1

GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics

Shannon I. Brow, RN, CDE, FNP-C

Medical Science Liaison

Amylin Pharmaceuticals, Inc

2

Faculty Disclosures:Faculty Disclosures:

• Shannon I. Brow, RN, CDE, FNP-C– Employee of Amylin Pharmaceuticals, Inc

– Stockholder: Amylin Pharmaceuticals, Inc

3

Learning ObjectivesLearning Objectives

• Discuss the progressive nature of diabetes

• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010

• Review incretin physiology in healthy individuals and in patients with type 2 diabetes

• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists

• Identify where incretin therapies can be used in the treatment of type 2 diabetes

4

Learning ObjectivesLearning Objectives

• Discuss the progressive nature of diabetes

• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010

• Review incretin physiology in healthy individuals and in patients with type 2 diabetes

• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists

• Identify where incretin therapies can be used in the treatment of type 2 diabetes

5

Microvascular changes

Macrovascular changesClinicalfeatures

Kendall DM, et al. Am J Med 2009;122:S37-S50.Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.

IFG, impaired fasting glucose; IGT, impaired glucose tolerance.

Years

Rel

ativ

e A

mo

un

t

-10 -5 0 5 10 15 20 25 30

Insulin resistance

Insulin level

0

50

100

150

200

250

-15

Incretin effect

-cell function

β-cell failure

Onsetdiabetes

Glu

cose

(m

g/d

L)

Diabetesdiagnosis

50

100

150

200

250

300

350

Fasting glucose

Prediabetes (Obesity, IFG, IGT)

Postmeal Glucose

-10 -5 0 5 10 15 20 25 30-15Years

Progressive Nature of Type 2 DiabetesProgressive Nature of Type 2 Diabetes

6

Postprandial Glucose Contribution to A1CPostprandial Glucose Contribution to A1C

% C

on

trib

uti

on

A1C Range (%)

0

20

40

60

80

100

FPG (Fasting Plasma Glucose)PPG (Postprandial Plasma Glucose)

>10.2

70%

30%

9.3-10.2

60%

40%

8.5-9.2

55%

45%

7.3-8.4

50%

50%

<7.3

30%

70%

Data from Monnier L, et al. Diabetes Care 2003; 26:881-885.

7

Pla

sm

a G

luc

os

e (

mg

/dL

)

Time of Day (h)

Plasma Glucose Is NormallyMaintained in a Narrow RangePlasma Glucose Is NormallyMaintained in a Narrow Range

Breakfast Lunch Dinner

400

300

200

100

0

06.00 10.00 14.00 18.00 22.00 02.00 08.00

N = 30; Mean (SE)Data from Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239

Healthy SubjectsType 2 Diabetes

8

A1C Goals Unmet in Majority of Patients With DiabetesA1C Goals Unmet in Majority of Patients With Diabetes

Upper limit of normal range (6%)

ACE recommended target (<6.5%)4

ADA recommended target (<7%)3

1. Data from Saydah SH, et al. JAMA 2004; 291:335-342.2. Calculated from Koro CE, et al. Diabetes Care 2004; 27:17-20. 3. Data from ADA. Diabetes Care 2003; 26(suppl 1):S33-S50.4. Data from ACE. Endocrine Practice 2002.

8.0

9.5

A1C (%)

6.0

8.5

10.0

6.5

5.5

9.0

7.0

7.5

37.2% have A1C >8%

20.2% have A1C >9%

12.4% have A1C >10%1

64.2% of patients with type 2 diabetes have A1C 7%2

9

Learning ObjectivesLearning Objectives

• Discuss the progressive nature of diabetes

• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010

• Review incretin physiology in healthy individuals and in patients with type 2 diabetes

• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists

• Identify where incretin therapies can be used in the treatment of type 2 diabetes

10

Criteria for the Diagnosis of DiabetesCriteria for the Diagnosis of Diabetes

1. A1c ≥ 6.5%. This test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.*

OR

2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*

OR

3. 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. This test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*

OR

4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l).

* In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing

American Diabetes Association. Diabetes Care 2010;33(suppl 1):S62-S69.

11

HyperglycemiaHyperglycemia

InsulinResistance

InsulinResistance

Insulin Deficiency

Insulin Deficiency

DiminishedBeta-Cell Response

(Insulin Deficiency)

DiminishedBeta-Cell Response

(Insulin Deficiency)

IncreasedBeta-Cell Workload

(Insulin Resistance)

The Pathogenesis of Type 2 DiabetesA New Perspective of the Core Defects ParadigmThe Pathogenesis of Type 2 DiabetesA New Perspective of the Core Defects Paradigm

Adapted from ©2005 International Diabetes Center, Minneapolis, MN All rights reserved

12

DecreasedDecreasedBeta-CellBeta-CellResponseResponse

DecreasedDecreasedBeta-CellBeta-CellResponseResponse

Insulin resistance

Obesity

Food intake

Gastric Emptying – Rate of nutrient absorption

Glucagon secretion

Hepatic glucose output

Insulin secretion in response to elevated glucose

First-phaseinsulin response

IncreasedIncreasedBeta-CellBeta-CellWorkloadWorkload

IncreasedIncreasedBeta-CellBeta-CellWorkloadWorkload

HyperglycemiaHyperglycemia

The Pathogenesis of Type 2 DiabetesAn Imbalance of Beta-Cell Workload and Beta-Cell ResponseThe Pathogenesis of Type 2 DiabetesAn Imbalance of Beta-Cell Workload and Beta-Cell Response

13

The Pathophysiology of Type 2 DiabetesThe Pathophysiology of Type 2 Diabetes

Insulin Resistance

Incretin“Defect”

Relative Insulin Deficiency

HyperglycemiaType 2 Diabetes

14

Clinical Challenges With Type 2 DiabetesClinical Challenges With Type 2 Diabetes

WeightA1C

Diet and ExerciseMETSFU

Insulin

6.2% A1C Upper limit of normal

0 2 4 6

Time From Randomization (y)

Med

ian

A1C

(%

)

8

9

7

6

Wei

gh

t (k

g)

0 2 4 6

Time From Randomization (y)

10

-5

5

0

n = 1704; A1C indicates glycosylated hemoglobin A1c; MET, metformin; SFU, sulfonylureaData from UKPDS Group (34). Lancet 1998;352:854-865.

Diet and ExerciseMETSFU

Insulin

15

Blood Glucose Concentrations Are Largely Determined by Beta-Cell FunctionBlood Glucose Concentrations Are Largely Determined by Beta-Cell Function

• Beta-Cell Function– Insulin synthesis

– Insulin secretion

• Beta-Cell Functional Capacity– Beta-cell mass (cell turnover and neogenesis)

– First-phase/second-phase insulin release

– Insulin processing (proinsulin to insulin)

– Glucose sensitivity

• Beta-Cell Functional Demand– Glucose absorption (diet, gastric emptying)

– Hepatic glucose production (glycolysis, gluconeogenesis)

– Peripheral glucose uptake (insulin sensitivity, exercise)

16

Multihormonal Regulation of Glucose Appearance and DisappearanceMultihormonal Regulation of Glucose Appearance and Disappearance

Time (min)

Mixed Meal (With ~85 g Dextrose)

0 120 240 360 480-0.6

-0.4

-0.2

0

0.2

0.4

0.6G

ram

s o

f G

luc

os

e (

flu

x/m

in)

-30

Insulin-mediatedglucose uptake

Balance of insulin suppression and

glucagon stimulation

Regulated by hormones: GLP-1, amylin, CCK, etc.

Meal-Derived Glucose

Hepatic Glucose Production

Total Glucose Uptake

N = 5; Mean (SE)Data from Pehling G, et al. J Clin Invest 1984;74:985-991.

17

Learning ObjectivesLearning Objectives

• Discuss the progressive nature of diabetes

• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010

• Review incretin physiology in healthy individuals and in patients with type 2 diabetes

• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists

• Identify where incretin therapies can be used in the treatment of type 2 diabetes

18

The Incretin Effect in Healthy Subjects The Incretin Effect in Healthy Subjects

C-P

ep

tid

e (

nm

ol/

L)

Time (min)

0.0

0.5

1.0

1.5

2.0

Incretin Effect*

*

**

* *

*

Oral Glucose Intravenous (IV) Glucose

Pla

sm

a G

luc

os

e (

mg

/dL

)

200

100

0

Time (min)

60 120 180060 120 1800

N = 6; Mean (SE); *P0.05Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:492-498.

19

IncretinsIncretins

• Gut-derived factors that potentiate insulin secretion following meal ingestion

• 2 principal incretins identified to date:

GIP 42-amino acid peptide

GLP-1 30-amino acid peptide

Adapted from Holst JJ, et al. Am J Physiol Endocrinol Metab 2004; 287:E199-E206. Drucker DJ. Diabetes Care 2003; 26:2929-2940.

20

YesYesPromotes insulin biosynthesis

NoYesReduces food intake

NoYesDecreases secretion in T2DM

YesYesKnockout mice (result in IGT)

YesYesStimulates beta-cell mass/growth

NoYesSlows gastric emptying

NoYesInhibits glucagon secretion postprandially

Site of Production

Adapted from Mayo KE, et al. Pharmacol Rev 2003;55:167-194.Adapted from Drucker DJ. Diabetes Care 2003;26:2929-2940.Adapted from Nauck M, et al. Diabetologia 1986;29:46-52.

Comparison of the IncretinsComparison of the Incretins

GIPK-cells

(Duodenumand Jejunum)

GLP-1L-cells

(Ileum and Colon)

21

Ins

uli

n (

mU

/L)

The Incretin Effect Is Reduced in Type 2 DiabetesThe Incretin Effect Is Reduced in Type 2 Diabetes

Time (min)

Healthy Subjects

Ins

uli

n (

mU

/L)

Time (min)

Type 2 Diabetes

N = 22; Mean (SE); *P0.05 Data from Nauck M, et al. Diabetologia 1986;29:46-52.

0

20

40

60

80

0 60 120 1800

20

40

60

80

0 60 120 180

Intravenous (IV) GlucoseOral Glucose

Incretin EffectIncretin Effect

*

*

*

*

*

**

***

22

Glucagon-Like Peptide-1 (GLP-1) is an Important Incretin HormoneGlucagon-Like Peptide-1 (GLP-1) is an Important Incretin Hormone

• The “incretin effect” started the search

• Incretins– Gut hormones that enhance insulin secretion in response to food

– Glucose-dependent insulin secretion

• GLP-1– Secreted from L cells of the intestines

– Most well-characterized incretin

– Diminished in type 2 diabetes

• Glucagon– Secreted from pancreatic alpha cells

– Counterregulatory hormone to insulin

– Elevated in type 2 diabetes

Adapted from Aronoff SL, et al. Diabetes Spectrum 2004;17:183-190.

23

600 120 180 240

Postprandial GLP-1 Concentrations Are Lower in Subjects With IGT and Type 2 DiabetesPostprandial GLP-1 Concentrations Are Lower in Subjects With IGT and Type 2 Diabetes

N = 102; Mean (SE); *P<0.05 between type 2 diabetes and healthy subjectsData from Toft-Nielsen MB, et al. J Clin Endocrinol Metab 2001;86:3717-3723.

20

15

10

5

0

Time (min)

GL

P-1

(p

mo

l/L

)

* * * * **

*

*

Meal

Healthy SubjectsImpaired Glucose ToleranceType 2 Diabetes

24

80

0

-60 120 180 240

Time (min)

120

60

100

120

140

140

360

300

240

Insulin and Glucagon Responses Are Altered in Type 2 DiabetesInsulin and Glucagon Responses Are Altered in Type 2 Diabetes

Healthy SubjectsType 2 Diabetes

600

N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med 1970;283:109-115.

Insulin(µU/mL)

Glucagon(pg/mL)

Glucose(mg/dL)

Carbohydrate MealCarbohydrate Meal

Me

al

25

GLP-1 Modulates Numerous Functions in HumansGLP-1 Modulates Numerous Functions in Humans

Stomach:Stomach: Helps regulate Helps regulate

gastric emptyinggastric emptying

Promotes satiety and Promotes satiety and reduces appetitereduces appetite

Liver:Liver: Glucagon Glucagon reduces reduces

hepatic glucose outputhepatic glucose outputBeta cells:Beta cells:EnhancesEnhances glucose- glucose-

dependent dependent insulin secretioninsulin secretion

Alpha cells:Alpha cells: Glucose-dependent Glucose-dependent

postprandialpostprandialglucagon secretionglucagon secretion

GLP-1: Secreted upon the ingestion of food

Data from Flint A, et al. J Clin Invest 1998;101:515-520. Data from Larsson H, et al. Acta Physiol Scand 1997;160:413-422.Data from Nauck MA, et al. Diabetologia 1996;39:1546-1553. Data from Drucker DJ. Diabetes 1998;47:159-169.

26

GLP-1 Effects Are Glucose Dependentin Type 2 DiabetesGLP-1 Effects Are Glucose Dependentin Type 2 Diabetes

Placebo

Glu

ca

go

n (

pm

ol/

L)

GLP-1

300

200

100

0

Ins

uli

n (

pm

ol/

L)

Time (min)

-30 0 60 120 180 240

PBOPBOGLP-1GLP-1

*** **

* *

*

Glu

co

se

(m

g/d

L)

270

180

90

0-30 0 60 120 180 240

*

*

*

*

* * *

PBOPBOGLP-1GLP-1

Time (min)

-30 0 60 120 180 240

20

10

0

** * *

PBOPBOGLP-1GLP-1

Time (min)

N = 10; Mean (SE); *P<0.05Data from Nauck MA, et al. Diabetologia 1993;36:741-744.

27

GLP-1 Has a Short Duration of Effect Due to Degradation by Dipeptidyl Peptidase IV (DPP-IV)GLP-1 Has a Short Duration of Effect Due to Degradation by Dipeptidyl Peptidase IV (DPP-IV)

His Ala Glu Gly Thr Phe Thr Ser Asp

Lys Ala Ala Gln Gly Glu Leu Tyr Ser

Ile Ala Trp Leu Val Lys Gly Arg Gly

Val

Ser

Glu

Phe

Lys

DPP-IV

7

37

9

Adapted from Mentlein R. Eur. J. Biochem 1993;214:829-835.

28

Leveraging the Therapeutic Potential of GLP-1Leveraging the Therapeutic Potential of GLP-1

• GLP-1– Short half-life (2 minutes)

Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV)

• DPP-IV inhibition– Extends endogenous GLP-1 half-life

Approved in US:

– Sitagliptin (Merck)

– Saxaglitpin (BMS and AZ) In development, e.g.,

– Alogliptin (Takeda)

– Denagliptin (Glaxo)

– Melogliptin (Glenmark)

– Vildagliptin – LAF 237 (Novartis)

29

Leveraging the Therapeutic Potential of GLP-1Leveraging the Therapeutic Potential of GLP-1

• GLP-1 receptor agonists– Mimic many of the glucoregulatory effects of GLP-1

– Resistant to DPP-IV Approved in US:

– Exenatide (Amylin and Lilly)

– Liraglutide (Novo Nordisk) In development, e.g.,

– Albiglutide (Glaxo Smith Kline)

– CJC 11134 (ConjuChem)

– Exenatide once weekly (Amylin, Lilly, Alkermes)

– Lixisenatide (Sanofi- Aventis)

– Taspoglutide (Roche)

30

Learning ObjectivesLearning Objectives

• Discuss the progressive nature of diabetes

• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010

• Review incretin physiology in healthy individuals and in patients with type 2 diabetes

• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists

• Identify where incretin therapies can be used in the treatment of type 2 diabetes

31

DPP-4 Inhibitor and GLP-1 Receptor Agonist DiscussionDPP-4 Inhibitor and GLP-1 Receptor Agonist Discussion

• The slides that follow include data from the first FDA approved agent in each class

• Concepts are broad, yet representative of drugs that are FDA approved in each class

• There is no intent to claim superiority of the drug discussed compared to the other same class agent

32

Continuously Infused GLP-1 Improved the Defects of T2DContinuously Infused GLP-1 Improved the Defects of T2D

T2D Defects1Continuously Infused

GLP-11,2

Insulin production

First-phase insulin response

Glucagon; glucose output

Gastric emptying

Food intake

1. Aronoff SL, et al. Diabetes Spectrum 2004;17:183-190. 2. Nielsen LL, et al. Regul Pep. 2004;117:77-88.

33

Effects of GLP-1 on the cell in Healthy SubjectsEffects of GLP-1 on the cell in Healthy Subjects

34

GLP-1 in T2DGLP-1 in T2D

35

GLP-1 Is Cleaved and Inactivated by DPP-4GLP-1 Is Cleaved and Inactivated by DPP-4

36

Mechanism of Action: DPP-4 InhibitorsMechanism of Action: DPP-4 Inhibitors

• Sitagliptin example

www.januvia.com/januvia/hcp/januvia/documents/MOAcard_JANUVIA.pdf

37

Sitagliptin Decreased A1C From Baseline Over 24 wksSitagliptin Decreased A1C From Baseline Over 24 wks

Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009

38

Sitagliptin Decreased A1C Over 52 wksSitagliptin Decreased A1C Over 52 wks

Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009

39

DPP-4 Inhibitors Prevent the Inactivation of GLP-1 DPP-4 Inhibitors Prevent the Inactivation of GLP-1

40

The BeginningThe Beginning

• Exenatide– Synthetic version of salivary protein found in

the Gila monster

– More than 50% amino acid sequence identity with human GLP-1 Binds to known human GLP-1 receptors on beta cells (in vitro) Resistant to DPP-IV inactivation

Adapted from Nielsen LL, et al. Regul Pept 2004;117:77-88.Adapted from Kolterman OG, et al. Am J Health-Syst Pharm 2005;62:173-181.

• Following injection, exenatide is measurable in plasma for up to 10 hours

Site of DPP-IV Inactivation

41

Exenatide Restored First-Phase Insulin ResponseExenatide Restored First-Phase Insulin Response

Time (min)

Evaluable; N = 25; Mean (SE)Fehse F, et al. J Clin Endocrinol Metab 2005;90(11):5991-5997.

Healthy Controls

IV Glucose IV Glucose

-180 -90 0 30 60 90 1200

10

20

30

-180 -90 0 30 60 90 120

Type 2 Diabetes

Exenatide

Exenatide

Placebo

Placebo0

10

20

30

Ins

uli

n (

pM

/kg

/min

)

Ins

uli

n (

pM

/kg

/min

)

Time (min)

42

Exenatide Suppressed Postprandial Glucose and Glucagon in Type 2 DiabetesExenatide Suppressed Postprandial Glucose and Glucagon in Type 2 Diabetes

N = 20; Mean (SE)Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089.

Pla

sm

a G

luc

ag

on

(p

g/m

L)

Pla

sm

a G

luc

os

e (

mg

/dL

)

0 120 1806050

100

150

200

Exenatide or PlaceboStandardized Breakfast

90

180

270

360

Exenatide or PlaceboStandardized Breakfast

0 60 120 180 240 300

Time (min)

Placebo0.10 µg/kg Exenatide

Time (min)

43

Exenatide Acutely Reduced Glucose Through Enhanced Glucose-Dependent Insulin SecretionExenatide Acutely Reduced Glucose Through Enhanced Glucose-Dependent Insulin Secretion

Type 2 Diabetes; N = 34; Mean (SE)Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089.

Time (h)

Pla

sm

a G

luc

os

e (

mg

/dL

)

0 2 4 6 890

135

180

225

SC Injection SC Injection

0 2 4 6 8

Placebo 0.05 µg/kg Exenatide 0.10 µg/kg Exenatide

Time (h)

Se

rum

In

su

lin

(p

mo

l/L

)

100

150

200

250

50

44

Exenatide Is Not Inactivated by DPP-4Exenatide Is Not Inactivated by DPP-4

45

Exenatide vs Sitagliptin MOA Study: Study DesignExenatide vs Sitagliptin MOA Study: Study Design

• Primary endpoint: comparison of the effects of exenatide and sitagliptin on 2-hour PPG concentrations in patients with T2D

MET background; MOA indicates mechanism of action; QAM, once per day in the morningDeFronzo RA, et al. Curr Med Res Opin 2008;24;2943-2952.

Study TerminationCrossover

Treatment Period 1 Treatment Period 2

Randomization

Placebo Lead-in

Exenatide 5 µg BID Exenatide 10 µg BID Exenatide 5 µg BID Exenatide 10 µg BID

StandardMeal Test

StandardMeal Test

StandardMeal Test

1 week 2 weeks 2 weeks

Sitagliptin 100 mg QAM Sitagliptin 100 mg QAM

Sequence A

Sequence B

46

Plasma GLP-1 Plasma Exenatide

Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1

Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE2-wk posttreatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.

BaselineExenatideSitagliptin

2-h

Po

stp

ran

dia

l Pla

sma

GL

P-1

(p

M)

2-h P

lasma E

xenatid

e (pM

)

0

25

50

75

0

25

50

75

7.2 7.9

15.1

63.8

47

-30 0 30 60 90 120 150 180 210 240120

160

200

240

280

PP

G (

mg

/dL

)

Time (min)Standard Meal

Exenatide Reduced PPG Concentrations To a Greater Extent Than Sitagliptin Exenatide Reduced PPG Concentrations To a Greater Extent Than Sitagliptin

Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, P<0.0001DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.

BaselineExenatideSitagliptin

Primary Endpoint

48

2-h

r P

PG

(m

g/d

L)

110

130

150

170

190

210

230

250

270

Baseline End of Period 1

End of Period 2

Patients with T2D; Evaluable population: exenatide-sitagliptin, n = 29; sitagliptin-exenatide, n = 32Mean ± SE; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.

Reductions in 2-Hour PPG Were Greater With Exenatide Than With SitagliptinReductions in 2-Hour PPG Were Greater With Exenatide Than With Sitagliptin

ExenatideSitagliptin

• After Period 1, patients were switched to the other therapy

49

Improvement in Insulinogenic Index Was Greater With Exenatide Than With SitagliptinImprovement in Insulinogenic Index Was Greater With Exenatide Than With Sitagliptin

Insu

lino

gen

ic In

dex

1

0.55

P = 0.02

0.82

Exenatide Sitagliptin

Patients with T2D; Evaluable population, n = 61 for both treatment groups; Geometric LS mean ± SE Standard meals administered at t = 0 min; 1. DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952. 2. Data on file, Amylin Pharmaceuticals, Inc.

Geometric Mean Baseline Insulinogenic Index2: 0.4

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.55

0.82

50

Exenatide Reduced Postprandial Glucagon Levels to a Greater Extent Than SitagliptinExenatide Reduced Postprandial Glucagon Levels to a Greater Extent Than Sitagliptin

-30 0 30 60 90 120 150 180 210 24070

80

90

100

110

120

Pla

sma

Glu

cag

on

(p

g/m

L)

Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SEDeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.

Time (min)Standard Meal

BaselineExenatideSitagliptin

51

-30 0 30 60 90 120 150 180 210 240

0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0

Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SD; Acetaminophen was administered immediately before the standard meal; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.

Pla

sma

Ace

tam

ino

ph

en (

µg

/mL

)Exenatide Slowed Gastric Emptying Compared to SitagliptinExenatide Slowed Gastric Emptying Compared to Sitagliptin

Time (min)Standard Meal

BaselineExenatideSitagliptin

52

ActionGLP-1 Receptor

Agonists1,2DPP-4

Inhibitors1,2

Insulin production +++ ++

First-phase insulin response

+++ ++

Glucagon; glucose output

+++ +

Gastric emptying Delayed No effect

Food intake Decreased No effect

Actions of Incretin-Based Therapies for T2D: GLP-1 Receptor Agonists and DPP-4 InhibitorsActions of Incretin-Based Therapies for T2D: GLP-1 Receptor Agonists and DPP-4 Inhibitors

1. DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952. 2. Drucker DJ and Nauck MA. Lancet 2006;368:1696-1705.

53

Learning ObjectivesLearning Objectives

• Discuss the progressive nature of diabetes

• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010

• Review incretin physiology in healthy individuals and in patients with type 2 diabetes

• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists

• Identify where incretin therapies can be used in the treatment of type 2 diabetes

54

Diagnosis:

Lifestyle+

Metformin

Lifestyle + Metformin+

Basal insulin

Lifestyle + Metformin+

Sulfonylurea

Lifestyle + Metformin+

Intensive insulin

Step 1 Step 2 Step 3

Lifestyle + Metformin+

Pioglitazone (no hypoglycemia /edema (CHF)/ bone loss)

Tier 1: well-validated core therapies

Tier 2: less well-validated core therapies

Lifestyle + Metformin+

GLP-1 agonist (no hypoglycemia/weight loss /nausea/vomiting )

Lifestyle + Metformin+

Pioglitazone +

Sulfonylurea

Lifestyle + Metformin+

Basal insulin

Algorithm for Type 2 Diabetes

Validation based on clinical trials & clinical judgmentNathan DM, et al. Diabetes Care 2008;31(12):1-11.

55

AACE/ACE Glycemic Control Algorithm: T2 DiabetesAACE/ACE Glycemic Control Algorithm: T2 Diabetes

6.5%

7.5%7.6%

9.0%>9.0

Lifestyle Modification

(to be considered throughout treatment)

MonotherapyCan include:• MET• DPP4• GLP-1• TZD• AGI

Dual Therapy• MET+GLP-

1, DPP4,or TZD

• TZD+GLP-1 or DPP4

• MET+Colsevelam or AGI

Dual Therapy• MET+GLP-

1, DPP4, or TZD

• MET+SFU or Glinide

Triple Therapy• MET+GLP-1

or DPP4 with TZD or SFU

Triple Therapy• MET+GLP-1

or DPP4 + TZD or SFU

• MET + TZD + SFU

After Orals• Insulin ±

other agents

Symptoms• Insulin ±

other agents

No Symptoms• MET+GLP-1 or

DPP4 + TZD or SFU

• MET + TZD + SFU• Insulin ± other

agents

A1CA1C

Adapted from AACE Glycemic Control Algorithm, Rodbard HW, et al. Endocr Pract 2009. Reproductions can be found at www.aace.com/pub

Increase therapy every 2-3 months if glycemic goal is not achieved

56

AACE/ACE Algorithm SummaryAACE/ACE Algorithm Summary

• The algorithm is intended for use in conjunction with more detailed and comprehensive information (e.g., prescribing information, ACE/AACE Road Maps, etc)

• The algorithm is intended to provide guidance

• A1C goal of ≤ 6.5% or less– Needs to be individualized to minimize risks of hypoglycemia

• Therapeutic pathways stratified based on current A1C values

• 8 major classes of medications– Prioritized by safety, efficacy, risk of hypo, simplicity, patient

adherence and cost of medication

– Combination medications that have complimentary mechanisms of action

Rodbard HW, et al. Endocr Pract 2009;15(6):541-559.