Més enllà del bloqueig del sistema renina angiotensina en el pacient diabètic: canvi de paradigma. Risc Cardiovascular

Transcripción

1 Més enllà del bloqueig del sistema renina angiotensina en el pacient diabètic: canvi de paradigma. Risc Cardiovascular Dr. Marco A. Paz Bermejo Cardiólogo Hospital Santa Caterina. Girona.

2 PREVENCIÓN CARDIOVASCULAR. REFLEXIONES CUÁL ES EL PRINCIPAL OBJETIVO EN LA PREVENCIÓN CARDIOVASCULAR?. MEJORAR EL PERFIL LIPÍDICO Y REDUCIR LA PA O LA HbA1c, SUPONEN SIEMPRE UNA MEJORÍA DE LA MORBI-MORTALIDAD?. QUÉ EVIDENCIAS DEBEMOS EXIGIR A UN FÁRMACO PARA UTILIZARLO?

3 EL LARGO CAMINO DE LA PREVENCIÓN CARDIOVASCULAR

4 EL LARGO CAMINO DE LA PREVENCIÓN CARDIOVASCULAR LO QUE NOS HAN ENSEÑADO LOS ESTUDIOS.

5 TODA MEJORÍA ANALÍTICA CONLLEVA UNA REDUCCIÓN DEL RIESGO CARDIOVASCULAR?

6 TODA MEJORÍA ANALÍTICA CONLLEVA UNA REDUCCIÓN DEL RIESGO CARIOVASCULAR? EL EJEMPLO DEL chdl

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8 Lipid Effects of CETP Inhibitors/Modulators % Change from Baseline CETP Agent Dose (Mg/day) HDL-C (%) LDL-C (%) TG (%) Torcetrapib Anacetrapib Evacetrapib Dalcetrapib Adapted from Cannon C et al. JAMA. 2011;306: Nicholls SJ et al. JAMA. 2011;306:

9 Torcetrapib: BUT Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality Patients Without Event (%) Atorvastatin only Torcetrapib plus atorvastatin Days After Randomization HR = 1.25 P = Is the toxicity of torcetrapib related to the mechanism or the molecule? Barter PJ et al. N Engl J Med. 2007;357:

10 Dalcetrapib Phase IIb Trial HDL-C Increase at Week 12 *P < vs placebo * Change From Baseline (%) * * placebo n = 73 dalcetrapib 300 mg n = 75 dalcetrapib 600 mg n = 67 dalcetrapib 900 mg n = 72 NOTE: Dalcetrapib 600 mg is the dose used in phase III Stein EA. Am J Cardiol. 2009;104:82-91.

11 ESTUDIO DAL-OUTCOMES EFECTOS SOBRE COLESTEROL

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14 Bueno..Y la diabetes, qué?

15 SEGURIDAD /EFICACIA

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21 Monami M et al: Metaanálisis 37 ensayos SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) con saxagliptina señaló que esta molécula no era inferior al placebo en eventos cardiovasculares (ECV) en pacientes de alto riesgo cardiovascular, pero mostró que hubieron más ingresos por ICC (3,5% frente a 2,8%; HR 1.27; IC 95% 1,07-1,51; P = 0,007)

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23 Y DE EFICACIA, CÓMO ANDAMOS?

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27 Primary Composite Cardiovascular Outcome Time to first occurrence of: Cardiovascular-related death Nonfatal myocardial infarction Nonfatal stroke Hospitalization for unstable angina A Clinical Endpoints Committee, blinded to therapy allocation, reviewed all potential CVD endpoints independently. Green JB et al. NEJM 2015; DOI: /NEJMoa

28 Glycemic Control Least Squares Mean HbA1c ± 1SD Overall LS Mean difference -0.29% (-0.32, -0.27), p< Green JB et al. NEJM 2015; DOI: /NEJMoa

29 * CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina Green JB et al. NEJM 2015; DOI: /NEJMoa

30 * CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina Green JB et al. NEJM 2015; DOI: /NEJMoa

31 Numbers of patients with events Sitagliptin n=7332 Green JB et al. NEJM 2015; DOI: /NEJMoa Placebo n=7339 Primary composite CV Outcome 839 (11.4%) 851 (11.6%) Individual components Primary Composite Cardiovascular Outcome ITT Population 4.06 per 100 pyrs 4.17 per 100 pyrs ITT HR=0.98 (0.89, 1.08), p=0.65 CV death 311 (4.2%) 291 (4.0%) Nonfatal MI 275 (3.8%) 286 (3.9%) Nonfatal stroke 145 (2.0%) 157 (2.1%) Hospitalization for unstable angina 108 (1.5%) 117 (1.6%)

