glp-1 receptor agonists dr. aronson has received …icdm2013.diabetes.or.kr/slide/ot3-3 ronnie...

GLP-1 Receptor Agonistslearnings in combination therapy

Ronnie Aronson MD, FRCPC, FACE

Executive Director

LMC Diabetes & Endocrinology

Toronto, Canada

Disclosures

Dr. Aronson has received

• research support from Merck, Pfizer, sanofi-aventis, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Boehringer Ingelheim, and Johnson & Johnson;

• consulting honoraria from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Novartis, sanofi-aventis and GlaxoSmithKline, Janssen

• No competing financial interests exist

Toronto

LMC Diabetes Sites Ontario

� Toronto

� Etobicoke

� Thornhill

� Oakville

� Brampton

� Barrie

� Markham

Quebec

� Montréal

Alberta

� Calgary

GLP-1 Receptor Agonistslearnings in combination therapy

• GLP-1 therapy mechanisms

• GLP-1 therapy in OAD combination therapies

• GLP-1 therapies – classification by timing

• Prandial GLP-1 therapy - clinical significance

• GLP-1 & Basal insulin – combination therapy

GLP-1: Secretion from L cells

Intracellular Signals

Endocrine Signals

Neural Signals

Carbohydrates

Lipids

Proteins

Phase I Phase II

Holst JJ. Physiol Rev 2007;87:1409-1439 Kieffer TJ and Habener JF. Endocrine Rev 1999;20:876-913 Buteau J. Diabetes Metab 2008;34(S2);S73-

S77

GLP-1 (pM/L)

50

25

00 30 60 90 120 150 180

Total GLP-1

Time (min)

GLP-1 Receptor:

10

COOH

Brain

Heart

Kidneys

Pancreas

Intestinal Tract

Exterior

Interior

Holst JJ. Physiol Rev 2007;87:1409-1439 Kieffer TJ and Habener JF. Endocrine Rev 1999;20:876-913

Underwood CR, et al. J Bio Chem 2010;285:723-730 Brubaker PL and Drucker DJ. Receptors and Channels 2002;8:179-188

NH2

GLP-1 & GLP-1 Receptor Binding:

11

Adenylate cyclase

ATP

GαsPKA

Pi3k

Down-

stream

Effects

Holst JJ. Physiol Rev 2007;87:1409-1439 Kieffer TJ and Habener JF. Endocrine Rev 1999;20:876-913

Buteau J. Diabetes Metab 2008;34(S2);S73-S77 Hayes MR, et al. Physiol Behav 2010;100:503-510

Portha B, et al. Exp Diab Res 2011;ID376509 Brubaker PL and Drucker DJ. Receptors and Channels 2002;8:179-188

cAMP Epac

Putative

Increase Insulin

Secretion

Decrease Glucagon Secretion

Increase Satiety

Limit β-cell Apoptosis

5

Delay Gastric Emptying

Holst JJ. Physiol Rev 2007;87:1409-1439 Kieffer TJ and Habener JF. Endocrine Rev 1999;20:876-913 Hayes MR, et al. Physiol Behav 2010;100:503-510

Buteau J. Diabetes Metab 2008;34(S2);S73-S77 Portha B, et al. Exp Diab Res 2011;ID376509

Hansen M, et al. J Clin Metab Diab 2011;2:7-13 Brubaker PL and Drucker DJ. Endocrinology 2004;145:2653-2659

Putative

GLP-1 & GLP-1 Receptor Binding:

Initial effects are manifested in distinct clinical

events

GLP-1 Receptor Agonists

learnings in combination therapy

● GLP-1 therapy mechanisms

● GLP-1 therapy in OAD combination therapies

● GLP-1 therapies – classification by timing

● Prandial GLP-1 therapy – clinical significance

● GLP-1 & Basal insulin – combination therapy

Exenatide BID: AMIGO trials

DeFronzo RA, et al. Diabetes Care 2005; 28:1092–1100; Buse JB, et al. Diabetes Care 2004; 27:2628–35;

Kendall DM, et al. Diabetes Care 2005; 28:1083–91.

Placebo BID Exenatide 5 µg BID

*p<.005 vs placebo ; MET (n = 336), SU (n = 377), MET + SU (n = 733).

Mean baseline HbA1c was 8.2%–8.7% across all trial arms

*

0.2

- 0.6*

- 0.8

*

0.1

- 0.5*

- 0.9

- 0.4

*

- 0.8

*- 1

- 0.5

0

0.5

0.1

-1

-0.5

0

0.5

- 1

- 0.5

0

0.5

Change in HbA1C(%)

Add-on to SU2Add-on to MET +

SU3Add-on to MET1

Exenatide 10 µg BID

0.0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

-1.4

SU combination

LEAD 1

Met combination

LEAD 2

Met + TZD combination

LEAD 4

Met + SU combination

LEAD 5

-1.6

-1.3*

-1.5*

-1.1*

MonotherapyLEAD 3

-1.1*-1.0 -1.0

-1.1*

-0.8*

-1.5*

-0.5

-1.0

-0.4

-1.1

-0.5

8.3 8.18.68.58.38.68.58.4 8.48.3 8.4 8.38.3 8.4

-1.1*

-0.8

Met and/or SU

LEAD 6

8.2 8.1

Change in HbA1C(%)

