Inhibidores de sglt2
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Posicionamiento respecto al papel de los inhibidores de la SGLT2 en el tratamiento farmacológico de la Diabetes Mellitus tipo II
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Inhibidores de sglt2
- 1. INHIBIDORES DE SGLT2 ¿CUÁL ES SU LUGAR EN T RATAMIENTO DE LA DM T IPO 2?
- 2. INHIBIDORES DE LA SGTL2 COMERCIALIZADOS EN ESPAÑA • Dapagliflozina • Empagliflozina • Canaglifozina
- 6. EFICACIA CLÍNICA • Descenso de Hb glicada: 0,5-0,8% de media
- 9. EFICACIA CLÍNICA • Descenso de Hb glicada: 0,5-0,8% de media • Disminución de la Glucemia en ayunas
- 11. EFICACIA CLÍNICA • Descenso de Hb glicada: 0,5-0,8% de media • Disminución de la Glucemia en ayunas • Disminución de la Glucemia postprandial
- 13. EFICACIA CLÍNICA • Descenso de Hb glicada: 0,5-0,8% de media • Disminución de la Glucemia en ayunas • Disminución de la Glucemia postprandial • Disminución de peso: media 3 Kg
- 16. EFICACIA CLÍNICA • Descenso de Hb glicada: 0,5-0,8% de media • Disminución de la Glucemia en ayunas • Disminución de la Glucemia postprandial • Disminución de peso: media 3 Kg • Reducción de la Presión arterial
- 18. CONSIDERACIONES PARA SU USO • Por su mecanismo de acción, no se deben usar en pacientes con Insuficiencia renal. (FG < 60 ml/min)
- 19. SEGURIDAD CLÍNICA • Los principales efectos secundarios son: • Infecciones genitourinarias • Depleción de volumen • Deterioro de función renal • Aumento del riesgo de fracturas (canagliflozina) • Aumento del riesgo de amputaciones (canagliflozina)
- 21. SEGURIDAD CLÍNICA • Los principales efectos secundarios son: • Infecciones genitourinarias • Depleción de volumen • Deterioro de función renal • Aumento del riesgo de fracturas (canagliflozina) • Aumento del riesgo de amputaciones (canagliflozina) • Riesgo de hipoglucemia
- 25. CRITERIOS DE INCLUSION Y EXCLUSION • Principales C. Inclusión: – Adultos con DM tipo 2 – IMC ≤45 kg/m2 – HbA1c 7–10%* – Enfermedad CV establecida: • IAM previo, enfermedad coronaria conocida, arteriopatía periférica, Ictus. • Principal C. De Exclusión: – eGFR <30 mL/min/1.73m2 (MDRD) 25
- 26. 26 • La medicación del estudio se añadió al tratamiento hipoglucemiante que ya tomaban, y no se podía modificar durante las primeras 12 semanas del estudio Randomised and treated (n=7020) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Placebo (n=2333) Screening (n=11531)
- 27. OBJETIVOS DEL ESTUDIO • Objetivo Primario • End-pint combinado: Tiempo hasta la primera aparición de muerte CV, IAM no fatal, Ictus no fatal • Objetivos secundarios: • End-point combinado: Tiempo hasta la primera aparición de muerte CV, IAM no fatal, Ictus no fatal, o hospitalización por Angina inestable 27 CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event
- 28. OTROS OBJETIVOS EVALUADOS • Muerte CV • IAM no fatal • Ictus no fatal • Hospitalización por Insuficiencia cardiaca • Mortalidad global 28 CV, cardiovascular; MI, myocardial infarction
- 29. CARACTERÍSTICAS BASALES Placebo (n=2333) Empagliflozina 10 mg (n=2345) Empagliflozina 25 mg (n=2342) Edad 63.2 (8.8) 63.0 (8.6) 63.2 (8.6) Varones 1680 (72.0) 1653 (70.5) 1683 (71.9) Region Europa 959 (41.1) 966 (41.2) 960 (41.0) Norteamérica* 462 (19.8) 466 (19.9) 466 (19.9) Asia 450 (19.3) 447 (19.1) 450 (19.2) Latinoamérica 360 (15.4) 359 (15.3) 362 (15.5) Africa 102 (4.4) 107 (4.6) 104 (4.4) Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug 29 *Includes Australia and New Zealand
- 30. Fármacos hipoglucemiantes* Metformina 1734 (74.3) 1729 (73.7) 1730 (73.9) Sulfonilurea 992 (42.5) 985 (42.0) 1029 (43.9) Tiazolidinediona 101 (4.3) 96 (4.1) 102 (4.4) Insulina 1135 (48.6) 1132 (48.3) 1120 (47.8) Dosis media, U** 65 (50.6) 65 (47.9) 66 (48.9) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) HbA1c, % 8.08 (0.84) 8.07 (0.86) 8.06 (0.84) Tiempo desde el debút de la DM (años) ≤5 423 (18.1) 406 (17.3) 434 (18.6) >5 to 10 571 (24.5) 585 (24.9) 590 (25.2) >10 1339 (57.4) 1354 (57.7) 1318 (56.3) CARACTERISTICAS BASALES: DIABETES TIPO 2 Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug 30 *Medication taken alone or in combination **Placebo, n=1135; empagliflozin 10 mg, n=1132; empagliflozin 25 mg,
- 31. END-POINT PRIMARIO: TIEMPO HASTA APARICION DE MUERTE CV, IAM NO FATAL, ICTUS NO FATAL
- 32. TIEMPO HASTA APARICION DE MUERTE CV
- 33. TIEMPO HASTA MUERTE POR CUALQUIER CAUSA
- 34. TIEMPO HASTA 1ª HOSPITALIZACIÓN POR I.C.
- 35. EVOLUCION DE LA HB GLICADA 6.0 6.5 7.0 7.5 8.0 8.5 9.0 Adjustedmean(SE)HbA1c(%) Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg 2294 2296 2296 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 2272 2272 2280 2188 2218 2212 2133 2150 2152 2113 2155 2150 2063 2108 2115 2008 2072 2080 1967 2058 2044 1741 1805 1842 1456 1520 1540 1241 1297 1327 1109 1164 1190 962 1006 1043 705 749 795 420 488 498 151 170 195 12 28 52 94 10880 12266 1360 150 164 178 192 20640 35
- 36. EVOLUCION DEL PESO 80 82 84 86 88 90 Adjustedmean(SE)weight(kg) Week 2285 2290 2283 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 1915 1893 1891 2215 2238 2226 2138 2174 2178 1598 1673 1678 1239 1298 1335 425 483 489 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 36 28 52 1080 164 22012
- 37. EVOLUCION DE LA T.A.SISTOLICA 37 125 127 129 131 133 135 137 139 141 143 145 Adjustedmean(SE)systolic bloodpressure(mmHg) Week 2322 2322 2323 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 2235 2250 2247 2203 2235 2221 2161 2193 2197 2133 2174 2169 2073 2125 2129 2024 2095 2102 1974 2072 2066 1771 1853 1878 1492 1556 1571 1274 1327 1351 1126 1189 1212 981 1034 1070 735 790 842 450 518 528 171 199 216 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 16 28 52 94 10880 12266 1360 150 164 178 192 20640
- 38. EVOLUCION DE LA T.A. DIASTOLICA 38 70 71 72 73 74 75 76 77 78 79 80 Adjustedmean(SE)diastolic bloodpressure(mmHg) Week2322 2322 2323 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 2235 2250 2247 2203 2235 2221 2161 2193 2197 2133 2174 2169 2073 2125 2129 2024 2095 2102 1974 2072 2066 1771 1853 1878 1492 1556 1571 1274 1327 1351 1126 1189 1212 981 1034 1070 735 790 842 450 518 528 171 199 216 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 16 28 52 94 10880 12266 1360 150 164 178 192 20640
- 39. ¿ SON ESTOS RESULTADOS UN “EFECTO DE CLASE”?
- 40. ESTUDIO CVD REAL
- 41. ESTUDIO OBSERVACIONAL, A PARTIR DE REGISTROS DE BASES DE DATOS NACIONALES
- 42. OBJETIVOS • Primario • Comparar el riesgo de hospitalización por IC en pacientes que comienzan tratamiento con un SGLT2 vs cualquier otro hipoglucemiante. • Secundario • Muerte por todas las causas en ambos grupos • Muerte + ingreso por IC en ambos grupos
- 43. CRITERIOS DE INCLUSION • Padecer DM tipo 2 • Edad >18 • Disponer de datos en el registro desde antes de un año a la inclusion en el estudio
- 45. TIPO DE SGLT2
- 48. INGRESOS POR I. CARDIACA
- 49. SEGURIDAD CARDIOVASCULAR • Ensayo clínico EMPA-REG: empagliflozina, añadida a la terapia basal, en enfermos con enfermedad CV previa, disminuye el riesgo CV. • Estudio Observacional REAL-CVD: efecto favorable de los SGLT2 en la disminución del riesgo de hospitalización por I.C. (debe confirmarse en EC)
- 50. RESUMIENDO • Eficacia modesta en el control de la glucemia • Efecto positivo en la disminución de peso • Buen perfil de seguridad • Empagliflozina disminuye el riesgo CV en pacientes con enfermedad CV previa. • Precio elevado (al nivel de I-DPP-4)
- 52. 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
- 53. 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
- 54. 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
- 55. OPINIÓN PERSONAL • Uso a partir del segundo escalón • Evitarlo en ancianos polimedicados (sobre todo si toman diuréticos o tienen disfunción renal leve) • En enfermos con enfermedad CV previa, es de elección Empagliflozina
Notas del editor
- tlr-1245_0025final—01-1501. Table 15.1.4.1: 1 Demographic data − treated set.
- Table 15.1.4.1: 1 Table 15.2.4.3.8: 5 but updated by MM (awaiting final PDF).
- 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.1.3: 1 HbA1c (%) change from baseline MMRM results over time − FAS (OC−AD)
- 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.3.3: 1 Weight (kg) change from baseline MMRM results over time − treated set (OC−AD)
- 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.5.3: 1 SBP (mmHg) change from baseline MMRM results over time − treated set (OC−AD)
- 1245_0025final--01-1502--study-report-body. Table 15.2.4.3.6.3: 1 DBP (mmHg) change from baseline MMRM results over time − treated set (OC−AD)
- If the A1c target is not achieved after ~3 months, there is no clearly preferred second agent after metformin. Each drug has its advantages and disadvantages, and what might be best for one patient may not be so for the next. In general, the clinician should consider one of 6 treatment options combined with metformin (i.e., dual combination): a sulfonylurea, TZD, DPP-4 inhibitor, SLGT2 inhibitor, GLP-1 receptor agonist or basal insulin. The major update to this figure from 2012 is the inclusion of the SGLT2 inhibitors. Note that the order in the chart is determined by historical introduction and route of administration and is not meant to imply any specific preference. Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects, especially hypoglycemia. Shared decision-making with the patient may help in the selection of therapeutic options. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider these in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects.
- If the A1c target is still not achieved after ~3 months and appropriate drug dosage titration, add a third agent (i.e., triple combination therapy), with mechanisms of action should complement each other. Options obviously become more limited as one progresses down the figure. When glucose levels are especially high, a regimen that incorporates basal insulin should be strongly considered, especially if the patient is symptomatic. One important benefit of insulin is its near universal effectiveness when dosed properly. Drug choice is based on patient preferences as well as various patient, disease, and drug characteristics, with the goal being to reduce glucose concentrations while minimizing side effects, especially hypoglycemia. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects.
- Previously, when combinations of multiple oral agents (i.e., up to triple combination therapy) were no longer effective at controlling blood glucose, insulin was typically added, initially as a single injection of basal insulin. If this was or became ineffective in controlling HbA1c, post-prandial hyperglycemia was usually to blame. Adding several injections of rapid-acting insulin analogues (‘basal-bolus’ insulin therapy) would be the next step to control meal time glycemic excursions. Over the past several years, there has been increasing evidence that the combination of basal insulin with a GLP-1 receptor agonist may provide equal glucose lowering effect as up to 3 injections of meal time insulin, yet with weight loss instead of weight gain, and with less hypoglycemia. This updated figure therefore underscores the potential value of this specific combination. It should be considered in patients who appear to need more than basal insulin, with or without oral agents. In those patients who do not respond adequately to the addition of a GLP-1 receptor agonist to basal insulin, the “basal–bolus” insulin strategy should be used instead (or twice daily premixed insulin.) In selected patients at this stage of disease, the addition of an SGLT2 inhibitor may further improve control and reduce the amount of insulin required. This is particularly an issue when large doses of insulin are required in obese, highly insulin-resistant patients. Another, older, option, the addition of a TZD (usually pioglitazone), also has an insulin-sparing effect and may also reduce HbA1c, albeit at the expense of weight gain, edema, and increased heart failure risk.