Diabetes mellitus tipo 2
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NUEVOS TRATAMIENTOS DE LA DIABETES MELLITUS TIPO 2
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Diabetes mellitus tipo 2
- 1. DIABETES MELLITUS TIPO 2 :Nuevos tratamientos Luis More Saldaña MD Profesor de Medicina Universidad San Martin de Porres Clínica San Felipe Consultorios El Golf Endocrinólogo Nacional Oncosalud Centro de Investigación en Diabetes y Enfermedades Metabólicas
- 2. INTRODUCCION La heterogeneidad y complejidad de la fisiopatológica de la Diabetes Mellitus hace que el tratamiento sea desde su diagnostico un abordaje de múltiples cambios en el estilo de vida hasta la presencia de tratamiento combinados multifactoriales. Dentro del diagnostico de la Diabetes Mellitus es evidente que se incluyen fenotipos con una base genética, fisiopatología y comportamiento clínicos muy diferentes. Así mismo, el momento de la historia natural de la enfermedad en el que se encuentra cada paciente demanda medidas diferentes. En las últimas décadas el tratamiento farmacológico de la DM ha incorporado interesantísimas nuevas opciones, tanto como modificaciones de clases terapéuticas ya conocidas (nuevas insulinas, sulfonilureas…) como por la aparición de familias de fármacos con mecanismos de acción nuevos.
- 3. Eficacia de los tratamientos actuales de la diabetes Eficacia antihiperglucemiante El tratamiento intensivo dirigido a alcanzar un nivel de hemoglobina glucosilada A1c (HbA1c) inferior al 7% disminuye sustancialmente la incidencia de enfermedad micro vascular en pacientes con DM 2 . La eficacia de los tratamientos orales para la DM (medida como reducción de HbA1c) está en torno al 1% . Si bien el tratamiento con insulina se ha considerado tradicionalmente como de potencia hipoglucemiante ilimitada, en la práctica clínica es difícil conseguir el objetivo de HbA1c con las estrategias y formulaciones actuales. Incluso utilizando estrategias intensivas para el control de la DM2 como el tratamiento con múltiples dosis de insulina basal-bolus se consigue una HbA1c < 7% en menos del 60% de los pacientes, como prueban los metanálisis . Giugliano D., Standl E., Vilsbøll T., Betteridge J., Bonadonna R., Campbell I.W., et al: Is the current therapeutic armamentarium in diabetes enough to control the epidemic and its consequences? What are the current shortcomings? Acta Diabetol 2009; 46: pp. 173-181
- 4. Eficacia hipoglucemiante de fármacos para la diabetes tipo 2 Fármaco Reducción media de HbA1c esperada (%) Inhibidores de alfa glucosidasas 0,5-0,8 Metformina 1-1,5 Sulfonilureas/glinidas 1,0-1,5 Inhibidores de DPPIV 0,7-1,0 Glitazonas 0,7-1,5 Agonistas del receptor de GLP1 0,8-1,2 Insulina 1,0-2,0 Hemoglobina glicosilada VN : 4 a 5,6 %
- 5. Eficacia de los tratamientos actuales de la diabetes Eficacia antihiperglucemiante De los nuevos fármacos : los agonistas del receptor de GLP1 (GLP1ar) pueden conseguir reducciones de HbA1c mayores que algunos fármacos orales (−0.97% [intervalo de confianza del 95% −1,13 a −0,81%]),especialmente los GLP1ar de larga duración respecto a los inhibidores de DPPIV . Además aportan ventajas asociadas en reducción de peso y presión arterial. Pero sigue siendo un tratamiento limitado por la presencia de efectos indeseados gastrointestinales, coste y falta de experiencia de uso a largo plazo. Deacon C.F., Mannucci E., and Ahrén B.: Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and metaanalysis. Diabetes Obes Metab 2012; 14: pp. 762-767
