DISLIPIDEMIAS

Dra. Pilar Cornejo Arenas2012

Apo B-48Remanentesde QuilomicrnApo B-100Apo B-48Apo EApo B-100Apo A- IA II, Apo- DColesterolTriglicridosApo C-IIComposicin de las Lipoprotenas

Naghavi et al. Circulation 2003; 108(14): 1664-1672

Ateroma TempranoAteroma AvanzadoOx LDLOx LDLLDLDiseminacinde agentesinfecciosos ?Complejos LipdicosApoptticosWilensky Curr Opin Card 2007 (Nov)

DislipidemiaInterpretacin, Clasificacin y ObjetivosLDL colesterolTriglicridosHDL colesterolNo HDL colesterolApolipoprotena BVariables

Riesgo Cardiovascular GlobalNivel srico

Factores de RiesgoStress OxidativoDisfuncin EndotelialActivacin del Msculo LisoSecuela Clnica VasoconstriccinTrombosisInflamacinRuptura de PlacaLesin Vascular &RemodelacinEndotelina CatecolaminasPAI-1, AgregacinPlaquetaria, FactorTisularVCAM, ICAMCitokinasProteolisisInflamacinFactoresCrecimientoCitokinasMatrixON Mediadores Locales ECA/AII TisularLDLPresin ArterialDiabetes MellitusTabaco

Principales Factores de Riesgo (Exclusivos del Colesterol LDL) que Modifican las Metas para los Valores del LDLHbito de fumarHipertensin (PA 140/90 mmHg o en medicacin antihipertensiva)Niveles bajos de colesterol HDL (

Factores de Riesgo para Enfermedad CardiovascularOtros factores de riesgoFactores hemostticos: Fibringeno, Factor VII, actividad fibrinoltica, inhibidor del activador plasminogenoHomocistenaAlcoholPersonalidad Tipo AAntioxidantes

DISLIPIDEMIAS SECUNDARIAS Relacionadas a elevacin de Colesterol totalDieta rica cidos grasos saturadosHipotiroidismoSndrome nefrticoEnfermedad heptica crnicaColestasisDisglobulinemiaSindrome de CushingAnticonceptivos oralesAnorexia nervosaPorfiria intermitente aguda

Dieta rca en carbohidratosHipotiroidismoInsuficiencia renal crnicaConsumo excesivo de alcoholPancreatitisDisglobulinemiaObesidadEmbarazoBulimiaPorfiria intermitente agudaSindrome de CushingHipopitituarismoDiabetes mellitusLupus eritematoso sistmicoDrogas: diureticos, beta Bloqueadores, estrogenos, glucocorticoides, isotretinoinaDISLIPIDEMIAS SECUNDARIAS Relacionadas a elevacin de Trigliceridos

Paciente de muy alto riesgoLDL ptimo < 70 mg/dl (Estudios HPS PROVE IT)Paciente con ECV establecida +Mltiples Factores de riesgo mayores y especialmente diabetesFactores de riesgo severos o pobremente controlados especialmente continuar con cigarrilloMltiples factores de riesgo del sndrome metablico (triglicridos > 200 mg/dl + no HDL-c >= 130 mg/dl con HDL-c

Diferentes guas, pero en general, una conducta similarTodas las guas admiten la importancia de reducir el C-LDL como blanco primarioEl HDL bajo y los TGs elevados son un blanco secundario del tratamientoSe considera importante la evaluacin de riesgo de una situacin especfica que conduce a un riesgo especialmente elevado (ej. diabetes)Algunas pequeas diferenciasNivel blanco o umbral del tratamiento en poblaciones especficasEstrategia de manejo teraputicoEscalas de riesgo alternativas

Nuevas Guas para los pacientes con Enfermedad Coronaria o Diabetes MellitusBrady A. 77th EAS Congress. Estambul (Turqua), Abril 2008

GuaCondicinCriterioLDL-C, mg/dLReferenciaNCEP ATP IIIAlto riesgo< 100< 70 (opcional)Grundy SM Circulation 2004; 110: 227-239Inglaterra JBS-2Alto riesgo< 77Jessani S Q J Med 2007; 100: 121-124EuropaDM con ECVDM sin ECV< 70< 97EEUUAHA/ACC 2007DM con ECVDM sin ECV< 70< 100Inglaterra JBS-2DM con ECVDM sin ECV< 77 < 77

Estrategia de prevencin y calificacin de riesgoLa prevencin es ms efectiva en el paciente de alto riesgoLos factores de riesgo CV se combinan entre s en un individuoLas escalas de screening para identificar tales pacientes son itles

Keevil J G.et al National Health and Nutrltion Examination Survey NHANES LDL-CCirculation et al. 2007;115:1363-1370Muy alto Riesgo Alto Riesgo Alto Moderado Moderado160

130

100

70

40 -

La meta principal es la de reducir el LDL-C de acuerdo a la categora del riesgoLDL-C (mg/dL)BajoRiesgo

Ballaytane et al. EHJ 2005; 7(Suppl A)Objetivos Terapeticos Actuales 2008Razonable IIa - AEvidencia a favor, multiples ensayosrandomizadosAHA/ACC Circulation 2006 (Junio 20)

ATP IIICategoras LDL-CNo HDL-CApo B TotalAlto Riesgo< 100< 70 opcional< 130< 100 opcional< 90Moderado AltoRiesgo< 130< 100 opcional< 160< 110ModeradoRiesgo< 130< 160< 110Bajo Riesgo< 160< 190< 130

La Evolucin de la Terapia Hipolipemiante

Placebo n=1267Gemfibrozilo, 1,200 mg/dn=1264n=2,531 Hombres 74 aos con ECC C-HDL 40 mg/dl C-LDL 140 mg/dl TGs 300 mg/dlDiseoApuntando al C-HDL bajo para mejorar los resultados: el Estudio VA-HIT Punto final primario: IM no fatal o muerte por ECC despus de 5 aosAleatorizacinRubins HB et al. N Engl J Med. 1999;341:410

WOSCOPS - PBOAFCAPS - PBOAFCAPS - RxWOSCOPS - Rx4S - RxLIPID - Rx4S - PBOCARE - RxLIPID - PBOCARE - PBO0102030406080100120140160180 Secondary Prevention Primary PreventionPBO - placeboRx - statin therapyPRA - pravastatinATV - atorvastatin200On-treatment LDL-C & CHD Events in Statin TrialsEvent rate (%)LDL-C achieved mg/dLAdapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425HPS - PBOHPS - Rx

WOSCOPS - PBOAFCAPS - PBOAFCAPS - RxWOSCOPS - Rx4S - RxLIPID - Rx4S - PBOCARE - RxLIPID - PBOCARE - PBO0102030406080100120140160180 Secondary Prevention Primary PreventionPBO - placeboRx - statin therapyPRA - pravastatinATV - atorvastatin200On-treatment LDL-C & CHD Events in Statin TrialsEvent rate (%)LDL-C achieved mg/dLHPS - PBOHPS - RxNCEP 2001Eur Joint 2003Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425

Changes in LDL-C By Treatment GroupFinalScreen031224364860P

Primary Endpoint: Major Cardiovascular Events**CHD death, nonfatal nonprocedure-related MI, resuscitated cardiac arrest, fatal or nonfatal strokeHR = 0.78 (95% CI 0.69, 0.89)P=0.0002Proportion of patients experiencing major cardiovascular event00.050.100.15atorvastatin 10 mgatorvastatin 80 mg0123456Relative risk reduction = 22%LaRosa JC, et al. N Eng J Med. 2005;352Time (years)

ASCOT - PBOASCOT - RxPROVE-IT - PRAPROVE-IT - ATV80TNT - ATV10TNT - ATV80AFCAPS - RxHPS - RxWOSCOPS - PBOAFCAPS - PBOAFCAPS - RxWOSCOPS - Rx4S - RxLIPID - Rx4S - PBOCARE - RxLIPID - PBOCARE - PBO0102030406080100120140160180 Secondary Prevention Primary PreventionPBO - placeboRx - statin therapyPRA - pravastatinATV - atorvastatin200On-treatment LDL-C & CHD Events in Statin TrialsEvent rate (%)LDL-C achieved mg/dLAdapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425HPS - PBONCEP 2001Eur Joint 2003

NCEP 2004ASCOT - PBOASCOT - RxPROVE-IT - PRAPROVE-IT - ATV80TNT - ATV10TNT - ATV80AFCAPS - RxHPS - RxWOSCOPS - PBOAFCAPS - PBOAFCAPS - RxWOSCOPS - Rx4S - RxLIPID - Rx4S - PBOCARE - RxLIPID - PBOCARE - PBO0102030 Secondary Prevention Primary PreventionOn-treatment LDL-C & CHD Events in Statin TrialsEvent rate (%)HPS - PBOHPS - RxNCEP 2001Eur Joint 2003406080100120140160180200LDL-C achieved mg/dLAdapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425

-1-0.500.511.525060708090100110120ASTEROID rosuvastatinA-Plus placeboACTIVATE placeboCAMELOTplaceboREVERSALpravastatinREVERSAL atorvastatinMean LDL-C (mg/dL)The Relationship Between Mean LDL-C and Change in Percent Atheroma Volume (PAV) in IVUS Studies Change in percent atheroma volume* (%)Nissen S et al. N Engl J Med 2006;354:1253-1263 Tardif J et al. Circulation 2004;110:3372-3377 Nissen S et al. JAMA2006;295 (13):1556-1565 Nissen S et al. JAMA 2004;292: 22172225 Nissen S et al. JAMA 2004; 291:10711080

************Diferentes guas, pero en general, una conducta similarEs de esperar que los contenidos de las guas ms recientes no sean discordantes entre ellas.Las posturas ms importantes y compartidas, con ligeras diferencias, si es que las hay, son:La evaluacin de riesgo de un paciente es un pre-requisito para cualquier decisin teraputica. La evaluacin de riesgo tiene que tomar en cuenta todas las caractersticas del paciente. Adems de las clsicas enfermedades CV (perfil lipdico, presin arterial...), algunas poblaciones especficas tienen un riesgo alto o muy alto de ECC y deberamos ponerle mucha atencin, concretamente, diabetes, sindrome metablico...El blanco primario de intervencin es el colesterol LDL, sin embargo, otros permetros lpdicos estn surgiendo como objetivos secundarios: C-HDL, triglicridos, y en menor grado, las protenas Lp(a) y APO.Los valores que definen hiperlipidemia, as como tambin, la meta teraputica, estn disminuyendo, en concordancia con los resultados de los recientes estudios, los cuales revelan la posibilidad de que quizs, mientras ms bajo, mejor.

Algunas diferencias todava persisten, pero pueden tener un mnimo impacto en el manejo:Para la calificacin de riesgo se usan diferentes escalas: la de Framingham por el NCEP y la de SCORE por la SEC (Sociedad Europea de Cardiologa). Los datos epidemiolgicos han mostrado claramente que el riesgo de ECC no es el mismo entre diferentes poblaciones y que estas diferencias deben ser consideradas en la valoracin del riesgo.El umbral para la definicin de hiperlipidemia es ligeramente diferente.El blanco de intervencin tambin.**Estrategia de prevencin y valoracin de riesgoDesde el punto de vista de un sistema de salud global, cualquier beneficio de alguna intervcencin dirigida a mejorar una enfermedad debe ser sopesado contra el costo, la factibilidad, la seguridad de esta intervencin en toda la poblacin tratada.Eso significa que el manejo de la ECC debe centrarse principalmente en el paciente con alto riesgo de eventos CV y abarcar posteriormente a la poblacin con riesgo CV medio o bajo.Los pacientes con enfermedad CV se presentan frecuentemente con riesgo CV combinado, por ejemplo, diabetes + dislipidemia, tabaquismo e historia antigua de infarto de miocardio, etc.En la evaluacin de un riesgo CV individual, es importante ponderar cada factor de riesgo CV en el riesgo total, con el fin de priorizar la intervencin teraputica, si es necesario.Teniendo en cuenta el gran nmero de parmetros que ingresan en la evaluacin del riesgo CV, los modelos y escalas ms familiares resultan ms tiles.Tales instrumentos permiten una valoracin rpida y reproducible, la cual puede facilitar la comunicacin entre el profesional de la salud y el paciente.****Apuntando al C-HDL bajo para mejorar los resultados: el estudio VA-HIT1El VA-HIT fue el primer ensayo en evaluar los beneficios del aumento del C-HDL en hombres con ECC y niveles basales casi ptimos de C-LDL y TG. El estudio de 7 aos compar los efectos de gemfibrozilo y placebo en 2,531 pacientes. La edad media basal de los pacientes fue 64 aos. El C-HDL medio fue 32 mg/dl, el C-LDL 111 mg/dl, t los TG 160 mg/dl. Adems, 57% de pacientes tenan hipertensin y 25% tenan diabetes.

1. Rubins HB et al. N Engl J Med. 1999;341:410

*A number of landmark studies have shown that the reduction of LDL-C with statin therapy improves cardiovascular morbidity and mortality in patients with and without established cardiovascular disease. In both primary and secondary prevention studies a greater reduction in LDL-C resulted in greater reductions in cardiovascular (CV) events. Achieving lower LDL-C levels is now increasingly accepted. The data clearly show that whether you have CV or not and whatever your baseline LDL-C is, however much you lower LDL-C you reduce CV risk and the lower you can get your LDL-C the better. The international guidelines for screening and intervention are based on evidence such as that presented together with epidemiological data. It is therefore reasonable that the achievement of evidence-based treatment guideline goals can be used as a good surrogate for outcomes data until that becomes available.

ReferencesBallantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:722.Sever, PS et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003;361:1149-58Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279.LaRosa JC, Grundy SM, Waters DD et al. N Engl J Med 2005;352:e-version.

Adapted from Am J Cardiol 1998;82:3Q-12Q with permission from Excerpta Medica Inc.

*A number of landmark studies have shown that the reduction of LDL-C with statin therapy improves cardiovascular morbidity and mortality in patients with and without established cardiovascular disease. In both primary and secondary prevention studies a greater reduction in LDL-C resulted in greater reductions in cardiovascular (CV) events. Achieving lower LDL-C levels is now increasingly accepted. The data clearly show that whether you have CV or not and whatever your baseline LDL-C is, however much you lower LDL-C you reduce CV risk and the lower you can get your LDL-C the better. The international guidelines for screening and intervention are based on evidence such as that presented together with epidemiological data. It is therefore reasonable that the achievement of evidence-based treatment guideline goals can be used as a good surrogate for outcomes data until that becomes available.

ReferencesBallantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:722.Sever, PS et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003;361:1149-58Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279.LaRosa JC, Grundy SM, Waters DD et al. N Engl J Med 2005;352:e-version.

Adapted from Am J Cardiol 1998;82:3Q-12Q with permission from Excerpta Medica Inc.

*During the open-label period, LDL cholesterol was reduced by 35% in the overall patient population from 152 mg/dL to 98 mg/dL. Following randomization, mean LDL cholesterol in the atorvastatin 10 mg group was maintained at around baseline level for the duration of the treatment period, with an average of 101mg/dL across the 5 years of follow-up.Among patients receiving atorvastatin 80 mg LDL cholesterol was further reduced to a mean level of 77 mg/dL. The LDL cholesterol level in the 80 mg group remained relatively stable over the course of the study.As expected, total cholesterol and triglyceride levels decreased significantly from baseline in the atorvastatin 80 mg group and levels remained stable over the treatment period. Atorvastatin 80 mg and atorvastatin 10 mg both produced non-significant increases over baseline in HDL cholesterol with no significant difference between groups throughout the duration of the study.*Over the course of the study, there was a highly significant reduction in major cardiovascular events in the atorvastatin 80mg group. The Kaplan-Meier analysis demonstrates a hazard ratio of 0.78 with a p-value of 0.0002.This represents a 22% reduction in relative risk in the atorvastatin 80mg group relative to the atorvastatin 10 mg group over-and-above the remarkably low absolute event rate of 10.9% recorded in the atorvastatin 10mg group.There was no statistical interaction for age or gender in the primary outcome measure. Further analyses of these categories are underway.*A number of landmark studies have shown that the reduction of LDL-C with statin therapy improves cardiovascular morbidity and mortality in patients with and without established cardiovascular disease. In both primary and secondary prevention studies a greater reduction in LDL-C resulted in greater reductions in cardiovascular (CV) events. Achieving lower LDL-C levels is now increasingly accepted. The data clearly show that whether you have CV or not and whatever your baseline LDL-C is, however much you lower LDL-C you reduce CV risk and the lower you can get your LDL-C the better. The international guidelines for screening and intervention are based on evidence such as that presented together with epidemiological data. It is therefore reasonable that the achievement of evidence-based treatment guideline goals can be used as a good surrogate for outcomes data until that becomes available.

ReferencesBallantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:722.Sever, PS et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003;361:1149-58Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279.LaRosa JC, Grundy SM, Waters DD et al. N Engl J Med 2005;352:e-version.

Adapted from Am J Cardiol 1998;82:3Q-12Q with permission from Excerpta Medica Inc.

*A number of landmark studies have shown that the reduction of LDL-C with statin therapy improves cardiovascular morbidity and mortality in patients with and without established cardiovascular disease. In both primary and secondary prevention studies a greater reduction in LDL-C resulted in greater reductions in cardiovascular (CV) events. Achieving lower LDL-C levels is now increasingly accepted. The data clearly show that whether you have CV or not and whatever your baseline LDL-C is, however much you lower LDL-C you reduce CV risk and the lower you can get your LDL-C the better. The international guidelines for screening and intervention are based on evidence such as that presented together with epidemiological data. It is therefore reasonable that the achievement of evidence-based treatment guideline goals can be used as a good surrogate for outcomes data until that becomes available.

ReferencesBallantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:722.Sever, PS et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003;361:1149-58Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279.LaRosa JC, Grundy SM, Waters DD et al. N Engl J Med 2005;352:e-version.

Adapted from Am J Cardiol 1998;82:3Q-12Q with permission from Excerpta Medica Inc.

*Whilst it is acknowledged that there are limitations in comparing data and results from different studies, this slide summarises the data from several IVUS studies and provides insight into the relationship between the LDL-C level achieved and PAV (Percent Atheroma Volume). The line of best-fit suggests there is a correlation between mean LDL-C achieved in the various studies and the progression rate for the most robust IVUS endpoint, PAV. This graph suggests that no apparent LDL-C threshold exists beyond which benefits of LDL-C reduction apply and that to achieve regression, lower is better.

ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin therapies but included placebo arms in which a considerable proportion of patients received background statin therapy (62%, 80% and 84% respectively).

ACTIVATE: ACAT Intravascular Atherosclerosis Treatment Evaluation1 A-Plus: Avasimibe and Progression of Lesions on UltraSound2 ASTEROID: A Study to Evaluate the Effect of Rosuvastatin On Intravascular Ultrasound-Derived Coronary Atheroma Burden3 CAMELOT: Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis4 REVERSAL: Reversal of Atherosclerosis With Aggressive Lipid-Lowering5

ReferencesNissen S, Tuzcu E, Brewer H, et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 2006;354:1253-1263 Tardif J, Gregoire J, L'Allier P, et al. Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 2004;110:3372-3377 Nissen, S, Nicholls S et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. The ASTEROID trial. JAMA2006;295 (13):1556-1565. Nissen S, Tuzcu E, Libby P et al., Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292: 22172225Nissen S. Tuzcu, E, Schoenhagen et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis a randomized controlled trial. JAMA 2004; 291:10711080