32 * Adjusted for history of heart failure at baseline Green JB et al. NEJM 2015; DOI: /NEJMoa

33 Clinical Outcomes with Alogliptin EXAMINE Safety Endpoints (n=5380) Hazard ratio (95% CI) P value Primary composite 0.96 ( 1.16)* 0.32 Primary endpoint components CV death 0.79 ( ) 0.10 Nonfatal MI 1.08 ( ) 0.47 Nonfatal stroke 0.91 ( ) 0.71 Primary secondary endpoint 0.95 ( 1.14)* 0.26 Death from any cause 0.85 ( ) 0.21 *Upper boundary of 1-sided repeated CI, alpha level Favors alogliptin CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina. CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; MI, myocardial infarction. White W, et al. N Engl J Med. 2013;369:

34 Clinical Outcomes with Saxagliptin SAVOR-TIMI Prespecified Composite Endpoints and Mortality (n=16,492) Hazard ratio (95% CI) P value Primary composite endpoint* 1.00 ( ) 0.99 Secondary composite endpoint 1.02 ( ) 0.66 Death from any cause 1.11 ( ) 0.15 CV death 1.03 ( ) 0.52 Favors saxagliptin *CV death, nonfatal MI, or nonfatal ischemic stroke; CV death, nonfatal MI, nonfatal ischemic stroke, hospitalization for HF, coronary revascularization, or unstable angina. CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction. Scirica BM, et al. N Engl J Med. 2013;369,

35 Individual Secondary Outcomes with Saxagliptin SAVOR-TIMI Prespecified Individual Endpoints (n=16,492) Hazard ratio (95% CI) P value Myocardial infarction 0.95 ( ) 0.52 Ischemic stroke 1.11 ( ) 0.38 Hospitalization for unstable angina 1.19 ( ) 0.24 Hospitalization for heart failure 1.27 ( ) Hospitalization for coronary revascularization 0.91 ( ) 0.18 Renal endpoint* 1.08 ( ) 0.46 Hospitalization for hypoglycemia 1.22 ( ) 0.33 Favors saxagliptin *Doubling of creatinine, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dl CI, confidence interval; CV, cardiovascular; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction. Scirica BM, et al. N Engl J Med. 2013;369,

36 ES ESO SUFICIENTE?

37 SIN EMBARGO.

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39 EMPA-REG OUTCOME Randomised, double-blind, placebo-controlled CV outcomes trial Objective To examine the long-term effects of empagliflozin versus placebo, in addition to standard of care, on CV morbidity and mortality in patients with type 2 diabetes and high risk of CV events CV, cardiovascular 39

40 Trial design Placebo (n=2333) Screening (n=11531) Randomised and treated (n=7020) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Study medication was given in addition to standard of care Glucose-lowering therapy was to remain unchanged for first 12 weeks Treatment assignment double masked The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event 40

41 Key inclusion and exclusion criteria Key inclusion criteria Adults with type 2 diabetes BMI 45 kg/m 2 HbA1c 7 10%* Established cardiovascular disease Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease Key exclusion criteria egfr <30 ml/min/1.73m 2 (MDRD) BMI, body mass index; egfr, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease *No glucose-lowering therapy for 12 weeks prior to randomisation or no change in dose for 12 weeks prior to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation 41

42 Primary outcome: 3-point MACE HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p ) 42

43 CV death HR 0.62 (95% CI 0.49, 0.77) p< Cumulative incidence function. HR, hazard ratio 43

44 CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p= Empagliflozin 25 mg HR 0.59 (95% CI 0.45, 0.77) p= Cumulative incidence function. HR, hazard ratio 44

45 CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/ / (0.74, 0.99)* CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) Favours empagliflozin Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction Favours placebo 45

46 Hospitalisation for heart failure HR 0.65 (95% CI 0.50, 0.85) p= Cumulative incidence function. HR, hazard ratio 46

47 Hospitalisation for heart failure Empagliflozin 10 mg HR 0.62 (95% CI 0.45, 0.86) p= Empagliflozin 25 mg HR 0.68 (95% CI 0.50, 0.93) p= Cumulative incidence function. HR, hazard ratio 47

48 All-cause mortality HR 0.68 (95% CI 0.57, 0.82) p< Kaplan-Meier estimate. HR, hazard ratio 48

49 All-cause mortality Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87) p= Empagliflozin 25 mg HR 0.67 (95% CI 0.54, 0.83) p= HR 0.68 (95% CI 0.57, 0.82) p< Kaplan-Meier estimate. HR, hazard ratio 49

