Ueda2016 symposium - glp-1 story,a closer look -yehia ghanem

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

cellsα cells

SkeletalMuscle

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

Pla

sm

a G

lucose (

mm

ol/

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 1800

Time (min)

Incretineffect

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 (

pm

ol/

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±SEMGIP, 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

EpacTriggering

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 1800

Time (min)15090

**

*

Insulin (

mU

/L)

0 30 60 120 180

40

Time (min)

20

0

80

Healthy Controls

60

90 150

***

****

Incretineffect

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

00 30 60 90 120

Time (min)

1000

2000

3000

4000

5000

6000

Insulin (

pm

ol/

L)

GLP-1 infusion period

(0.5 pmol/kg/min)

Plasma GLP-1:46 pmol/L

Healthy


T2DM

Pharmacological levels of GLP-12

(15 mM hyperglycaemic clamp)

0

1000

2000

3000

4000

0 45 90 135 180

Time (min)

Insulin (

pm

ol/

L)

5000

6000GLP-1 infusion period

(1.0 pmol/kg/min)


T2DM

n=8GLP-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

Pla

sm

a G

lucose (

mm

ol/

L)

5

10

20

25

15

04 12 00 0408 16 20

16-h GLP-1 infusion

Agenda





ADA\EASD position statement 2015-2016Early combination therapy is recommended

Healthy eating, weight control, increased physical activity, and diabetes education

MetforminMono-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 agonistInzucchi SE et al. Diabetes Care 2015;38:140–149

ADA\EASD 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-1RAInsulin (basal)

Efficacy (↓HbA1c)

High High Intermediate Intermediate High Highest

Hypoglycaemia risk

Moderate Low Low Low Low High

Weight effect ↑ ↑ ↔ ↓ ↓ ↑

Major side effects

Hypo-glycaemia

OedemaHeart failure

Bone fracturesRare

GenitourinaryDehydration

GIHypo-

glycaemia

Inzucchi SE et al. Diabetes Care 2015;38:140–149

Strictly Confidential. Proprietary

information of Novartis. For internal

use ONLY. March 2010. GAL10.497. 19

Agenda





Liraglutide is a once-daily, human GLP-1 analogue

glutamoyl spacer

3426

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

Liraglutide10

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, thiazolidinedioneSource: 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 metTo be finished in 2020

LIRA-LIXI™ (n=400)vs lixisenatideAdd-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 placeboAdd-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= 702Duration= 52 w Previous : Diet

(272)

n= 1026Duration= 26 wPrevious: 1 OAD

(385)

n= 1026Duration= 26 w

Previous: 1 or more

OAD

n= 492Duration= 26 w

Previous: 1 or more

OAD

n= 570Duration= 26 wPrevious: 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





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 liraglutideGLP-1, glucagon-like peptide-1; OD, once daily; OGTT, oral glucose tolerance test1. 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.

OGTT2 h (n=55)

Active GLP-12

Hours Postdose

GLP-1

, (p

mol/

L)

GLP-1 levels after 7 days’ liraglutide6 µg/kg OD* (n=13)1

120

90

60

30

0

0 2 4 6 24 26 288 12 16 20 24

GLP-1

recepto

r agonis

t(p

mol/

L)

Time (h)

Liraglutide dose

Placebo Sitagliptin 200 mg

OGTT24 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

Incre

asin

g P

lasm

a G

LP-1

Concentr

ations

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


Higher percentage of patients reaching ADA/EASD target vs. Sitagliptin

ADA, American Diabetes Association


Similar very low rate of minor hypoglycaemia weeks 0-52 vs. Sitagliptin


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 liraglutideBID, 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.

Ch

an

ge in

Hb

A1

c(%

)

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]

http://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

-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.

Ch

an

ge in

bo

dy w

eig

ht

(K

g)

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

http://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

Odds ratio of achieving composite end point with liraglutide 1.8 mg is superior, with *p<0.001; †p<0.01; ‡p<0.0001Odds ratio of achieving composite end point with liraglutide 1.2 mg is superior, with § p<0.0001HbA1c, 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

86

15

0

5

10

15

20

25

30

35

40

45

Liraglutide 1.8mg

Liraglutide 1.2mg

Exenatide Insulin glargine Sitagliptin SU TZD

Patients

Reachin

g

Com

posite E

nd P

oin

t (%

)

(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

45

THANK YOU

Ueda2016 symposium - glp-1 story,a closer look -yehia ghanem

Health & Medicine

Transcript of Ueda2016 symposium - glp-1 story,a closer look -yehia ghanem