1. Nuevas estrategias en el manejo de la diabetes mellitus tipo 2 El efecto incretina Argemiro Fragozo MD Internista Endocrinólogo Coordinador Cátedra Medicina Interna Profesor Asistente de Medicina U. El Bosque - Bogotá

2. Wild S et al. Diabetes Care 27:1047-1053, 2004 WHO-IDF, 2004 Los diez países lideres son: India China USA Indonesia Japan Pakistan Russia Brazil Italy Bangladesh Las Americas 2000: 33 millones 2030: 66.8 millones Africa 2000: 7 2030: 18.2 millones millones Europa 2000: 33.3 2030: 48 millones millones Oriente 2000: 15.2 2030: 42.6 Medio millones millones Asia y Australia 2000: 82.7 2030: 190.5 millones millones Prevalencia de diabetes (%) en personas 35-64 años PREVALENCIA DE DIABETES 2000 = Número de personas con diabetes en el 2000 2030 = Número de personas con diabetes en el 2030 < 3 3 -5 6 - 8 > 8 Año Categoría 1 2 3 India China Estados Unidos de America 31.7 20.8 17.7 79.4 42.3 30.3 País Personas con diabetes (millones) 2000 2030

3. La diabetes es una enfermedad vascular Retinopatía diabética ~ 50% La causa principal de ceguera en adultos en edad laboral 1 Nefropatía diabética ~ 35% La causa principal de enfermedad renal terminal 2 Enfermedad cardiovascular ~ 45% Accidente cerebrovascular Incremento de 2 a 4 veces en la mortalidad cardiovascular y accidente cerebrovascular 3 Neuropatía diabética ~ 40% La causa principal de amputaciones no traumáticas de las extremidades inferiores 5 8/10 pacientes diabéticos fallecen por eventos CV 4 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. 5 Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79. Decision Resources., Inc.1999.

5. 65% de los diab é ticos no alcanzan los objetivos de HbA 1c Saydah SH, et al. JAMA 2004; 291:335–342. Liebl A, et al. Diabetologia 2002; 45:S23–S28.

6. Guías de manejo de la diabetes: HbA 1c ADA (US) 1 HbA 1c < 7% IDF (Europe) 3 HbA 1c  6.5% CDA (Canada) 4 HbA 1c  7% NICE (UK) 5 HbA 1c 6.5–7.5% AACE (US) 2 HbA 1c  6.5% ALAD (Latin America) 6 HbA 1c < 6 – 7% APPG (Asia Pacific) 7 HbA 1c < 6.5% Australia 8 HbA 1c  7% 1 American Diabetes Association. Diabetes Care 2004; 27 (Suppl. 1):S15–S34. 2 American Association of Clinical Endocrinologists. Endocr Pract 2002; 8 (Suppl. 1):40–82. 3 European Diabetes Policy Group. Diabet Med 1999; 16:716–730. 4 Canadian Diabetes Association. Can J Diabetes 2003; 27 (Suppl. 2):S1–S152. 5 National Institute for Clinical Excellence. 2002. Available at: http://www.nice.org.uk. 6 ALAD. Rev Asoc Lat Diab 2000; Suppl. 1. 7 Asian-Pacific Policy Group. Practical Targets and Treatments (3rd Edition). 8 NSW Health Department. 1996.

7. Historia Natural de la DM Tipo 2 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 15 20 25 30 10 5 0 – 5 – 10 At risk for diabetes  -cell failure Insulin level Fasting glucose Insulin resistance PPG Glucose (mg/dL) Relative  -Cell Function (%) Diabetes (yr) 350 300 250 200 100 200 100 0 150 50 250 150 50

8. EMBS = Tamaño corporal metabólico estimado Weyer C et al J Clin Invest 1999;104:787–794. Acción de Insulina (mg/kg EMBS por min) Secreción Insulina (µU/ml) TGN TGN Diabetes Respuesta de célula β Sensibilidad a insulina TGA 0 100 200 300 400 500 0 1 2 3 4 5 Progresión a Diabetes: Falla de la Célula β en Compensación a la Insulino Resistencia TGN TGN

9. Años desde el diagnóstico Adapted from Levy J et al Diabet Med 1998;15:290–296. 0 40 60 HOMA (%) 20 0 0 40 60 80 HOMA ( %) 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 Beta Mientras se Mantiene la Resistencia a la Insulina HOMA%: Expresado como % de los valores en jovenes, magros y sanos

11. Insulina y Glucagón en Respuesta a las Comidas en Diabetes Tipo 2 -60 0 60 120 180 240 360 330 300 270 240 110 80 120 90 60 30 0 Glucose (mg %) Insulin ( µ U/mL) Glucagon (pg/mL) Meal Time (min) Delayed/depressed insulin response Nonsuppressed glucagon Normal subjects, n=11; Type 2 diabetes, n=12. Adapted from M ü ller WA et al. N Engl J Med . 1970;283:109–115. 140 130 120 110 100 90 Type 2 diabetes Normal subjects

12. Proporción de pacientes con A1c <7% con monoterapia UKPDS 49. JAMA 1999; 281: 2005-2012. 1 0 0 Y e a r s f r o m r a n d o m i s a t i o n 3 6 9 0 2 0 4 0 6 0 8 0 3 6 9 3 6 9 3 6 9 D i e t I n s u l i n M e t f o r m i n S u l p h o n y l u r e a Overweight patients Proportion of patients (%) 50%

13. Regimen  HbA 1c  FBG Sulfonylurea + metformin ~1.7% ~65 mg/dL Sulfonylurea + acarbose ~1.3% ~45 mg/dL Repaglinide + metformin ~1.4% ~50 mg/dL Nateglinide + metformin ~1.4% ~50 mg/dL Metformin + Rosiglitazone ~1.2% ~40 mg/dL Pioglitazona+sulfonylurea ~1.3% ~45mg/dL Glib / Met (2.5/500) ~1.5% ~50 mg/dL Insulin open open DeFronzo, et al. N Engl J Med . 1995;333:541-549; Horton, et al. Diabetes Care . 1998;21:1462-1469; Coniff, et al. Diabetes Care . 1995;18:817-824; Moses, et al. Diabetes Care . 1999;22:119-124, Horton, et al. Diabetes Care 2000;23:1660-65, Fonseca, et al. JAMA 2000; 183:1695-1702. Takeda Pharmaceuticals America,Inc.Data on file. Terapia Combinada Control glicémico – Mejoras alcanzadas

15. . Adapted from Butler AE et al. Diabetes . 2003;52:102–110. Obesos Magros Obesos Magros Disminución del Volumen de Células β en DM2 50 100 150 200 250 ND GAA Diabetes Tipo 2 ND Diabetes Tipo 2 GPA (mg/dL) 0 1 2 3 4 ND IFG Diabetes Tipo 2 ND Diabetes Tipo 2 Volumen Célula β (%)

16. Fernando Botero “Picnic” 1997

17. *p  0.05 Adapted from Nauck M et al Diabetologia 1986;29:46–52. 0 – 10 10 15 20 Glucosa plasmática(mmol/L) 5 60 120 180 Tiempo(min) 0 40 60 80 Insulina (mU/L) 20 Controles Sanos Diabetes tipo 2 0 10 15 20 Glucosa plasmática (mmol/L) 5 Tiempo (min) 0 40 60 80 Insulina(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 Glucosa oral glucosa IV isoglicémica

20. GLP-1 Aumenta Proliferación e Inhibe Apoptosis de Células β en Ratas Zucker Diabéticas Study in Zucker diabetic rats that received a two-day infusion of GLP-1 followed by a glucose tolerance test Adapted from Farilla L et al Endocrinology 2002;143:4397–4408. Apoptosis Célula β 0 5 10 Control Tratamiento GLP-1 Apoptotic Células beta (%) 30 25 20 15 0 0.5 1.0 Control Tratamiento GLP-1 Células beta proliferadoras (%) 2.5 2.0 1.5 Proliferación Célula β Aumento 1,4 vece (p<0.05) Disminución 3,6 veces (p<0.001)

21. GLP-1 Preservó la Morfología de Islotes Humanos In Vitro Día 1 Células tratadas Con GLP-1 Control 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.

22. Ratón diabético Ratón 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. Verde : células beta productoras de insulina Rojo : células alfa productoras de glucagon Inhibidor de DPP-4 Restauró las Células β en Ratones Diabéticos Ratón magro control

25. Nauck MA, et al. Diabetologia 1993; 36:741-744 Data : Media ± E Es * P <0.05 25 20 15 10 5 0 Glucagon (pmol/L) Tiempo (min) -30 0 60 120 180 240 * * * * 17.5 15.0 12.5 10.0 7.5 5.0 2.5 0.0 * Glucosa (mmol/L) GLP-1/PBO infusion * * * * * * -30 0 60 120 180 240 350 300 250 200 150 100 50 0 Insulina (pmol/L) GLP-1/PBO infusion Tiempo (min) * * * * * * * * GLP-1/PBO infusion Tiempo (min) -30 0 60 120 180 240 Placebo GLP-1 Acciones de GLP-1 Glucosa Dependientes en Diabetes Tipo 2

26. 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) GLP-1 (pmol/L) * Niveles de GLP-1 disminuyen en Diabetes Tipo 2 p < 0,05 * * * * * *

27. 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. Insulina (nmol liter –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

28. *tasa baja=0.8 pmol kg –1 min –1 **tasa alta=2.4 pmol kg –1 min –1 Adapted from Nauck MA et al J Clin Invest 1993;91:301–307. TGN (n=9) diabetes tipo 2 (n=9) Insulina (nmol liter –1 min) 0 5 10 15 20 4 18 3 7.7 GIP infusión (tasa baja)* GIP infusión (tasa alta)** p=0.047 Acción de GIP Disminuye mas No Ausente en DM 2

29. Acciones GLP-1 Comida mixta GLP-1(7-36) Activo Plasma Liberación GLP-1 intestinal GLP-1(9-36) Inactivo DPP-IV Inactivación rápida (>80% del pool) Depuración Renal DPP-IV = dipeptidilpeptidasa-IV Deacon et al. Diabetes 1995; 44:1126 Secreción y Metabolismo de GLP-1

30. 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 - Novartis Saxagliptin - BMS

32. Estudio OGTT Una dosis Una Dosis de Sitagliptin Inhibió Actividad de DPP- 4 en Plasma 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. Inhibición de DPP-4 en relación al basal(%) 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% Inhibición valor más bajo 24 H Sitagliptin 25 mg Sitagliptin 200 mg Placebo N=56

34. Disminución ~8–14% con sitagliptin vs. placebo (p<0.015 para 25 mg, p<0.001 para 200 mg) 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. Glucagon Plasma (pg/ml) Hora 50 60 70 80 0 1 2 3 4 5 TGO Sitagliptin 25 mg Sitagliptin 200 mg Placebo N=56 Estudio OGTT una Dosis Una Dosis de Sitagliptin Suprimió Glucagon post Glucosa

35. Pancreatic sections from all the groups were stained with anti-insulin antibody or anti-glucagon antibody. Shown are images with the overlay of the insulin green and glucagon red staining. A. Insulin positive beta-cell:total islet area ratio B. and glucagon positive -cell:total islet area C were measured from these images. *p<0.003 vs. the diabetic control group, # p=0.011 vs. diabetic control, n = 40 islets in each group. ADA 2006 Diabetico control Des-F-sitaglipitn Glipizida No diabetico control Rosiglitazoa A. B. C. Diabetic control Des-F-sitagliptin Rosiglitazone Glipizide Nondiabetic control 0.0 0.1 0.2 0.3 0.4 0.5 * * C é lula α /area total islote 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 * * # C é lula β /area total islote Diabetic control Des-F-sitagliptin Rosiglitazone Glipizide Nondiabetic control Uso Crónico de Des-F-Sitagliptin Mejoró la Morfología de las Células α y β en Modelo de Ratas con DM2

40. Sitagliptin Produce Mayores Reducciones de A1c Mientras mas Alta sea A1c de Base Reducciones en relación a placebo Adapted from Raz I et al. PN023; Aschner P et al. PN021. Abstracts presented at: ADA2006 Baseline A 1c (%) Mean (%) Reduction in A 1c (%) Criterios inclusi ó n: 7% – 10% Reducci ó n A 1c (%) <8% 8 – 9% > 9% 7.37 8.40 9.48 <8% 8 – 9% > 9% 7.39 8.36 9.58 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 N=96 N=130 N=70 N=62 N=27 N=37

41. 200 400 600 800 1000 1200 1400 160 180 200 220 240 260 Concentración glucosa (mg/dL) Secreción insulina (pmol/min) Pool de estudios – Subgrupo de pacientes Basado Modelo de Bergman Función Célula Beta Basal Final tratamiento Basal Final tratamiento Sitagliptin 100 mg q.d Placebo Sitagliptin Mejora la Respuesta de la Célula β en Respuesta a Glucosa: Estudios en Monoterapia

42. 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 : Basal Solido = 24 semanas ∆ de Basal vs Placebo = 0.078 (95% CI -0.114, -0.023 Placebo Sitagliptin 100 mg Relaci ó n(pmol/L / pmol/L) Sitagliptin Mejora Marcadores de Función Célula β Estudio de Monoterapia 24 semanas 0,3 0,35 0,4 0,45 0,5 0,55 HOMA- β p< 0.001* ∆ de basal vs Placebo = 13.2 (95% CI 3.9, 21.9) Placebo Sitagliptin 100 mg

44. Sitagliptina una vez al día agregada a Metformina o 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 Placebo (n=174) Sitagliptin 100 mg (n=163)  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) Placebo (n=224) Sitagliptin 100 mg (n=453) Estudio Sita + Met 7.0 7.2 7.4 7.6 7.8 8.0 8.2 0 6 12 18 24 Semanas A1C (%)

45. Estudio de Tratamiento Adición a Metformina Sitagliptina + Metformina mejoró el perfil de glucosa de 24 horas vs. Metformina sola Diferencia entre tratamientos: –32.8 mg/dL (p<0.001)* *Diferencia de la media de los cuadrados mínimos en la glucosa promedio ponderada Glucosa (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 0:00 Día 2 7:30 100 120 140 160 180 240 200 220 Dosis 1 7:30 Dosis 2 18:30 Desayuno Comida Cena Período 1

46. Sitagliptin Agregado a Metformina Mejoró Perfil de Glucosa en 24 Horas en DM2 Adapted from Brazg RL et al. Poster presented: at American Diabetes Association; June 10–14, 2005; San Diego, Calif.

47. Rosenstock J et al. PN019. Hashomer T et al. PN020. Abstracts presented at: ADA2006  in A1C vs Pbo* = – 0.65% (p<0.001)  in A1C vs Pbo* = – 0.70% (p<0.001) Reducción Significativa de A1c al Adicionar Sitagliptin a Metformina o Pioglitazona Estudio Adicionando Metformina 7,0 7,2 7,4 7,6 7,8 8,0 8,2 0 6 12 18 24 Tiempo (semanas) A1C (%) Estudio Adicionando Pioglitazona 7,0 7,2 7,4 7,6 7,8 8,0 8,2 0 6 12 18 24 Tiempo (semanas) A1C (%) Placebo (n=224) Sitagliptin 100 mg (n=453) Placebo (n=174) Sitagliptin 100 mg (n=163)

48. Combinación de Vildagliptin+ Metformina Reducción Sostenida sobre A1c en un Año Semanas Tatamiento Ahren B et al.Diabetes Care 2004;27:2874-2880

49. *per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis Eficacia en A1c de Sitagliptin + Metformina Similar que con Glipizida+ Metformina

50. % A1C < 7% después de 52 semanas Poblaci ó nPer Protocol Metas Obtenidas con Sitagliptin en Combinación con Metformina vs Glipizida 20 30 40 50 60 70 80 Sitagliptin Glipizida

51. Criterios de inclusi ó n 6.5-10% Cambios del valor base de A1C (%) Sitagliptin 100 mg q.d. Glipizida N=112 N=167 N=82 N=21 N=117 N=179 N=82 N=33 Poblaci ó n per protocol Reducción de A1c según valor basal de A1c Valores de A1c basales

52. Sitagliptin una Vez por Día mas Metformina tiene Mayor Seguridad y Tolerabilidad Comparado con Glipizida (52 Sem)

56. Sitagliptina ocasiona significativa y progresivamente mayor disminución en A1c con mayor A1c basal. Reductions are placebo-subtracted Adapted from Raz I et al. PN023; Aschner P et al. PN021. Abstracts presented at: ADA2006 Basal A 1c (%) Mean (%) Reducci ó n en A1c A 1c (%) Criterio de inclusi ó n: 7% – 10% Reducci ó n en 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=130 N=70 N=62 N=27 N=37

57. Reducción de A1c: JANUVIA 100 mg/dia n=27 n=57 n=21 – 1.2 – 1.52 – 1.68 > 9% A 1c basal(%) > 9% > 9% Semana 18 Semana 24 Semana 52

59. Sitagliptina mejora respuesta de célula beta a glucosa en monoterapia. 200 400 600 800 1000 1200 1400 160 180 200 220 240 260 Concentración de glucosa (mg/dL) Secreción de insulina (pmol/min) Φ s = static component, describes relationship between glucose concentration and insulin secretion Basal Final de tratamiento Basal Final de tratamiento Sitagliptina100 mg q.d Placebo

60. Sitagliptina mejora marcadores de función célula beta a 24-semanas en monoterapia Aschner P et al. PN021; Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC. *P para el cambio desde el basal comparado a placebo Discontinuo = Basal Solido = Semana 24 Proinsulina/insulina p< 0.001* ∆ de basal vs pbo = 0.078 (95% CI -0.114, -0.023 Placebo Sitagliptina 100 mg Radio (pmol/L / pmol/L) HOMA- β p< 0.001* ∆ de basal vs pbo = 13.2 (95% CI 3.9, 21.9) Placebo Sitagliptina 100 mg

61. Adición de Sitagliptina a Metformina o Pioglitazona Terapia en pacientes con DM 2: Cambio en el peso corporal Cambio desde la basal en peso corporal (kg) 0.0 -0.4 -0.6 -0.8 -0.2 0 12 24 Semanas -1.0 Karasik A et al. Presented at: The 66th Scientific Session of the American Diabetes Association; June 11, 2006; Washington, D.C. Abstract 020. Rosenstock J et al. Presented at: The 66th Scientific Session of the American Diabetes Association; June 11, 2006; Washington, D.C. Abstract 019. Placebo + Met (n=169) Sita 100 mg qd = Met (n=399) 0.0 0.5 1.0 1.5 2.0 -0.5 -1.0 0 6 12 18 24 Semana Placebo + pioglitazona (n=174) Sita 100 mg qd + pioglitazona (n=163)

62. Sitagliptina una vez al día incrementa significativamente la cantidad de pacientes en meta con monoterapia o combinación Sitagliptina Placebo Con metformina. Porcentaje P <0.001 18% 47% Aschner P et al. PN021. Rosenstock J et al. PN019. Hashomer T et al. PN020. ADA2006 Con TZD Porcentaje P <0.001 23% 45% P <0.001 Monoterapia Porcentaje 17% 41% Meta A1C < 7%

64. Sitagliptina una vez al día muestra similar eficacia que Glipizida cuando se añade a metformina (52 Semanas) Mean Change in HbA 1c 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) *an á lisis por protocolo; -0.51% and -0.56% para sitagliptina y glipizida en LOCF analysis Sitagliptina 100 mg qd (n= 382 ) Glipizida (n=411)

65. Estudio de 52 semanas de Sitagliptina vs. Tx de adición de Glipizida a Metformina Reducciones progresivamente mayores en HbA1c con HbA1c basal progresivamente más alta Categor í a HbA 1C basal Criterios de inclusi ó n estudio 6.5% – 10% = Media (%) = Cambio respecto valor basal en HbA 1c (%) Sitagliptina 100 mg/d í a 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%

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

67. Proporcion de Pacientes en meta con Sitagliptina una vez al día + Metformina % A1C < 7% despues de 52 Semanas Per Protocol Population

69. Sitagliptina + Metformina Diseño factorial del estudio. N = 1091 Aleatorizados Basal media A1C = 8.8% Periodo de Screening Simple ciego Placebo 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

70. Combinación inicial de Sitagliptina y Metformina Producen una Marcada disminución en A1C -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 Label Sita 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

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

72. Alto numero de pacientes llegaron a la meta de A1C A1C <6.5% A1C <7.0% % to Goal 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

73. Aún grandes reducciones en A1C en altos valores basales (Open Label Arm) Open Label Sita 50 mg + MF 1000 mg b.i.d. Open Label Mean A1C = 11.2% Sita 50 mg + MF 1000 mg b.i.d. Sita 50 mg + MF 500 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 analysis A1C -3.5% change from baseline in Completer’s Analysis

75. Resumen de los Eventos Adversos Clínicos Sitagliptina Similar a Placebo Dosis Recomendada: 100 mg/d í a 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

77. Estrategias Tratamiento en DM T2 Inhb. DPP-4 SUs Meglitinidas TZDs Inhb.  -gluc. Insulina Inhb. DPP-4 SUs Meglitinidas TZDs Inhb.  -gluc. Insulina IDF, ADA, EASD, ALAD, Canadian, NOM México 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%

81. Dosificaci ó n en pacientes con Enf Renal Cr ó nica 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.

83. 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

84. Combining antihyperglycaemic agents: major sites of action Hyperglycaemia Liver GI tract + Pancreas Muscle/fat – Carbohydrate Absorption Glucose Production Insulin Secretion Glucose Uptake Insulin Secretion Injected Insulin GLP-1 analogues DPP-4 inhibitors DDP-4=dipeptidyl-peptidase-4; GLP-1=glucagon-like peptide-1  -Glucosidase inhibitors (–) Glitazones (+) Metformin (–) Sulfonylureas Meglitinides (+) (–) (+)  Glucagon Glucagon Secretion X

89. DPP-4 Is a Member of a Family of Proline Specific Peptidases Dipeptidyl peptidase 9 (DPP-9) Dipeptidyl peptidase 8 (DPP-8) Fibroblast activation protein a (FAP) (seprase) Dipeptidyl peptidase 4 (DPP-4) Dipeptidyl peptidase 6 (DPP-6) Prolyl endopeptidase (PEP) Quiescent cell prolyl peptidase (DPP7, DPP-11)/DPP-11 Aminopeptidase P (APP) Prolidase DPP-4 Gene Family Other Proline Specific Peptidases

90. Selectivity of oral DPP-4 enzyme inhibitors Herman et al. ADA. 2004 Enzyme Sitagliptin IC 50 (nM) Vildagliptin IC 50 (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 –

91. Selective DPP-4 Inhibitors Are Not Associated With Preclinical Toxicities Observed With Non-Selective Inhibitors – + + Decreased Proliferation Study of T-Cell Proliferation 1 2-Week Rat Toxicity Study 2 – + + Bloody diarrhea Acute Dog Toxicity Study 2 – + + 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. 64 th ADA;2004. 2. Lankas GK et al. Diabetes. 2005;54:2988 – 2994.

92. A single dose of sitagliptin increased active GLP-1 and GIP over 24 hours Herman et al. Diabetes . 2005 Active GLP-1 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 (pg/ml) 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 GLP-1 (pg/ml) OGTT 2 hrs (n=55) 2-fold increase in active GLP-1 P <0.001 vs placebo

93. Sitagliptin increased insulin, decreased glucagon, and reduced glycaemic excursion after a glucose load Crossover Study in Patients With Type 2 Diabetes ~12% Stein. ADA. 2006. Late-breaking clinical presentation Placebo Sitagliptin 25 mg Sitagliptin 200 mg 0 10 20 30 40 0 1 2 3 4 mcIU/ml Glucose load Drug dose Insulin P <0.05 for both dose comparisons to placebo for AUC 22% 50 55 60 65 70 75 0 1 2 3 4 Time (hours) pg/ml Glucagon P <0.05 for both dose comparisons to placebo for AUC Glucose load Drug dose 120 160 200 240 280 320 0 1 2 3 4 5 6 Time (hours) Glucose P <0.001 for both dose comparisons to placebo for AUC ~26% mmol/l

98. DPP-4 inhibitors provide progressively greater reductions in HbA 1c with progressively higher baseline HbA 1c Reductions are placebo-subtracted Raz et al. ADA . 2006. Abstract 1996-PO; Aschner et al. ADA. 2006. Abstract 1995-PO Baseline HbA 1c (%) Mean (%) Reduction in HbA 1c (%) Inclusion Criteria: 7%–10% Reduction in HbA 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

99. Sitagliptin improved the β -cell response to glucose: monotherapy studies 200 400 600 800 1000 1200 1400 160 180 200 220 240 260 Glucose concentration (mg/dl) Insulin secretion (pmol/min) Pooled Monotherapy Studies – Subset of Patients With Frequently Sampled MTT Model-based assessment of β -cell function MTT=meal tolerance test Φ s=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

100. Sitagliptin improved markers of β -cell function: 24-week monotherapy study Proinsulin/insulin ratio Aschner et al. ADA. 2006. Abstract 1995-PO P <0.001* * P value for change from baseline compared with placebo Hatched=Baseline Solid=Week 24 ∆ from baseline vs pbo = 0.078 (95% CI: -0.114, -0.023) Placebo Sitagliptin 100 mg Ratio (pmol/l/pmol/l) P <0.001* ∆ from baseline vs pbo = 13.2 (95% CI: 3.9, 21.9) Placebo Sitagliptin 100 mg HOMA- β

102. Sitagliptin once daily lowered HbA 1c when added to metformin or pioglitazone *Placebo-subtracted difference in LS means Rosenstock et al. ADA. 2006. Abstract 556-P; Karasik et al. ADA. 2006. Abstract 501-P  in HbA 1c vs Pbo* = -0.65% ( P <0.001)  in HbA 1c vs Pbo* = -0.70% ( P <0.001) Placebo (n=224) Sitagliptin 100 mg (n=453) Placebo (n=174) Sitagliptin 100 mg (n=163)

103. Sitagliptin added to metformin improved 24-hour glucose profile in Type 2 diabetes 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 Glucose (mg/dl) 8:00 Day 1 13:00 19:00 0:00 Day 2 7:30 100 120 140 160 180 240 200 220 Dose 1 7:30 Dose 2 18:30 Breakfast Lunch Dinner Placebo + metformin (n=13) Sitagliptin 50 mg BID + metformin (n=15) Time

104. Sitagliptin added to ongoing metformin or pioglitazone: change in body weight over time Placebo + pioglitazone (n=174) Sitagliptin 100 mg QD + pioglitazone (n=163) LS mean change from baseline body weight (kg) 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 6 12 18 24 Time (weeks) Placebo + metformin (n=169) Sitagliptin 100 mg QD + metformin (n=399) 0.0 0.5 1.0 1.5 2.0 -0.5 -1.0

105. Sitagliptin Once Daily Significantly Increases Proportion of Patients Achieving Goal in Mono- or Combination Therapy Sitagliptin Placebo Monotherapy Study Add-On to Metformin Study Add-On to TZD Study Percentage Percentage Percentage P <0.001 P <0.001 P <0.001 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%

107. Sitagliptin once daily showed similar glycaemic efficacy to glipizide when added to metformin (52 weeks) Mean change in HbA 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 analysis Stein. ADA. 2006. Late-breaking clinical presentation Sitagliptin 100 mg QD (n=382) Glipizide (n=411)

108. Sitagliptin once daily showed better safety and tolerability profile compared with glipizide (52 weeks) Stein. ADA. 2006. Late-breaking clinical presentation  between groups = -2.5 kg ( P <0.001) Hypoglycaemia Week 52 Incidence (%) Glipizide (n=584) Sitagliptin 100 mg (n=588) Sitagliptin 100 mg QD (n=382) Glipizide (n=411) P <0.001 32% 4.9% 0 10 20 30 40 50

109. Progressively Greater Reductions in A1C as Baseline A1C Rises Baseline A1C Category Study 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

110. Sitagliptin + metformin factorial study design N=1091 randomized Mean baseline HbA 1c =8.8% Screening Period Single-blind Placebo Double-blind Treatment Period Diet/Exercise Run-in Period Eligible if HbA 1c 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 Sitagliptin 50/Met 500 BID Week 24 Duration up to 12 weeks based on prior therapy Open-Label Cohort Sitagliptin 50/Met 1000 BID R A N D O M I Z A T I O N Aschner et al. EASD. 2006

111. Initial Combinations of Sitagliptin + Metformin Produced Substantial Additive Improvements in A1C Sita 50 mg + MF 1000 mg b.i.d. Sita 50 mg + MF 500 mg b.i.d. MF 1000 mg b.i.d. MF 500 mg b.i.d. Sita 100 mg q.d. Placebo Open Label Sita 50 mg + MF 1000 mg b.i.d. Open Label Mean A1C = 11.2%

114. Summary Measures of Clinical Adverse Events for Sitagliptin is Similar to Placebo Recommended dose in proposed label: 100 mg q.d. 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

115. Only Small Differences in Incidence of AEs: Pooled Phase III Population Recommended dose in proposed label: 100 mg q.d. AEs with at least 3% incidence and Numerically Higher in Sitagliptin than Placebo Group 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

118. Sitagliptin AUC 0-inf vs. creatinine clearance: AUC increased with decreasing creatinine clearance AUC GMR increase < 2-fold when CrCl > 50 mL/min Dose adjustments < 30 mL/min – ¼ dose 30 – 50 mL/min – ½ dose > 50 mL/min – full dose Dose-Adjusted (to 50 mg) AUC (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