- 6. Eficacia en control global de factores de riesgo cardiovascular El efecto beneficioso de la terapia intensiva sobre la enfermedad macrovascular no está completamente probado. Dos metanálisis que evaluaron el tratamiento estándar vs. intensivo en reducción de riesgo cardiovascular (CV) concluyeron que la terapia intensiva redujo significativamente el riesgo de eventos CV . En 2013 se publicaron en New England Journal of Medicine los resultados del estudio correspondientes al periodo 1999-2010 . Pese a constatar mejoría en estos años, entre el 33,4 y el 48,7% de los pacientes no cumplen los objetivos relativos a control glucémico (HbA1c), lipídico (colesterol LDL), peso y presión arterial. En el Estudio español con 286.791 , solo el 12,1% de los adultos con DM2 alcanzan los objetivos de HbA1c < 7%, colesterol LDL <100 mg/dL y presión arterial < 130/80 mmHg . Ray K.K., Seshasai S.R., Wijesuriya S., Sivakumaran R., Nethercott S., Presiss D., et al: Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: A meta-analysis of randomised controlled trials. Lancet 2009; 373: pp. 1765-1772
- 7. Posibles problemas asociados a las opciones de tratamiento farmacológico Problemas potenciales Evitar o reconsiderar Ganancia de peso SU, glinidas, Glitazonas, insulina Síntomas Gl Metformina, acarbosa, IDPPIV, GLP1ar Hipoglucemia SU, glinidas, insulina IRC Metformina, SU Hepatopatía SU, glinidas, Glitazonas Insuficiencia respiratoria Metformina, Glitazonas Insuficiencia cardíaca Metformina, Glitazonas, insulina Rydén L., Standl E., Bartnik M., van den Berghe G., Betteridge J., de Boer M.J., et al: Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007; 28: pp. 88-136
- 8. Tendencias en las tasas de mortalidad total y cardiovascular (CV) e índice de masa corporal (IMC) entre adultos estadounidenses (n=242.383) con (DM) y sin diabetes (sin DM) entre 1997 y 2004.
- 9. Tendencias seculares en el cambio de peso en personas con DM2 (A) e impacto de tratamientos antihiperglucemiantes alternativos (B). IDPPIV:inhibidores de dipeptidil peptidasa IV; GLP1ar: agonistas del receptor del péptido similar al glucagón tipo 1); SUs: sulfonilureas.Fuentes: Modificado de Morgan C et al. 1
- 10. Tratamientos antihiperglucemiantes e hipoglucemia Posiblemente el efecto adverso más limitante en el uso de fármacos para la DM es la hipoglucemia. Las insulinas y los agentes antidiabéticos orales se situaron en segundo y cuarto lugar respectivamente en frecuencia como causas de ingresos hospitalarios .Los tratamientos de tipo endocrinológico supusieron el 42,1% de todos los ingresos urgentes en esta población, y en el 94,6% de ellos el motivo fue la hipoglucemia . El riesgo de hipoglucemia es muy diferente según el tratamiento empleado y sus combinaciones. Es menor con los tratamientos más recientes (incretinmiméticos, inhibidores de la proteína cotransportador de sodio-glucosa tipo 2…) .
- 11. Riesgo de hipoglucemia asociado a diferentes tratamientos para la diabetes tipo 2 añadidos a metformina. IAGs: inhibidores de alfa glucosidasas; iDPPIV: Inhibidores de dipeptidil peptidasa IV; GLP1ar: agonistas del receptor del péptido similar al glucagón tipo 1; SUs: sulfonilureas; TZDs: tiazolidindionas. Phung O.J., Scholle J.M., Talwar M., and Coleman C.I.: Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 2010; 303: pp. 1410-1418
- 12. Sostenibilidad de la eficacia a largo plazo: preservación de la célula beta La pérdida de la secreción adecuada de insulina es el fenómeno fisiopatológico clave en el comienzo y desarrollo de la DM 2. En las personas con DM2 incluye alteraciones cualitativas (pérdida de la primera fase de secreción en respuesta a la ingesta, pérdida de pulsatilidad normal…) y cuantitativas (reducción de masa celular beta/reserva insular endógena). La disminución de la reserva insular endógena marca la progresión en la historia natural de la DM2 y la constante necesidad de incrementar el tratamiento farmacológico hasta la introducción del tratamiento con insulina exógena . Varias clases farmacológicas (Glitazonas, incretinmiméticos) han mostrado resultados in vitro que indican mejoría en la masa/función celular beta . ecker M., Hofflich H., and Elias A.N.: Thiazolidinediones and the preservation of beta-cell function, cellular proliferation and apoptosis. Diabetes Obes Metab 2008; 10: pp. 617-625
