(ADA – 2016) – Dra. Mónica Barraza
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LO MEJOR DEL 76° CONGRESO DE LA AMERICAN DIABETES ASSOCIATION, JUNIO 2016 Presentado por: MONICA BARRAZA GERARDINO Médico Internista Endocrinólogo TEMÁTICA Results of the Liraglutide Effect and Action in Diabetes – Evaluation of Cardiovascular Outcome Results (LEADER) trial Update from the EMPA-REG Outcome trial Discusión LIRAGLUTIDE EFFECT AND ACTION IN DIABETES – EVALUATION OF CARDIOVASCULAR OUTCOME RESULTS (LEADER) TRIAL Steering Committee Academic Members John Buse USA (Chair) Steven P Marso USA (Co-Chair) Richard Bergenstal USA Gilbert Daniels USA Johannes Mann Germany Michael Nauck Germany Steven Nissen USA Stuart Pocock UK Neil Poulter UK William Steinberg USA Bernard Zinman Canada Sponsor (Novo Nordisk) Kirstine Brown-Frandsen Peter Kristensen Mette Stockner Lasse S Ravn (2011-2016) Alan Moses (2009-2014) Marcin Zychma (2009-2011) Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. LEADER: DISEÑO Occurrence of an acute coronary or cerebrovascular event within 14 days before screening and randomization CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; HbA1c: glycated hemoglobin; MEN-2: multiple endocrine neoplasia type 2; MTC: medullary thyroid cancer; OAD: oral antidiabetic drug; OD: once daily; T2DM: type 2 diabetes mellitus. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Desenlaces primarios y secundarios CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. LEADER guías de tratamiento CV: cardiovascular; CVA: cerebrovascular accident; HbA1c: glycated hemoglobin; LDL: low-density lipoprotein; MI: myocardial infarction. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Características Poblacionales de Base *Heart failure includes New York Heart Association class I, II and III. BMI: body mass index; HbA1c: glycated hemoglobin. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Riesgo Cardiovascular Basal > 50 años Data are number of patients (%). CHD: coronary heart disease; CKD: chronic kidney disease; CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate; NYHA: New York Heart Association; TIA: transient ischemic attack. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Riesgo Cardiovascular Basal > 60 años Data are number of patients (%). CVD: cardiovascular disease. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. HbA1c Data are estimated mean values from randomization to month 48. CI: confidence interval; ETD: estimated treatment difference; HbA1c: glycated hemoglobin. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Antidiabéticos de base TZD: thiazolidinediones. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Antidiabéticos introducidos durante el estudio DPP-4: dipeptidyl peptidase-4; GLP-1RA: glucagon-like peptide-1 receptor agonist; SGLT-2: sodium-glucose co-transporter-2; TZD: thiazolidinedione. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Peso corporal Data are estimated mean values from randomization to last scheduled visit for body weight measurement (month 48). CI: confidence interval; ETD: estimated treatment difference. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Desenlace primario Muerte cardiovascular, IM no fatal o ACV no fatal The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Muerte Cardiovascular The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Desenlaces primarios y secundarios cardiovasculares *Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate. †The primary composite outcome in the time-to-event analysis consisted of the first occurrence of death from cardiovascular causes (181 patients in the liraglutide group vs. 227 in the placebo group), non-fatal (including silent) myocardial infarction (275 vs. 304), or non-fatal stroke (152 vs. 163). The p-value is for superiority. ‡The expanded composite outcome included death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure. §This analysis was not prespecified. CI: confidence interval; CV: cardiovascular; UAP: unstable angina pectoris. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Número necesario a tratar para prevenir… CV: cardiovascular; MACE: major adverse cardiovascular event. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Hipoglucemia Confirmed hypoglycemia was defined as plasma glucose level of less than 56 mg per deciliter (3.1 mmol per liter) or a severe event. Severe hypoglycemia was defined as hypoglycemia for which the patient required assistance from a third party. Analyzed using a negative binomial regression model. CI: confidence interval; PG: plasma glucose. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. Hipoglucemia Full analysis set. Confirmed hypoglycemia was defined as plasma glucose level of less than 56 mg per deciliter (3.1 mmol per liter) or a severe event. Hypoglycemic episodes on and after randomization date and up to visit 15 (end of treatment) are included (episodes with a missing date are included). %: proportion of subjects; ADA: American Diabetes Association; N: number of subjects; PG: plasma glucose; R: event rate per 100 observation years. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA. UPDATE FROM THE EMPAREG OUTCOME TRIAL Comité directivo EMPA-REG OUTCOME® Bernard Zinman [Chair], Lunenfeld-Tanenbaum Research Institute, Toronto, Canada Christoph Wanner, Würzburg University Clinic, Würzburg, Germany John M. Lachin, The George Washington University, Rockville, MD, USA David Fitchett, University of Toronto, Toronto, Canada Erich Bluhmki, Boehringer Ingelheim, Biberach, Germany Odd Erik Johansen, Boehringer Ingelheim KS, Asker, Norway Hans J. Woerle, Boehringer Ingelheim, Ingelheim, Germany Uli C. Broedl, Boehringer Ingelheim, Ingelheim, Germany Silvio E. Inzucchi, Yale University School of Medicine, CT, USA 23 Países participantes 590 sites in 42 countries Asia North America, Australia, New Zealand Latin America Europe Africa 24 Diseño Placebo (n=2333) Tamizaje (n=11531) Aleatorización y tratamiento (n=7020) Empagliflozina 10 mg (n=2345) Empagliflozina 25 mg (n=2342) Duración 2.6 años Observación 3,1 años – Antidiabéticos sin cambios durante las primeras 12 semanas • Medicacación de acuerdo a las guías de manejo • Doble ciego • El estudio continuó hasta que al menor 691 hallan presentado un desenlace primario 25 Criterios de inclusión y exclusión • Criterios de Inclusión – Adultos con diabetes tipo 2 – IMC ≤45 kg/m2 – HbA1c 7–10%* – Enfermedad cardiovascular establecida • Infarto de miocardio previo, enfermedada coronaria, ACV, angina inestable o enfermedad arterial periférica oclusiva • Criterios de exclusión – eGFR <30 mL/min/1.73m2 (MDRD) 26 Desenlaces • Desenlace primario – 3-point MACE: Tiempo para la primera ocurrencia de muerte cardiovascular, IM no fatal o ACV no fatal • Desenlace secundario – 4-point MACE: Tiempo para la primera ocurrencia de muerte cardiovasccular, IM no fatal, ACV no fatal, y hospitalización por angina inestable • Desenlaces microvasculares – Fotocoagulación de retina, hemorragia vítrea, ceguera relacionada con diabetes – Inicio o deterioro de Nefropatía 27 Desenlaces Renales • Inicio o deterioro de nefropatía – Progresión a macroalbuminuria – Duplicación de la creatinina + TFG < 45 ml/min x 1,73 calculado por MDRD – Inicio de terapia de reemplazo renal – Muerte por enfermedad renal • Análisis post hoc subgrupo Enfermedad Renal preexistente (TFG de 59 ml/min o macroalbuminuria) • Análisis post hoc de duplicación de creatinina, inicio de terapia reemplazo renal o muerte por enfermedad renal 28 Características de Base Características de Base Características de Base Características de Base Inicio o deterioro de nefropatía 12.5% vs 18.8% Reducción del 39% Desenlaces renales Eventos Adversos DISCUSION Caracteristicas ELIXA LEADER EMPA-REG n 6068 9340 7020 Seguimiento 2,1 años 3,8 años 3,1 años Riesgo cardiovascular Muy alto Muy alto-Alto Alto Edad 59+ 9,7 64.3+ 7,2 años 63,1 + 8,6 años HbA1c de base 7.7% 8.7% 8,10% HR 0,78 (0,66-0,93) HR 0,62 (0,49-0,77) HR 0,87 (0,78-0,97) HR 0,86 (0,74-0,99) Muerte Cardiovascular MACE HR 1,02 (0,89-1,17) LEADER EMPA-REG • Potencial beneficio en enfermedad cardiovascular establecida y TFG < 60 ml/min • Perfil de seguridad • Beneficios cardiovasculares, renales, supervivencia • Cambios en factores de riesgo…? • Desenlace no medido • Descenso volumen plasmático • Fuente alterna de energia / cuerpos cetónicos