50 Manejo de las infecciones genitourinarias relacionadas Más frecuentes en mujeres con empagliflozina Informar al paciente del riesgo y recomendar extremar la higiene personal Normalmente responden al tratamiento habitual (dosis única de fluconazol 100 mg), pero hasta un 20% pueden ser recidivantes Antes de retirar el fármaco, pensar el balance riesgo beneficio Infección

51 Riesgo de amputaciones en extremidades inferiores y fracturas óseas La incidencia de amputaciones en extremidades inferiores y fracturas óseas fue similar al placebo Placebo + SOC (n=2333) Jardiance 10 mg + SOC (n=2345) Jardiance 25 mg + SOC (n=2342) Pooled Jardiance + SOC (n=4687) Amputación de miembros inferiores 1 43 (1,8) 42 (1,8) 46 (2,0) 88 (1,9) Fractura ósea 2 91 (3,9) 92 (3,9) 87 (3,7) 179 (3,8) Los datos se expresan como n (%) 1. Kohler S et al. Adv Ther 2017;34:1707 (supplementary appendix); 2. Zinman B et al. N Engl J Med 2015;373:2117

52 Número necesario para tratar (NNT) para prevenir una muerte en ensayos clínicos en pacientes con alto riesgo CV Simvastatina 1 por 5,4años Ramipril 2 por 5años Empagliflozina por 3años Alto Riesgo CV 5% DM, 26% HTA Era pre-estatina Alto Riesgo CV 38% DM, 46% HTA Era pre-ieca/ara <29% estatina DM 2 con alto riesgo CV 92% HTA >80% IECA/ARA >75% estatina S Investigators. Lancet 1994; 344: Disponible en: 2. Yusuf S, Sleight P, Pogue J, et al. N Engl J Med 2000;342: Disponible en:

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56 Clinical Outcomes with Antihyperglycemic Agents LEADER (LIRAGLUTIDE EFFECT AND ACTION IN DIABETES: EVALUATION OF CARDIOVASCULAR OUTCOME RESULTS)

57 Clinical Outcomes with Liraglutide LEADER (N=9340) Hazard ratio (95% CI) P value Primary composite endpoint* 0.87 ( ) 0.01 Expanded composite endpoint 0.88 ( ) Death from any cause 0.85 ( ) 0.02 CV death 0.78 ( ) Fatal or nonfatal MI 0.86 ( ) Nephropathy 0.78 ( ) Favors liraglutide *CV death, nonfatal MI (including silent MI), or nonfatal stroke; CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF. CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. Marso SP, et al. N Engl J Med Jun 13. [Epub ahead of print] 57

58 The Research Medical Center, Kansas City, MO (S.P.M.); School of Medicine, Swansea University, Swansea, United Kingdom (S.C.B.); Department of Medicine and Aging Science and Center of Excellence on Aging and Translational Medicine, G. d Annunzio University, Chieti-Pescara, Italy (A.C.); CPClin Research Center/Hospital Israelita Albert Einstein, São Paulo (F.G.E.); Hospital Universitario Quirón Salud Madrid, Facultad de Ciencias de la Salud, Universidad Europea de Madrid, Madrid (E.J.); Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael s Hospital, University of Toronto, Toronto (L.A.L.), and the University of Manitoba, Winnipeg (V.W.) both in Canada; University of Texas Southwestern Medical Center (I.L.) and Dallas Diabetes Research Center at Medical City (J.R.) both in Dallas; University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany (J.S.); Physicians East, Greenville, NC (M.L.W.); and Novo Nordisk, Søborg (O.H., A.G.H., J.P.), and the Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup (T.V.) both in Denmark.

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60 EMPA-REG OUTCOME : What effect will these results have on clinical practice guidelines? 60

61 CDA (Canadian Diabetes Association): Update of Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada (Nov 2016*) Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2015; 39(4):250-2.

62 Guías prevención CV ESC 2016 Piepoli MF, Hoes AW, Agewall S,et al. Rev Esp Cardiol. 2016; 69(10):939.e1-e87.

63 Guías SEC Rev Esp Cardiol Qué dicen las guías de la IC?

64 CONCLUSIONES La prevención no consiste sólo en maquillar cifras analíticas o de PA, sino de reducir la morbi-mortalidad. No toda mejoría analítica o conlleva una reducción de morbimortalidad. Es indispensable conocer el perfil de seguridad de los fármacos que empleamos. En pacientes diabéticos en prevención secundaria, diversos fármacos parecen aportar un beneficio más allá del mero control metabólico y debe considerarse su uso en determinadas circunstancias clínicas.

65 GRACIAS DE TODO CORAZÓN.