PresentacióN Dr. Ketzeff

Nuevas estrategias en el manejo de la Nuevas estrategias en el manejo de la diabetes mellitus tipo 2 diabetes mellitus tipo 2

Nuevas estrategias en el manejo de la Nuevas estrategias en el manejo de la diabetes mellitus tipo 2 diabetes mellitus tipo 2

El efecto incretina

Argemiro Fragozo MDInternista Endocrinólogo

Coordinador Cátedra Medicina InternaProfesor Asistente de Medicina

U. El Bosque - Bogotá

La diabetes es una enfermedad vascularLa diabetes es una enfermedad vascular

Retinopatía diabética~ 50%La causa principal de ceguera en adultos en edad laboral1

Nefropatía diabética~ 35%La causa principal de enfermedad renal terminal2

Enfermedad cardiovascular~ 45%

Accidente cerebrovascularIncremento de 2 a 4 veces en la mortalidad cardiovascular y accidente cerebrovascular3

Neuropatía diabética~ 40%La causa principal de amputaciones no traumáticas de las extremidades inferiores5

8/10 pacientes diabéticos fallecen por eventos CV4

1 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 2 Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 3 Kannel WB, et al. Am Heart J 1990; 120:672–676. 4 Gray RP & Yudkin JS. In Textbook of Diabetes 1997.

5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79. Decision Resources., Inc.1999.

ADA. Clinical Practice Recommendations 2006

• Glicemia casi-normal

– A1c <7.0%

• Evitar las crisis agudas

– Hipoglicemia

– Hiperglicemia

– CAD/Estado hiperosmolar

• Reducir las complicaciones crónicas

• Mejorar calidad de vida

Metas del Manejo Intensivo de la DiabetesMetas del Manejo Intensivo de la Diabetes

65% de los diab65% de los diabééticos no alcanzan los objetivos de ticos no alcanzan los objetivos de HbAHbA1c1c

Saydah SH, et al. JAMA 2004; 291:335–342.

Liebl A, et al. Diabetologia 2002; 45:S23–S28.

Guías de manejo de la diabetes: HbAGuías de manejo de la diabetes: HbA1c1c

ADA (US)1

HbA1c < 7% IDF (Europe)3

HbA1c 6.5%

CDA (Canada)4

HbA1c 7%

NICE (UK)5

HbA1c 6.5–7.5%

AACE (US)2

HbA1c 6.5% ALAD (Latin America)6

HbA1c < 6–7%

APPG (Asia Pacific)7

HbA1c < 6.5%

Australia8

HbA1c 7%

1American Diabetes Association. Diabetes Care 2004; 27 (Suppl. 1):S15–S34. 2American Association of Clinical Endocrinologists. Endocr Pract 2002; 8 (Suppl. 1):40–82. 3European Diabetes Policy Group. Diabet Med 1999; 16:716–730. 4Canadian Diabetes Association. Can J Diabetes 2003; 27 (Suppl. 2):S1–S152.

5National Institute for Clinical Excellence. 2002. Available at: http://www.nice.org.uk. 6ALAD. Rev Asoc Lat Diab 2000; Suppl. 1.7Asian-Pacific Policy Group. Practical Targets and Treatments (3rd Edition). 8NSW Health Department. 1996.

Historia Natural de la DM Tipo 2Historia Natural de la DM Tipo 2Historia Natural de la DM Tipo 2Historia Natural de la DM Tipo 2

15 20 25 301050–5–10

At risk for diabetes

-cell failure Insulin level

Fasting glucose

Insulin resistance

PPGG

luc

ose

(mg

/dL

)R

elat

ive

-C

ell

Fu

nct

ion

(%

)

Diabetes (yr)

350

300

250

200

100

200

100

0

150

50

250

150

50

PPG=post-prandial glucose

Adapted with permission from Bergenstal R et al. In: DeGroot L, Jameson J, eds. Endocrinology. 4th ed. Philadelphia, Pa: W.B. Saunders Company; 2001:821

Años desde el diagnóstico

Adapted from Levy J et al Diabet Med 1998;15:290–296.

0

40

60

HO

MA

(%

)

20

00

40

60

80

HO

MA

(%

)

20

2 4 6 0 2 4 6

Años desde el diagnóstico

Función Célula Beta Sensibilidad a la insulina

Deterioro de la Función de la Célula BetaMientras se Mantiene la Resistencia a la Insulina

HOMA%: Expresado como % de los valores en jovenes, magros y sanos

• Anomalías funcionales presentes:– Liberación de insulina

oscilatoria alterada– Niveles de proinsulina

Aumentados – Pérdida 1ª fase secreción

insulina– Respuesta anormal de 2ª

fase de respuesta insulínica– Perdida progresiva de la

masa funcional de células β

*p<0.05 entre gruposAdapted from Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Polonsky KS et al N Engl J Med 1988;318:1231–1239; Quddusi S et al Diabetes Care 2003;26:791–798; Porte D Jr, Kahn SE Diabetes 2001;50(suppl 1):S160–S163; Vilsbøll T et al Diabetes 2001;50:609–613.

Insu

lina

(pm

ol/L

)

Comida mixtaSujetos normalesDiabéticos tipo 2

Tiempo (min)

**

500

400

300

200

100

00 60 120 180

La Función de la Célula β Se Encuentra Alterada en DM2

Insulina y Glucagón en Respuesta a las Comidas en Insulina y Glucagón en Respuesta a las Comidas en Diabetes Tipo 2Diabetes Tipo 2

-60 0 60 120 180 240

360

330

300

270

240

110

80

140

130

120

110

100

90

120

90

60

30

0

Glucose (mg %)

Insulin (µU/mL)

Glucagon (pg/mL)

Meal

Time (min)

Type 2 diabetes

Normal subjects

Delayed/depressedinsulin response

Nonsuppressed glucagon

Normal subjects, n=11; Type 2 diabetes, n=12.Adapted from Müller WA et al. N Engl J Med. 1970;283:109–115.

Proporción de pacientes con A1c <7% con Proporción de pacientes con A1c <7% con monoterapiamonoterapia

UKPDS 49. JAMA 1999; 281: 2005-2012.UKPDS 49. JAMA 1999; 281: 2005-2012.

100

Years from randomisation3 6 9

0

20

40

60

80

3 6 9 3 6 9 3 6 9

Diet Insulin MetforminSulphonylureaOverweight patients

Prop

ortio

n of

pat

ient

s (%

)

50%

*p0.05Adapted from Nauck M et al Diabetologia 1986;29:46–52.