- 26. Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Metformin + Metformin + Metformin + Metformin + high low risk gain edema, HF, fxs low Thiazolidine- dione intermediate low risk neutral rare high DPP-4 inhibitor highest high risk gain hypoglycemia variable Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Basal Insulin + Sulfonylurea + TZD DPP-4-i GLP-1-RA Insulin§ or or or or Thiazolidine- dione + SU DPP-4-i GLP-1-RA Insulin§ TZD DPP-4-ior or or GLP-1-RA high low risk loss GI high GLP-1 receptor agonist Sulfonylurea high moderate risk gain hypoglycemia low SGLT2 inhibitor intermediate low risk loss GU, dehydration high SU TZD Insulin§ GLP-1 receptor agonist + SGLT-2 Inhibitor + SU TZD Insulin§ Metformin + Metformin + or or or or SGLT2-i or or or SGLT2-i Mono- therapy Efficacy* Hypo risk Weight Side effects Costs Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Triple therapy or or DPP-4 Inhibitor + SU TZD Insulin§ SGLT2-i or or or SGLT2-i or DPP-4-i If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable therapy‡ GLP-1-RAMealtime Insulin Insulin (basal) + Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 27. Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Metformin + Metformin + Metformin + Metformin + high low risk gain edema, HF, fxs low Thiazolidine- dione intermediate low risk neutral rare high DPP-4 inhibitor highest high risk gain hypoglycemia variable Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Basal Insulin + Sulfonylurea + TZD DPP-4-i GLP-1-RA Insulin§ or or or or Thiazolidine- dione + SU DPP-4-i GLP-1-RA Insulin§ TZD DPP-4-ior or or GLP-1-RA high low risk loss GI high GLP-1 receptor agonist Sulfonylurea high moderate risk gain hypoglycemia low SGLT2 inhibitor intermediate low risk loss GU, dehydration high SU TZD Insulin§ GLP-1 receptor agonist + SGLT-2 Inhibitor + SU TZD Insulin§ Metformin + Metformin + or or or or SGLT2-i or or or SGLT2-i Mono- therapy Efficacy* Hypo risk Weight Side effects Costs Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Triple therapy or or DPP-4 Inhibitor + SU TZD Insulin§ SGLT2-i or or or SGLT2-i or DPP-4-i If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable therapy‡ GLP-1-RAMealtime Insulin Insulin (basal) + Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 28. Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Metformin + Metformin + Metformin + Metformin + high low risk gain edema, HF, fxs low Thiazolidine- dione intermediate low risk neutral rare high DPP-4 inhibitor highest high risk gain hypoglycemia variable Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Basal Insulin + Sulfonylurea + TZD DPP-4-i GLP-1-RA Insulin§ or or or or Thiazolidine- dione + SU DPP-4-i GLP-1-RA Insulin§ TZD DPP-4-ior or or GLP-1-RA high low risk loss GI high GLP-1 receptor agonist Sulfonylurea high moderate risk gain hypoglycemia low SGLT2 inhibitor intermediate low risk loss GU, dehydration high SU TZD Insulin§ GLP-1 receptor agonist + SGLT-2 Inhibitor + SU TZD Insulin§ Metformin + Metformin + or or or or SGLT2-i or or or SGLT2-i Mono- therapy Efficacy* Hypo risk Weight Side effects Costs Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Triple therapy or or DPP-4 Inhibitor + SU TZD Insulin§ SGLT2-i or or or SGLT2-i or DPP-4-i If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable therapy‡ GLP-1-RAMealtime Insulin Insulin (basal) + Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 29. Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Metformin + Metformin + Metformin + Metformin + high low risk gain edema, HF, fxs low Thiazolidine- dione intermediate low risk neutral rare high DPP-4 inhibitor highest high risk gain hypoglycemia variable Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Basal Insulin + Sulfonylurea + TZD DPP-4-i GLP-1-RA Insulin§ or or or or Thiazolidine- dione + SU DPP-4-i GLP-1-RA Insulin§ TZD DPP-4-ior or or GLP-1-RA high low risk loss GI high GLP-1 receptor agonist Sulfonylurea high moderate risk gain hypoglycemia low SGLT2 inhibitor intermediate low risk loss GU, dehydration high SU TZD Insulin§ GLP-1 receptor agonist + SGLT-2 Inhibitor + SU TZD Insulin§ Metformin + Metformin + or or or or SGLT2-i or or or SGLT2-i Mono- therapy Efficacy* Hypo risk Weight Side effects Costs Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Triple therapy or or DPP-4 Inhibitor + SU TZD Insulin§ SGLT2-i or or or SGLT2-i or DPP-4-i If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable therapy‡ GLP-1-RAMealtime Insulin Insulin (basal) + Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 30. Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Metformin + Metformin + Metformin + Metformin + high low risk gain edema, HF, fxs low Thiazolidine- dione intermediate low risk neutral rare high DPP-4 inhibitor highest high risk gain hypoglycemia variable Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Basal Insulin + Sulfonylurea + TZD DPP-4-i GLP-1-RA Insulin§ or or or or Thiazolidine- dione + SU DPP-4-i GLP-1-RA Insulin§ TZD DPP-4-ior or or GLP-1-RA high low risk loss GI high GLP-1 receptor agonist Sulfonylurea high moderate risk gain hypoglycemia low SGLT2 inhibitor intermediate low risk loss GU, dehydration high SU TZD Insulin§ GLP-1 receptor agonist + SGLT-2 Inhibitor + SU TZD Insulin§ Metformin + Metformin + or or or or SGLT2-i or or or SGLT2-i Mono- therapy Efficacy* Hypo risk Weight Side effects Costs Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Triple therapy or or DPP-4 Inhibitor + SU TZD Insulin§ SGLT2-i or or or SGLT2-i or DPP-4-i If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable therapy‡ GLP-1-RAMealtime Insulin Insulin (basal) + Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 HbA1c ≥9% Metformin intolerance or contraindication Uncontrolled hyperglycemia (catabolic features, BG ≥300-350 mg/dl, HbA1c ≥10-12%)
- 31. Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Metformin + Metformin + Metformin + Metformin + high low risk gain edema, HF, fxs low Thiazolidine- dione intermediate low risk neutral rare high DPP-4 inhibitor highest high risk gain hypoglycemia variable Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Basal Insulin + Sulfonylurea + TZD DPP-4-i GLP-1-RA Insulin§ or or or or Thiazolidine- dione + SU DPP-4-i GLP-1-RA Insulin§ TZD DPP-4-i GLP-1-RA high low risk loss GI high GLP-1 receptor agonist Sulfonylurea high moderate risk gain hypoglycemia low SGLT2 inhibitor intermediate low risk loss GU, dehydration high SU TZD Insulin§ GLP-1 receptor agonist + SGLT-2 Inhibitor + SU TZD Insulin§ Metformin + Metformin + or or or or SGLT2-i or or or SGLT2-i Mono- therapy Efficacy* Hypo risk Weight Side effects Costs Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Triple therapy or or DPP-4 Inhibitor + SU TZD Insulin§ SGLT2-i or or or SGLT2-i or DPP-4-i If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable therapy‡ GLP-1-RAMealtime Insulin or or or Insulin (basal) + Figure 2A. Anti-hyperglycemic therapy in T2DM: Avoidance of hypoglycemia Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 32. Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Metformin + Metformin + Metformin + Metformin + high low risk gain edema, HF, fxs low Thiazolidine- dione intermediate low risk neutral rare high DPP-4 inhibitor highest high risk gain hypoglycemia variable Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Basal Insulin + Sulfonylurea + TZD DPP-4-i GLP-1-RA Insulin§ or or or or Thiazolidine- dione + SU DPP-4-i GLP-1-RA Insulin§ TZD DPP-4-i GLP-1-RA high low risk loss GI high GLP-1 receptor agonist Sulfonylurea high moderate risk gain hypoglycemia low SGLT2 inhibitor intermediate low risk loss GU, dehydration high SU TZD Insulin§ GLP-1 receptor agonist + SGLT-2 Inhibitor + SU TZD Insulin§ Metformin + Metformin + or or or or SGLT2-i or or or SGLT2-i Mono- therapy Efficacy* Hypo risk Weight Side effects Costs Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Triple therapy or or DPP-4 Inhibitor + SU TZD Insulin§ SGLT2-i or or or SGLT2-i or DPP-4-i If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable therapy‡ GLP-1-RAMealtime Insulin Insulin (basal) + or or or Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Figure 2B. Anti-hyperglycemic therapy in T2DM: Avoidance of weight gain
- 33. Healthy eating, weight control, increased physical activity & diabetes education Metformin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Metformin + Metformin + Metformin + Metformin + high low risk gain edema, HF, fxs low Thiazolidine- dione intermediate low risk neutral rare high DPP-4 inhibitor highest high risk gain hypoglycemia variable Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Basal Insulin + Sulfonylurea + TZD DPP-4-i GLP-1-RA Insulin§ or or or or Thiazolidine- dione + SU DPP-4-i GLP-1-RA Insulin§ TZD DPP-4-ior or or GLP-1-RA high low risk loss GI high GLP-1 receptor agonist Sulfonylurea high moderate risk gain hypoglycemia low SGLT2 inhibitor intermediate low risk loss GU, dehydration high SU TZD Insulin§ GLP-1 receptor agonist + SGLT-2 Inhibitor + SU TZD Insulin§ Metformin + Metformin + or or or or SGLT2-i or or or SGLT2-i Mono- therapy Efficacy* Hypo risk Weight Side effects Costs Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Triple therapy or or DPP-4 Inhibitor + SU TZD Insulin§ SGLT2-i or or or SGLT2-i or DPP-4-i If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable therapy‡ GLP-1-RAMealtime Insulin Insulin (basal) + Figure 2C. Anti-hyperglycemic therapy in T2DM: Minimization of costs Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 36. DIABETES Y NUEVOS FARMACOS Hasta el año 1920, en que se descubrió la insulina, no se disponía de fármacos , por casi 60 años solo hemos dispuesto de tres fármacos para su tratamiento : 1.- Insulina ( 1920 ) 2.- Sulfonilureas ( 1955 ) 3.- Biguanidas ( 1957 ) Luego aparecen : 4.- Inhibidores de las alfa glucosidasas ( 1990 ) 5.- Tiazolidinedionas ( 1995 ) y glimepirida ( 1995 ) pioglitazona ( 1997 ) 6.- Metiglinidas ( repaglinida ,Neteglinida ) y aparece la primera sulfonilurea modificada * Glicazida . ( 1997 ) White J.R.: A brief history of the development of diabetes medications - feature article. Diabetes Spectrum 2014; 27: pp. 82-86
- 37. DIABETES Y NUEVOS FARMACOS En la década del 2000, De Fronzo describe al “octeto ominoso” 9 , para referirse a los múltiples y complejos mecanismos patogénicos de la DM2. Este mayor conocimiento de la fisiopatología de la DM2 da origen al desarrollo de nuevos fármacos con novedosos mecanismos de acción. 7.- Farmacos con efecto incretina : .- agonista del peptido similar al glucagon tipo 1 ( AR –GLP1 ) ( 2005 ) .- Inhibidores de la dipeptidil peptidasa ( 2006 ) 8.-Inhibidores de los cotransportadores de sodio-glucosa tipo 2 ( ISGLT 2 ) ( 2012 ) 9.- Agonista de la dopamina con mecanismos e accion central no bien definidos ( 2013 ) 10 .- Analogos de amilina ,que disminuyen el glucagon postprandial y el vaciamiento gastrico ,con modesto efecto en la HBA1c . ( 2013 )
- 39. CANDIDATOS PARA LOS INHIBIDORES DE LA DPP4 1.- Los inhibidores de la DPP-4 no se consideran una terapia inicial . 2.-La terapia inicial en la mayoría de los pacientes con diabetes tipo 2 debe comenzar con dieta, reducción de peso, ejercicio y metformina.(en ausencia de contraindicaciones). 3.-Los inhibidores de DPP-4 se pueden considerar como monoterapia en pacientes que son intolerantes o tienen contraindicaciones para la metformina, las sulfonilureas o las tiazolidinIdiona, como los pacientes con enfermedad renal crónica o que tienen un riesgo particularmente alto de hipoglucemia. 4.-Los inhibidores de DPP-4 se pueden considerar como terapia farmacológica complementaria para pacientes que no están controlados adecuadamente con metformina, una tiazolidinIdiona o una sulfonilureas. Sin embargo, su modesta eficacia y gasto para disminuir la glucemia disminuyen nuestro entusiasmo por estos medicamentos. Diabetes tipo 2: terapia con inhibidores de dipeptidil peptidasa IV. Demuth HU, McIntosh CH, Pederson RA Biochim Biophys Acta. 2005; 1751 (1): 33
