are all glp-1 ras the same? intensification of basal...

28th Congress of Northern Greece Diabetes Association

Thessaloniki, 14 November 2014

Are all GLP-1 RAs the same?

Intensification of basal insulin treatment

with the addition of prandial GLP-1 RAs

Geremia B. BolliDepartment of Medicine

Section of Internal Medicine, Endocrinology and Metabolism

Perugia University School of Medicine, Italy, EU

Geremia B.Bolli

CONFLICT OF INTERESTover past two years

Sanofi

Eli Lilly

Novartis

Roche Pharma

Bristol Mayer Squibb

Menarini

Lifescan

AGENDA

• What is Type 2 DM today ?

• Can we treat Type 2 DM to prevent

long-term vascular complications ?

UNTREATED DIABETES LEADS OVER TIME TO A MICRO-and MACRO-VASCULAR DISEASE

International Diabetes Federation. Diabetes Atlas. Second Edition, 2003

70-80% of people with diabetes die of cardiovascular disease

Diabetic foot

(ulceration and

amputation)

Lower limbs

(peripheral

vascular disease)

Brain and

cerebral

circulation

(cerebrovascular

disease)

Peripheral nervous

(system neuropathy)

Kidney

(nephropathy)

Heart and coronary

circulation

Eyes

(retinopathy)

HYPERGLYCEMIA IS A VASCULAR POISON

post-UKPDS Era

• early diagnosis of Type 2 DM

• early, aggressive treatment of

hyperglycemia to lower A1C <7.0%

PREVENTION OF LONG-TERM

COMPLICATIONS IS POSSIBLE

Diabetes Care, Diabetologia. 19 April 2012

SGLT2 inhibitors


SGLT2 inhibitors

non-insulin insulin

24-Hour Plasma Glucose in failure to OHA

Time of Day

22.2

16.6

11.1

5.5

0

0600 06001000 1400 1800 2200 0200

courtesy of Jay Skyler

adapted from Polonsky et al, N Engl J Med 1988

Glucose

(mmol/L)

Diabetic

T2

Normal

Effect of treatment with basal insulin

24-Hour Plasma Glucose in failure to OHA

Time of Day

22.2

16.6

11.1

5.5

0

0600 06001000 1400 1800 2200 0200



Glucose

(mmol/L)Diabetic T2

Normal

Effect of treatment with basal insulin

A1C 7.0%

1. Riddle M et al. Diabetes Care 2003;26:3080–862. Janka H et al. Diabetes Care 2005;28:254–259

3. Rosenstock J et al. Diabetes Care 2006 4. Gerstein HC et al. Diab. Med. 2006

5. Rosenstock J et al. Diabetologia, 2008

About 40-50% of subjects on basal insulin + OHA do not reach the target A1C <7.0%

despite FBG 100-120 mg/dl

TTT2003

Triple Therapy2006

Rosenstock2008

Glargine

Comparator

Insight2005

0

10

20

30

40

50

60

70

Laptop2005

% O

F PA

TIEN

TS W

HO

D

O N

OT

REA

CH

A1

c <7

.0%

Why ?

in 50% of T2DM subjects A1C remains >7.0% despite titration of basal insulin to FBG 100-120 mg/dl

deficiency of prandial insulin at meal-time !

Time of Day

22.2

16.6

11.1

5.5

0

0600 06001000 1400 1800 2200 0200



Glucose

(mmol/L)Diabetic T2

Normal

A1C >7.0%


SGLT2 inhibitors

Incretin Hormones Regulate

Insulin and Glucagon Levels

GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptide Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes Care. 2003;26:2929–2940. Nauck MA et al. Diabetologia. 1993;36:741–744. Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979 Springer-Verlag. 13

PancreasGut

Nutrient signals ● Glucose

Glucagon(GLP-1)

Insulin(GLP-1,GIP)

Neural signals cells

cells

Hormonal signals

• GLP-1

• GIP

The Incretin Effect in Subjects

Without and With Type 2 Diabetes

IR=Immune Reactive.Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag. 12

Time, min

IR I

nsu

lin

, m

U/L

nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Control Subjects(n=8)

Patients With Type 2 Diabetes(n=14)

Time, min

IR I

nsu

lin

, m

U/L

nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Oral glucose load Intravenous (IV) glucose infusion

Incretin

Effect

The incretin effect

is diminished

in type 2 diabetes.


SGLT2 inhibitors

questions

Are all GLP-1 Receptor Agonists

the same ?

Saline

GLP-1

750

600

450

300

150

00-15 15 30 45 60 75

IV Glucose

control

GLP-1

Insulin (pmol/L)

Glucagon(pg/mL)

#2

#1 Insulin

Glucagon

GLP-1 modulates pancreatic - and -cell functions

GLP-1 Slows Gastric Emptying

Placebo

500

400

300

200

100

0

*

-30 0 30 60 90 120 150 180 210 240

Time (min)

*

*

*

*

Liquid meal nGLP-1

p<0.0001

Gastric volume

(mL)

#3

Nauck , et al. Diabetologia 1996;39:1546-1553

Meier JJ, et al. J Clin Endocrinol Metab 2003;88:2719–25.

GLP-1 Inhibits Gastric Emptying in People with T2DM

0 60 120 180 240

0

20

40

60

80

100

1.2 pmol . kg -1 . min -1

0.8 pmol . kg -1 . min -1

0.4 pmol . kg -1 . min -1

Placebo

Time (min)

Gas

tric

co

nte

nt

(% o

f in

itia

l val

ue

)

p < 0.0001 for between-dose differences, differences over time and differences due to interaction of experiment and time

#3

~1/3 due to Gastric emptying*

~1/3 due to Insulin

GLP-1RAs can reduce post-prandial glucose through 3 main mechanisms

IV GLP-1RA

7.4 mmol/L

(138 mg/dL)

11.4 mmol/L (206 mg/dL)

~1/3 due to Glucagon

PPG

Cervera A, et al. Am J Physiol Endocrinol Metab. 2008;294:E846-852

T2DM subjects (n=12) participated in mixed-meal tolerance tests where IV exenatide was administered

and enhanced splanchnic glucose uptake

Gastric emptying rate is an important determinant of PPG in type 2 diabetes

Blood glucose

Slowing gastric

emptying

FAST SLOW

Gastric Emptying Rate

Blo

od

Glu

co

se

Co

nc

en

tra

tio

n

Po

st

Ora

l G

luc

os

e C

ha

lle

ng

e (

mm

ol/

L)

R= –0.61,

P<0.05

Rapid gastric

emptying associated

with higher

glucose levels

Slow gastric

emptying associated

with lower

glucose levels

Gastric emptying

20

18

16

14

12

10

8

40 50 60 70 80 90 100

Jones KL, et al. J Nucl Med 1996;37:1643–8

Holst JJ, Physiol Rev, 2007

physiology of the incretin system

fasting and post-prandial state

Continuous GLP-1 Administration Produces Rapid Tachyphylaxis of Gastric Emptying

GLP-1(pmol/l)

*

0 120 240 360 4800

20

40

60

80

p < 0.0001

Meal 2

*

**

Meal 1

* * * **

** * *

*

0 120 240 360 480

0

100

200

300

400

500

p < 0.0001

*

*

**

*

**

Gastric Volume

(ml)

Meal 2Meal 1

Time (min)

Placebo

nGLP-1

Nauck MA, Diabetes 2011;60:1561–65.

*Significant difference from corresponding time point after first meal during exogenous administration of GLP-1

placebo

placebo placebo

Differential dose-dependent effects of GLP-1 on glucose and insulin levels in the fasting state

Fasting

Meier JJ, et al. J Clin Endocrinol Metab 2003

Differential dose-dependent effects of GLP-1 on glucose and insulin levels in the post-prandial state

Mixed meal

GLP-1 dose

-8000

-6000

-4000

-2000

0

2000

4000

6000

0.0

0.4 0.8 1.2

p < 0.001 *

**

-400

-200

0

200

400

600

800

∫ G

luco

se6

0-3

00

min

[mg

.d

l-1

. min

]

[mm

ol

l-1

.m

in]

0

1000

2000

3000

4000

5000

6000

0.0 0.4 0.8 1.2

*

p = 0.0031

*

*

0

5000

10000

15000

20000

25000

30000

35000

∫ In

sulin

60

-30

0 m

in[m

U.

l-1

.m

in] [p

mo

l.

l-1

.m

in]

.

Meier JJ, et al. J Clin Endocrinol Metab 2003;88:2719–25

• GLP-1-induced reduction of fasting hyperglycemiais mediated primarily through its effects on the α- β-cells of pancreatic islets

• Post-prandial glucose control seems to be largelymediated through the delaying effect of GLP-1 ongastric emptying after meal ingestion

Key points

Differential glucose lowering effects of GLP-1 in the fasting and postprandial states

Red and blue circles = differences vs. native GLP-1

LiraglutideDPP4 ExenatideNative human

GLP-1

Lixisenatide

GLP-1R agonists: ‘similar’ structure to native

human GLP-1

Adapted from Werner U, et al Regul Pept. 2010;164:58–64

Exenatide QWAlbiglutide

| 28

Common Properties

● Stimulate insulin secretion (glucose-dependent)

● Suppress glucagon secretion (glucose-dependent)

● Control appetite leading to weight loss

Differentiation of GLP-1 Receptor Agonists

Short-acting (Prandial)

GLP-1 RAs Long-acting GLP-1 RAs

No tachyphylaxis for

delay of gastric emptying

Tachyphylaxis and minimal

effect on gastric emptying

• Marked reduction of PPG

• Modest stimulation of insulin

secretion

• Modest effect on FPG

• Modest reduction of PP

• Marked stimulation of insulin

secretion

• Marked effect on FPG

Exenatide

Lixisenatide

reduce POST-PRANDIAL PG

by slowing gastric emptying

Liraglutide

Exenatide LAR (qw)

Albiglutide, Dulaglutide

reduce FASTING PG

by stimulating insulin

secretion

| 29

Duration of Exposure Drives Main Mechanism for Glucose-lowering

Long-acting Formulation

Exenatide QW

Short-acting Formulation

Exenatide BID

Half-life 12 hours – several days 2-5 hours

Gastric emptying No effect Marked delay

Postprandial glycemia Modest reduction Marked reduction

Fasting glycemia Marked reduction Modest reduction

BID = Twice Daily; QD = Once Daily; QW = Once Weekly

| 30

Pla

sma

GLP

-1R

A

Liraglutid 1x daily Exenatide 1x weekly

Pharmacokinetic differences in GLP-1/Exenatide levelswith different GLP-1 RA’s

Pla

sma

GLP

-1R

A

Time (days)

876543210

Exenatid 2x daily

Drucker DJ, et al. Lancet 2008;372:1240–50.

Time profiles of postprandial plasma glucose concentrationswith Short-acting (Exenatide) and Long-acting (Exenatide-LAR)

GLP-1 Receptor Agonists

Exenatide once weekly Exenatide twice daily

n = 26BaselineWeek 14

Baselinen = 26

Week 14

Drucker DJ, et al. Lancet 2008;372:1240–50.

Inhibition of Gastric Emptying with Short-acting (Exenatide) and Long-acting (Exenatide-LAR) GLP-1 Receptor Agonists

50 100 150 200 250 3000

Baseline

Exenatide twice daily

Time (min)

Exenatide once weekly

500

100 150 200 250 30000

50

1000

1500

2000

2500

Time (min)

n = 26BaselineWeek 14

500

0

1000

1500

2000

2500 n = 26

Week 14

μg*

min

/mL

Cumulative acetaminophen AUC

Lixisenatide is a Selective GLP-1 RA

Lixisenatide’sresistance to DPP-IV proteolysis is due to the substitution of an N-terminal alanine with a glycine residue — this results in sustained in vivo activity

1.5-4.5 h plasma half-life

Lixisenatide’s high affinity for the GLP-1 receptor (approximately 4-fold higher affinity for GLP-1 receptor than native human GLP-1) effectively uncouples plasma half-life from

pharmacologic half-life and enables once-a-day dosing

Source: Werner U. et al. Regulatory Peptides 164: 58-64 (2010)

DPP-IV cleavage site in human GLP-1

N-terminal

C-terminal

0 60 120 180 240 300 360

0

10

20

30

40

50L

IXIS

EN

AT

IDE

- p

mo

l.L-1

TIME - min

MEAN (SD)