Glucosa oral glucosa IV isoglicémica

0

–10

10

15

20

Glu

cosa

p

lasm

átic

a(m

mo

l/L)

5

60 120 180

Tiempo(min)

0

40

60

80

Insu

lina

(mU

/L)

20

Controles Sanos Diabetes tipo 2

0

10

15

20

Glu

cosa

pla

smát

ica

(mm

ol/L

)

5

Tiempo (min)

0

40

60

80

Insu

lina(

mU

/L)

20

–5 –10 60 120 180–5

–10 60 120 180–5 –10 60 120 180–5

** * * * * *

* **

Efecto Incretina Normal

Efecto Incretina Disminuido

Efecto Incretina en Diabetes tipo 2 y Normales

Disminución salida de glucosa

Aumento de la disponobilidad de glucosa en tejidos

Tracto GI

GLP-1 y GIP

activos

Liberación de

incretinasPancreas

Bloodglucose control

Glucagon Glucosa

dependiente (GLP-1)

Células AlfaCélulas Alfa

InsulinaGlucosa dependiente

(GLP-1 and GIP)

Células Células ββ

InhibiciónDPP4

Ingestión de comida

Adapted from Brubaker PL, Drucker DJ. Endocrinology. 2004;145:2653–2659; Zander M et al. Lancet. 2002;359:824–830; Ahrén B. Curr Diab Rep. 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

GLP-1 (9-36)y GIP (3-42)

inactivos

X

Control Glucosa Sangre

Las Incretinas Regulan la Homeostasis de Glucosa a Través de la Función de los Islotes

GLP-1 es secretado de

las células Ldel intestino

Esto a su vez…

• Estimula la secreción de

insulina glucosa dependiente

• Suprime secreción Glucagon

• Enlentece vaciamiento

gástrico

• Aumenta masa célula β

y mantiene su eficiencia

• Mejora sensibilidad insulina

• Reduce ingesta de alimento

Al ingerir alimento…

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

GLP-1 Mecanísmo de Acción en Humanos

GLP-1 Aumenta Proliferación e Inhibe GLP-1 Aumenta Proliferación e Inhibe Apoptosis de Apoptosis de Células Células ββ en Ratas Zucker en Ratas Zucker

DiabéticasDiabéticas

Study in Zucker diabetic rats that received a two-day infusion of GLP-1 followed by a glucose tolerance testAdapted from Farilla L et al Endocrinology 2002;143:4397–4408.

Apoptosis Célula β

0

5

10

Control TratamientoGLP-1

Ap

op

toti

c C

élu

las

bet

a (%

) 30

25

20

15

0

0.5

1.0

Control

TratamientoGLP-1

Cél

ula

s b

eta

pro

lifer

ado

ras

(%)

2.5

2.0

1.5

Proliferación Célula β

Aumento 1,4 vece (p<0.05)

Disminución 3,6 veces(p<0.001)

Admin

Having the arrow sit in the bar as they do is not 100% accurate because the 'fold' difference resides in the 'difference' between the two bars, not in the full height of one of the bars. It is also too promotional and distracts from the data and message.Recommend deleting the arrow and reformatting. For clarity - this slide has been ammended with this objective in mind.

GLP-1 Preservó la Morfología deGLP-1 Preservó la Morfología de Islotes Humanos Islotes Humanos In VitroIn Vitro

Día 1

Células tratadas Con GLP-1Control

Día 3

Día 5

Adapted from Farilla L et al Endocrinology 2003;144:5149–5158.

Los islotes tatados con

GLP-1 en cultivos

mantuvieron su

integridad por

mayor tiempo.

Ratón diabéticoRatón diabético +Inhibidor DPP-4

Adapted from Zhang BB et al. Poster presented at the 64th Scientific Session of the ADA, Orlando, Florida, USA, June 2004.

Ratón magro control

Verde: células beta productoras de insulina

Rojo: células alfa productoras de glucagon

Inhibidor de DPP-4 Restauró las Células β en Ratones Diabéticos

** *

*

**

Adapted from Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:3717–3723.

TGN (n=33)Diabetes tipo 2 (n=54)

0

5

10

15

20

0 60 120 180 240

Tiempo (min)

GL

P-1

(p

mo

l/L

)

*

Niveles de GLP-1 disminuyen en Diabetes Tipo 2

p < 0,05

TGN (n=9) Diabetes tipo 2 (n=9)

* Baja tasa =0.4 pmol kg–1 min–1

** Alta tasa=1.2 pmol kg–1 min–1

Adapted from Nauck MA et al J Clin Invest 1993;91:301–307.

Insu

lin

a (n

mo

l li

ter –1

min

)

0

10

20

30

40

50

60

7.4

51.4

7.5

38.2

GLP-1 infusión (tasa baja)*GLP-1 infusión (Tasa alta)**

La Acción de GLP-1 se Mantiene Normal en DM2

Acciones GLP-1Acciones GLP-1Acciones GLP-1Acciones GLP-1

Comida mixtaComida mixta

GLP-1(7-36)GLP-1(7-36)ActivoActivo

PlasmaPlasma

LiberaciónLiberaciónGLP-1GLP-1

intestinalintestinal

GLP-1(9-36)GLP-1(9-36)InactivoInactivo

DPP-IVDPP-IV

Inactivación rápida(>80% del pool)

DepuraciónDepuraciónRenalRenal

DPP-IV = dipeptidilpeptidasa-IV DPP-IV = dipeptidilpeptidasa-IV Deacon et al. Diabetes 1995; 44:1126Deacon et al. Diabetes 1995; 44:1126

Secreción y Metabolismo de GLP-1

Análogos de GLP-1: Exendin 4 [Exenatide] Byetta®

Liraglutide

Inhibidores de DPP-IV Intensificadores de Incretinas

Estrategias Para Estimular el Efecto Incretina

Monstruo Gila(Heloderma suspectum)

Sitagliptin - Merck Vildagliptin - NovartisSaxagliptin - BMS

Sitagliptin - RevisiónSitagliptin - Revisión

• Inhibidor DPP-4 en desarrollo para el tratamiento de pacientes con diabetes tipo 2, aprobada por FDA

• Produce una inhibición potente y altamente selectiva sobre la enzima DPP-4

• Inhibición totalmente reversible e inhibidor competitivo

N

ONH2

NN

CF3

F

F

F

N

Estudio OGTT Una dosisEstudio OGTT Una dosis

Una Dosis deUna Dosis de Sitagliptin Inhibió Sitagliptin Inhibió Actividad de DPP- 4 en Actividad de DPP- 4 en

PlasmaPlasma

Adapted from Herman GA et al. Poster presented at the 40th Annual Meeting of the European Association for the Study of Diabetes (EASD), Munich, Germany, September 5–9, 2004.

Inh

ibic

ión

de

DP

P-4

en

re

laci

ón

al b

asal

(%)

Hora

0 1 2 4 8 12 16 20 24

TGO

~80%

–10

0

40

50

60

80

100

90

70

30

20

10

~50%

Inhibiciónvalor más bajo 24 H

Sitagliptin 25 mgSitagliptin 200 mgPlacebo

N=56


Aumento ~22 to 23% con Sitagliptin vs. placebo (p<0.001 para ambas dosis)

0

10

20

30

40

Hora

Insu

lin

a P

lasm

a(µ

IU/m

l)

TGO

0 1 2 3 4

• Péptido C en plasma 13–21% mas elevados con sitagliptin vs. placebo

• (p<0.001 para ambas dosis).


N=56

5

Estudio OGTT Una dosis

Una Dosis de Sitagliptin Estimuló Secreción de Insulina Post Glucosa

Disminución ~8–14% con sitagliptin vs. placebo (p<0.015 para 25 mg, p<0.001 para 200 mg)


Glu

cag

on

Pla

sma

(pg

/ml)

Hora

50

60

70

80

0 1 2 3 4 5

TGO


N=56

Estudio OGTT una Dosis

Una Dosis de Sitagliptin Suprimió Glucagon post Glucosa

• Estudios Multinacionales

– Duración promedio de DM2 4,4 años

– A1C media de base = 8.0%

•54% de pacientes tuvieron A1C < 8%

– 53% recibieron ADO antes, IMC medio 31 kg/m2, edad media 54 años, 55% hombres

• Estudio Japonés

– Duración media de DM2 ~ 4 años

– A1C media de base = 7.6%

•~ 65% tuvieron A1C < 8%

– ~ 45% recibieron ADO antes, IMC medio 25 kg/m2, edad media 55 años, 60% hombres

Estudios con Monoterapia: Pacientes estudiados

• 3 Estudios aleatorios, doble ciegos en pacientes con DM2 – 1 estudio en Japón: 12 Semanas periodo de trataminto– 2 Estudios multinacionales: 18-, 24 Semanas periodo de

tratamiento

• Diseño General– Ambos grupos de pacientes con o sin tratamiento previos elegibles– Criterios A1C estudios multinacionales: 7-10%, En japonés: 6.5-

10%– Grupos de tratamiento

• Multinacionales: placebo, sitagliptin 100 mg q.d. o 200 mg q.d.• Japonés : placebo or100 mg q.d.

Screening

Single-blindplacebo

Periodo doble ciego de tratamiento

Periodo inicio dieta/ejercicio

Elegible A1c 6,5-7 a 10%

DescontinuarADO

Sem - 2 Día 1Aleatorización

Estudios con Monoterapia-Pacientes

Sitagliptin Redujo significativamente A1C conSitagliptin Redujo significativamente A1C conuna Sola Dosis Diaria una Sola Dosis Diaria

Raz I et al; PN023; Aschner P et al. PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006

7.2

7.6

8.0

8.4

Placebo (n=244)

Sitagliptin 100 mg (n=229)

Estudio 24 sem

Tiempo

(semanas)

0 5 10 15 20 25

-0.79%(p<0.001)

*between group difference in LS means

Estudio Japonés

-1.05%(p<0.001)

Placebo (n=75)


Tiempo (semanas)

0 4 8 12

A1C

(%

)

7.6

8.0

8.4

7.2

6.8

cambio vs placebo*

Estudio 18 sem

Placebo (n=74)


Tiempo (semanas)

0 6 12 18

A1C

(%

)

7.2

7.6

8.0

8.4

-0.6%(p<0.001)

A1C

(%

)

=

Sitagliptin Una Vez por Día Reduce GlicemiaSitagliptin Una Vez por Día Reduce Glicemia

en Ayunas y PP en Monoterapia en Ayunas y PP en Monoterapia

* LS Diferencia media con placebo en 24 semanas Aschner P et al, PN021. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC

Glucosa en Ayunas

Glu

cosa

Pla

sma m

g/d

L

Tiempo (semanas)

0 5 10 15 20 25144

153

162

171

180

189

Placebo (n=247)Sitagliptin 100 mg (n=234)

GPA* = – 17.1 mg/dL (p<0.001)

Glucosa Post Prandial

Tiempo (minutos)

Glu

cosa

Pla

smam

g/dL

i2-hr GPP* = – 46.7 mg/dL (p<0.001)

0 60 120 0 60 120

144

180

216

252

288

Placebo (N=204) Sitagliptin (n=201)

Baseline24 semanas

Baseline24 semanas

Sitagliptin Produce Mayores Reducciones de A1c Sitagliptin Produce Mayores Reducciones de A1c

Mientras mas Alta sea A1c de Base Mientras mas Alta sea A1c de Base

Reducciones en relación a placeboAdapted from Raz I et al. PN023; Aschner P et al. PN021. Abstracts presented at: ADA2006

Baseline A1c (%)

Mean (%)

Red

ucti

on

in

A1

c (%

)

Criterios inclusión: 7%–10%

Red

ucció

n A

1c (%

)

<8% 8–9% >9%

7.37 8.40 9.48

<8% 8–9% >9%

7.39 8.36 9.58

N=96

N=130N=70

N=62

N=27

N=37

Estudio 18 Sem

-0,44

-0,61

-1,2

-1,8

-1,6

-1,4

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

Estudio de 24 sem

-0,57

-0,8

-1,52-1,8

-1,6

-1,4

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

Proinsulin/insulin ratio

Aschner P et al. PN021; Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC.

p< 0.001*

*P value for change from baseilne compared to placebo

Rayas : BasalSolido = 24 semanas

∆ de Basal vs Placebo= 0.078(95% CI -0.114, -0.023

Placebo Sitagliptin 100 mg

Rela

ción

(pm

ol/L

/ pm

ol/L)

HOMA-β

30

35

40

45

50

55

60

65

70

75

80

p< 0.001*

∆ de basal vs Placebo = 13.2 (95% CI 3.9, 21.9)


Sitagliptin Mejora Marcadores de Función Célula β Estudio de Monoterapia 24 semanas

0,3

0,35

0,4

0,45

0,5

0,55

Sitagliptina una vez al día agregada a Metformina o Sitagliptina una vez al día agregada a Metformina o Pioglitazona disminuye significativamente la A1C Pioglitazona disminuye significativamente la A1C

*Placebo Subtracted Difference in LS Means.Rosenstock J et al. PN019. Hashomer T et al. PN020. Abstracts presented at: ADA2006


A1C –0.70% (p<0.001)

Estudio Sita + Pio

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24

Semanas

A1C

(%

)

A1C –0.65% (p<0.001)


Estudio Sita + Met

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24

Semanas

A1C

(%

)

Diferencia entre tratamientos: –32.8 mg/dL (p<0.001)*

*Diferencia de la media de los cuadrados mínimos en la glucosa promedio ponderada

Estudio de Tratamiento Adición a Metformina Estudio de Tratamiento Adición a Metformina

Sitagliptina + Metformina mejoró el perfil de Sitagliptina + Metformina mejoró el perfil de glucosa de 24 horas vs. Metformina solaglucosa de 24 horas vs. Metformina sola

Glu

cosa (

mg

/dL)

8:00 Día 1

Metformina 1500 mg/día (n=13)Sitagliptina 50 mg 2/día + metformina 1500 mg/día (n=13)

13:00 19:00 0:00Día 2

7:30

100

120

140

160

180

240

200

220

Dosis 17:30

Dosis 218:30

Desayuno Comida Cena

Período 1

Sitagliptina una vez al día incrementa significativamente la Sitagliptina una vez al día incrementa significativamente la cantidad de pacientes en meta con monoterapia o cantidad de pacientes en meta con monoterapia o

combinacióncombinación

SitagliptinaPlacebo

0

10

20

30

40

50

Con metformina.

Porc

en

taje

P<0.001

18%

47%

0

10

20

30

40

50

Con TZD

Porc

en

taje

P<0.001

23%

45%

Aschner P et al. PN021. Rosenstock J et al. PN019. Hashomer T et al. PN020. ADA2006

P<0.001

0

10

20

30

40

50

Monoterapia

Porc

en

taje

17%

41%

Meta A1C < 7%

Estudio de 52 semanas de Sitagliptina vs. Terapia de adición de Glipizida a Estudio de 52 semanas de Sitagliptina vs. Terapia de adición de Glipizida a metforminametformina

Estudio de adición controlada de agente de comparación activo (Glipizida) para Estudio de adición controlada de agente de comparación activo (Glipizida) para Metformina—DiseñoMetformina—Diseño

Diseño• Pacientes con DMT2 (en cualquier monoterapia o combinación dual con metformina)• Diseño de no inferioridad, con análsis primario por protocolo

Período deselección

Ciego sencilloplacebo

Período de tratamiento doble ciego:Glipizida o sitagliptina 100 mg/día.

Monoterapia introductoria con

metformina

Semana -2:Elegible si A1C

6.5% a 10%

Si no toman un HGO, los

pacientes D/C continúan/inician monoterapia con

metforminaDía 1

Aleatorización

Metformina (dosis estable > 1500 mg/día)

Semana 52

Glipizida: 5 mg/día se incrementaron a 10 mg cada 12hrs (mantener si GPA <110 mg/dL o hipoglucemia)

GPA=glucosa plasmática en ayunas; MTT=prueba de tolerancia a la comida; D/C=suspendidos; T2DM=diabetes mellitus tipo 2Datos en archivo MSD.

• Puntos finales primarios

– No inferioridad en el cambio de HbA1c respecto al valor inicial vs. glipizida

– Seguridad y tolerabilidad de sitagliptina en comparación con glipizida• Los puntos finales secundarios incluyeron:

– GPA, Peso corporal, Incidencia de hipoglucemia– Índices de secreción de insulina en un subgrupo de pacientes sometidos a MTT

Sitagliptina una vez al día muestra similar eficacia que Sitagliptina una vez al día muestra similar eficacia que Glipizida cuando se añade a metformina (52 Semanas)Glipizida cuando se añade a metformina (52 Semanas)

Sitagliptina 100 mg qd (n=382)

Glipizida (n=411)

Mean

Ch

an

ge in

Hb

A1c Cambio desde la basal (ambos grupos)*: - 0.67%

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

0 12 24 38 52

Time (weeks)

*análisis por protocolo; -0.51% and -0.56% para sitagliptina y glipizida en LOCF analysis

Estudio de 52 semanas de Sitagliptina vs. Tx de adición de Glipizida a Estudio de 52 semanas de Sitagliptina vs. Tx de adición de Glipizida a Metformina Metformina

Reducciones progresivamente mayores en HbA1c con HbA1c basal Reducciones progresivamente mayores en HbA1c con HbA1c basal progresivamente más altaprogresivamente más alta

Categoría HbA1C basalCriterios de inclusión estudio

6.5%–10% =Media (%) =

Cam

bio

resp

ecto

valo

r b

asal en

Hb

A1c

(%)

Sitagliptina 100 mg/día

Glipizida

n=112

n=167

n=82

n=21

n=117

n=179

n=82

n=33

6.60 6.67 7.41 7.40 8.32 8.33 9.35 9.19

Población por protocolo(Resumen de estadística)

-0.14

-0.59

-1.11

-1.76

-0.26

-0.53

-1.13

-1.68

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

<7% 7-<8% 8<9% >9%

Sitagliptina muestra mayor seguridad y Sitagliptina muestra mayor seguridad y tolerabilidad (52 semanas)tolerabilidad (52 semanas)

Glipizida (n=584)

Sitagliptina 100 mg (n=588)

p<0.001

Cambio en peso

86

88

90

92

94

0 12 24 38 52

Tiempo (semanas)

Pe

so

(k

g)

Sitagliptina 100 mg qd (n=382)

Glipizida (n=411)

PN024.

Entre grupos = –2.5 kg (p<0.001)

Hipoglucemia

32%

4.9%

0

10

20

30

40

50

52 semanasIn

cid

en

cia

(%)

Sitagliptina + Metformina Diseño Sitagliptina + Metformina Diseño factorial del estudio.factorial del estudio.

N = 1091 Aleatorizados

Basal media A1C = 8.8%

Periodo deScreening

Simple ciegoPlacebo Doble ciego Periodo de

tratamieno

Dieta/ejercicio Periodo de inicio

Eligible si A1C 7.5 a 11%

Si tiene HGO, D/C’ed

Semana- 2 Día 1

Sitagliptina 50/Met 1000 2/D

Placebo

Sitagliptina 100 mg 1/D

Metformina 500 2/D

Metformina 1000 2/D

Sitagliptina 50/Met 500 2/D

Semana 24

Duración de 2 semanas basado en terapia previa

Cohorte de etiqueta abierta Sitagliptina

50/Met 1000 2/D

ALEATORIZACIÓN

Combinación inicial de Sitagliptina y MetforminaCombinación inicial de Sitagliptina y Metformina Producen una Marcada disminución en A1C Producen una Marcada disminución en A1C

-2.5

-2.0

-1.5

-1.0

-0.5

A1

C (

%)*

-0.8-1.0

-1.3

-1.6

-2.1

Basal media A1C = 8.8%

Cambio con placebo de la basal = 0.17 %

*Placebo-subtracted LS mean change from baseline at Week 24

Open LabelSita 50 mg + MF 1000 mg b.i.d.

Sita 50 mg + MF 1000 mg 2xd.

Sita 50 mg + MF 500 mg 2xd.

MF 1000 mg 2xd.

MF 500 mg 2xd.

Sita 100 mg 1xd

Alto numero de pacientes llegaron a Alto numero de pacientes llegaron a la meta de A1C la meta de A1C

A1C <6.5% A1C <7.0%

% to

Goa

l

0

10

20

30

40

50

60

70

Sita 50 mg b.i.d+ Met 1000 mg b.i.d.

Sita 50 mg b.i.d + Met 500 mg b.i.d.

Met 1000 mg b.i.d.

Met 500 mg b.i.d.

Sita 100 mg q.d.

Placebo

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

LS

Mea

n A

1C C

hang

efr

om B

asel

ine

(%)

Aún grandes reducciones en A1C en altos valores Aún grandes reducciones en A1C en altos valores basales basales

(Open Label Arm)(Open Label Arm)


Open Label

Mean A1C = 11.2%

Sita 50 mg + MF 1000 mg b.i.d.


MF 1000 mg b.i.d.

MF 500 mg b.i.d.

Sita 100 mg q.d.

Placebo

A1C -2.9% change from baseline in APT analysisA1C -3.5% change from baseline in Completer’s Analysis

Resumen de los Eventos Adversos Clínicos Resumen de los Eventos Adversos Clínicos

Sitagliptina Similar a PlaceboSitagliptina Similar a Placebo

Pool de Pacientes en Fase III Placebo

(N=778)

Sitagliptina 100 mg

(N=1082)

Sitagliptina 200 mg

(N=456)

% de pacientes con % % %

Uno o más EA 55.5 55.0 54.2

EA Relacionados al medicamento 10.0 9.5 9.4

EA Serios 3.2 3.2 3.3

EA Serios relacionados al medicamento 0.1 0.3 0.0

Fallecimientos 0.0 0.0 0.0

Descontinuación debido a EA 1.9 2.6 0.9

Descontinuación debido a EA relacionado con el medicamento 0.8 0.6 0.0

Descontinación debido a EA serio 0.6 1.3 0.7

Descontinuación debido a EA serio relacionado con el medicamento 0.1 0.1 0.0

Dosis Recomendada: 100 mg/día

PlaceboSitagliptina 100

mg/díaSitaglitpina 200

mg/día

Pacientes con hipoglucemia (%) 0.9% 1.2% 0.9%

Sitagliptina disminuye A1C sin incrementar Sitagliptina disminuye A1C sin incrementar incidencia de Hipoglucemia / ganancia de incidencia de Hipoglucemia / ganancia de

pesopeso

• Efecto neutral– En monoterapia pequeño decremento del basal (~ 0.1 a 0.7 kg) con

sitagliptina; similar a placebo (~ 0.7 a 1.1 kg)

• En terapia combinada sin ninguna diferencia a placebo

Hipoglucemia

Cambio de peso

Estrategias Tratamiento en DM T2Estrategias Tratamiento en DM T2

Cambios al Estilo de Vida (Dieta y Ejercicio)

Metformin

Tratamiento Combinado

Insulina

A1c 6.0 % 7.0 % 8.0 % 9.0 % 10.0 % > 11.0%

Inhb. DPP-4SUsMeglitinidasTZDsInhb. -gluc.Insulina

Inhb. DPP-4SUsMeglitinidasTZDsInhb. -gluc.Insulina

IDF, ADA, EASD, ALAD, Canadian, NOM México

ConclusionesConclusiones

• Con base en un programa exhaustivo de estudios clínicos en pacientes con diabetes tipo 2 y control glucémico inadecuado, sitagliptina ya sea como:– Monoterapia, o– Terapia de adición

• Mejoró significativamente el control glucémico

• Indujo una mayor reducción de HbA1c en pacientes con HbA1c basal más alta

• Produjo reducciones estadística y clínicamente importantes en los parámetros glucémicos (HbA1c, GPA, Glucosa Plasmática Postprandial)

ConclusionesConclusiones

• Condujo a mejorías en los índices de secreción de insulina y de la función de las células beta

• Generalmente fue bien tolerada y no promovió el aumento de peso

• Exhibió un riesgo bajo de hipoglucemia (similar al placebo)

PrescripciónPrescripción

• Cuánto?• Dosis única diaria (100 mg)• Con o sin alimentos

• En quién?• Pacientes con diabetes tipo 2 con A1c mayor de

7% en cualquier etapa de la enfermedad• Monoterapia• Combinación (metformina, glitazonas)• Combinación con insulina – en investigación

• Amplio rango de edad (18 – 80)• Independiente de género o raza• Independiente de IMC

Dosificación en pacientes con Enf Renal Crónica

ERC en estadios tempranos (CrCl > de 50 ml/min y/o creatinina sérica menor de 1.7 mg/dl).

Dosis Recomendada: 100 mg al día

ERC estadio 3 (CrCl <50 a > 30 ml/min y/o creatinina sérica > 1.7 mg/dl).

Dosis Recomendada: 50 mg al día

ERC estadio 4 en adelante (CrCl < 30 ml/min y/o creatinina sérica > 3 mg/dl.

Dosis Recomendada: 25 mg al día.

Harvey L. Katzeff

Merck Research Laboratories Rahway, New Jersey, USA

An update on DPP-4 inhibitors in the management of Type 2 diabetes:

potential roles in monotherapy and combination therapy

Hyperglycaemia

Liver

GI tract

+

Pancreas

Muscle/fat

–

Carbohydrate

Absorption GlucoseProduction

InsulinSecretion

GlucoseUptake

InsulinSecretion

-Glucosidaseinhibitors

(–)

GlitazonesGlitazones

(+)(+)

Metformin (–)

SulfonylureasMeglitinides

(+)

Combining antihyperglycaemic agents: Combining antihyperglycaemic agents: major sites of actionmajor sites of action

InjectedInsulin

(–) (+)

GLP-1 analoguesGLP-1 analoguesDPP-4 inhibitorsDPP-4 inhibitors

Glucagon

GlucagonSecretion X

DDP-4=dipeptidyl-peptidase-4; GLP-1=glucagon-like peptide-1

DPP-4

Active GLP-1

Inactive GLP-1

Active GIP

Inactive GIP

• Increased insulin secretion• Decreased glucagon release

Glucose control improved

DPP-4 inhibitorΧ

Inhibition of DPP-4 increases active incretin Inhibition of DPP-4 increases active incretin levels, enhancing downstream incretin actionslevels, enhancing downstream incretin actions

GIP=glucose-dependent insulinotropic peptideGIP=glucose-dependent insulinotropic peptide

Sitagliptin OverviewSitagliptin Overview

• DPP-4 inhibitors for the treatment of patients with Type 2 diabetes: sitagliptin has recently been FDA approved

• Provide potent and highly selective inhibition of the DPP-4 enzyme

• No CYP or drug-drug interaction

• 85% excretion via the urine

N

ONH2

NN

CF3

F

F

F

N

Clinical Pharmacology of JANUVIA™ (sitagliptin Clinical Pharmacology of JANUVIA™ (sitagliptin phosphate): Pharmacokineticsphosphate): Pharmacokinetics

Pharmacokinetics

Tmax (median): 1 to 4 hours postdose

Apparent t½ (mean): 12.4 hours

Absolute bioavailability: approximately 87% High-fat meal had no effect on pharmacokinetics;

JANUVIA can be administered with or without food

Metabolism: approximately 79% excreted unchanged in urine

Drug Interactions and PharmacokineticsDrug Interactions and Pharmacokinetics

Sitagliptin:• No known clinically meaningful drug interactions

• Did not have clinically meaningful effects on the pharmacokinetics of metformin, simvastatin, rosiglitazone, warfarin, glyburide, and oral contraceptives

• Based on in vitro data, sitagliptin does not inhibit CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6 or induce CYP3A4

• Based on in vivo assessment, sitagliptin has a low propensity for causing drug interactions with substrates of CYP3A4, 2C8, and 2C9

• Digoxin: No dosage adjustment of digoxin or of JANUVIA™ (sitagliptin phosphate) is recommended

Dipeptidyl peptidase 9 (DPP-9)


Fibroblast activation protein a (FAP) (seprase)



Prolyl endopeptidase (PEP)

Quiescent cell prolyl peptidase (DPP7, DPP-11)/DPP-11

Aminopeptidase P (APP)

Prolidase

DPP-4 Gene

Family

Other Proline Specific Peptidases

DPP-4 Is a Member of a DPP-4 Is a Member of a Family of Proline Specific PeptidasesFamily of Proline Specific Peptidases

Selectivity of oral DPP-4 enzyme inhibitorsSelectivity of oral DPP-4 enzyme inhibitors

Herman et al. ADA. 2004

Enzyme Sitagliptin IC50 (nM) Vildagliptin IC50 (nM)

DPP-4 18 120

DPP-8 48,000 9000

DPP-9 >100,000 –

DPP-2, DPP-7 >100,000 >100,000

FAP >100,000 –

PEP >100,000 –

APP >100,000 –

Selective DPP-4 Inhibitors Are Not Associated WithSelective DPP-4 Inhibitors Are Not Associated With

Preclinical Toxicities Observed With Non-Selective InhibitorsPreclinical Toxicities Observed With Non-Selective Inhibitors

–++Decreased Proliferation

Study of T-Cell Proliferation1

2-Week Rat Toxicity Study2

–++Bloody diarrhea

Acute Dog Toxicity Study2

–++Mortality

–++Enlarged spleen

–++Anemia

–++Thrombocytopenia

–++Alopecia

Sitagliptin – highly selective DPP-4 inhibitor

Selective DPP-8/9

inhibitor

Nonselective inhibitor

(DPP-8/9 and DPP-4)

1. Leiting B et al. Abstract 6-OR. 64th ADA;2004. 2. Lankas GK et al. Diabetes. 2005;54:2988–2994.

Herman et al. Diabetes. 2005

Active GLP-1

A single dose of sitagliptin increased A single dose of sitagliptin increased active GLP-1 and GIP over 24 hoursactive GLP-1 and GIP over 24 hours

Crossover Study in Patients With Type 2 Diabetes Placebo

Sitagliptin 25 mg

Sitagliptin 200 mg

Active GIP

0

10

20

30

40

50

60

70

80

90

0 2 4 6 24 26 28

Hours postdose

GIP

(p

g/m

l)

OGTT 24 hrs (n=19)

OGTT 2 hrs (n=55)

2-fold increase in active GIP

P<0.001 vs placebo

OGTT 24 hrs (n=19)

0

5

10

15

20

25

30

35

40

0 2 4 6 24 26 28

Hours postdose

GL

P-1

(p

g/m

l)

OGTT 2 hrs (n=55)

2-fold increase in active GLP-1

P<0.001 vs placebo

Sitagliptin increased insulin, decreased glucagon, and Sitagliptin increased insulin, decreased glucagon, and reduced glycaemic excursion after a glucose loadreduced glycaemic excursion after a glucose load

Placebo

Sitagliptin 25 mg

Sitagliptin 200 mg

Crossover Study in Patients With Type 2 Diabetes

0

10

20

30

40

0 1 2 3 4

mcI

U/m

l

Glucoseload

Drug dose

Insulin

P<0.05 for both dose comparisons to placebo for AUC

22%

~12%

50

55

60

65

70

75

0 1 2 3 4Time (hours)

pg

/ml

Glucagon


Glucoseload

Drug dose

120

160

200

240

280

320

0 1 2 3 4 5 6

Time (hours)

Glucose


~26%

mm

ol/

l

Stein. ADA. 2006. Late-breaking clinical presentation

Monotherapy Studies – Design and Monotherapy Studies – Design and PatientsPatients

• 3 randomized, double-blind, studies in patients with T2DM – 1 study in Japan: 12 wk treatment period– 2 multinational studies: 18-, 24-wk treatment periods

• General design features– Both patients on OHA and not on treatment with an OHA eligible– A1C criteria multinational studies: 7-10%, in Japanese study: 6.5-

10%– Treatment groups

• Multinational studies: placebo, sitagliptin 100 mg q.d. or 200 mg q.d.

• Japanese study: placebo or 100 mg q.d.

ScreeningPeriod

Single-blindplacebo

Double-blind Treatment Period

Diet/exercise run-in period

Eligible if A1C 6.5 or 7 to 10%

If on an OHA, D/C’ed

Week - 2 Day 1Randomization

Monotherapy Studies – Patients StudiedMonotherapy Studies – Patients Studied

• Multinational studies

– Mean duration of T2DM of 4.4 years

– Baseline mean A1C - 8.0%

• 54% of patients had A1C < 8%

– 53% prior OHA, mean BMI 31 kg/m2, mean age 54 years, 55% male

• Japanese study

– Mean duration of T2DM of ~ 4 years

– Baseline mean A1C 7.6%

• ~ 65% had A1C < 8%

– ~ 45% on prior OHA, mean BMI 25 kg/m2, mean age 55 years, 60% male

Sitagliptin Consistently and Significantly Lowers Sitagliptin Consistently and Significantly Lowers

A1C with Once-Daily Dosing in MonotherapyA1C with Once-Daily Dosing in Monotherapy

Raz I et al; PN023; Aschner P et al. PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006

7.2

7.6

8.0

8.4

Placebo (n=244)


24-week Study

Time (weeks)

0 5 10 15 20 25

-0.79%(p<0.001)

*between group difference in LS means

Japanese Study

-1.05%(p<0.001)

Placebo (n=75)


Time (weeks)

0 4 8 12

A1C

(%

)

7.6

8.0

8.4

7.2

6.8

change vs placebo*

18-week Study

Placebo (n=74)


Time (weeks)

0 6 12 18

A1C

(%

)

7.2

7.6

8.0

8.4

-0.6%(p<0.001)

A1C

(%

)

=

Sitagliptin improved both fasting and post-meal Sitagliptin improved both fasting and post-meal glucose in monotherapy vs placeboglucose in monotherapy vs placebo

*Least-squares (LS) mean difference from placebo after 24 weeks Aschner et al. ADA. 2006. Abstract 1995-PO

Fasting Glucose

Pla

sma g

luco

se (

mg

/dl)

Time (weeks)

0 5 10 15 20 25144

153

162

171

180

189


FPG* = -17.1 mg/dl (P<0.001)

Post-meal Glucose

Time (minutes)

Pla

sma

gluc

ose

(mg

/dl)

in 2-hr PPG* = -46.7 mg/dl (P<0.001)

0 60 120 0 60 120

144

180

216

252

288

Placebo (N=204) Sitagliptin (n=201)

Baseline24 weeks

Baseline24 weeks

24-Week Study

-0.57

-0.8

-1.52-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

18-Week Study

-0.44

-0.61

-1.2

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

DPP-4 inhibitors provide progressively greater reductionsDPP-4 inhibitors provide progressively greater reductions in HbA in HbA1c1c with progressively higher baseline HbA with progressively higher baseline HbA1c1c

Reductions are placebo-subtractedRaz et al. ADA. 2006. Abstract 1996-PO; Aschner et al. ADA. 2006. Abstract 1995-PO

Baseline HbA1c (%)

Mean (%)

Red

uct

ion

in H

bA

1c (%

)

Inclusion Criteria: 7%–10%

Red

uct

ion

in H

bA

1c (

%)

<8% 8%–9% 9%

7.37 8.40 9.48

<8% 8%–9% 9%

7.39 8.36 9.58

N=96

N=70

N=27

N=130

N=62

N=37

Sitagliptin improved the Sitagliptin improved the ββ-cell response -cell response to glucose: monotherapy studies to glucose: monotherapy studies

200

400

600

800

1000

1200

1400

160 180 200 220 240 260

Glucose concentration (mg/dl)

Ins

uli

n s

ec

reti

on

(p

mo

l/m

in)

Pooled Monotherapy Studies – Subset of Patients With Frequently Sampled MTTModel-based assessment of β-cell function

MTT=meal tolerance testΦs=static component; describes relationship between glucose concentration and insulin secretion Stein. ADA. 2006. Late-breaking clinical presentation

Baseline

End-Treatment

Baseline

End-Treatment

Sitagliptin 100 mg QD Placebo

Sitagliptin improved markers of Sitagliptin improved markers of ββ-cell function:-cell function: 24-week monotherapy study 24-week monotherapy study

Proinsulin/insulin ratio

Aschner et al. ADA. 2006. Abstract 1995-PO

0.3

0.35

0.4

0.45

0.5

0.55

P<0.001*

*P value for change from baseline compared with placebo

Hatched=BaselineSolid=Week 24

∆ from baseline vs pbo=0.078(95% CI: -0.114, -0.023)


Rat

io (

pm

ol/

l/p

mo

l/l)

30

35

40

45

50

55

60

65

70

75

80

P<0.001*

∆ from baseline vs pbo=13.2 (95% CI: 3.9, 21.9)


HOMA-β

Combination Studies for Combination Studies for Sitagliptin - OverviewSitagliptin - Overview

Design

• 2 multinational studies of add-on use in patients failing monotherapy– Add-on to metformin (> 1500 mg/day)

– Add-on to pioglitazone (30 or 45 mg/day)

Patient population

• Mean age 55 years, ~55% male

• Mean duration of T2DM 6 years, baseline mean A1C = ~8.0%

Rosenstock J et al. PN019. Hashomer T et al. PN020. Abstracts presented at: ADA2006

ScreeningPeriod

Single-blindplacebo

Double-blind Treatment Period:

Placebo or Sitagliptin 100 mg q.d.

Monotherapy Run-In Period

Week -2:Eligible if A1C

7 to 10%

Patients started on regimen of

monotherapyDay 1

Randomization

Monotherapy with metformin or with pioglitazone

Sitagliptin once daily lowered HbASitagliptin once daily lowered HbA1c1c

when added to metformin or pioglitazonewhen added to metformin or pioglitazone

*Placebo-subtracted difference in LS meansRosenstock et al. ADA. 2006. Abstract 556-P; Karasik et al. ADA. 2006. Abstract 501-P

in HbA1c vs Pbo* = -0.65% (P<0.001) in HbA1c vs Pbo* = -0.70% (P<0.001)

Add-on to Metformin Study

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24

Time (weeks)

Hb

A1c

(%)

Placebo (n=224)

Sitagliptin 100 mg (n=453)Placebo (n=174)


Add-on to Pioglitazone Study

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24

Time (weeks)

Hb

A1c

(%

)

Difference in 24-hour weighted LS mean glucose: -32.8 mg/dl(-1.82 mmol/l), P<0.001

Stein. ADA. 2006. Late-breaking clinical presentation; adapted from Brazg et al. ADA. 2005.Abstract 11-OR

Sitagliptin added to metformin improvedSitagliptin added to metformin improved

24-hour glucose profile in Type 2 diabetes 24-hour glucose profile in Type 2 diabetesG

luco

se (

mg/

dl)

8:00 Day 1

13:00 19:00 0:00Day 2

7:30

100

120

140

160

180

240

200

220

Dose 17:30

Dose 218:30

Breakfast Lunch Dinner

Placebo + metformin (n=13)

Sitagliptin 50 mg BID + metformin (n=15)

Time

Placebo + pioglitazone (n=174)Sitagliptin 100 mg QD + pioglitazone (n=163)

Sitagliptin added to ongoing metforminSitagliptin added to ongoing metformin or pioglitazone: change in body weight over time or pioglitazone: change in body weight over time

LS

mea

n c

han

ge

fro

m b

asel

ine

bo

dy

wei

gh

t (k

g)

Placebo + metformin (n=169)Sitagliptin 100 mg QD + metformin(n=399)

0.0

-0.4

-0.6

-0.8

-0.2

0 12 24

Time (weeks)

-1.0

Karasik et al. ADA. 2006. Abstract 020. Rosenstock et al. ADA. 2006 Abstract 019

0.0

0.5

1.0

1.5

2.0

-0.5

-1.0

0 6 12 18 24

Time (weeks)

0

10

20

30

40

50

0

10

20

30

40

50

Sitagliptin Once Daily Significantly Increases Proportion of Sitagliptin Once Daily Significantly Increases Proportion of Patients Achieving Goal in Mono- or Combination TherapyPatients Achieving Goal in Mono- or Combination Therapy

0

10

20

30

40

50

SitagliptinPlacebo

Monotherapy Study Add-On to Metformin Study

Add-On to TZD Study

Perc

en

tage

Perc

en

tage

Perc

en

tage

P<0.001

P<0.001P<0.00

1

17%

41%

18%

47%

23%

45%

Aschner P et al. PN021. Rosenstock J et al. PN019. Hashomer T et al. PN020. ADA2006

Goal A1C < 7%

Active-Comparator (Glipizide) Controlled Add-on to Active-Comparator (Glipizide) Controlled Add-on to Metformin Study – Design and PatientsMetformin Study – Design and Patients

Design

• Patients with T2DM (on monotherapy or combination OHA) ➜ started/continued on metformin monotherapy (at least 1500 mg/d) during run-in period, randomized if A1C 6.5–10% after run-in period

Patient population

• 1172 randomized patients, mean age 57 years, ~60% male

• Mean duration of T2DM 6 years, baseline mean A1C = 7.5%

ScreeningPeriod

Single-blindplacebo

Double-blind Treatment Period:

Glipizide or Sitagliptin 100 mg q.d.

Metformin monotherapy Run-In Period

Week -2:eligible if A1C

6.5 to 10%

Continue/startregimen of met

monotherapy

Day 1Randomization

monotherapy with metformin (stable dose > 1500 mg/d)

Week 52

Glipizide: 5 mg qd increased to 10 mg bid (held if FS < 110 mg/dL or hypoglycemia)

Sitagliptin once daily showed similar glycaemic Sitagliptin once daily showed similar glycaemic efficacy to glipizide when addedefficacy to glipizide when added

to metformin (52 weeks) to metformin (52 weeks)

Sitagliptin 100 mg QD (n=382)

Glipizide (n=411)

Mea

n c

han

ge

in H

bA

1c Mean change from baseline (for both groups)*: 0.67%

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

0 12 24 38 52

Time (weeks)

*Per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysisStein. ADA. 2006. Late-breaking clinical presentation

Change in Body Weight

86

88

90

92

94

0 12 24 38 52

Time (weeks)

Bo

dy

we

igh

t (k

g)

Stein. ADA. 2006. Late-breaking clinical presentation

Sitagliptin once daily showed better safety Sitagliptin once daily showed better safety and tolerability profile comparedand tolerability profile compared

with glipizide (52 weeks) with glipizide (52 weeks)

Glipizide (n=584)Sitagliptin 100 mg (n=588)Sitagliptin 100 mg QD (n=382)

Glipizide (n=411)

between groups = -2.5 kg (P<0.001)

Hypoglycaemia

P<0.001

32%

4.9%

0

10

20

30

40

50

Week 52

Inci

den

ce

(%)

Progressively Greater Reductions in A1C Progressively Greater Reductions in A1C as Baseline A1C Risesas Baseline A1C Rises

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

<7% 7-<8% 8<9% > 9%

Baseline A1C CategoryStudy

inclusion criteria 6.5-

10%

Change from

baseline in A1C

(%)

Sitagliptin 100 mg q.d.

Glipizide

N=112

N=167

N=82

N=21

N=117

N=179

N=82

N=33

Per Protocol Population

Sitagliptin + metformin factorial study design Sitagliptin + metformin factorial study design

N=1091 randomized

Mean baseline HbA1c=8.8%

ScreeningPeriod

Single-blindPlacebo Double-blind Treatment Period

Diet/Exercise Run-in Period

Eligible if HbA1c

7.5% to 11%

If on an OHA, D/C’ed

Week 2 Day 1

Sitagliptin 50/Met 1000 BID

Placebo

Sitagliptin 100 mg QD

Metformin 500 BID

Metformin 1000 BID


Week 24

Duration up to 12 weeks based on prior therapy

Open-Label Cohort


RANDOMIZATION

Aschner et al. EASD. 2006

Initial Combinations of Sitagliptin + Metformin Initial Combinations of Sitagliptin + Metformin Produced Substantial Additive Improvements in A1CProduced Substantial Additive Improvements in A1C

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

LS

Mea

n A

1C C

hang

efr

om B

asel

ine

(%)



MF 1000 mg b.i.d.

MF 500 mg b.i.d.

Sita 100 mg q.d.

Placebo


Open Label

Mean A1C = 11.2%

Metabolic effects of DPP-4 inhibitorsMetabolic effects of DPP-4 inhibitors

• Small decrease in VLDL with corresponding increase in HDL

– No change in LDL

• Small decrements in blood pressure

• Small decrease in high-sensitivity C-reactive protein

• Animal models may reveal improvement in β-cell mass

– Studies in humans have not yet been performed to validate these findings

Safety and Tolerability Overview Safety and Tolerability Overview

• Well tolerated in Phase I through III trials – in completed and ongoing studies more than 4000 patients on sitagliptin (to doses of 200 mg q.d. in Phase III studies)

• Pre-specified Pooled Phase III analysis, including monotherapy and combination studies: over 1500 patients on sitagliptin and over 750 patients on placebo

– Summary measures of adverse experiences (AEs) were similar to placebo

• Including overall clinical AEs, serious AEs, discontinuations due to AEs, drug-related AEs, laboratory AE summary measures

– Small differences in incidence of specific AEs

• Between group difference (sitagliptin 100 mg – placebo group) in incidence > 1% for only 1 specific AE (nasopharyngitis 1.2% difference)

Summary Measures of Clinical Adverse Events for Summary Measures of Clinical Adverse Events for Sitagliptin is Similar to PlaceboSitagliptin is Similar to Placebo

Pooled Phase III Population Placebo

(N=778)

Sitagliptin 100 mg

(N=1082)

Sitagliptin 200 mg

(N=456)

% of Patients with % % %One or more AEs 55.5 55.0 54.2

Drug-related AEs 10.0 9.5 9.4

Serious AEs 3.2 3.2 3.3

Drug-related SAEs 0.1 0.3 0.0

Deaths 0.0 0.0 0.0

Discontinued due to AE 1.9 2.6 0.9

Discontinued due to drug-related AE 0.8 0.6 0.0

Discontinued due to SAE 0.6 1.3 0.7

Discontinued due to drug-related SAE 0.1 0.1 0.0

Recommended dose in proposed label: 100 mg q.d.

Only Small Differences in Incidence of AEs: Only Small Differences in Incidence of AEs:

Pooled Phase III Population Pooled Phase III Population

Placebo (N = 778)

Sitagliptin 100 mg (N = 1082)

% % Difference vs Pbo

(95% CI)

Upper Respiratory Tract Infection

6.7 6.8 0.1 (-2.3, 2.4)

Headache

3.6 3.6 0

Nasopharyngitis

3.3 4.5 1.2 (-0.7, 3.0)

Diarrhea 2.3 3.0 0.7 (-0.9, 2.2)

Arthralgia

1.8 2.1 0.3 (-1.1, 1.6)

Urinary Tract Infection

1.7 1.7 0

Recommended dose in proposed label: 100 mg q.d.

AEs with at least 3% incidence and Numerically Higher in Sitagliptin than Placebo Group

Sitagliptin Lowers A1C Without Increasing the Incidence Sitagliptin Lowers A1C Without Increasing the Incidence

of Hypoglycemia or Leading to Weight Gainof Hypoglycemia or Leading to Weight Gain

PlaceboSitagliptin 100

mg q.d.Sitaglitpin 200

mg q.d.

Patients with hypoglycemia (%) 0.9% 1.2% 0.9%

• Neutral effect on body weight– In monotherapy studies, small decreases from baseline

(~ 0.1 to 0.7 kg) with sitagliptin; slightly greater reductions with placebo (~ 0.7 to 1.1 kg)

– In combination studies, weight changes with sitagliptin similar to placebo-treated patients

Pooled Phase III Population Analysis: no statistically significant difference in incidence for either dose vs placebo

Hypoglycemia

Weight Changes

Patients With Renal InsufficiencyPatients With Renal Insufficiency

Renal Insufficiency

Mild ModerateSevere and

ESRD*

Increase in Plasma AUC of

Sitagliptin†

~1.1 to 1.6-fold increase‡

~2-fold increase

~4-fold increase

Recommended Dose

100 mg no dose

adjustment required

50 mg 25 mg

To achieve plasma concentrations similar to patients with normal renal function, lower doses of JANUVIA™ (sitagliptin phosphate)

are recommended in moderate and severe renal insufficiency.

ESRD=end-stage renal disease; AUC=area under the curve.*Includes patients on hemodialysis or peritoneal dialysis†Compared with normal healthy control subjects‡Not clinically relevant

Sitagliptin AUC Sitagliptin AUC 0-inf0-inf vs. creatinine clearance: AUC vs. creatinine clearance: AUC

increased with decreasing creatinine clearanceincreased with decreasing creatinine clearance

AUC GMR increase < 2-foldwhen CrCl > 50 mL/min

Dose adjustments< 30 mL/min – ¼ dose30 – 50 mL/min – ½ dose> 50 mL/min – full dose

Do

se-A

dju

ste

d (

to 5

0 m

g)

AU

C (

uM

.hr)

0

4

8

12

16

20

24

28

Creatinine Clearance (mL/min)10 30 50 70 90 110 130 150 170 190 210 230

Dose Adjustment Study for JANUVIA™ (sitagliptin phosphate)Dose Adjustment Study for JANUVIA™ (sitagliptin phosphate)in Patients With Renal Insufficiencyin Patients With Renal Insufficiency

• Study design– 12-week, multinational, randomized, double-blind, placebo-

controlled– 91 patients with renal insufficiency (CrCl <50 mg/dL)– Dosing based on level of renal insufficiency

• 50 mg JANUVIA daily for moderate renal insufficiency• 25 mg JANUVIA daily for severe renal insufficiency or

ESRD on dialysis

• Conclusions– Safety and tolerability generally similar to placebo– Small mean increases in serum creatinine

(0.12 mg/dL JANUVIA; 0.07 placebo; [0.05 difference]) were observed in patients with moderate renal insufficiency

– Reductions in A1C and FPG with JANUVIA generally similar to those observed in the monotherapy trials

CrCl=creatinine clearance.

Dosage and AdministrationDosage and AdministrationUsual Dosing for JANUVIA™ (sitagliptin phosphate)*

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a

PPAR agonist.

Patients With Renal Insufficiency*†

50 mg once daily 25 mg once daily

Moderate Severe and ESRD‡

CrCl 30 to <50 mL/min(~Serum Cr levels [mg/dL]

Men: >1.7–≤3.0; Women: >1.5–≤2.5)

CrCl <30 mL/min(~Serum Cr levels [mg/dL]Men: >3.0; Women: >2.5)

*JANUVIA can be taken with or without food. †Patients with mild renal insufficiency—100 mg once daily.‡ESRD = end-stage renal disease requiring hemodialysis or peritoneal dialysis.

Assessment of renal function is recommended prior to initiationof JANUVIA and periodically thereafter.

SummarySummary• Sitagliptin is a potent and selective DPP-4 inhibitor administered

once-daily for the for the treatment of T2DM

Once-daily regimen of sitagliptin provides

– Significant reductions in A1C across a range of starting A1C levels in monotherapy and combination use

– Sustained A1C reduction to 1 year

– Improvements in multiple measures of beta-cell function

• Compared to a sulfonylurea agent, sitagliptin provides

– Similar efficacy

– Superior improvements in beta-cell function, less hypoglycemia, and weight loss (vs weight gain)

• Able to be used in renal insufficiency patients with dose reduction

• Sitagliptin was well tolerated with summary measures of AEs similar to placebo

Health & Medicine

PresentacióN Dr. Ketzeff