- 40. Incretinas Son hormonas enteroendócrinas producidas en el intestino en respuesta a una comida ( es decir, en presencia de glucosa): GLP-1 (Glucagon like peptide 1) GIP (Glucose dependent insulinotropic peptide) Mantienen el control glucémico aumentando la producción de insulina y disminuyendo la producción de glucagon en respuesta a una elevación de la glucemia. Estudios experimentales in vitro han demostrado que las incretinas tienen un papel importante en la replicación de las células beta y en el descenso de la apoptosis, aunque la relevancia clínica de esto en pacientes con diabetes tipo 2 es desconocido. GLP-1 y GIP
- 41. La glucosa oral estimula en mayor medida la secreción de insulina ( en comparación con la vía IV) El “efecto incretina” es responsable de 50-70% de la insulina secretada dependiente de glucosa La enzima DPP 4 es responsable de la degradación rápida de las incretinas biológicamente activa (en menos de dos minutos). En la DM tipo 2, el “efecto incretina” esta ausente o reducido de manera significativa Incretinas
- 43. Fisiopatología de la Diabetes Mellitus tipo 2 Los efectos del GLP-1 sobre la insulina y el glucagón se ha visto que dependen de la glucosa *p<0,05 GLP-1 frente al placebo Nauck MA et al Diabetologia 1993;36:741–744. Con hiperglucemia, el GLP-1 estimuló la insulina y suprimió el glucagón. Placebo Infusión de GLP-1 Cuando los niveles de glucosa eran casi normales, los niveles de insulina bajaron y el glucagón dejó de estar suprimido. Glucosa (mmol/L) Glucagón (pmol/L) Tiempo (minutos) 250 200 150 100 50 15,0 12,5 10,0 7,5 5,0 20 15 10 5 0 60 120 180 240 Insulina (pmol/L) * * * * * * * * * * * * * * * * * * * Infusión
- 53. INHIBIDORES DEL COTRANSPORTADOR DE SODIOGLUCOSA TIPO 2 (ISLGT2)
- 56. ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Long (Detemir) Rapid (Lispro, Aspart, Glulisine) Hours Long (Glargine) 0 2 4 6 8 10 12 14 16 18 20 22 24 Short (Regular) Hours after injection Insulinlevel (Degludec) 3. ANTI-HYPERGLYCEMIC THERAPY • Therapeutic options: Insulins
- 58. • Start: 10U/day or 0.1-0.2 U/kg/day • Adjust: 10-15% or 2-4 U once-twice weekly to reach FBG target. • For hypo: Determine & address cause; ê dose by 4 units or 10-20%. Basal Insulin (usually with metformin +/- other non-insulin agent) Figure 3. Approach to starting & adjusting insulin in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 59. Add ≥2 rapid insulin* injections before meals ('basal-bolus’† ) Change to premixed insulin* twice daily Add 1 rapid insulin* injections before largest meal • Start: Divide current basal dose into 2/3 AM, 1/3 PM or 1/2 AM, 1/2 PM. • Adjust: é dose by 1-2 U or 10-15% once- twice weekly until SMBG target reached. • For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. • Start: 10U/day or 0.1-0.2 U/kg/day • Adjust: 10-15% or 2-4 U once-twice weekly to reach FBG target. • For hypo: Determine & address cause; ê dose by 4 units or 10-20%. Basal Insulin (usually with metformin +/- other non-insulin agent) If not controlled after FBG target is reached (or if dose > 0.5 U/kg/day), treat PPG excursions with meal-time insulin. (Consider initial GLP-1-RA trial.) If not controlled, consider basal- bolus. If not controlled, consider basal- bolus. • Start: 4U, 0.1 U/kg, or 10% basal dose. If A1c<8%, consider ê basal by same amount. • Adjust: é dose by 1-2 U or 10-15% once- twice weekly until SMBG target reached. • For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. • Start: 4U, 0.1 U/kg, or 10% basal dose/meal.‡ If A1c<8%, consider ê basal by same amount. • Adjust: é dose by 1-2 U or 10-15% once-twice weekly to achieve SMBG target. • For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. Figure 3. Approach to starting & adjusting insulin in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 60. Add ≥2 rapid insulin* injections before meals ('basal-bolus’† ) Change to premixed insulin* twice daily Add 1 rapid insulin* injections before largest meal • Start: Divide current basal dose into 2/3 AM, 1/3 PM or 1/2 AM, 1/2 PM. • Adjust: é dose by 1-2 U or 10-15% once- twice weekly until SMBG target reached. • For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. • Start: 10U/day or 0.1-0.2 U/kg/day • Adjust: 10-15% or 2-4 U once-twice weekly to reach FBG target. • For hypo: Determine & address cause; ê dose by 4 units or 10-20%. Basal Insulin (usually with metformin +/- other non-insulin agent) If not controlled after FBG target is reached (or if dose > 0.5 U/kg/day), treat PPG excursions with meal-time insulin. (Consider initial GLP-1-RA trial.) low mod. high more flexible less flexible Complexity # Injections Flexibility 1 2 3+ If not controlled, consider basal- bolus. If not controlled, consider basal- bolus. • Start: 4U, 0.1 U/kg, or 10% basal dose. If A1c<8%, consider ê basal by same amount. • Adjust: é dose by 1-2 U or 10-15% once- twice weekly until SMBG target reached. • For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. • Start: 4U, 0.1 U/kg, or 10% basal dose/meal.‡ If A1c<8%, consider ê basal by same amount. • Adjust: é dose by 1-2 U or 10-15% once-twice weekly to achieve SMBG target. • For hypo: Determine and address cause; ê corresponding dose by 2-4 U or 10-20%. Figure 3. Approach to starting & adjusting insulin in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
- 61. RESINAS DE INTERMBIO Y DIABETES
- 62. RESINAS DE INTERCAMBIO : COLESEVELAM El colesevelam no sólo es beneficioso en bajar los niveles de colesterol si no en modular los niveles de glucosa con HBA1 c ( 0.9 % ) y tener otros efectos en la diabetes : — Leve acción sobre el descenso de la glucemia postprandial y la glucemia basal. — Sin efecto sobre la esteatosis hepática y sin riesgo de uso en caso de insuficiencia renal o hepática. — Tampoco tiene efecto sobre la insuficiencia cardíaca. — No se ha visto ninguna relación con el incremento del riesgo de fracturas. — No produce hipoglucemias ni aumento de peso. — Moderados síntomas gastrointestinales. Tener cuidado en su administración en pacientes con severa hipertrigliceridemias y en presencia de neuropatía vegetativa gastrointestinal. Steals B, Fonseca V. Bile Acids and Metabolic Regulation. Mechanisms and clinical responses to bile acid sequestration. Diabetes Care. 2009;32 Suppl 2:s237-45
Notas del editor
- Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). The figure denotes relative glucose lowering efficacy, risk of hypoglycemia, effect on body weight, other side effects and approximate relative cost for each drug class. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications.
- Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). The figure denotes relative glucose lowering efficacy, risk of hypoglycemia, effect on body weight, other side effects and approximate relative cost for each drug class. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications.
- Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). The figure denotes relative glucose lowering efficacy, risk of hypoglycemia, effect on body weight, other side effects and approximate relative cost for each drug class. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications.
- Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). The figure denotes relative glucose lowering efficacy, risk of hypoglycemia, effect on body weight, other side effects and approximate relative cost for each drug class. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications.
- Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). The figure denotes relative glucose lowering efficacy, risk of hypoglycemia, effect on body weight, other side effects and approximate relative cost for each drug class. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications.