*Significant vs. comparator

Liraglutide 1.8 mgLiraglutide 1.2 mg Glimepiride Rosiglitazone GlarginePlacebo Exenatide

Liraglutide: LEAD Program

Marre et al. Diabet Med 2009 (LEAD-1); 26:268-78; Nauck et al. Diabet Care 2009 (LEAD-2); 32:84–90;

Garber et al. Lancet 2009 (LEAD-3); 373:473–81; Zinman et al. Diabetologia 2008 (LEAD-4); Russell-

Jones et al. Diabetologia 2010 (LEAD 5); 52:2046–55; Buse et al. Lancet 2009 (LEAD-6); 4:39-47

Baseline HbA1C0.0

–0.5

–1.0

–1.5

–2.0

–2.5

DURATION-1 DURATION-5 DURATION-2

Exenatide QWExenatide BID

Sitaglitpin

Pioglitazone

–0.3%*

–0.7%* –0.6%*

–0.3%*

Change in HbA1C(%)

Add-on to MetAdd-on to SU Add-on to various OADsa

Exenatide QW: DURATION trials

Most common side effects: nausea, diarrhoea.MET= metformin; SU= sulphonylurea; OAD= oral anti-diabetic.*p<0.005; anot all patients on OADs

Buse JB, et al. Diabetes Care 2010; 33:1255–61;

Blevins T, et al. J Clin Endocrinol Metab 2011; 96:1301–10;

Wysham C, et al. Diabet Med 2011; 28:705–14.

S

GetGoal series: Lixisenatide add-on to OAD

1. Bolli G et al. Diabetologia 2011;54(Suppl.1):A784. 2. Ahrén B et al. Diabetes Care 2013; Epub ahead of print;

3. Sanofi Key Results Memo. 4. Pinget M et al. Diabetes Obes Metab. 2013; Epub ahead of print;

5. Ratner R et al. Diabetologia 2011;54(Suppl. 1):A785. Data presented includes Sanofi unpublished data.

Mean change in HbA1C(%

)

F1 M M-Asia P

am

***

GetGoal-F11 GetGoal-M2 GetGoal-M-Asia3

MET MET± SUMETBackground Tx:

GetGoal-P4

PIO ± MET

GetGoal-S5

SU ± MET

- 0,38- 0,47

- 0,1

- 0,87- 0,83 - 0,85

- 0,8

- 0,7

- 0,5

- 0,4

- 0,2

- 0,1

0

** ***

- 0,3

- 0,6

- 1

- 0,34

- 0,9***

pm

- 0,75***

- 0,92- 0,83

- 0,42

1s

2s

***

***- 0,9

Placebo Lixisenatide 20 µg QD0.11

-0.25 -0.21-0.32 -0.36

-0.53

-1.19

-0.69

-1.16

-0.99

-0.56

-0.81

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Mean change in FPG from

baseline (mmol/L)

F1 M M-Asia P S

1s 2s

am

pm

***

***

** **

***

*†

GetGoal: Lixisenatide add-on to OADChange in FPG

Placebo

Lixisenatide 20 µg QD


MET MET± SUMET

GetGoal-P4

PIO ± MET

GetGoal-S5

SU ± MET

1. Bolli G et al. Diabetologia 2011;54(Suppl.1):A784. 2. Aronson R et al. 2011; abstract O-0591:

presented at IDF. 3. Sanofi Key Results Memo. 4. Pinget M et al. Diabetes 2012; 61(Suppl.

1):A258 (poster 1010-P). 5. Ratner R et al. Diabetologia 2011;54(Suppl. 1):A785. Data represented

also includes Sanofi unpublished data.

-1.41 -1.33

-0.21

-5.92-5.61

-6.19-6.5

-6

-5.5

-5

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

Mean change in PPG

from baseline (mmol/L)

GetGoalstudy:

F1 M M-Asia P S

am

******

***Placebo

Lixisenatide 20 µg QD

GetGoal-M2 GetGoal-M-Asia3

MET MET± SU

GetGoal-S5

SU ± MET



1):A258 (poster 1010-P). 5. Ratner R et al. Diabetologia 2011;54(Suppl. 1):A785. Data presented

includes Sanofi unpublished data.

GetGoal: Lixisenatide add-on to OADChange in 2-hour PPG

-1.63 -1.64

-1.24

0.21

-0.93

-2.63

-2.01

-1.5

-0.21

-1.76

-2.68

-2.02

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

Mean change in bodyweight

from baseline (kg)

F1 M M-Asia P S

1s 2s am pmNS

***NS NS

* *

NS

GetGoal: Lixisenatide as add-on to OADChange in bodyweight at 24 weeks


MET MET± SUMET

GetGoal-P4

PIO ± MET

GetGoal-S5

SU ± MET

PlaceboLixisenatide 20 µg QD



1):A258 (poster 1010-P). 5. Ratner R et al. Diabetologia 2011;54(Suppl. 1):A785. Data presented

includes Sanofi unpublished data.

Liraglutide - body weight loss

Victoza Product Monograph, Novo Nordisk Canada Inc., 2010; Nauck M et al. Diabetes Care.

2009;32(1):84-90; Data on file.

GetGoal-X: Lixisenatide vs Exenatide

Rosenstock J et al. Diabetologia 2011 54 Supp 1 S1-S542, Sanofi-unpublished data

Lixisenatide 20 µg QD (n=297) Exenatide 10 µg BID (n=295)

LS mean change in HbA1c(%)

0

-1.0 -0.96%

LS mean change in body weight (kg)

-0.2

-0.4

-0.6

-0.8-0.79%

7.957.97

-2.96

-4.0

-3.6

-3.2

-2.8

-2.4

-2.0

-1.6

-1.2

-0.8

-0.4

0

-3.98

Lixisenatide - Nausea

Exenatide

Placebo

Lixisenatide (2-step) AM


Lixisenatide (2-step) PM

35.4

26.1

4.4

22.721.2

7.6

16.3

2.6

23.5

10.6

25.3

7

24.5

35.1

0

5

10

15

20

25

30

35

40

Incidence of nausea

(% of patients)

F1 M M-Asia

P S X

Placebo-controlled

Activecomparator

GetGoal-F11 GetGoal-M2GetGoal-M-Asia3


GetGoal-P4

PIO ± MET

GetGoal-S5

SU ± MET

GetGoal-X6

MET

1. Bolli G et al. Diabetologia 2011;54(Suppl.1):A784. 2. Aronson R et al. 2011; abstract O-0591: presented at IDF. 3. Sanofi Key

Results Memo. 4. Pinget M et al. Diabetes 2012; 61(Suppl. 1):A258 (poster 1010-P). 5. Ratner R et al. Diabetologia 2011;54(Suppl.

1):A785. Data represented also includes Sanofi unpublished data. 6. Rosenstock J et al. 2011 Diabetes 60(Suppl. 1): Poster 33-LB:

presented at ADA 71st Scientific Sessions.

Lixisenatide - Nausea

Exenatide

Placebo



Lixisenatide (2-step) PM

35.4

26.1

4.4

22.721.2

7.6

16.3

2.6

23.5

10.6

25.3

7

24.5

35.1

0

5

10

15

20

25

30

35

40

Incidence of nausea

(% of patients)

F1 M M-Asia

P S X

Placebo-controlled

Activecomparator

GetGoal-F11 GetGoal-M2GetGoal-M-Asia3


GetGoal-P4

PIO ± MET

GetGoal-S5

SU ± MET

GetGoal-X6

MET

1. Bolli G et al. Diabetologia 2011;54(Suppl.1):A784. 2. Aronson R et al. 2011; abstract O-0591: presented at IDF. 3. Sanofi Key

Results Memo. 4. Pinget M et al. Diabetes 2012; 61(Suppl. 1):A258 (poster 1010-P). 5. Ratner R et al. Diabetologia 2011;54(Suppl.

1):A785. Data represented also includes Sanofi unpublished data. 6. Rosenstock J et al. 2011 Diabetes 60(Suppl. 1): Poster 33-LB:

presented at ADA 71st Scientific Sessions.

Discontinuation

and tolerability

Lixisenatide

QD

Exenatide

BID

Discontinuation

due to AEs33 (10.4%) 41 (13.0%)

% patients

continuing on

target dose

93% 83%

Hypoglycaemic events

LIXI

EXE

8

48

6x less hypoglycemia

with lixisenatide QD








Liraglutide H A E G T F T S D V S - S Y L E Q A A K E F I A W L V A G R G - - - - - - - - - - - -

Lixisenatide H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P S K K K K K

* . * * * * * * * : * . * : * . : * * * * *

Exenatide H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S - - - -

Native GLP-1 H A E G T F T S D V S - S Y L E Q A A K E F I A W L V K G R G - - - - - - - - - - - -

Endogenous GLP-1 & GLP-1 RA’s:

16/30 residues identical 3/30 residues conserved 3/30 residues semi-conserved

Native GLP-1 H A E G T F T S D V S - S Y L E Q A A K E F I A W L V K G R G - - - - - - - - - - - -

Exenatide H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S - - - -

GLP1 LIRAGLUTIDE* EXENATIDE LIXISENATIDE**

*Model generated from native GLP-1 (PDB ID: 1D0R) ; **Model generated from Exendin-4 (PDB ID: 1JRJ)

Underwood CR, et al. J Bio Chem 2010;285:723-730 Runge S, et al. J Biol Chem 2008;283:11340-11347 Holst JJ. Physiol Rev 2007;87:1409-1439

Willard FS and Sloop KW. Exp Diab Res 2012;ID470851 Kieffer TJ and Habener JF. Endocrine Rev 1999;20:876-913

Buteau J. Diabetes Metab 2008;34(S2);S73-S77 Hayes MR, et al. Physiol Behav 2010;100:503-510

Portha B, et al Exp Diab Res 2011;ID376509

GLP-1 RA’s - Cleavage by DPP4

LIRAGLUTIDE*

EXENATIDE LIXISENATIDE**

*Model generated from native GLP-1 (PDB ID: 1D0R)

GLP-1

; **Model generated from Exendin-4 (PDB ID: 1JRJ)

Native ligand (HAEG);

full activity

Native ligand (HAEG);

albumin

sequestration

Non-Native ligand (HGEG);

reduced activity

Non-Native ligand (HGEG);

reduced activity

Holst JJ. Physiol Rev 2007;87:1409-1439 Meier JJ. Nat Rev Endocrinol 2012;8:728-

742

GLP-1 Receptor Agonists: Half-life

Exenatide

BID

2.4h

Lixisenatide

QD

4.5h

Exenatide

QW

>24h

GLP-1

2-3min

Liraglutide

QD

13h

Meier JJ. Nat Rev Endocrinol 2012;8:728-742 Werner U, et al. Regul Pept 2010;164:58-64

Thorkildsen C, et al. J Pharmacol Exp Ther 2003;307:490-496 Nielsen LL, et al. Regul Pept 2004;117:77-88

28

12 h

6 h18 h

24 h

GLP-1 RA concentration over 1 week

0 1 2 3 4 5 6 7 8

Time (days)

Plasma GLP.1RA

Exenatide BID

administration

Aroda V, Young M. Postgrad Med. 2011 Sep;123(5):228-38

GLP-1 RA concentration over 1 week

Aroda V, Young M. Postgrad Med. 2011 Sep;123(5):228-38

0 1 2 3 4 5 6 7 8

Time (days)

Plasma GLP.1RA

Exenatide BID

administration

Exenatide QW

administration

Gastric emptying – exenatide vs. liraglutide

Baseline 14 days

Jelsing J, et al. Diabetes, Obesity and Metabolism 2012; 14: 531–538.

Rats randomised to four groups (n= 8 per group). Gastric emptying assessed using oral paracetamol at baseline and again after 14 days of

twice daily GLP1 or vehicle. * Exenatide 3, 10 mcg/kg and liraglutide 200 mcg/kg significantly different from vehicle, P< 0.05

AUC paracetamol (mcg/ml/min)

Vehicle Liraglutide

200 mcg/kg

Exenatide

3 mcg/kg

Exenatide

10 mcg/kg

AUC paracetamol (mcg/ml/min)

Vehicle Liraglutide

200 mcg/kg

Exenatide

3 mcg/kg

Exenatide

10 mcg/kg

Lixisenatide vs. liraglutide – PPG effects

32

148 adults with T2DM insufficiently controlled (HbA1c 6.5−9.0%) on ≥1.5 g/day of metformin

Kapitza et al. Abstract D-0740; Presented at IDF 2011, Dubai

| 33

Effect on

FPG

PRANDIALGLP-1 Receptor Agonists

NON PRANDIALGLP-1 Receptor Agonists

Two Types of GLP-1 Receptor Agonists

Effect on

PPGEffect on

FPGEffect on

PPG

Adapted from: Fineman MS, et al. Diabetes Obes Metab. 2012. [published

online ahead of print Jan 10 2012]. doi: 10.1111/j.1463-1326.2012.01560.x

Prandial vs. Nonprandial GLP-1 RA

6

7

8

9

10

11

12

13

14

Mean plasma

glucose

(mM)

Pre Post Pre Post Pre Post 3AM

Breakfast Lunch Dinner

Exenatide QW, week 0

Exenatide QW, week 30

Exenatide BID, week 0

Exenatide BID, week 30

n=129

n=130

Adapted from Drucker. Lancet. 2008;372:1240-1250.

The primary endpoint of the study was a change in HbA1C at 30 weeks.








Basal insulin - effective insulin initiation

58

33.2

57.3

26.7

0

10

20

30

40

50

60

70

HbA1c ≤7% HbA1c ≤7% without a documented

episode of hocturnal hypoglycaemia

% patients

Insulin glargine (n=367)

NPH insulin (n=389)

p<0.05 vs NPH insulin

• Patients with T2DM inadequately controlled on stable doses of one or two oral antihyperglycaemic agents• Randomized to insulin glargine or human NPH insulin

Proportion of patients in the Treat-to-Target study achieving HbA1c goal at 24 weeks

HbA1c ≤7% without a documented

episode of nocturnal hypoglycaemia

HbA1c=glycated haemoglobin; NPH=neutral protamine Hagedorn

HbA1c ≤7%

Riddle et al. Diabetes Care 2003;26:3080–6

Achieving FPG - but not HbA1c - targets

19%

39%40%

Data are from the 2011 Adelphi Disease Specific Programme for T2DM1; OAD=oral antidiabetic drug; FBG=fasting blood glucose;

PPG=postprandial blood glucose

Patients receiving basal insulin plus OADs (N=481)1

FBG and HbA1c controlled

Neither FBG nor HbA1c controlled

FBG controlled but HbA1cnot controlled

Achieving targets of FPG but not HbA1c suggests

incomplete PPG control2

1. Colclough et al. Abstract 2416-PO; Presented at ADA 2012, Philadelphia, PA

2. Woerle et al. Diabetes Res Clin Pract 2007; 77(2): 280–5

Relative Contribution of PPG to A1C

Riddle M, et al. Diabetes Care. 2011;34:2508-

2514.

Basal hyperglycemia

Postprandial hyperglycemia

100

80

60

40

20

0

Total Hyperglycemia (%)

<8.0 8.0-<8.5 8.5-<9.0 9.0-<9.5 ≥9.5

A1C Category (%)

Baseline*100

80

60

40

20

0

<6.5 6.5-<7.0 7.0-<7.5 7.5-<8.0 ≥8.0

A1C Category (%)

After 24/28 Weeks Treatment

* Adult patients with type 2 diabetes with suboptimal

glycemic control on oral antihyperglycemic therapy

Options beyond basal insulin

Prandial insulin

Advantages Disadvantages

Effective in controlling PPG Increased risk of hypoglycaemia

Weight gain

Prandial GLP-1 RA’s

Advantages Disadvantages

Effective in controlling PPG GI side effects

Low rates of hypoglycaemia

Weight loss in some patients

A New Therapeutic Strategy:

Basal Insulin + GLP-1 Receptor Agonist

Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

Inzucchi SE, et al. Diabetologia. 2012;55:1577-1596.

GLP-1 co-therapy with basal insulin

GLP-1 therapy nA1c

change

Weight

change

(kg)

TDD

change

(U)

N Yoon et al.* exenatide 188 - 0.66% - 2.4 - 18

K Thong et al.* exenatide 1921 - 0.40% - 6.5 ---

U Nayak et al.* exenatide 166 - 0.20% - 10.7 - 95

J Rosenstock

et al.albiglutide vs lispro 279 - .16% - 1.54 ---

JB Buse et al. exenatide vs placebo 137 - 0.75 -2.8 kg ---

Nayak U, et al. Q J Med 2010;103:687-94; Yoon N, et al. Clinical Therapeutics 2009;31:1511-23 ; Thong K, et al.

Diabetes Obes Metab. 2011; 13 :703-10; Rosenstock J et al. [ADA abstract ], Diabetes. 2012;61 (suppl 1): A55-OR;

Buse JB, et al. Ann Intern Med, 2011;154:103-112

*Results following six months treatment are presented

Exenatide BID in insulin glargine-treated patients

*At randomization, patients with HbA1c > 8.0% continued on current glargine dose; those with HbA1c ≤ 8.0%

decreased glargine dose by 20%. These doses were maintained for 5 weeks, then titrated to target FBG < 5.6 mmol/L

Buse JB, et al. Ann Intern Med 2011;154:103–112.

Exenatide 5mcg bid for 4 weeks then 10 mcg bid

R

Treatment period 30 weeks

Placebo

Screening

Criteria:

T2DM, HbA1c

7.1-10.5%;

BMI <45kg/m2;

insulin glargine

>20U od

Exenatide BID in insulin glargine-treated patients:

HbA1c after 30 weeks

Buse JB, et al. Ann Intern Med 2011;154:103–112.

*p <0.001 for between-group comparisons

-1.0

-0.5

0.0

0 10 30

*-1.5

-2.0

-2.5

20

Change in HbA1cLevel, %

Insulin glargine + exenatide

Insulin glargine + placebo

Week

*

-1.7%

-1.0%

Exenatide BID in insulin glargine-treated patients

Time Point

Glucose level (mmol/L)

13

12

11

10

9

8

7

6

*

7

*

*

*

* *

Insulin glargine + exenatide, baseline

Insulin glargine + placebo, baseline

Insulin glargine + exenatide, 30 wk

Insulin glargine + placebo, 30 wk

Buse JB, et al. Ann Intern Med 2011;154:103–112

**

**

**

**

**

*

*p<0.010 **p<0.001

Exenatide BID in insulin glargine-treated patients:

Weight change after 30 weeks

Buse JB, et al. Ann Intern Med, 2011;154:103-112

2.0

1.5

1.0

0.5

0.0

- 0.5

-1.0

- 1.5

- 2.0

- 2.5

- 3.0 0 2 3 6 8 10 14 18 22 26 30

Week

Change in body weight, kg

Insulin glargine + placebo

Insulin glargine + exenatide

-1.8 kg

+1.0 kg

Harmony-6: Glargine-treated patientsOnce-Weekly Albiglutide vs. Prandial Lispro

Rosenstock J et al. [ADA abstract]. Diabetes. 2012;61(suppl 1):A55-OR.

-0.82

-1.01

-0.66

-0.85

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

26 Weeks 52 Weeks

Mean average change from baseline %

Difference=-

0.16%

Difference=0.16%

(-0.32, 0.0) p<0.0001;

Non-inferiority

HbA1c change

* p = not significant

Albiglutide

(n=279)

Lispro

(n=278)P –

Value

FPG change (mmol/L) -0.99 -0.72 NS

Weight change (kg ) -0.73 +0.81 <0.001

Lixisenatide: GetGoal-Duo1: study design

*This was changed from ≤126 mg/dL in July 2010; ClinicalTrials.gov Identifer: NCT00975286; MET=metformin

2-weekscreening

Screening Criteria:•T2DM for ≥1 year

•MET ≥1.5 g/day

±TZDs ± SU or

Glinide•HbA1c: 7 - 10%

N=1470

n=898

Glargine titrated to FPG target 80–100 mg/dL

10

15

10

15

20

20

Glargine + metformin + PLACEBO ± TZDs

Glargine + metformin + LIXISENATIDE ± TZDs

12-week Run-In

Rn=446

n=825

Glargine + metformin

(±TZDs) Randomized if criteria met:• HbA1C ≥7% and ≤9%

• Mean FPG ≤ 7.8 mmol/L* (7 days end of Run-in)

Lixisenatide titrationLixisenatide maintenance

(n=223)

(n=223)

24-week-double-blind period

Glargine weekly titration;

target FPG 4.4–5.6 mmol/L

SU/Glinides discontinued at Run-In start

(SU use in 580 candidates [65%] and

Glinide use in 7 candidates [1%])

Rosenstock et al. Abstract 062-OR; Presented at ADA

2012, Philadelphia, PA

GetGoal-Duo1: HbA1c

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)

Mean HbA1c (%) ±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)



2-hour PPG*

+0.1

–3.1

LS mean change (mmol/L)

0.5

0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

p<0.0001

GetGoal-Duo1: adverse events over 24 weeks

Adverse event, n (%)

Lixisenatide +

insulin glargine

+ metformin

(n=223)

Placebo +

insulin glargine

+ metformin

(n=223)

GI disorders (all)

Nausea

Vomiting

Diarrhea

89 (39.9)

61 (27.4)

21 (9.4)

15 (6.7)

36 (16.1)

11 (4.9)

3 (1.3)

7 (3.1)

Increases in pancreatic enzymes

Pancreatitis

5 (2.2)

0

10 (4.5)

1 (0.4)

Injection site reactions 15 (6.7)* 5 (2.2)

*Two patients (0.9%) discontinued due to injection site reactions; Data are for the safety population (all patients who received ≥1 dose of study

treatment)



GetGoal-L - Lixisenatide added to insulin

Lixisenatide + basal insulin (n=304)

Aronson et al; Presented at EASD 2012, Berlin

8.6

8.4

8.2

8.0

7.8

7.6

7.4

Mean HbA1c(%) ±

SE

7.2

Week

0 4 8 12 16 20 24

Placebo + basal insulin (n=158)

2-hour PPG*

–1.7

–5.5

0

–1

–2

–3

–4

–5

–6

p<0.0001

GetGoal-L-Asia – Lixisenatide added to insulin

Placebo + basal insulin (n=154)

Seino et al. Diabetes Obes Metab 2012

doi: 10.1111/j.1463-1326.2012.01618.x

Lixisenatide + basal insulin (n=146)

8.8

Week

8.6

8.4

8.2

8.0

7.8

7.6

7.4

7.2

7.0

Baseline 4 8 12 16 20 24

Mean HbA1c(%) ±SE

Week 24

LOCF*

8.6%

7.6%

Basal Insulin Intensification:

GLP-1 RA vs Prandial Insulin

–1.6

–1.2

–0.8

–0.4

B.H.R. Wolffenbuttel1, M.A. Nauck, et al, EASD 2013.

. Mathieu C et al. ADA Annual Meeting 2013.

Rosenstock J et al. ADA Annual Meeting 2012. Abstract 55-OR.

0

0.4

-1.1

EXE bid LIRA od

-0.74*

Liraglutide

vs Aspart

∆ Weight (kg): -2.5* 2.1 -2.8* 0.9 -0.7* 0.8

Hypos: 2.1 5.2 1.0 * 8.2 1.0 2.1

(/10000 patient-years)

Mean ∆A1C from baseline (%)

4B Study

Lispro tid

-1.1

Aspart od

-0.39

EXE noninferior

Albiglutide QW

vs

Lispro TID

-0.82

-0.66

ALBI noninferior

ALBI qw Lispro tid

285 patients

GetGoal DUO 2:

Lixisenatide vs. Bolus insulin

26-week open-label treatment periodRun-inScreening

T2 patientsHbA1c ≥7.5% & ≤10% Basal insulin ±OADs

Lantus 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

Lantus introduced and/or optimized

12 weeks

- HbA1c ≥7 and <9%

- Mean fasting SMBG ≤

(140mg/dl)

285 patients

285 patients

R

ClinicalTrials.gov Identifier: NCT01768559

Conclusions

● GLP-1 therapies ● improve FPG and glycemic control;

● improve PPG elevation by delaying gastric emptying

● “Prandial” GLP-1 RA’s - more effective in reducing PPG

● Prandial GLP-1 RA’s – eg - exenatide & lixisenatide● an effective add-on to Basal insulin therapy

● vs. adding Bolus insulin – may have advantages in

weight loss, with no increased risk of hypoglycemia

Back-up

Adapted from Kjems LL, et al. Diabetes. 2003;52:380-386.

500

1000

1500

2000

2500

3000 Controls T2D

Normal glucose-stimulated

insulin secretion in

healthy controls

Reduced insulin

secretion in T2D

InsulinSecretionRate

pmol/kg•min

Saline GLP-10.5 pmol/kg/min

GLP-11.0 pmol/kg/min

GLP-12.0 pmol/kg/min

GLP-1 infusion restores

insulin secretion to

supranormal levels

Normal insulin

secretion in

healthy controls

GLP-1 Stimulates Glucose-Dependent Insulin Secretion

0

GLP-1 Suppresses PP Glucagon Secretion

● Plasma glucagon

AUC 0-210 min

● measured during

mixed meal

Adapted from: Gutniak M, et al. N Engl J Med. 1992;326:1316-1322.

Normals Type 2Diabetes

GlucagonAUC 0-210 min

ng/ml•min

Markedly elevatedglucagon levels

in T2D

Reduced by 61%

with GLP-1

IV saline

IV GLP-1

GLP-1 Potently Inhibits Gastric Emptying

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

Gastric Volume

mL

Minutes

500

400

300

200

100

0

0 60 120 180 240

Placebo

SC GLP-1*

Delay in gastric emptying

*1.5 nmol/kg body weight

P < 0.0001

0

Meal

Injection

Jones KL, et al. J Nucl Med. 1996;37:1643-1648.

Gastric Emptying Rate - PPG Determinant

Gastric Retention at 60 min (%)

FAST SLOWGastric Emptying Rate

Blood Glucose Concentration

60 min Post 75 g Oral

Glucose Challenge

mmol/L

r = -0.61 P<0.05Rapid gastric emptying associated with high

glucose levels

Slow gastric emptying associated with low

glucose levels

Lixisenatide BID vs OD: A1c

61

-0.76p<0.0001

-0.69p<0.0001

-0.50p=0.0033

-0.47p=0.0056

-0.87p<0.0001

-0.75p<0.0001-0.78

p<0.0001

-0.65p<0.0001

-0.18Reference

LS Mean Change in A1C (%)

at endpoint

ODODODOD BDBDBIDBID

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Placebo

Ratner RE, et al. Diab Med 2010;27:1024-1032

5mcg 10mcg 20mcg 30mcg 40mcg 60mcgTotal Dose

Frequency BID/OD

Lixisenatide BID vs OD: A1c

LS M

ea

n%

Ch

an

ge

in

Hb

A1

C a

t e

nd

po

int

% o

f su

bje

cts

wit

h

Hb

A1

C<

7%

at

en

dp

oin

t

Once-a-day Twice-a-day

30 µg20 µg10 µg5 µg 30 µg20 µg10 µg5 µg Placebo

68.6P<0.0001

67.9P<0.0001

52.0P=0.0133

47.3P=0.0460

77.4P<0.0001

61.5P=0.0006

64.8P<0.0001

51.0P=0.0217

0

31.8

10

20

30

40

50

60

70

80

90

-0.76P<0.0001

30 µg

-0.69P<0.0001

20 µg

-0.50P=0.0033

10 µg

-0.47P=0.0056

5 µg 30 µg

-0.87P<0.0001

-0.75P<0.0001

20 µg

-0.78P<0.0001

10 µg

-0.65P<0.0001

5 µg

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

-0.18

Placebo

62

Ratner RE, et al. Diab Med 2010;27:1024-1032

Weight Nausea

Vomiting

To

tal

nu

mb

er

of

sub

ject

s (%

) w

ith

vo

mit

ing

18.5

30 µg

5.5

20 µg

5.8

10 µg

3.6

5 µg

Once-a-day30 µg

3.7

9.3

20 µg

7.1

10 µg

5.7

5 µg

Twice-a-day

0

0.9

Placebo

5

10

15

20

25

30

35

LS m

ea

n c

ha

ng

e i

n w

eig

ht

(kg

) a

t e

nd

po

int

-3.47P<0.0001

n=52

30 µg

-3.01P=0.0099

n=53

20 µg

-2.39P=0.2962

n=51

10 µg

-2.0P=0.9299

5 µg 30 µg

-3.89P<0.0001

-2.61P=0.1058

20 µg

-2.21P=0.5010

n=54

10 µg

-2.1P=0.6920

5 µg

Twice-a-day

0

-1.94

Placebo

-4.5

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

-4

To

tal

nu

mb

er

of

sub

ject

s (%

) w

ith

dia

rrh

ea

7.4

30 µg

9.1

20 µg

7.7

10 µg

5.5

5 µg

Once-a-day

30 µg

25.9

11.1

20 µg

7.1

10 µg

5.7

5 µg

Twice-a-day

0

7.3

Placebo

5

10

15

20

25

30

35

To

tal

nu

mb

er

of

sub

ject

s (%

) w

ith

na

use

a 35.2

30 µg

25.5

20 µg

11.5

10 µg

7.3

5 µg

Once-a-day

30 µg

33.3

22.2

20 µg

14.3

10 µg

7.5

5 µg

Twice-a-day

0

4.6

Placebo

5

10

15

20

25

30

40

35

Once-a-day

Diarrhea

Lixisenatide BID v OD: Efficacy & Tolerability

Ratner RE, et al. Diab Med 2010;27:1024-1032 Nayak U, et al. Q J Med 2010;103:687-94.

Effect on

TDDEffect on

WeightEffect on

A1c

- .54% - 10.7 kg - 95 U

N = 160, treated with Basal insulin , at 6 months

Nayak U, et al. Q J Med 2010;103:687-94. Nayak U, et al. Q J Med 2010;103:687-94.

Yoon N, et al. Clinical Therapeutics 2009;31:1511-23. Yoon N, et al. Clinical Therapeutics 2009;31:1511-23.

Yoon N, et al. Clinical Therapeutics 2009;31:1511-23. Yoon N, et al. Clinical Therapeutics 2009;31:1511-23.

Thong K, et al. Diabetes Obes Metab. 2011; 13 :703-10.

40% combined

insulin and

exenatide


Thong K, et al. Diabetes Obes Metab. 2011; 13 :703-10. Thong K, et al. Diabetes Obes Metab. 2011; 13 :703-10.


Safety & Efficacy of Saxagliptin Plus Insulin

Safety & Efficacy of Saxagliptin Plus Insulin

Long-term Extension: Variable duration, fixed end24 weeks + LPI + x weeks + 3 days F/U

24 weeks + LPI + x weeks + 3 days F/U

24 weeks + LPI + x weeks + 3 days F/U (am or pm

dosing)



All patients: background treatment at a stable dose

Diet & lifestyle counselling every 3 months from D1

Lixisenatide

PlaceboVariable extension periodMain double-blind treatment periodScreening

Single-blindrun-in 3 d F/U

W-1W-3 W0 W12 W44W4

End of

treatment

Primary

endpoin

t

20 µg

20 µg

15 µg

10 µg

10 µg

15 µg

Key Inclusion

Criteria:

• Type 2 DM

• HbA1C ≥7.0% –

≤10.0%

• Stratified by

HbA1C(<8.0%/≥8.0%)

R

FU

Visit

1 wk

1 wk

1 wk

1 wk

Combination placebo-controlled GetGoal

studies

W24

Lixisenatide in combinationwith:GG-M Asia: Sulfonylurea ±metformin

GG-F1: Metformin

GG-M: Metformin

GG-P: Pioglitazone ± metformin

GG-S: Metformin ± sulfonylurea

Adding incretin-based therapies to insulin.

Vora J Dia Care 2013;36:S226-S232

Harmony-6: secondary endpoints

Albiglutide

(n=279)

Lispro

(n=278) P - Value

FPG, model-adjusted

change from baseline,

mmol/L

-0.99 -0.72 0.2390

Weight, model-adjusted

change from baseline, kg

-0.73 +0.81 <0.0001

Rosenstock J et al. [ADA abstract ], Diabetes. 2012;61 (suppl 1): A55-OR.

GLP-1 RA: Receptor Affinity

GLP-1

Study 1: RINm5F cells

Exenatide GLP-1

Study 2: CHO-K1 cells

Lixisenatide

Kd

0.345nM

Kd

0.136nM

~2.5 X greater

affinity

IC50

1.4nM

IC50

5.5nM

~4 X greater

affinity

Thorkildsen C, et al. J Pharmacol Exp Ther 2003;307:490-496 Goke R, et al. J Biol Chem 1993;268:19650-

19655

Radiolabelled

endogenous

GLP-1

Change in paracetemol absorption (AUC0-5h) between baseline and week 14

GLP-1 RA half-life: gastric emptying

83

PRANDIAL GLP-1 RA = Non-continuous receptor agonism

NON-PRANDIAL GLP-1 RA = Sustained receptor agonism

Reduction in gastric

emptying (%)

Exenatide

BID

Exenatide

QW

-20%

-4%

-25

-20

-15

-10

-5

0EXE BD EXE QW

Drucker DJ, et al. Lancet 2008;372:1240-1250

5 –fold difference

IV GLP-1 effect - tachyphylaxis at 4 hours

Nauck et al. Diabetes 2011; 60:1561–1565.

Placebo

GLP-1 [7-36 amide]

Glucose (mmol/L)

Time (min)

Insulin [mU/l]

Time (min)

Small increase in PPG after the second meal with continuous GLP-1

infusion despite significantly higher insulin levels after second meal

IV GLP-1 effect - tachyphylaxis at 4 hours

Nauck et al. Diabetes 2011; 60:1561–1565.

Placebo

GLP-1 [7-36 amide]

600

500

400

300

200

100

0

Gastric volume (ml)

- 60

Liquid meal Liquid meal

**

** *

* *

†

p<0.0001

Time (min)

0 60 120 180 240 300 360 420 480

Continuous IV GLP-1 decelerated gastric emptying significantly more after

the first meal compared with the second meal – rapid tachyphylaxis?

PP effects - lixisenatide vs. liraglutide

Data shown are changes from baseline in each parameter at 28 days

Kapitza et al. Abstract D-0740; Presented at IDF 2011, Dubai

Lixisenatide (n = 75)

Liraglutide (n = 68)

Insulin C-peptide

5.3

- 64.2

p < 0.0001

0

-10

-20

-30

-40

-50

-60

-70

AUC0:30-4:30 (h.µIU/mL)

p < 0.0001

1

0

-1

1.04

- 5.03

-2

-3

-4

-5

-6

2

AUC0:30-4:30 (h.ng/mL)

Glucagon

AUC0:30-4:30 (h.pg/mL)

- 46.7-50

p = 0.032

0

-5

-20

-25

-30

-40

-45

-35

-15

-10

- 25.3

The PPG reduction with lixisenatide occurred despite a

reduction in postprandial insulin

Yoon N, et al. Clinical Therapeutics 2009;31:1511-23.

Effect on

TDDEffect on

WeightEffect on

A1c

- .54% - 6.2 kg - 3.4 U

N = 188, treated with Basal insulin (some with Basal-Bolus), at 12 months

Nayak U, et al. Q J Med 2010;103:687-94.

Effect on

TDDEffect on

WeightEffect on

A1c

- .2% - 10.7 kg - 95 U

N = 160, treated with Basal insulin , at 6 months


Effect on

WeightEffect on

A1c

- .3% - 5.8 kg

glp-1 receptor agonists dr. aronson has received …icdm2013.diabetes.or.kr/slide/ot3-3 ronnie...

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