PLACEBO

2.5 µg

5 µg

10 µg

20 µg

Lixisenatide

GLP-1R agonists improve insulin secretion in

T2DM

GLP-1 Exenatide Lixisenatide

S Quddusi, Diabetes Care, 2003 M Nauck, JCEM 2005 R Becker, EASD, 2010

Liraglutide

A Chang, Diabetes, 2003

| 36

Lixisenatide Slows Gastric Emptying in T2DM Patients

-100

-50

0

50

100

150

200

250

300

Lixisenatide

Once-a-day

T1/2

(min)

Placebo

Adapted from Lorenz et al. Regulatory Peptides 185 (2013) 1–8

13C-octanoic acid breath test

Lixisenatide

Liraglutide

2-Week

Treatment

Initiation

n=120

10 µg

20 µg

0.6 mg

1.2 mg

1.8 mg

2-Week Maintenance

Treatment Period

Screening Period

PPGPrimary

Endpoint

A1C 6,5--9%

T2DM ≥ 1

year

MET≥ 1.5g/d

Kapitza C et al, Diabetes Obesity and Metabolism 2013

Meal Test

Meal Test

Proof of Concept Study Design

Lixisenatide vs Liraglutide Postprandial Glucose Effects in Type 2 DM

PPG Effects

Lixisenatide vs Liraglutide Postprandial Glucose Effects in Type 2

DM

Glucose Insulin

Liraglutide

Lixisenatide


Liraglutide

Lixisenatide

PPG Effects

Lixisenatide vs Liraglutide Postprandial Glucose Effects in Type 2 DM

Glucose Glucagon

Liraglutide

Lixisenatide


Liraglutide

Lixisenatide

For internal training only – do not distribute

Study Design

*stopped at run-in start; ABPM: ambulatory blood pressure monitoring; DPP-4: dipeptidyl peptidase-4;

GEBT: gastric emptying breath tests; HbA1c: glycated haemoglobin; NPH: neutral protamine Hagedorn;

R: randomisation; SMPG: self-monitored plasma glucose; SU: sulphonylurea

Meier J et al. Effect of Lixisenatide vs Liraglutide on

Glycemic Control, Gastric Emptying, and Safety Parameters in Optimized

Insulin Glargine T2DM ± Metformin. 74th ADA meeting 2014; abstract: 1017-P

Mean (SEM) PPG Levels at Baseline and Week 8

(mITT population)




Statistical test compared treatment arms at each timepoint at Week 8

*p<0.05 for Lixisenade 20 μg versus Liraglude 1.2 mg; †p<0.05 for Lixisenade 20 μg versus Liraglude 1.8 mgmITT: modified intent to treat; PPG: post-prandial plasma glucose; SEM: standard error of the mean

24-hour Heart Rate-monitoring Results (hourly mean [SEM]) for

Lixisenatide and Liraglutide at (A) Baseline and (B) Week 8(mITT population)




Statistical tests compared treatment arms at each timepoint at Week 8

*p<0.05 for Liraglude 1.2 mg versus Lixisenade 20 μg; †p0.05 for Liraglude 1.8 mg versus Lixisenade 20 μgbpm: beats per minute; mITT: modified intent-to-treat; SEM: standard error of the mean

| 44

Lixisenatide in the treatment of Type 2 diabetes in its natural history

Diet and

exercise

1 OAD

2 OADs

Basal

insulin OADs

GetGoal-Mono

Monotherapy

GetGoal-Mono Japan

Monotherapy

GetGoal-F1

Add-on to MET

GetGoal-X

Add-on to MET

GetGoal-M

Add-on to METGetGoal-P

Add on to pioglitazone

± MET

GetGoal-M-Asia

Add on to MET± SU

GetGoal-S

Add on to SU ± MET

GetGoal-L-Asia

Add on to basal

insulin ± SU

GetGoal-Duo1

Add on to insulin

glargine ± MET

GetGoal-L

Add on to basal insulin

± MET

| 45

Consistent Reduction in HbA1C

-0,7

3

-0,8

5

-0,1

9

-0,9

9

-0,7

4

-0,8

7

-0,7

5

-0,3

8

-0,8

3

-0,9

2

-0,4

2

-0,7

9

-0,9

6

-0.8

5

-0,1

0

-0,9

0

-0,3

4

-0,8

3

-0,4

7

-0,7

4

-0,3

8

-0,7

7

0,1

1

-0,7

1

-0,4

0

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

0,2

GG

Mono

GG

-M

GG

-F1

GG

-S

GG

-P

GG

-L

GG

Duo1

GG

-X

GG

Mono

Japan*

GG

-M Asia

GG

-L Asia

Ch

an

ge

in

Hb

A1C

fro

m b

as

eli

ne

(%

)

Lixisenatide

Exenatide BID

Placebo

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

*24 week data, longer-term data was pooled; ** 2-step PM dosing; *** 2-step AM dosing

Note: All lixisenatide dosing is 1-step AM regimen, unless otherwise noted

Source: Previous GetGoal sources, Sanofi unpublished data

| 46

Fasting glucose levels

-0,6

8

-0,8

9

0,1

9

-1,1

6

-0,5

6

-1,1

9

-0,8

1

-0,2

5

-0,5

6

-0,5

3

0,1

1

-1,2

2

-1,4

5

-0,9

9

-0,3

6

-1,1

6

-0,3

2

-0,2

1

-0,6

9

-0,6

3

-0,5

5

-0,4

2

0,2

5

0,3

4 0,4

6

-2,0

-1,5

-1,0

-0,5

0,0

0,5

1,0

Ch

an

ge

in

FP

G f

rom

ba

se

lin

e (

mm

ol/

L)

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

***

***




Lixisenatide

Exenatide BID

Placebo

GG

Mono

GG

-M

GG

-F1

GG

-S

GG

-P

GG

-L

GG

Duo1

GG

-X

GG

Mono

Japan*

GG

-M Asia

GG

-L Asia

| 47

Post-prandial glucose levelsC

ha

ng

e in

PP

G f

rom

ba

se

lin

e (

mm

ol/

L)

-4,5

1

-5,4

7

-0,6

5

NA

NA

-5,9

2

NA

-1,4

1

NA

NA

NA

NA

NA

-6,1

9

-0,2

1

NA

NA

-5,6

1

-1,3

3

-5,5

4

-1,7

2

-7,9

6

-0,1

4

-3,0

9

0,0

8

-9,0

-8,0

-7,0

-6,0

-5,0

-4,0

-3,0

-2,0

-1,0

0,0

1,0

**

***

***

***

*** ***

***

***

*** ******




Lixisenatide

Placebo

GG

Mono

GG

-M

GG

-F1

GG

-S

GG

-P

GG

-L

GG

Duo1

GG

-X

GG

Mono

Japan*

GG

-M Asia

GG

-L Asia

| 48

Body weight change

-1,9

6

-1,9

2

-1,9

8

-0,4

3

-1,0

8

-2,0

1

-2,0

2 -1,6

4

-2,6

8

-2,6

3

-1,6

3

-2,9

6

-3,9

8

-1,7

6

-0,9

3

-0,2

1

0,2

1

-1.2

4

-1,5

0

-1,8

0

-0,5

0

-0,3

8

0,0

6

0,2

8

1,1

6

-5,0

-4,0

-3,0

-2,0

-1,0

0,0

1,0

2,0

Ch

an

ge

in

bo

dy w

eig

ht

fro

m b

as

eli

ne (

kg

)

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

***

***




Lixisenatide

Exenatide BID

Placebo

GG

Mono

GG

-M

GG

-F1

GG

-S

GG

-P

GG

-L

GG

Duo1

GG

-X

GG

Mono

Japan*

GG

-M Asia

GG

-L Asia

| 49

Incidence of gastro-intestinal eventsIn

cid

en

ce o

f n

au

se

a (

%)

15

10

5

0

0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Treatment period (weeks)

>2/3 patients reported only 1 GI event

>95% are mild or moderate

Serious GI events were rare (1.1 vs 0.8%)

Discontinuation for events was low (5.1 vs 0.9%)

Previous GetGoal sources

Lixisenatide

Placebo

| 50

Treatment with Lixisenatide was evaluated along the natural history of Type 2 diabetes

