Tratamiento farmacológico de diabetes mellitus 8po 2. Conflictos de interés. Agenda 23/12/12

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1 Tratamiento farmacológico de diabetes mellitus 8po 2 Dr. Chih Hao Chen Ku, FACE Servicio de Endocrinología, Hospital San Juan de Dios Departamento de Farmacología y Toxicología Clínica, Universidad de Costa Rica Conflictos de interés He recibido honarios p conferencias, advisy board y/o inves8gación clínica de: Astra Zeneca Novar8s Pharma Logis8cs Inc Novar8s Oncology Novo Ndisk Merck Sharp & Dohme Roche Glaxo SmithKline Sanofi Aven8s Boehringer Organon Agenda Nuevas guías de tratamiento ADA/EASD y ADA/AGS Pros y contras de cada intervención Esquemas de insulinización en DM- 2 1

2 METAS DE HBA1C PREVENCIÓN PRIMARIA: DATOS NUEVOS Impact of Intensive Therapy f Diabetes: Summary of Maj Clinical Trials Study Microvasc CVD Mtality UKPDS ê! ê! ç è! ê! ç è! ê! DCCT / EDIC* ê! ê! ç è! ê! ç è! ç è! ACCORD ê! ç è! é! ADVANCE ê! ç è! ç è! VADT ê! ç è! ç è! Kendall DM, Bergenstal RM. International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckwth W et al. N Engl J Med 2009;360:129. (erratum: Mitz T. N Engl J Med 2009;361:1024) IniNal Trial Long Term Fol- up * in T1DM 2

3 23/12/12 Olofsson KE. EASD Olofsson KE. EASD Olofsson KE. EASD

4 Olofsson KE. EASD NUEVAS GUÍAS ADA/EASD 2012 Approach to management of hyperglycemia: me stringent less stringent Patient attitude and expected treatment effts ly motivated, adherent, excellent self-care capacities less motivated, non-adherent, po self-care capacities Risks potentially associated with hypoglycemia, other adverse events Disease duration newly diagnosed long-standing Life expectancy long sht Imptant combidities absent few / mild severe Established vascular complications absent few / mild severe Resources, suppt system readily available limited Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554) 4

5 Initial drug monotherapy Side effects Two drug combinations* Maj side effect(s) Three drug combinations moderate risk Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): edema, HF, fx s Inhibit intermediate neutral rare Inhibit GLP-1 recept loss GI If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (der not meant to denote any specific preference): GLP-1 recept SU est risk variable Me complex insulin strategies If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with 1-2 non-insulin agents: Insulin # (multiple daily doses) T2DM AnNhyperglycemic Therapy: General RecommendaNons Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print] Myocardial Infarc8on Hazard Ra8o (fatal non- fatal myocardial infarc9on sudden death) Intensive (meumin) vs. ConvenNonal glucose control HR (95%CI) All- cause Mtality Hazard Ra8o Intensive (meumin) vs. ConvenNonal glucose control HR (95%CI) 5

6 Initial drug monotherapy Side effects Two drug combinations* Maj side effect(s) Three drug combinations moderate risk Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): edema, HF, fx s Inhibit intermediate neutral rare Inhibit GLP-1 recept loss GI If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (der not meant to denote any specific preference): GLP-1 recept SU est risk variable Me complex insulin strategies If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with 1-2 non-insulin agents: Insulin # (multiple daily doses) T2DM AnNhyperglycemic Therapy: General RecommendaNons Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print] ADVANCE The ADVANCE Collaba8ve Group. N Engl J Med. 2008;358: Metanálisis SU- meimin Eventos cardiovasculares combinados Rao AD. Diabetes Care. 2008;31:

7 Initial drug monotherapy Side effects Two drug combinations* Maj side effect(s) Three drug combinations moderate risk Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): edema, HF, fx s Inhibit intermediate neutral rare Inhibit GLP-1 recept loss GI If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (der not meant to denote any specific preference): GLP-1 recept SU est risk variable Me complex insulin strategies If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with 1-2 non-insulin agents: Insulin # (multiple daily doses) T2DM AnNhyperglycemic Therapy: General RecommendaNons Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print] Yki- Järvinen H. N Engl J Med. 351:1106 Otros efectos Aumenta riesgo de insuficiencia cardíaca Aumenta riesgo de fracturas En extremidades inferies y superies, más en mujeres que en hombres Usualmente en si8os no asociados a osteoposis P su mecanismo de acción, may preservación de células beta y p lo tanto men agotamiento pancreá8co 7

8 Precauciones Combinación con insulina Insuficiencia cardíaca Insuficiencia renal Falla hepá8ca Cáncer de vejiga con pioglitazona Initial drug monotherapy Side effects Two drug combinations* Maj side effect(s) Three drug combinations moderate risk Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): edema, HF, fx s Inhibit intermediate neutral rare Inhibit GLP-1 recept loss GI If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (der not meant to denote any specific preference): GLP-1 recept SU est risk variable Me complex insulin strategies If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with 1-2 non-insulin agents: Insulin # (multiple daily doses) T2DM AnNhyperglycemic Therapy: General RecommendaNons Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print] 8

9 DPP- 4 Inhibits Improve Glucose Control by Increasing Incre8n Levels in Type 2 Diabetes Ingestion of food DPP- 4 Inhibit GI tract Release of incretins from the gut X DPP- 4 Enzyme InacNve increnns Pancreas β-cells α-cells Glucose dependent é Insulin from beta cells (GLP-1 and GIP) ä Glucagon from alpha cells (GLP-1) Glucose dependent = dipeptidyl peptidase 4 Insulin increases peripheral glucose uptake insulin and glucagon reduce hepatic glucose output Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145: ; Zander M et al Lancet 2002;359: ; Ahrén B Curr Diab Rep 2003;3: ; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003: Improved Hyperglycemia Physiologic Glucose Control Diferencias entre inhibides de DPP- 4 Saxaglip8na: metabolizado p CYP3A4/5 Precaución con inhibides de proteasas, claritromicina y otros inhibides potentes del CYP3A4/5 Linaglip8na: excreción hepá8ca Vildaglip8na Aloglip8na linaglip8na Sitagliptin: reduction in Hba1c in monotherapy Results adjusted by placebo Median change in A1C, % HbA 1c Basal Media: 8.0% n= P<0.001* n= Monotherapy study at 18 weeks (95% CI: -0.8, -0.4) Monotherapy study at 24 weeks (95% CI: -1.0, -0.6) A1C Basal, % Meidan change in A1c, % Inclusion criteria: 7%-10% Prespecified combined analysis at 18 weeks Total <8 8 <9 9 n=239 n=411 n= n= CI=Confidence interval. *Comparado con el placebo. Ajuste de los cuadrados mínimos según el estado de la terapia antihiperglucémica previa y el val basal. Diferencia respecto al placebo. Número combinado de pacientes tratados con JANUVIA o un placebo. P<0.001 total y para las interacciones del tratamiento p subgrupo. 1. Raz I et al. Diabetologia. 2006;49: Aschner P et al. Diabetes Care. 2006;29:

10 Estudio 1860 (liraglutida vs sitagliptina) Evaluation to week 26: mean changes in body weight Time (weeks) 0, Changes in body weight (kg) -0,5-1,0-1,5-2,0-2, Ambos p< , ,5 Liraglutida 1.2 mg Liraglutida 1.8 mg Sitagliptina 100 mg -4,0 Pratley et al. Lancet 2010;375: Reduc8on in Hba1c with liraglu8de A1c basal % # Change in HbA1c (%) 0,0-0,2-0,4-0,6-0,8-1,0-1,2-1,4-1,6 Combined with Combined Combination Combination Monotherapy metfmin with SU MET Met SU 8,4 8,6 8,6 8,4 8,2 8,2 8,5 8,6 8,3 8,5 8,6 8,4 8,3 8,1-0,5-0,8-0,9-1,1-1,1-1,2-1,3-1,3-1,3-1,4-1,5-1,5-1,5-1,6 Liraglutida 1.2 mg Liraglutida 1.8 mg Glimepirida Rosiglitazona Glargina Placebo Significativo *vs. el comparad; #Cambio en HbA1c a partir del val basal en la población global (LEAD 4,5) agregado al fallar la dieta y ejercicio (LEAD 3); o agregado a monoterapia previa con hipoglucemiantes ales (LEAD 2,1). Marre et al. Diabetes 2008;57(Suppl. 1):A4 (LEAD 1); Nauck et al, Diabetes Care, published online / dc (LEAD 2); Garber et al, The Lancet, early online publication, 25 Sept 2008 (LEAD 3); Zinman et al. Diabetologia 2008;51(Suppl. 1): Poster 898 (LEAD 4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD 5). 29 Metanalisis: presión sistólica Vilsbol T. BMJ. 2012:344 10

11 Metanalisis: colesterol total Vilsbol T. BMJ. 2012:344 Metanalisis: efectos en ALT Vilsbol T. BMJ. 2012:344 Metanalisis: cambios en peso cpal Vilsbol T. BMJ. 2012:344 11

12 Initial drug monotherapy Side effects Two drug combinations* Maj side effect(s) Three drug combinations moderate risk Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): edema, HF, fx s Inhibit intermediate neutral rare Inhibit GLP-1 recept loss GI If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (der not meant to denote any specific preference): GLP-1 recept SU est risk variable Me complex insulin strategies If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with 1-2 non-insulin agents: Insulin # (multiple daily doses) T2DM AnNhyperglycemic Therapy: General RecommendaNons Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print] Initial drug monotherapy Side effects Two drug combinations* Maj side effect(s) Three drug combinations moderate risk Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): edema, HF, fx s Inhibit intermediate neutral rare Inhibit GLP-1 recept loss GI If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (der not meant to denote any specific preference): GLP-1 recept SU est risk variable If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with 1-2 non-insulin agents: Me complex insulin strategies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] Insulin # (multiple daily doses) Esquemas no insulínicos Número de inyecciones Complejidad de régimen Insulina basal (usualmente con agentes ales) 1 bajo Insulina basal 1 insulina rápida prandial Insulina premezcla (dos veces al día) 2 mod Insulina basal 2 insulinas rápidas prandial >3 alto Más flexible Menos flexible Flexibilidad Recomendaciones con may evidencia Recomendaciones con men evidencia 12

13 INSULINIZACIÓN BASAL Basal and postprandial contribu8ons to hyperglycemia by A1c range T2DM patients on diet ± OAD Mean A1c 8.86% Standard meals at 0800, 1200 hrs 4-point daytime glucose profiles (0800, 1100, 1400, 1700 hrs) Calculations assume hyperglycemia is >6.1 mmol/l (110 mg/dl) 30% 50% 55% 60% 70% Basal hyperglycemia 40 70% 50% 20 45% 40% 30% 0 < >10.2 A1c ranges (quin8les) Postprandial hyperglycemia is most imptant except at A1c Monnier L et al. Diabetes Care 2003;26: Postprandial hyperglycemia Basal and postprandial contribu8ons to hyperglycemia by A1c range Pooled baseline data from 6 Treat-to-Target design studies 1699 T2DM patients on diet ± OAD Mean A1c 8.69%, FPG 10.8 mmol/l (194 mg/dl) 7-point ambulaty SMBG profiles (ac, 2hr-pc, and hs) Calculations assume hyperglycemia is >5.6 mmol/l (100 mg/dl) Basal hyperglycemia < Baseline A1c ranges On al therapy, fas8ng hyperglycemia dominates over a wide range of A1c Riddle et al, Diabetes Care 34: , 2011 Postprandial hyperglycemia 13

14 Pre- insulina Glicemias Post- insulina Insulina basal Desayuno Almuerzo Cena Basal Insulin: Percent of patients with HbA1c < 7% 29 trials, with 17,588 patients HbA1c < 7% was achieved in 41.4% (95% CI, %). Predicts of response: - first insulin treatment, - er insulin dose - use of 2 al drugs Hypoglycemic events: 0 to 4.71 events/patient/30 days ~1.75 kg ( ) Final Insulin dose: 0.48 ( ) Giugliano et al. Diabetes Research & Clinical Prac8ce 92 (2011) 1 10 HAY FORMAS DE INTENSIFICAR MÁS SENCILLOS? 14

15 STEPwise : diseño Randomisation ExtraSTEP IAsp 1 IAsp 2 IAsp 3 Largest measured PPG increment Target postprandial: 4 8 mmol/l IAsp 1 Insulin detemir initiated Run-in period detemiroads SimpleSTEP IAsp 2 IAsp 3 Largest perceived meal Target preprandial: 4 6 mmol/l Weeks Period 1 Period 2 Period 3 Inclusion criteria: Type 2 diabetes >6 months HbA 1c % Basal insulin 3 months1 3 OADs Meneghini L. Endocr Pract. 2011;17(5):727 STEPwise : cambio en HbA 1c 0.0 Change to week 11 Change to week 23 Change to week HbA 1c (%) ExtraSTEP SimpleSTEP Change was adjusted f baseline HbA 1c p=ns Meneghini L. Endocr Pract. 2011;17(5):727 STEPwise : adicion del primer bolus 70 Percentage of patients (%) ExtraSTEP SimpleSTEP 0 Breakfast Lunch Dinner ExtraSTEP group added insulin based on PPG measurement SimpleSTEP group added insulin based on patient assessment Meneghini L. Endocr Pract. 2011;17(5):727 15

16 Basal Bolus Insulin: Percent of patients with HbA1c < 7% 12 trials, with 2114 patients HbA1c < 7% was achieved in 53.9% (95% CI, ) Hypoglycemic events (mean/ patient/30 days): 0.88 ( ) ~2.75 kg ( ) Final insulin dose: 0.89 U/kg ( ) Escalation from basal to basal-bolus increases success rate in an additional ~12% to 14% of patients - HbA1c < 7% is achieve in ~54% of patients Giugliano et al. Diabetes Research & Clinical Prac8ce 92 (2011) 1 10 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTRAS CONSIDERACIONES Edad: adultos mayes - Men expecta8va de vida - May enfermedad cardiovascular - Reducción TFG - May riesgo de eventos adversos p polifarmacia - May riesgo de complicaciones p hipoglicemia ü Metas menos estrictas ü HbA1c < % si metas más estrictas no se alcanzan fácilmente ü Foco en seguridad de fármacos Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] 16

17 DM en adultos mayes Prevalencia 22-33% 1/3 no diagnos8cados No es lo mismo el diabé8co que llega a la tercera edad al que inicia en la tercera edad May prevalencia de complicaciones Tamizar si el tratamiento va a proveer beneficios No hay ensayos clínicos específicos para esta población ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTRAS CONSIDERACIONES Combilidades - Enf conaria - Falla cardíaca - Enfermedad renal - Disfunción hepánca - Hipoglicemia Ø Meimin: beneficio cardiovascular (UKPDS) Ø Evita hipoglicemia Ø? SUs & precondicionamiento cardíaco Ø? Pioglitazone & eventos CV Ø? Efectos de terapias basados en incre8nas Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin 17

18 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTRAS CONSIDERACIONES Combilidades - Enf conaria - Falla cardíaca - Enfermedad renal - Disfunción hepánca - Hipoglicemia Ø Meimin: Puede usarse a menos que la condición sea severa o inestable Ø Evitar s Ø? Efectos de terapias basadas en incre8nas Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTRAS CONSIDERACIONES Combilidades - Enf conaria - Falla cardíaca - Enfermedad renal - Disfunción hepánca - Hipoglicemia Ø May riesgo de hipoglicemia Ø Meimin & acidosis lácitca US: evitar si Cr 1.5 (1.4 mujeres) UK: dosis si TFG <45 & evitar si TFG <30 Ø Cuidado con SUs (esp. glibenclamida) Ø Ajustar dosis para mayía de IDPP- 4 Ø Evitar exena8de si TFG <30 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTRAS CONSIDERACIONES Combilidades - Enf conaria - Falla cardíaca - Enfermedad renal - Disfunción hepánca - Hipoglicemia Ø Mayía de medicamentos no han sido evaluados en falla renal avanzada Ø Pioglitazone puede ayudar en esteatosis Ø Insulina es la mej opción en enfermedad avanzada Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin 18

19 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTRAS CONSIDERACIONES Combilidades - Enf conaria - Falla cardíaca - Enfermedad renal - Disfunción hepánca - Hipoglicemia Ø Alguna preocupación en relación a asociación a mtalidad Ø selección adecuada de medicamentos en el paciente en may riesgo de sufrirla Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin Initial drug monotherapy Side effects Two drug combinations* Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): Inhibit GLP-1 recept Maj side effect(s) moderate risk edema, HF, fx s intermediate neutral rare loss GI est risk variable Three drug combinations Inhibit GLP-1 recept SU Me complex insulin strategies Insulin # (multiple daily doses) Recomendaciones si la meta es no aumentar de peso Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] Initial drug monotherapy Side effects Two drug combinations* Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): Inhibit GLP-1 recept Maj side effect(s) moderate risk edema, HF, fx s intermediate neutral rare loss GI est risk variable Three drug combinations If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (der not meant to denote any specific preference): Inhibit GLP-1 recept SU Me complex insulin strategies Insulin # (multiple daily doses) Recomendaciones para evitar hipoglicemia Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print] 19

20 Initial drug monotherapy Side effects Two drug combinations* Healthy eating, weight control, increased physical activity neutral/loss GI / lactic acidosis If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (der not meant to denote any specific preference): Inhibit GLP-1 recept Maj side effect(s) moderate risk edema, HF, fx s intermediate neutral rare loss GI est risk variable Three drug combinations If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (der not meant to denote any specific preference): Inhibit GLP-1 recept SU If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with 1-2 non-insulin agents: Me complex insulin strategies Insulin # (multiple daily doses) Recomendaciones para minimizar costos Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print] Conclusiones Meta de Hba1c debe establecerse de fma individual según las caracterís8cas propias de cada paciente En pacientes jóvenes, con menos 8empo de evolución, men mbilidad, prevención primaria se debe ser más estrictos Recdar siempre los beneficios de le memia metabólica o efecto legado PREGUNTAS CHENKU2409@GMAIL.COM 20