presentación de powerpoint...3 6 9 12 15 18 21 24 27 treatment period follow-up period 0.8 mg...

Agonistas del Receptor de GLP-1 en el tratamiento de la diabetes mellitus tipo 2

Manel Puig DomingoServei d´Endocrinologia

Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona

Conflictos de interés

• Comités de asesoramiento internacional: Lilly, Novartis

• Comités de asesoramiento nacional: Lilly, Novartis, Novo-Nordisk, Sanofi-Aventis

• Conferencias: Lilly, Novo-Nordisk

Opciones Terapéuticas en la Diabetes Tipo 2 hasta el 2012

19821982--55 19951995 2001200119221922 19501950’’ss 19961996 2003 2003

SulfonilureasSulfonilureasSulfonilureasInsulina HumanaInsulina HumanaInsulina Humana

MetforminaMetforminaMetforminaLisproLisproLispro

GlinidasGlinidasGlinidasGlarginaGlarginaGlargina

??

Insulina animalInsulina animalInsulina animal

GlitazonasGlitazonasGlitazonas

AspartAspartAspart

Inhibidores de DPPInhibidores de DPP--44Agonistas Agonistas del R de GLPdel R de GLP--11

DetemirDetemir

La DM2 es una enfermedad progresiva: UKPDS 6-Year Data

Time from randomization (Years)0 1 2 3 4 5 6

HbA

1C (M

edia

n %

)

0

6

7

8

9

6.2% HbA1c upper limit of normal

ConventionalChlorpropamideGlibenclamideInsulinMetformin

Time from Randomisation (Years)

HbA

1c(M

edia

n %

)

Los tratamientos clásicos no modifican la historia natural de

la DM2Los tratamientos clásicos producen hipoglicemias,

ganancia ponderal, y actualmente se discute su

seguridad, y esto también es válido para la insulina

(y tampoco la terapia insulínica)

UKPDS. Lancet. 1998;352:854-865.

La función de la célula β disminuye a lo largo del tiempo en pacientes con Diabetes Tipo 2

Tiempo desde el Diagnóstico (años)

Func

ión

de la

Cél

ula β

(%)

Holman RR. Diabetes Res Clin Pract. 1998;40(suppl 1):S21-S25.; UKPDS. Diabetes. 1995;44:1249-1258.

-12 -10 -8 -6 -4 -2 0 2 4 6

Es posible que la función de la célula βya haya disminuido

en un 50% en el momento del diagnóstico

La función de la célula β disminuye

progresivamente con el tiempo

aproximadamente un 6% por año

100

80

60

40

20

0

La función de la célula β disminuye a lo largo del tiempo en pacientes con Diabetes Tipo 2

100

Tiempo desde el Diagnóstico (años)

Func

ión

de la

Cél

ula β

(%)

Holman RR. Diabetes Res Clin Pract. 1998;40(suppl 1):S21-S25.; UKPDS. Diabetes. 1995;44:1249-1258.

-12 -10 -8 -6 -4 -2 0 2 4 6

Es posible que la función de la célula βya haya disminuido

en un 50% en el momento del diagnóstico

La función de la célula β disminuye

progresivamente con el tiempo

aproximadamente un 6% por año

80

60

40

20

0

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

ND IFG T2DM ND T2DM

β-C

ell v

olum

e (%

)

Obese Lean

-50%-50%

-63%-63% -41%-41%

βcell mass in T2 DM

ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitusButler AE et al. Diabetes. 2003;52:102-110.

The ideal antidiabetic drug• Longer durability of glucose control/efficacy • Agents that delay/prevent loss of β-cell function • Agents that increase β-cell mass and function • Therapies that provide superior control of

postprandial glucose • Agents that do not cause increased weight gain,

and/or increase cardiovascular risk in any manner

• Agents that improve metabolic syndrome risk factors

• Agents that directly affect the progression of diabetic complications

Acciones clásicas y nuevas de la molécula de supervivencia GLP-1

Tejido Adiposo

Cerebro Estómago

Absorción de glucosa y almacenamiento

Sensibilidad a la Insulina

Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157.

HígadoPáncreas

Músculo

Secreción de Insulina

Secreción de Glucagón

Biosíntesis de Insulina

Proliferación de la célula Beta

Apoptosis de la célula Beta

Vaciamiento Gástrico

ApetitoNeuroprotección

Cardioprotección

Función Cardiaca

Producción de Glucosa

Corazón

GLP-1

Intestino

{

Structure of native GLP-1 and two GLP-1 R agonists

11

Agonistas del Receptor GLP-1 de acción prolongada

Exenatide LAR: Microsphere Delivery Exenatide LAR: Microsphere Delivery System for Continuous Therapeutic Levels System for Continuous Therapeutic Levels

♦ Exenatide is incorporated into PLG microspheres1

• PLG is a medical biodegradable polymer (degraded to CO2 and water)2

• Via hydration, exenatide at or near the surface dissolves and diffuses away (initial release)3

• PLG degrades, creating pores for exenatide diffusion and release from microspheres (sustained release)4

• Allows gradual drug delivery at a controlled rate2

PLG indicates poly(D,L-lactide-co-glycolide).1. Malone J et al. Expert Opin Investig Drugs. 2009;18:359-367. 2. Tracy MA et al. Biomaterials. 1999;20:1057-1062. 3. Langer R, Folkman J. Nature. 1976;263:797-800. 4. Bawa R. et al. J. Controlled Release. 1985:1:259-267.

Plasma Exenatide LAR reachesPlasma Exenatide LAR reaches SteadySteady--State State Concentrations Within 6Concentrations Within 6--7 Weeks 7 Weeks

0

50

100

150

200

250

300

350

400

450

500

3 6 9 12 15 18 21 24 27

Treatment Period Follow-up Period

0.8 mg exenatide QW2.0 mg exenatide QW

10 µg exenatide BID(single dose)

12 hours

0 1

Time (weeks)

Plas

ma

Exen

atid

e (p

g/m

L)

• Data are mean ± SD

Fineman M et al. Clin Pharmacokinet. 2010;50(1):65-74.

HbA1c Changes Over 52 Weeks of Exenatide LAR treatment

Exe LAR, n = 120; BL = 8.3%

Time (Weeks)

LS M

ean

Cha

nge

(SE)

in H

bA1c

(%)

-2.0%-2.0%

*

**

* * * * *

40 5244 48363330262218141060-2.5

-2.0

-1.5

-1.0

-0.5

0.0Controlled Extension (All Exe LAR)

Exenatide BID EQW, n = 121; BL = 8.2%

• *p<.05Buse et al. Diabetes Care 2010;33(6):1255-61.

<7.0% ≤6.5% ≤6.0%0

25

50

75

100EQW, 2-Year Completers (N = 216)EQW, Intent-to-Treat (N = 295)

60%55%

39% 36%

17% 16%

Target HbA1c

% A

chie

ving

Tar

get

Exenatide LAR: Subjects Achieving HbA1c Target Goals After 2 YearsTarget Goals After 2 Years

• EQW: exenatide once a week (Exenatide LAR)

Taylor, et al. BMC Endocr Disord. 2011;11(1):9 [Epub].

Changes in HbA1c vs. ComparatorsLS

Mea

n C

hang

e (S

E) In

HbA

1c(%

)

-1.9*

-1.5*-1.5*-1.5

-1.2

-0.9

-1.3

DURATION-11 DURATION-23 DURATION-34

0

-0.5

-1.0

-1.5

-2.0

Baseline (%) 8.3 8.38.6 8.5 8.58.3 8.3

-1.6*

-0.9

DURATION-52

8.5 8.4

Exenatide BID

Insulin Glargine

Sitagliptin

Exe LAR

Pioglitazone

N = 233 223160 166 165148 147 129 123

• *p<.05 vs. comparator, intent-to-treat population

1. Drucker et al. Lancet 2008;372(9645):1240-50.2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):2010-81.

3. Bergenstal et al. Lancet 2010;376(9739):431-9.4. Diamant et al. Lancet 2010;375(9733):2234-43.

Proportion of Subjects Achieving HbA1cTarget of ≤7% (or <7%) vs. Comparators

• DURATION-1: evaluable population; DURATION-5, -2, and -3: intent-to-treat population; DURATION-5 and -3: target of <7%

1. Drucker et al. Lancet 2008;372(9645):1240-50.2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):2010-81. 3. Bergenstal et al. Lancet 2010;376(9739):431-9.

4. Data on file, Amylin Pharmaceuticals, Inc. 5. Diamant et al. Lancet 2010;375(9733):2234-43.

Prop

ortio

n (%

)

DURATION-11

0

80

50

40

10

70

60

30

20

77

61

p<.05

DURATION-23,4

36

49

p<.05

62

p<.05DURATION-35

60

48

p = .01

100

90

DURATION-52

58

30

p<.0001

Exenatide BID

Insulin Glargine

Sitagliptin

Exe LAR

Pioglitazone

N = 129 130 129 123 160 166 165 233 223

Postprandial Glucose Changes: Exenatide LAR vs Exenatide twice a day

Exenatide LAR 2 mg, n = 27 Exenatide 10 mg BID, n = 24

Mea

n G

luco

se (m

mol

/L) 15.0

10.0

5.0

12.5

7.5

• p =.0124, Exenatide LAR vs. exenatide twice a day

Drucker et al. Lancet 2008;372(9645):1240-50.

Time (Hours)

-1 0 1 2 53 4 -1 0 1 2 3 4 5M

ean

Glu

cose

(mm

ol/L

) 15.0

10.0

5.0

Time (Hours)

12.5

7.5

Baseline (Dotted line, circle)Week 14 (Solid line, square)

Changes in Fasting Glucose vs. Comparators

LS M

ean

Cha

nge

(SE)

in F

G (m

mol

/L)

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

0

-2.3*

-1.4

-1.9*

-0.7

-1.8‡

-0.9

-1.5

-2.1§

-2.8

Exenatide BID

Insulin Glargine

Sitagliptin

EQW

Pioglitazone

Baseline (mmol/L)DURATION-11 DURATION-52,3 DURATION-23, 4 DURATION-35

9.9 9.2 9.6 9.3 9.2 9.2 9.1 9.9 9.7N = 148 147 228 220160 166 165129 123

• *p<.001 vs. exenatide BID, ‡p=.004 vs. sitagliptin, §p=.001 vs. insulin glargine• Intent-to-treat population

1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Data on file, Amylin Pharmaceuticals, Inc.

4. Bergenstal et al. Lancet 2010;376(9739):431-9. 5. Diamant et al. Lancet 2010;375(9733):2234-43.

Changes in Body Weight vs. Comparators

4

-5

Exenatide BID

Insulin Glargine

Sitagliptin

Exe LAR

Pioglitazone

-3.6-3.7

0

-2

-3

-4

-1

2

3

1

-2.6†-2.3*

-0.8

1.4

-2.3

-1.4

2.8

LS M

ean

Cha

nge

(SE)

in

Bod

y W

eigh

t (kg

)DURATION-11

102 102Baseline (kg)DURATION-52

97 94DURATION-23 DURATION-34

91 9189 87 88N = 148 147 233 223160166 165129 123

• *p<.001 vs. sitagliptin and p<.0001 vs. pioglitazone †p<.05 vs. insulin glargine, intent-to-treat population


1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.

Changes in HbA1c and Body Weight: Exenatide LAR vs insulin glargine

Wei

ght C

hang

e fr

om B

asel

ine

(kg)

HbA1c (%) Change from Baseline

16

12

8

4

0

-4

-8

-12

-16-6 -4 -2 0 2 4 6

79.4%31.4%

0.0%4.5%

4.4%1.4%

16.2%62.7%

Insulin Glargine (N = 223)Exenatide LAR (N = 233)

• Intent-to-treat population

Diamant et al. Lancet 2010;375(9733):2234-43.

Changes in Systolic Blood Pressure vs. Comparators

LS m

ean

chan

ge (S

E) in

SB

P (m

mH

g)

-14

-12

-10

-8

-6

-4

-2

0

2

DURATION-11 DURATION-52 DURATION-23,5 DURATION-34

Baseline (mmHg) 128 130 130 128 126 126 127 135 133

EQWExenatide BIDSitagliptinPioglitazoneInsulin Glargine

-4.7-3.4 -2.9

-1.2

-3.6

+0.2

-1.6-3.0

-1.0

N = 129 123148 147 233 223160 166 165

*

ITT Patients

• *p =.010 vs. sitagliptin, intent-to-treat (ITT) population4. Diamant et al. Lancet 2010;375(9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.

1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Bergenstal et al. Lancet 2010;376(9739):431-9.

Changes in Diastolic Blood Pressure vs. Comparators

LS m

ean

chan

ge (S

E) in

DB

P (m

mH

g)

-8

-6

-4

-2

0

2

78 80 78 77 80 79 80 81 80

-1.7 -1.7

+0.2

-0.1

-1.4 -0.4

-2.5

-1.0 -1.0

129 123148 147 233 223160 166 165Baseline (mmHg)

N =

DURATION-11 DURATION-52 DURATION-23,5 DURATION-34

EQWExenatide BIDSitagliptinPioglitazoneInsulin Glargine

ITT Patients

• No statistically significant between-group differences in diastolic blood pressure reduction were observed.• Intent-to-treat (ITT) population• EQW: exenatide once a week (LAR), BID: twice a day1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Bergenstal et al. Lancet 2010;376(9739):431-9.

4. Diamant et al. Lancet 2010;375(9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.

Changes in LDL-C: Exenatide LAR vs Comparators

LS M

ean

Cha

nge

(SE)

in L

DL-

C (m

mol

/L)

0

-0.05

-0.10

-0.15

-0.20

-0.25

0.05

0.10

0.15

-0.13*

0.03

0.07

-0.17†

0.050.05

-0.03

0.04

-0.05

Exenatide BID

Insulin Glargine

Sitagliptin

Exe LAR

Pioglitazone

Baseline (mmol/L)

DURATION-11,5 DURATION-52 DURATION-23,5 DURATION-34

2.4 2.6 2.7 3.1 2.7 2.7 2.9 2.7 2.7N = 148 147 233 223160 166 165129 123

• *p=.02 vs. exenatide BID, †p<.01 vs. exenatide BID, intent-to-treat population



Changes in HDL-C: Exenatide LAR vs Comparators

-0.05

-0.10

0

0.05

0.10

0.15

0.20

LS M

ean

Cha

nge

(SE)

in H

DL-

C (m

mol

/L)

-0.03-0.02

0.00

0.03 0.05*0.05

0.16

0.00 0.01

Baseline (mmol/L)DURATION-11,5 DURATION-52 DURATION-23,5 DURATION-34

1.1 1.2 1.1 1.2 1.1 1.1 1.1 1.2 1.2N = 148 147 233 223160 166 165129 123

• *p<.001 EQW vs. pioglitazone, intent-to-treat population

Exenatide BID

Insulin Glargine

Sitagliptin

Exenatide LAR

Pioglitazone



Changes in Triglycerides: Exenatide LAR vs. Comparators

• *p=.006 EQW vs. pioglitazone, intent-to-treat population

Geo

met

ric L

S M

ean

(SE)

Rat

io

Endp

oint

to B

asel

ine

0

0.5

1.5

1.00.85 0.89

0.940.99 0.95* 0.960.84

0.95 0.89

1. Drucker et al. Lancet 2008;372(9645):1240-50.2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Bergenstal et al. Lancet 2010;376(9739):431-9.

4. Diamant et al. Lancet 2010;375 (9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.

Exenatide BID

Insulin Glargine

Sitagliptin

Exenatide LAR

Pioglitazone

Baseline (mmol/L) DURATION-11,5 DURATION-52,5 DURATION-23,5 DURATION-34,5

1.78 1.87 1.78 1.99 1.70 1.64 1.96 1.85 1.82N = 148 147 233 223160 166 165129 123

Fasting Lipid Profile Changes After 2 Years of Exenatide LAR treatment

Total Cholesterol LDL-C HDL-C TriglyceridesBaseline (mmol/L) 4.5 2.4 1.2 1.8

0.01

-15%*

-0.12*

-0.22*Cha

nge

from

Bas

elin

e (m

mol

/L)

Cha

nge

from

Bas

elin

e (%

)0

-0.05

-0.15

-0.25

-0.10

-0.20

-5

-10

-20

-15

0

Exenatide LAR(N = 148)

• *p<.05 vs. baseline, completer sample

Kim et al. 69th ADA 2009.

Changes in Cardiovascular Risk Biomarkers under exenatide LAR

-7

-4

-16*

p<.0001

p = .014

LS M

ean

Cha

nge

(SE)

fr

om B

asel

ine

(%)

-1

-23*

33*

50403020100

-10-20-30

-5

-10

-15

-20

-25

0

BNP ACR

-24*

-14*

-33*

-10

-20

-30

-30

0

hs-CRP

Sitagliptin (N = 166)Exenatide LAR (N = 160)

Pioglitazone (N = 165)

• *p<.05 vs. baseline, intent-to-treat population• BNP: B-type natriuretic peptide, ACR: albumin-to-creatine ratio, hs-CRP: high-sensitivity C-reactive proteinBergenstal et al. Lancet 2010;376(9739):431-9.

Exenatide LAR: Adverse Events ≥5%

ExeLAR1-5

N=670n (%)

ExeBID1,2,5

N=268n (%)

SITA3,5

N=166n (%)

PIO3,5

N=165n (%)

Insulin Glargine4,5

N=223n (%)

Nausea 126 (18.8) 93 (34.7) 16 (9.6) 8 (4.8) 4 (1.8)

Diarrhea 83 (12.4) 24 (9.0) 16 (9.6) 12 (7.3) 8 (3.6)

Headache 55 (8.2) 17 (6.3) 15 (9.0) 7 (4.2) 20 (9.0)

Nasopharyngitis 51 (7.6) 9 (3.4) 4 (2.4) 5 (3.0) 40 (17.9)

Vomiting 51 (7.6) 38 (14.2) 4 (2.4) 5 (3.0) 3 (1.3)

Injection site pruritus 43 (6.4) 3 (1.1) - - 1 (0.4)

• Intent-to-treat population, SITA: sitagliptin, PIO: pioglitazone1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10. 3. Bergenstal et al. Lancet 2010;376(9739):431-9.


Incidence of Hypoglycemia by SU use

0

20

40

60

80

100

• *p<.05 Exenatide LAR vs. insulin glargine, intent-to-treat population1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Data on file, Amylin Pharmaceuticals, Inc.


Concomitant SU

DURATION 11

DURATION 52.3

DURATION 35

No SU

Inci

denc

e (%

) of M

inor

Hyp

ogly

cem

ia

DURATION 11

DURATION 52,3

DURATION 35

DURATION 24

Exenatide BID

Insulin Glargine

Sitagliptin

Exenatide LAR

Pioglitazone

0

20

40

60

80

100

0 1.1 1.3

15.4

3.0

19.114.5

3.012.5 11.8

20.3

42.4

0 0

n = 93 93 89

0.6

89 160 166 165 164 157 55 52 40 34 69 66

*

*

Exenatide LAR:Changes in Heart Rate M

ean

Cha

nge

in H

eart

Rat

e fr

om

Bas

elin

e (b

pm)

0

2

4

6

8

10

4.51*

DURATION-11 DURATION-52 DURATION-21 DURATION-33

4.12*

2.51*

4.03*

• *p<.05 vs. baseline• bpm: beats per minute1. Data on file, Amylin Pharmaceuticals, Inc.2. Blevins et al. J Clin Endocrin Metab 2011;96(5):1301-103. Diamant et al. Lancet 2010;375(9733):2234-43.

Are GLP-1 R agonists the ideal antidiabetic drugs ?

• Longer durability of glucose control/efficacy • Agents that delay/prevent loss of β-cell function • Agents that increase β-cell mass and function • Therapies that provide superior control of postprandial

glucose • Agents that do not cause increased weight gain, and/or

increase cardiovascular risk in any manner • Agents that improve metabolic syndrome risk factors • Agents that directly affect the progression of diabetic

complications

??

Gracias por vuestra atención

presentación de powerpoint...3 6 9 12 15 18 21 24 27 treatment period follow-up period 0.8 mg...

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