Diet and

exercise

1 OAD

2 OADs

Basal

insulin OADs

GetGoal-Mono

Monotherapy

GetGoal-Mono Japan

Monotherapy

GetGoal-F1

Add-on to MET

GetGoal-X

Add-on to MET

GetGoal-M

Add-on to METGetGoal-P

Add on to pioglitazone

± MET

GetGoal-M-Asia

Add on to MET± SU

GetGoal-S

Add on to SU ± MET

GetGoal-L-Asia

Add on to basal

insulin ± SU

GetGoal-Duo1

Add on to insulin

glargine ± MET

GetGoal-L

Add on to basal insulin

± MET

Controls primarily PPG

No increase in hypoglycemia

Weight

Basal Insulin

Controls primarily FPG

Hypoglycemia risk

Weight

GLP-1 RAs short-acting

Add-on GLP-1 RA short-acting to basal insulin

Rationale: to lower post-prandial hyperglycaemia

Mutual benefits from combination

in physiology insulin and GLP-1 are integrated

question

Intensification of basal insulin treatment

with the addition of prandial GLP-1 RAs

–2

–1.5

–1

0.5

0

0.5

0 18 30

7.4%

Time (weeks)

Optimized Glargine + Placebo

Me

an C

han

ge i

n A

1C

(%

)

Combination of Exenatide BID with Optimized Insulin Glargine QD in Type 2 DM

A1C Changes Over Time

8.5%

Optimized Glargine + Exenatide

6.7%

8.3%

-1.74% vs -1.04% [CI, 1.22% Difference -0.69% [CI -0.93% to -0.46%]

P 0.001

Buse JB, et al. Ann Intern Med, 2011



Effect of Exenatide on post-prandial PG

Glargine + exenatide

Glargine+

placebo


Optimized Glargine + Placebo

Optimized Glargine + Exenatide

Week

Ch

ange

in B

od

y W

eig

ht,

kg

0 2 4 6 8 10 14 18 22 26 30

2.0

1.5

1.0

0.5

0.0

-0.5

-1.5

-2.0

-2.5

-3.0

-1.0

+ 0.96 kg

- 1.78 kg

95.4 kg

93.8kg

Body Weight Changes Over time


HypoglycemiaNOT different

6,0

6,5

7,0

7,5

8,0

8,5

9,0

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26

7.6

Mean (2SE); data are from the full analysis set (FAS) no imputation

A1

c (%

)

Run-In Phase(weeks 12 to 0)

Randomized Phase(weeks 0 to 26)

7.6

6.4

7.5

6.6

7.1

8.3

Time (weeks)

8.2

7.7

.

A1c Changes Over Time

MET + LIRA1.8 mg

MET + LIRA 1.8 mg + IDet

Observational MET + LIRA 1.8 mg

DeVries et al. Diabetes Care 2012; 35: 1446-54

LS mean difference vs placebo: –0.36% (95% CI: –0.55 to –0.17)

p <0.001

0

–0.1

–0.2

–0.3

–0.4

–0.5

–0.6

–0.7

–0.8

LS m

ean

ch

ange

in A

1C

(%

)Glargine ±MET + Placebo (n = 158)

Glargine±MET + lLxisenatide (n = 304)

mITT population, LS Mean Change from baseline to Week 24 (LOCF)

Riddle M, et al. Diabetes Care 2013;36:2489-96

8.4%

A1C Changes at Week 24

Once-daily Lixisenatide as Add-on to Non-Titrated Basal

Insulin Plus OADs : GetGoal-L

0

–1.0

–2.0

–3.0

–4.0

–5.0

–6.0

2-hour PPG*

–1.7

–5.5

Glucose Excursion†

–0.3

–4.1

0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

–4.0

–4.5

*After a standardized breakfast meal test: Ensure Plus® Drink (Abbot; 600 kcal; 54% carbohydrate; 17% protein; 29% fat)†2-hour PPG – plasma glucose 30 minutes prior to meal test (before study drug administration)

LS mean difference vs placebo: –3.8 mmol/L(95% CI: –4.7 to –2.9)

LS mean difference vs placebo: –3.8 mmol/L(95% CI: –4.6 to –3.0)

p <0.0001 p <0.0001

LS m

ean

ch

ange

(m

mo

l/L)

LS m

ean

ch

ange

(m

mo

l/L)

PPG Changes at Week 24Glargine±MET + Placebo (n = 123)Glargine±MET + Lixisenatide (n = 235)


Once-daily Lixisenatide as Add-on to Non-Titrated Basal

Insulin Plus OADs : GetGoal-L

Seino Y, et al. Diabetes Obes Metab 2012;14:910-7

GetGoal-L-ASIALixisenatide add-on basal insulin sulphonylurea

with Lixisenatide:

• BW lower

• TEAE higher

• Hypoglycaemia

driven by SU

SU+ 33%

SU- 28%

GetGoal-Duo1: Lixisenatide add-on basal insulin

glargine –continued titration

12-week run in phase 24-week-double-blind period

Target fasting SMBG between 80 and 100 mg/dl (both inclusive)

+ Lixisenatide (n=225)

+ Placebo (n=225)

Randomised if

7 ≤Hb A1c ≤9% and

Mean fasting

SMBG ≤140 mg/dl

HbA1c

≥7 ≤10%

Metformin

±TZDs

± SUs*

or

Glinides*

2-weekscreening

RGlargine (morning) ** + metformin ( TZDs)

*Stopped at Lantus initiation ** Lantus dose adjusted as necessary to maintain fasting SMBG target

Lantus forced weekly

titration 8–12 weeks

10μg15μg

20μg

GetGoal-Duo1:change in HbA1c from baseline to week 24

mITT population; * LOCF (on treatment value available) analysis for least squared mean or mean change at Week 24; SCR=screening

Placebo + insulin glargine + metformin (n=221)Lixisenatide + insulin glargine + metformin (n=215)

Me

an

Hb

A1c (

%) ±

SE

SCR–12 24

Week

6.6

6.8

–8 –4 –1 4 8 16

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.8

0

8.6

7.6

7.6

Glargine + MET (±TZDs) Lixisenatide OR placebo + MET (±TZDs)

Week 24

LOCF*

7.3%

7.0%

LS mean difference vs placebo: –0.3% (95% CI: –0.5 to –0.2)

0

–0.2

–0.4

–0.6

–0.8

LS

me

an

ch

an

ge in

Hb

A1c

(%)

Week 24 LOCF*

p<0.0001


question

differences between GLP-1RAs short-acting

vs prandial insulin

on top of basal insulin

Exenatide BID vs Insulin Lispro TID with Insulin Glarginefor Intensified Treatment of T2DM

The 4B Study

Diamant M, et al. Diabetes Care 2014.

Values are LS Mean ± SE calculated using MM8M

ExBID + IG 7.19% (N=247)

LisTID+ IG 7.16% (N=263)

Hb

A1

c(%

)

0 2 4 6 8 12 18

Time (wk)

24 306.5

7.0

7.5

8.0

8.5

49.6% 49.0%

Pat

ien

ts (

%)

HbA1c at 30 weeks

HbA1c ≤7%


LS Mean ± SE calculated using MMRM, *P<0.0001

ExBID + IG (N=247); Baseline 9117

LisTID + IG (N=263); Baseline 8917

Ch

ange

in b

od

y w

eig

ht

(kg)

0 2 4 6 8 12 18

Time (wk)

24 30-4

-2

0

1

3

44.6%

22.9%

2

-1

-3

**

* **

** *

-2.5 kg

+2.1 kg

-4.6 kg (-5.2, -3.9)

P<0.0001

Ex BID + IG (N=242)LisTID + IG (N=262)

HbA1c ≤7% and Weight gain ≤1kg

P value calculated using logistic regression analysis

Body weight and composite endpoint


Ex BID + IG (n=315) ListTID + IG (n=312)

Overall rate per patient-year (Minor and Major): 2.1 (ExBID + IG) vs (LisTID + IG)

As treated population; Fisher’s exact test

P=0.004

P=0.106

P<0.001

P=0.648

Incidence of hypoglycemia


Change in HbA1c and body weight

Mathieu C, et al. Diabetes Obes Metab 2014;Published online 11 Feb 2014.


285 patients

GetGoal DUO-2: Lixisenatide added to insulin

glargine versus basal-plus and basal-bolus

26-week open-label treatment periodRun-inScreening

T2DM patientsBasal insulin ± OADsHbA1c 7.5% & ≤10%

Insulin glargine adjusted in all groups (fasting SMPG 80-100 mg/dL)

10 µg 20 µg

Lixisenatide

R

Basal Bolus = 3 RAI injections per day

Discontinue DPPIV and SU

Basal Plus = 1 RAI injection per day

Insulin glargine introducedand/or optimized

12 weeks

- HbA1c between 7- 9%

- Mean fasting SMBG ≤ (140mg/dL)

285 patients

285 patients

R

www.clinicaltrials.gov. NCT01768559.

question

fixed combinations

basal insulin + GLP-1 RAs

IDegLira vs Degludec or Liraglutide alone: resultsH

bA

1c,

%

Effect on Hba1c at Week 26

Baseline

At 26wks

Weight loss: - 2.22 kg for IDegLira vs IDeg (P< 0.0001)

Buse J , et al. ADA , 2013. Abstract 65 OR; Lancet Endocrinology 2014

8.3 8.3 8.3

6.4

6.97.0

6

6.5

7

7.5

8

8.5

9

IDegLira Degludeg Liraglutide

T2DMs on basal insulin + OHA

randomized to

-IDeg + met

-IDegLira (1U/0.036 mg) + met

Insulin Degludec vs Insulin Degludec + Liraglutide

in T2DM

Buse J et al., Diabetes Care 2014

Degludec

Degludec + Liraglutide


Lantus: • 1 injection• Predominant FPG lowering• Significant A1c reduction• Potential Weight gain• Hypoglycemia

Lyxumia: • 1 injection• Predominant PPG lowering• A1c reduction on top of Lantus• Weight loss• Low risk of hypoglycemia

LixiLan:• 1 injection, 2 therapies• FPG + PPG control• Greater A1c reduction• More patients with controlled A1c• Potential Weight loss• No additional risk of hypos vs. basal

LixiLan: Benefits of an “All-in-one“ Therapeutic StrategyCOMBINATION THERAPY

Fixed-Ratio combination administered via a disposable pen device combining

Lantus® and lixisenatide in a single daily injection

LixiLan

glargine 2 U/lixisenatide 1 μg

Benefits of a fixed-ratio formulation of once-daily insulin glargine/lixisenatide

(LixiLan) vs glargine in type 2 DM inadequately controlled on metformin monotherapy

Julio Rosenstock, Michaela Diamant, Louise Silvestre, Elisabeth Souhami, Tianyue Zhou, Vivian Fonseca

for the LixiLan PoC Study Group

Rosenstock J, et al. Diabetologia 2014;57 (Suppl 1):S108 [Abstract 241]

stratified by screening values of A1c

(<8, ≥8%) and BMI (<30, ≥ 30 kg/m2)

R

Open label treatment period (24 weeks)

On top of stable dose of Metformin ≥1.5g per day

N = 155

N = 155

LixiLan Combination Titration (maximum dose 60U/30 µg)

Insulin Glargine titration(No upper limit fixed)

T2DM ≥ 1 year

Metformin: stable dose ≥ 1.5 g/day

7 ≤ A1c ≤ 10%

24-week, open-label, 1:1 randomized, active-control, 2-arm, parallel trial

Primary Endpoint A1c change from baseline

(non inferiority; once shown, superiority can be tested)

Secondary Endpoints Glycemic control in

relation to a meal 7-point SMPG Body weight Insulin doses FPG Composite endpoints

Safety Hypoglycemia GI Adverse events

Study Design and Endpoints


Efficacy Results

Titrated LixiLan added-on to metformin resulted in:

Improved HbA1c from 8.1% to 6.3%

Reduced PPG following administration

Reduced body weight (-1kg)

84% of patients reached A1C <7%

– 64% reaching this target with no documented hypoglycemia

– 56% reaching it with no weight gain

– 46% with no weight gain and no documented hypoglycemia


• GLP-1 RAs effectively reduce A1C in T2DM alone/in

combination with other glucose lowering agents

• GLP-1 RAs can be initiated either before/after basal

insulin

• The physiological combination basal insulin + GLP-1

RAs should be ideally include:

-the most physiological basal insulin (glargine)

-a short-acting GLP-1 RAs with strong prandial

effects such as lixisenatide

CONCLUSIONS

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