data are mean (1.96 SE) from FAS, LOCF
Pratley et al. Int J Clin Pract 2011;65:397–407

Consistent better HbA1c reduction by baseline
category vs. Sitagliptin – 52 weeks
Pratley et al. Int J Clin Pract 2011;65:397–407

Higher percentage of patients reaching ADA/EASD target
vs. Sitagliptin
ADA, American Diabetes Association
Pratley et al. Int J Clin Pract 2011;65:397–407

Similar very low rate of minor hypoglycaemia weeks 0-52 vs.
Sitagliptin
Pratley et al. Int J Clin Pract 2011;65:397–407
Event/patient/year
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Liraglutide 1.2 mg Liraglutide 1.8 mg Sitagliptin 100 mg

Significant reduction in body weight vs.
sitagliptin
Mean (1.96 SE); data are from the FAS, LOCF
Pratley et al. Lancet 2010:375;1447–56; Pratley et al. Int J Clin Pract 2011;65:397–407

-2.0
-1.8
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Liraglutide has unsurpassed efficacy in GLP-1
RA comparative studies
*Treatment difference (nominal 95% CI)=-0.06 (-0.19, 0.07), p<0.0001 for non inferiority vs liraglutide
BID, twice a day; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin
Buse JB et al. Lancet 2009;374:39–47 (LEAD-6); Buse JB et al. Lancet 2013;381:117–24 (DURATION-6); Pratley RE et al. Lancet Diabetes Endocrinol 2014;2:289–97 (Harmony-7); Dungan KM et
al. Lancet 2014; 384(9951):1349–1357 (AWARD-6); Nauck MA et al. European Association for the Study of Diabetes 2015 Annual Meeting, Abstract #75 (LIRA-LIXI)
www.easdvirtualmeeting.org/resources/once-daily-liraglutide-vs-lixisenatide-as-add-on-to-metformin-in-type-2-diabetes-a-26-week-randomised-controlled-clinical-trial--2 Accessed August 2015.
ChangeinHbA1c(%)
p<0.0001
Baseline HbA1c (%):
LEAD-6
8.2 8.1
HARMONY-7
8.2 8.2
DURATION-6
8.58.4
AWARD-6
8.1 8.1
-1.12
-0.79
-1.28
-0.98
-0.79
-1.42
p=0.0001
-1.36
-1.48
LIRA-LIXI
8.4 8.4
p<0.0001
-1.83
-1.21
Liraglutide 1.8 mg Exenatide 10 µg BID
Dulaglutide 1.5 mgAlbiglutide 50 mg
Exenatide 2 mg
Lixisenatide 20 µg
95% CI
[0.08,0.34]
95% CI
[-0.19,0.07]

-5.0
-4.5
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
Liraglutide has unsurpassed weight reduction in
GLP-1 RA comparative studies
*
BID, twice a day; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin
Buse JB et al. Lancet 2009;374:39–47 (LEAD-6); Buse JB et al. Lancet 2013;381:117–24 (DURATION-6); Pratley RE et al. Lancet Diabetes Endocrinol 2014;2:289–97 (Harmony-7); Dungan
KM et al. Lancet 2014; 384(9951):1349–1357 (AWARD-6); Nauck MA et al. European Association for the Study of Diabetes 2015 Annual Meeting, Abstract #75 (LIRA-LIXI)
www.easdvirtualmeeting.org/resources/once-daily-liraglutide-vs-lixisenatide-as-add-on-to-metformin-in-type-2-diabetes-a-26-week-randomised-controlled-clinical-trial--2 Accessed August
2015.
Changeinbodyweight(Kg)
Baseline weight (Kg):
LEAD-6
93.1 93.0
HARMONY-7
92.8 91.7
DURATION-6
90.991.1
AWARD-6
93.8 94.4
LIRA-LIXI
101.9 100.6
Liraglutide 1.8 mg Exenatide 10 µg BID
Dulaglutide 1.5 mgAlbiglutide 50 mg
Exenatide 2 mg
Lixisenatide 20 µg
p=0.22
-2.87
-3.24
p<0.001
-2.68
-3.57
-0.60
-2.20
p<0.0001
p<0.01
-2.90
-3.60-3.67
-4.26
p=0.2347

Odds ratio of achieving composite end point with liraglutide 1.8 mg is superior, with *p<0.001; †p<0.01; ‡p<0.0001
Odds ratio of achieving composite end point with liraglutide 1.2 mg is superior, with § p<0.0001
HbA1c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione, LEAD: Liraglutide effect and action in diabetes.
Zinman B et al. Diabetes Obes Metab 2012;14:77–82
Meta-analysis of LEAD program :Composite end point:
HbA1c <7.0%, no weight gain, no hypoglycaemia
40
32
25
11
8
6
15
0
5
10
15
20
25
30
35
40
45
Liraglutide 1.8
mg
Liraglutide 1.2
mg
Exenatide Insulin glargine Sitagliptin SU TZD
PatientsReaching
CompositeEndPoint(%)
(n=1513) (n=1077)
(n=186) (n=210) (n=447) (n=226)(n=225)
5.2‡
3.7§
7.4 ‡
5.2 § 10.5 ‡
7.4 §
3.7 ‡
2.0†

Summary
• Incretin-based therapies are considered early in the treatment in different
guidelines
• Liraglutide is a human GLP-1 analogue with 97% homology to the native
hormone
• Liraglutide is effective on glycaemic control without increasing risk of
Hypoglycaemia and weight benefit.
• Compared with DPP-4I, GLP-1 receptor agonists are associated with
greater reduction in HbA1c and weight loss and same vey low rate of
Hypoglycaemia

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