- Here is a diagrammatic representation of the approximate pharmacokinetic properties of various insulin formulations. Understanding the onset, peak and duration of action of insulin products is key for successful management of patients with diabetes.
- Basal insulin alone is usually the optimal initial regimen, beginning at 0.1-0.2 U/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 1-2 non-insulin agents, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. In patients still not at target after basal insulin has been adequately titrated, and the patient is willing to take >1 injections, there are several options. First, consider GLP-1 receptor agonists (see Fig. 2). The combination of basal insulin + GLP-1RA is becoming well established after several studies confirmed its efficacy on par with more complex multi-dose insulin regimens, but with less hypoglycemia and with weight loss instead of weight gain. If such an approach is not possible or has been tried and proven unsuccessful, there are 3 possible advanced insulin regimens: Adding 1 injection of a rapid acting insulin analogue before the largest meal, Adding 2-3 injections of a rapid acting insulin analogue before 2-3 meals, or Using premixed insulin BID Each approach has its advantages and disadvantages. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. A fourth, less common method (not shown) is referred to as ‘self-mixed split’ and involves 2 injections of NPH mixed with regular human insulin (or mixed with a rapid acting insulin analogue), administered before breakfast and the evening meal. This is a more cost-effective approach, using human insulins in vials, and allows self-adjustment by the patient of the short/rapid-acting component, based on pre-meal blood glucose or anticipated carbohydrate intake (or both.) Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing BG levels as reported by the patient. Comprehensive education regarding self-monitoring of BG, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy.
- Basal insulin alone is usually the optimal initial regimen, beginning at 0.1-0.2 U/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 1-2 non-insulin agents, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. In patients still not at target after basal insulin has been adequately titrated, and the patient is willing to take >1 injections, there are several options. First, consider GLP-1 receptor agonists (see Fig. 2). The combination of basal insulin + GLP-1RA is becoming well established after several studies confirmed its efficacy on par with more complex multi-dose insulin regimens, but with less hypoglycemia and with weight loss instead of weight gain. If such an approach is not possible or has been tried and proven unsuccessful, there are 3 possible advanced insulin regimens: Adding 1 injection of a rapid acting insulin analogue before the largest meal, Adding 2-3 injections of a rapid acting insulin analogue before 2-3 meals, or Using premixed insulin BID Each approach has its advantages and disadvantages. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. A fourth, less common method (not shown) is referred to as ‘self-mixed split’ and involves 2 injections of NPH mixed with regular human insulin (or mixed with a rapid acting insulin analogue), administered before breakfast and the evening meal. This is a more cost-effective approach, using human insulins in vials, and allows self-adjustment by the patient of the short/rapid-acting component, based on pre-meal blood glucose or anticipated carbohydrate intake (or both.) Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing BG levels as reported by the patient. Comprehensive education regarding self-monitoring of BG, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy.
- Basal insulin alone is usually the optimal initial regimen, beginning at 0.1-0.2 U/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 1-2 non-insulin agents, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. In patients still not at target after basal insulin has been adequately titrated, and the patient is willing to take >1 injections, there are several options. First, consider GLP-1 receptor agonists (see Fig. 2). The combination of basal insulin + GLP-1RA is becoming well established after several studies confirmed its efficacy on par with more complex multi-dose insulin regimens, but with less hypoglycemia and with weight loss instead of weight gain. If such an approach is not possible or has been tried and proven unsuccessful, there are 3 possible advanced insulin regimens: Adding 1 injection of a rapid acting insulin analogue before the largest meal, Adding 2-3 injections of a rapid acting insulin analogue before 2-3 meals, or Using premixed insulin BID Each approach has its advantages and disadvantages. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. A fourth, less common method (not shown) is referred to as ‘self-mixed split’ and involves 2 injections of NPH mixed with regular human insulin (or mixed with a rapid acting insulin analogue), administered before breakfast and the evening meal. This is a more cost-effective approach, using human insulins in vials, and allows self-adjustment by the patient of the short/rapid-acting component, based on pre-meal blood glucose or anticipated carbohydrate intake (or both.) Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing BG levels as reported by the patient. Comprehensive education regarding self-monitoring of BG, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy.