DM2 tratamiento más allá glucosa
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El documento resume los hallazgos de varios estudios sobre el control glucémico intensivo en el tratamiento de la diabetes tipo 2. Mientras que estudios tempranos como el UKPDS mostraron que el control glucémico temprano reduce las complicaciones cardiovasculares, estudios más recientes como ACCORD no encontraron este beneficio cuando la intervención fue más tardía. La hipoglucemia severa se asocia con un mayor riesgo de mortalidad cardiovascular. Los agonistas de GLP-1 representan una opción de tratamiento prometedora para mejorar el control glucémico sin el
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DM2 tratamiento más allá glucosa
- 1. Rompiendo el Paradigma Glucocéntrico en el Tratamiento de la DM2 13 de Agosto, 2010 México DF Dr. Marino Fernández
- 5. Historia natural de la DMT2 Disminución del efecto Incretina ´ ´
- 6. La adiposidad central se a asociado al desarrollo de resistencia a la insulina Obesidad periférica Ginecoide “ Pera” Obesidad central Androide “ Manzana”
- 7. Islote pancreático en ratones sanos y diabéticos Diabetes 55:1695–1704, 2006
- 8. El Efecto Incretina está reducido en pacientes con Diabetes Tipo 2 Insulina (mU/L) 0 30 60 90 120 150 180 Tiempo (min) 0 20 40 60 80 0 30 60 90 120 150 180 Tiempo (min) Pacientes con Diabetes Tipo 2 Sujetos Control Glucosa Intravenosa Glucosa Oral Diabetologia . 1986;29:46-52. 0 20 40 60 80
- 12. UKPDS 0 6 7 8 9 0 3 6 9 12 15 HbA 1c (%) Años desde el inicio del estudio Convencional Intensivo Lancet 352: 837–53, 1998 6.2% Limite superior del rango normal
- 13. Control glucémico intensivo redujo complicaciones microvasculares Lancet 1998; 572: 837-851 Cualquier complicación de diabetes ↓ 12% p=0.029 Complicaciones microvasculares ↓ 25% p=0.0099 Necesidad de fotocoagulación ↓ 29% p=0.031 Extracción de cataratas ↓ 24% p=0.046 Infarto al Miocardio ↓ 16% p=0.052
- 16. Características Basales ACCORD N Engl J Med 2008;358:2545 ADVANCE N Engl J Med 2008;358:2560 VADT N Engl J Med 2009;360:129 VADT ACCORD ADVANCE N 1,791 10,251 11,140 Edad 60 62 66 Sexo Masculino 97% 62% 58% Duración DM 11 10 8 Enf CV previa 40% 35% 32% A1c basal 9.40% 8.30% 7.50% IMC 31 32 28 Tabaquismo activo 17% 14% 14%
- 17. Efecto del tratamiento en la A1c a lo largo de los estudios ACCORD ADVANCE VADT
- 18. A1c media alcanzada ACCORD N Engl J Med 2008;358:2545 ADVANCE N Engl J Med 2008;358:2560 VADT N Engl J Med 2009;360:129 VADT ACCORD ADVANCE Grupo Convencional 8.4% 7.5% 7.3% Grupo Intensivo 6.9% 6.4% 6.5% Diferencia -1.5% -1.1% -0.8% Desde basal (gpo intens) -2.5% -1.9% -1.0%
- 19. Efecto del control intensivo en la disminución de complicaciones macrovasculares * p=0.04 Diabetologia (2009) 52:1219–1226 ACCORD ADVANCE VADT Objetivo primario Muerte CV IM No fatal EVC No Fatal Muerte CV IM No fatal EVC No Fatal Muerte CV IM No fatal EVC No Fatal Hosp x ICC Revascularizac Razón de Riesgo Obj primario (IC 95%) 0.9 (0.78-1.04) 0.94 (0.84-1.06) 0.87 (0.73-1.04) Razón de Riesgo Mortalidad (IC 95%) 1.22 * (1.01-1.46) 0.93 (0.83-1.06) 1.07 (0.80-1.42)
- 22. DCCT/EDIC El control glucémico reduce eventos CV en pacientes con DM1 N Engl J Med 2005;353:2643
- 23. Seguimiento del UKPDS El control glucémico reduce eventos CV en DM2
- 24. Beneficios 10 años después de concluido el estudio (subgrupo de SU – Insulina) Lancet 1998; 572: 837-851 N Engl J Med 2008;359:1577-89 Al termino del estudio Diez años después Cualquier complicación de diabetes ↓ 12% p=0.029 ↓ 9% p=0.04 Complicaciones microvasculares ↓ 25% p=0.001 ↓ 24% p=0.001 Infarto al Miocardio ↓ 16% p=0.052 ↓ 15% p=0.01
- 25. Diferencias entre UKPDS y ACCORD et al Duración de la Diabetes (años ) Proporción de pacientes con enfermedad CV UKPDS (N=5,102) ADVANCE (N=11,140) ACCORD (N=10,251) VADT (N=1,791)
- 26. Mal “legado metabólico” Diabetologia (2009) 52:1219–1226 Antes de entrar al VADT/ACCORD Despues de entrar al VADT/ACCORD Diabetologia (2009) 52:1219–1226 El mal “legado” metabólico incrementa el riesgo de complicaciones
- 27. Efecto de la terapia en el objetivo primario en diferentes subgrupos de ACCORD
- 29. Eventos adversos - Hipoglucemia 1 p=0.0001, 2 p=0.02, 3 p<0.001 ACCORD N Engl J Med 2008;358:2545 ADVANCE N Engl J Med 2008;358:2560 VADT N Engl J Med 2009;360:129 VADT ACCORD ADVANCE Intens Conv Intens Conv Intens Conv Hipoglucemia SAE (%px) 8.5% 1 3.10% Hipoglucemia requiriendo asistencia (%px) 16.2% 2 5.10% Hipoglucemia Severa (%px) 2.7% 3 1.5%
- 30. La hipoglucemia severa incrementa el riesgo de muerte BMJ. 2010 Jan 8;340:b4909.
- 32. Ganancia de peso en ACCORD, ADVANCE y VADT 1 p=0.01, 2 p<0.0001 VADT ACCORD ADVANCE Intens Conv Intens Conv Intens Conv Gananc Peso (Kg) 8.1 1 4.05 3.5 0.4 0.1 2 -1 Diferencia 4.05 3.1 1.1
- 36. Reducción en complicaciones microvasculares del 37% por cada 1 % que disminuye la A1c BMJ 2000;321:405–12 BMJ 2000;321:405–12
- 37. Metas de Control Glucémico ADA NOM OMS IDF AACE HbA1c <7% <6.5% GPA 70-130 mg/dL <110 mg/dL GPP <180 mg/dL <140 mg/dL
- 38. Control metabólico de diabéticos mayores de 20 años hemoglobina glucosilada
- 39. Historia natural de la DMT2 Disminución del efecto Incretina ´ ´ Compl. microvasculares Compl. macrovasculares
- 40. Manejo multifactorial de la DM2 Estudio STENO-2 N Engl J Med 2008;358:580-91.
- 41. Manejo multifactorial de la DM2 Estudio STENO-2 N Engl J Med 2008;358:580-91.
- 42. Metas de Control Glucémico ADA NOM OMS IDF AACE HbA1c <7% <6.5% GPA 70-130 mg/dL <110 mg/dL GPP <180 mg/dL <140 mg/dL LDL <100 mg/dL HDL >40 mg/dL Trigliceridos <150 mg/dL
- 44. HbA1c 6.5 a 7.5% ENDOCRINE PRACTICE 2009 15(6) HbA1c 6.5 a 7.5%
- 46. El efecto Incretina se demuestra en la respuesta a la glucosa oral frente a la glucosa IV Glucemia Venosa (mmol/L) Tiempo (min) Péptido C (nmol/L) 11 5.5 0 0 1 60 120 180 0 1 60 120 180 0.0 0.5 1.0 1.5 2.0 Tiempo (min) 0 2 0 2 Efecto Incretina Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498. Glucosa Oral Glucosa IV * * * * * * *
- 47. GLP-1 y GIP Células L (ileum+ colon) Proglucagon GLP-1 [7-37] GLP-1 [7-36NH 2 ] Células K (yeyuno) ProGIP GIP [1-42]
- 48. Secreción y degradación del GLP-1 DPP4 L L L GLP-1 GLP-1 GLP-1
- 49. Efectos del GLP-1 en Humanos Promueve la saciedad y reduce el apetito Células beta: Mejora la secreción de insulina dependiente de glucosa Adaptado de Flint A, et al. J Clin Invest . 1998;101:515-520.; Adaptado de Larsson H, et al. Acta Physiol Scand . 1997;160:413-422.; Adaptado de Nauck MA, et al. Diabetologia . 1996;39:1546-1553.; Adaptado de Drucker DJ. Diabetes. 1998;47:159-169. Hígado: ↓ glucagón, reducción de la producción hepática de glucosa Células alfa: ↓ Secreción postprandial de glucagón Estómago: Ayuda a regular el vaciamiento gástrico GLP - 1 secretado ante la ingesta de alimentos Célula beta Célula alfa
- 52. Estudios Clínicos de Fase 3 SFU MET + SFU MET Cambio en la HbA 1c (%) Placebo 2 x día Exenatida 5 µg 2 x día Exenatida 10 µg 2 x día * 0,2 - 0,6 * -0,8 Población ITT; Media (EE); DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.; Kendall DM, et al. Diabetes Care. 2005;28:1083-1091. * 0,1 -0,5 * -0,9 -0,4 * -0,8 * -1 -0,5 0 0,5 0,1 MET (N = 336), SFU (N = 377), MET + SFU (N = 733) A1c basal media 8,2% a 8,7% Duración de la DM 4.9 (MET), 6.6 (SU), 8.7 (MET+SU) años
- 53. Exenatida Reduce la Glucosa Postprandial a lo largo de 30 Semanas Media (EE); N = 138; Cohorte evaluable con tolerancia a las comidas. p <,0001 para el cambio en la PPG desde el inicio hasta la semana 30, grupo de exenatida vs placebo. Datos de archivo, Amylin Pharmaceuticals, Inc. Placebo 2 / día Exenatida 5 mcg Exenatida 10 mcg Tiempo (min) Basal Glucosa (mg/dL) Semana 30 Alimento Placebo Tiempo (min) 90 -30 0 30 60 90 120 150 180 288 108 126 144 162 180 198 216 232 252 270 Alimento Exenatida -30 0 30 60 90 120 150 180 90 288 108 126 144 162 180 198 216 232 252 270 MET (N = 336), SFU (N = 377), MET + SFU (N = 733) A1c basal media 8,2% a 8,7% Duración de la DM 4.9 (MET), 6.6 (SU), 8.7 (MET+SU) años
- 54. Efecto de Exenatida a largo plazo - Control glucémico sostenido N=217; Media; lC = intervalo de confianza Adaptado de Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286. HbA 0 26 52 78 104 130 156 4 5 6 7 8 9 10 Basal 8.2% Semana 156 -1.0% Tratamiento (semanas) (%)
- 55. Cambios en glucemia y peso en 3 estudios comparativos vs. insulina *Results from first crossover treatment period 1. Heine RJ, et al. Ann Int Med. 2005;143:559-569. 2. Barnett AH, et al. Clin Ther. 2007;29:2333-2348. 3. Nauck M, et al. Diabetologia . 2007;50(2):259-267. 6 7 8 9 10 HbA 1C (%) Peso (kg) Heine et al 1 Glargina, una vez al dia -1.1% +1.8 kg Insulina Aspart, 70/30 -0.9% Nauck et al 3 +2.9 kg -1.4% Barnett et al 2 -2.0 kg -1.0% Nauck et al 3 -2.5 kg Exenatida -1.1% Heine et al 1 -2.3 kg ADA GOAL -3 -2 -1 0 1 2 3 4 -1.4% Barnett et al 2 +1.0 kg
- 56. Comparación de Exenatida vs. Insulina Glargina – Estudio HEELA Diabetes, Obesity and Metabolism, 11, 2009, 1153–1162 235 pacientes con DM2 en 2 ADO’s a quienes se les agrego Exenatida o Insulina glargina A1c Basal 8.5% Duración de la DM2 9 años Duración 26 semanas Reduccion A1c 1.25 en ambos grupos Reduccion de peso 2.73 Kg con exenatida. Ganancia de peso de 3 Kg con glargina
- 57. Efecto de Exenatida a largo plazo - Perdida de peso progresiva N=217; Media; lC = intervalo de confianza Adaptado de Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286. Basal 99.3 1.2 kg 0 26 52 78 104 130 156 -6 -4 -2 0 Semana 156 -5.3 kg Tratamiento (semanas) Weight Change from Baseline (kg)
- 58. Mejoría de los Factores de Riesgo Cardiovascular a los 3.5 años de Tratamiento con Exenatida TG = triglicéridos; TAS = TA S sistólica; TAD = TA diastólica Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286. Controlado con Placebo/Extensión Fase-Abierta (Combinada) Media de Cambio (%) N=151; *p<.001 **p<.05 TG LDL TC * * * +24% -5% -6% -12% -20 -15 -10 -5 0 5 10 15 20 25 30 TAS TAD - 4% * -2% HDL * **
- 59. Estudios Clínicos de Fase 3 (Combinados): Eventos Adversos Comunes 10 µg Exenatida (N = 483) 5 µg Exenatida (N = 480) Placebo (N = 483) Resultados Combinados de los Estudios de Fase 3 de Exenatida de 30 Semanas 25% 15% 8% Hipoglucemia 48% 39% 18% Náusea 7% 10% 6% Cefalea 10% 9% 4% Sensación de nerviosismo 13% 13% 4% Vómito 15% 11% 6% Diarrea
- 60. Incidencia de Hipoglucemia con Exenatida o Insulina Glargina Exenatida (n=136) Insulina Glargina (n=127) Incidencia de Hipoglucemia(%) 0 5 10 15 20 25 30 35 40 Total Total MET Total SFU * ITT muestra, N=138; LS media (SEM); *p=0.010 Barnett AH, et al. Clin Ther. 2007;29:2333-2348. 25.2 14.7 2.6 17.4 34.5 30.0
- 61. iDPP-4 vs. Agonistas de GLP-1 Adaptado de: Capitulo 12. Nauck et al. The Incretin Modulators – Incretin Mimetics and Incretin Enhancers. En: Pharmacotherapy of Diabetes: New Developments. Springer, 2007 Parametro Agonistas de GLP-1 Inhibidores de DPP-4 Administración Inyección subcutánea Tableta oral Efecto a través de Directamente estimulando el receptor de GLP-1 Inhibiendo DPP-4 e incrementando los niveles de GLP-1 endógeno Reducción de A1c 0.8 a 1.8% 0.5 a 1.1% Efecto en peso ↓ 3 a 5 Kg Nulo
- 63. Muchas Gracias!
Notas del editor
- ANÁLISIS La respuesta secretora de las células a la ingestión de glucosa, medida por los aumentos en la insulina plasmática, se vio reducida en pacientes con diabetes. Los pacientes con diabetes exhibieron una mayor respuesta secretora de las células que los sujetos control, según lo indicado por los niveles más elevados de secreción de insulina, durante el curso de 180 minutos de la infusión intravenosa de glucosa. ANTECEDENTES Las diferencias en la respuesta de la insulina a la administración de glucosa oral e intravenosa, que se atribuyen a otros factores aparte de la glucosa en sí misma, describen el efecto incretina; el efecto incretina parece verse reducido en pacientes con diabetes tipo 2. Respuestas de insulina y péptido C medidas ante una carga de glucosa oral y una infusión intravenosa isoglucémica de 50 g. Además, se intentó correlacionar los efectos incretina con las respuestas de GIP. Aquí se muestran las mediciones de la insulina. Se estudiaron las respuestas de la insulina plasmática correspondientes a 14 pacientes. Estudio con diabetes tipo 2 y 8 sujetos control metabólicamente sanos.
- ANÁLISIS A pesar de exhibir los mismos perfiles de glucemia, hay diferencias significativas en la respuesta de las células a la glucosa oral versus (vs) la glucosa intravenosa, conforme a la medición del péptido C. ANTECEDENTES Este fue un estudio cruzado en el que participaron sujetos sanos. Seis sujetos jóvenes sanos recibieron una carga de glucosa oral o infusiones intravenosas isoglucémicas de glucosa de 25, 50, o 100 g. Arriba se muestran los datos correspondientes a 50 g. El péptido C puede ser una mejor medida de secreción de insulina que la insulina plasmática, dado que los niveles de péptido C no se ven afectados por la extracción hepática de la insulina. Esta diferencia en los niveles de péptido C en respuesta a la glucosa oral versus intravenosa sugiere que otros factores (incretinas), y no simplemente las acciones directas de la glucosa plasmática, afectan la respuesta secretora de insulina.
- GIP is synthesized predominantly in the proximal small bowel, principally in gut endocrine K cells residing within the duodenum and jejunum. In contrast, GLP-1 is liberated following posttranslational processing of proglucagon in enteroendocrine L cells residing within the ileum and colon. Nevertheless, a small amount of GLP-1 may also be derived from more proximally located L cells in the upper small bowel. Both peptides are rapidly released within minutes of nutrient ingestion.
- ANALISIS Al disminuir la carga de trabajo de las células β y mejorar la respuesta de las células β , el GLP-1 es un regulador importante de la homeostasis de la glucosa. Ante la ingesta de alimentos, GLP-1 es segregado en la circulación. El GLP-1 aumenta la respuesta de las células β mejorando la secreción de insulina dependiente de la glucosa. ANTECEDENTES El GLP-1 es segregado por las células L del intestino delgado. El GLP-1 disminuye la carga de trabajo de las células β , por lo tanto, la demanda de secreción de insulina, de las siguientes maneras: Regulando el índice de vaciamiento gástrico de modo tal que los nutrientes de los alimentos son enviados al intestino delgado y, a su vez, absorbidos en la circulación de manera más uniforme, reduciendo el pico de absorción de nutrientes y la demanda de insulina (carga de trabajo de las células β ) Disminuyendo la secreción postprandial de glucagón de las células alfa pancreáticas, lo que ayuda a mantener el equilibrio contrarregulador entre la insulina y el glucagón. Reduciendo la secreción postprandial de glucagón, el GLP-1 ejerce un beneficio indirecto sobre la carga de trabajo de las células β , ya que la secreción reducida de glucagón generará menor producción de glucosa hepática postprandial Produciendo efectos en el sistema nervioso central, lo que da lugar a mayor saciedad (sensación de satisfacción con la ingesta de alimentos) y a una reducción de la ingesta de alimentos Efecto en las célula Beta: Drucker DJ. Diabetes . 1998;47:159-169. Efecto en las células Alfa: Larsson H, et al. Acta Physiol Scand . 1997;160:413-422. Efectos en el Hígado: Larsson H, et al. Acta Physiol Scand . 1997;160:413-422. Efectos en el Estómago: Nauck MA, et al. Diabetologia . 1996;39:1546-1553. Efectos en el SNC: Flint A, et al. J Clin Invest . 1998;101:515-520.
- DISCUSSION Reptilian exendin-4 is capable of binding to the human glucagon-like peptide 1 (GLP-1) receptor in vitro BACKGROUND Exendin-4 is a naturally occurring incretin hormone in the Gila monster Heloderma suspectum Gila monsters produce exendin-4, which is a separate and distinct protein compared to human GLP-1 Exendin-4 mimics some of the actions of GLP-1 in vivo Exendin-4 exerts some of its antidiabetic actions via unknown mechanisms
- DISCUSSION At Week 30, compared to placebo, significant HbA1c reductions were seen in patients treated with exenatide across all 3 AMIGO studies The percentage reduction in HbA1c was greater in patients who received an increased exenatide dose of 10 µg compared to those who received 5 µg exenatide throughout the study Exenatide treatment was associated with reduced HbA1c independent of oral therapy (metformin [MET] and/or sulphonylurea [SFU] ) BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of MET, SFU, or MET + SFU Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed in the United States This slide presents combined data Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomised to placebo (PBO), 5 µg exenatide BID, or 10 µg exenatide twice daily (BID), N = 1446. All subjects also continued current medication. MET study: PBO n = 113, baseline HbA1c = 8.2%; exenatide 5 µg n = 110, baseline HbA1c = 8.3%; exenatide 10 µg n = 113, baseline HbA1c = 8.2% SFU study: PBO n = 123, baseline HbA1c = 8.7%; exenatide 5 µg n = 125, baseline HbA1c = 8.5%; exenatide 10 µg n = 129, baseline HbA1c = 8.6% MET + SFU study: PBO n = 247, baseline HbA1c = 8.5%; exenatide 5 µg n = 245, baseline HbA1c = 8.5%; exenatide 10 µg n = 241, baseline HbA1c = 8.5% The Last Observation Carried Forward (LOCF) method was applied to the data Exenatide was associated with reduced HbA1c independent of disease duration
- ANALISIS En la Semana 30 los resultados combinados de los tres estudios demostraron una reducción significativa (P <,0001) en la glucosa postprandial (PPG) versus el Día 1 tanto para la rama de tratamiento a la que se administraron 5 µg como para las ramas de tratamiento a las que se administraron 10 µg de exenatida. ANTECEDENTES Los 3 estudios AMIGO se emprendieron para evaluar la capacidad de exenatida para mejorar el control glucémico en pacientes con diabetes de tipo 2 que no pudieron lograr el control glucémico con dosis máximamente efectivas de MET, SFU, o MET + SFU. En Estados Unidos se completaron tres estudios de Fase 3 de 30 semanas de duración, controlados con placebo, a doble ciego. Esta diapositiva presenta datos combinados. Se randomizó a sujetos con diabetes tipo 2 (que en ese momento estaban tomando MET, SFU, o MET + SFU) a placebo (PBO), 5 µg de exenatida 2 veces por día, o 10 µg de exenatida 2 veces por día, N = 1446. Todos los sujetos también continuaron con su medicación actual. Se aplicó el método LOCF a los datos. Un subgrupo de sujetos de cada rama de tratamiento fue sometido a pruebas de tolerancia a la comida en la línea basal, en la Semana 4, y en la Semana 30. Aquí se muestran los datos correspondientes a la línea basal y la Semana 30. El tamaño de la comida se calculó en forma individual a fin de proporcionar un 20% de las calorías diarias totales (composición macronutriente: 55% de carbohidratos/15% de proteínas/30% de grasas), administrando el desayuno estándar 15 minutos después de la inyección de exenatida. La Cohorte Evaluable de Tolerancia a las Comidas exhibió el siguiente desglose de los tratamientos: MET (n = 36); SFU (n = 25); MET + SFU (n = 77) Subgrupo tratado con 5 µg de exenatida 2 veces por día (n = 42); subgrupo tratado con 10 µg de exenatida 2 veces por día subgroup (n = 52); subgrupo tratado con placebo (n = 44)
- CITATION Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275-286. SEE pg 279 Figure 2-A,D (for slide data); pg 278 2nd column 1st and 3rd paragraph (for DISCUSSION) DISCUSSION At Week 156, patients completing 3 years of exenatide treatment (n=217) had reduced HbA1c (-1.0 ± 0.1%; 95% confidence interval [CI]: ‑1.1 to ‑0.8%; p .0001), FPG (‑1.30 ± 0.21 mmol/L; 95% CI: ‑1.73 to ‑0.89 mmol/L; p .0001), body weight (-5.3 ± 0.4 kg; 95% CI: ‑6.0 to ‑4.5 kg; p .0001) The reductions in HbA1c and FPG were evident as early as Week 12 (‑1.1 ± 0.1% and ‑1.27 ± 0.15 mmol/L, respectively), indicating a sustained glycaemic effect 46% of patients achieved HbA1c of ≤7%; 30% achieved HbA1c ≤6.5% Similar trends were observed for a more conservative analysis using the ITT population. Changes from baseline to Week 156 in the ITT population were HbA1c: ‑0.6 ± 0.1%, FPG: ‑0.78 ± 0.14 mmol/L, and weight: ‑3.9 ± 0.2 kg HbA1c reductions were similar across different baseline body BMI stratifications: ‑0.9 ± 0.2% for baseline BMI 30 kg/m 2 (n=63) and ‑1.0 ± 0.1% for baseline BMI 30 kg/m 2 (n=154) In the 170 patients with baseline HbA1c 9% (mean 7.8%), HbA1c change was ‑0.6 ± 0.1%. In the 47 patients with baseline HbA1c 9% (mean 9.7%), HbA1c change was ‑2.1 ± 0.2% Alanine aminotransferase (ALT) declined progressively (p .0001 versus baseline). No change in aspartate aminotransferase (AST; p=.2029). Weight change was mildly correlated with baseline ALT (r=‑.01) or ALT change (r=.31) The correlation between HbA1c change and ALT change (r=.25) was also low In a subgroup of the 3-year completer population in whom data were collected for analyses (N=92), baseline HOMA‑B was 52.4 ± 3.9%. Exenatide treatment was associated with sustained HOMA-B improvement over time (70.1 ± 4.4%; p .0001 versus baseline). No consistent change was observed in HOMA of insulin sensitivity (HOMA-S) SLIDE BACKGROUND Patients with T2D treated with MET and/or SFU were randomised to receive placebo or exenatide in the original placebo-controlled, double-blind, Phase 3, randomised trials and received exenatide in the subsequent open-label extensions At the time of this analysis, all patients (N=217) had received 3 years of exposure to exenatide A subgroup of 151 patients completed 3.5 years of exenatide and also had serum lipid measurements available for analysis ALT and AST are hepatic biomarkers
- CITATION Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143:559-569. SEE pg 562 2nd column 1st paragraph, and pg 563 “Body weight” (for slide data) CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2337 “Change in Glycosylated Hemoglobin” and pg 2338 “Change in Body Weight” (for slide data) CITATION Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267. SEE pg 264 Table 2 (for slide data) DISCUSSION The preceding slide showed landmark studies that did not involveexenatide. Those studies demonstrated that insulin helps to lower A1C and is usually accompanied by weight gain In all the exenatide vs insulin studies, exenatide was just as effective as insulin in lowering A1C. In contrast, insulin, on average, consistently caused weight gain, whereas exenatide, on average, was consistently associated with weight loss
- CITATION Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275-286. SEE pg 279 Figure 2-A,D (for slide data); pg 278 2nd column 1st and 3rd paragraph (for DISCUSSION) DISCUSSION At Week 156, patients completing 3 years of exenatide treatment (n=217) had reduced HbA1c (-1.0 ± 0.1%; 95% confidence interval [CI]: ‑1.1 to ‑0.8%; p .0001), FPG (‑1.30 ± 0.21 mmol/L; 95% CI: ‑1.73 to ‑0.89 mmol/L; p .0001), body weight (-5.3 ± 0.4 kg; 95% CI: ‑6.0 to ‑4.5 kg; p .0001) The reductions in HbA1c and FPG were evident as early as Week 12 (‑1.1 ± 0.1% and ‑1.27 ± 0.15 mmol/L, respectively), indicating a sustained glycaemic effect 46% of patients achieved HbA1c of ≤7%; 30% achieved HbA1c ≤6.5% Similar trends were observed for a more conservative analysis using the ITT population. Changes from baseline to Week 156 in the ITT population were HbA1c: ‑0.6 ± 0.1%, FPG: ‑0.78 ± 0.14 mmol/L, and weight: ‑3.9 ± 0.2 kg HbA1c reductions were similar across different baseline body BMI stratifications: ‑0.9 ± 0.2% for baseline BMI 30 kg/m 2 (n=63) and ‑1.0 ± 0.1% for baseline BMI 30 kg/m 2 (n=154) In the 170 patients with baseline HbA1c 9% (mean 7.8%), HbA1c change was ‑0.6 ± 0.1%. In the 47 patients with baseline HbA1c 9% (mean 9.7%), HbA1c change was ‑2.1 ± 0.2% Alanine aminotransferase (ALT) declined progressively (p .0001 versus baseline). No change in aspartate aminotransferase (AST; p=.2029). Weight change was mildly correlated with baseline ALT (r=‑.01) or ALT change (r=.31) The correlation between HbA1c change and ALT change (r=.25) was also low In a subgroup of the 3-year completer population in whom data were collected for analyses (N=92), baseline HOMA‑B was 52.4 ± 3.9%. Exenatide treatment was associated with sustained HOMA-B improvement over time (70.1 ± 4.4%; p .0001 versus baseline). No consistent change was observed in HOMA of insulin sensitivity (HOMA-S) SLIDE BACKGROUND Patients with T2D treated with MET and/or SFU were randomised to receive placebo or exenatide in the original placebo-controlled, double-blind, Phase 3, randomised trials and received exenatide in the subsequent open-label extensions At the time of this analysis, all patients (N=217) had received 3 years of exposure to exenatide A subgroup of 151 patients completed 3.5 years of exenatide and also had serum lipid measurements available for analysis ALT and AST are hepatic biomarkers
- CITATION Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275-286. SEE pg 275 2nd column 1st paragraph and pg 280 1st column 2nd paragraph (for slide data and DISCUSSION) DISCUSSION In a subset of exenatide-treated patients who completed 3.5 years of treatment, improvements in triglycerides, LDL-C, TC, and HDL-C were noted Mean percentage changes from baseline were: triglycerides -12%, LDL-C -6%, TC -5%, and HDL-C 24% Although 25% of subjects who lost the most weight had the greatest improvements in triglycerides and HDL-C, overall there was a minimal correlation between weight change and serum lipid change BACKGROUND Patients with T2D treated with MET and/or SFU were randomised to receive placebo or exenatide in the original placebo-controlled, double-blind, Phase 3, randomised trials and received exenatide in the subsequent open-label extensions At the time of this analysis, all patients (N=151) had received 3.5 years of exposure to exenatide
- DISCUSSION In assessing combined results from all 3 AMIGO studies, the most common adverse events were nausea and hypoglycaemia BACKGROUND Three 30-week, double-blind, Phase 3 studies have been completed in the United States: Patients with type 2 diabetes randomised to placebo, 5 µg exenatide twice daily (BID), or 10 µg exenatide BID with metformin (MET), Intent to Treat (ITT) N = 336 Patients with type 2 diabetes randomised to placebo, 5 µg exenatide BID, or 10 µg exenatide BID with a sulphonylurea (SFU), ITT N = 377 Patients with type 2 diabetes randomised to placebo, 5 µg exenatide BID, or 10 µg exenatide BID with MET and SFU, ITT N = 733 In general, nausea was mild-to-moderate and had a minimal to moderate effect on daily activities. The incidence of nausea decreased over time. Likewise, hypoglycaemia was mostly mild-to-moderate in intensity. One severe hypoglycaemic event occurred in a patient receiving SFU (within the 5 µg exenatide treatment regimen). Exenatide did not increase the incidence of hypoglycaemia when combined with MET. Mild-to-moderate hypoglycaemia incidence increased in groups where exenatide was added to a SFU. Hypoglycaemia was defined as follows: Mild-to-moderate hypoglycaemia: subject reported symptoms consistent with hypoglycaemia that may have been documented by a plasma glucose concentration value (<3.33 mmol/L) Severe hypoglycaemia: subject required the assistance of another person to obtain treatment for their hypoglycaemia; treatment included oral carbohydrate, intravenous glucose, or intramuscular glucagon
- CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2342 “Hypoglycemia” (for slide data); pg 2335 “Study design” (for background information) DISCUSSION Incidence of hypoglycaemia in patients taking adjunctive SFU was not different but was significantly less with exenatide/MET compared with glargine/MET Three patients experienced 8 episodes of severe hypoglycaemia during glargine treatment, but no occurrences of severe hypoglycaemia were observed during exenatide treatment STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with T2D previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued Exenatide was administered BID as an SC injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean FSG level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted